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Id Subject Object Predicate Lexical cue
T1 0-152 Sentence denotes Role of specialized pro-resolving lipid mediators and their receptors in virus infection: a promising therapeutic strategy for SARS-CoV-2 cytokine storm
T2 154-162 Sentence denotes Abstract
T3 163-288 Sentence denotes Unexpected viral infections outbreaks, significantly affect human health, leading to increased mortality and life disruption.
T4 289-514 Sentence denotes Among them is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged as a deadly pandemic, calling for intense research efforts on its pathogenicity mechanism and development of therapeutic strategies.
T5 515-625 Sentence denotes In the SARS-CoV-2 cytokine storm, systemic inflammation has been associated with severe illness and mortality.
T6 626-826 Sentence denotes Recent studies have demonstrated special pro-resolving lipids mediators (SPMs) lipoxins, resolvins, maresins, and protectins as potential therapeutic options for abnormal viral-triggered inflammation.
T7 827-1007 Sentence denotes Pro-resolving lipids mediators have shown great promise for the treatment of Herpes simplex virus, respiratory syncytial virus, human immunodeficiency virus, and hepatitis C virus.
T8 1008-1104 Sentence denotes Based on this, studies are being conducted on their therapeutic effects in SARS-CoV-2 infection.
T9 1105-1254 Sentence denotes In this review, we discussed SPMs and reviewed evidence from recent studies on SPMs as therapeutic options for viral infections, including SARS-CoV2.
T10 1255-1397 Sentence denotes Based on our analysis of the previous study, we argue that SPMs are a potential treatment for SARS-CoV-2 infection and other viral infections.
T11 1398-1568 Sentence denotes We expect further research on how SPMs modulate viral-triggered inflammation through G-protein-coupled receptors (GPCRs), and chemical stability and druggability of SPMs.
T12 1570-1582 Sentence denotes Introduction
T13 1583-1839 Sentence denotes The unexpected emergence of deadly coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS- CoV) significantly affected human health, leading to increased mortality and life disruption.
T14 1840-2105 Sentence denotes Recently, a third highly pathogenic and infectious coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged as a deadly pandemic calling for intense research efforts on its pathogenicity mechanism and development of therapeutic strategies.
T15 2106-2474 Sentence denotes Among others, pro-resolving mediators have been investigated as a therapeutic opportunity for treatment and management of SARS-CoV-2; cytokine storm has been associated with severe illness and mortality, with many studies reporting higher concentrations of pro-inflammatory cytokines in severely ill SARS-CoV-2 patients as compared to those with less severe infection.
T16 2475-2628 Sentence denotes Hence, resolution of inflammation through selective counter-regulation of cytokines has been identified as a potential therapeutic target for SARS-CoV-2.
T17 2629-2889 Sentence denotes In this review, we discussed the characteristics of specialized pro-resolving lipid mediators (SPMs) that induce the resolution of inflammation and reviewed evidence from recent studies on SPMs as therapeutic options for viral infections, including SARS-CoV-2.
T18 2890-3027 Sentence denotes We hope that this review will be of great help in guiding researchers who are exploring SPMs as therapeutic targets for viral infections.
T19 3029-3077 Sentence denotes Specialized pro-resolving lipid mediators (SPMs)
T20 3078-3350 Sentence denotes Inflammation is an extremely important, self-limiting immune response; however, uncontrolled or unresolved inflammation has been established as a pathophysiological mechanism for various diseases including viral infections, and a cause for prolonged homeostasis imbalance.
T21 3351-3592 Sentence denotes Resolution of inflammation occurs in an overlapping stage dominated by the spatial and temporal biosynthesis of pro-resolved mediators (Headland and Norling 2015), SPMs, from essential polyunsaturated fatty acids (PUFAs) during inflammation.
T22 3593-3921 Sentence denotes The SPMs initiate the process of resolution which include restriction or cessation of neutrophil infiltration, counter-regulation of chemokines and cytokines, induction of the neutrophils apoptosis and subsequent efferocytosis (the process by which apoptotic cells are removed by phagocytic cells) by macrophages (Reville et al.
T23 3922-4179 Sentence denotes 2006), the conversion of macrophages from classically activated (M1) to alternatively activated cells (M2), return of non-apoptotic cells to the vascular system or lymphatic vessels, and the start of the healing process (Fig. 1) (Headland and Norling 2015).
T24 4180-4263 Sentence denotes These events facilitate proper return homeostasis balance (Serhan and Savill 2005).
T25 4264-4359 Sentence denotes For a comprehensive review, including structural explanations of SPMs, see reviews (Park et al.
T26 4360-4400 Sentence denotes 2020; Chiang and Serhan 2017; Lee 2012).
T27 4402-4416 Sentence denotes Lipoxins (LXs)
T28 4417-4652 Sentence denotes Lipoxin A4 (LXA4; 5S, 6R, 15S-trihydroxy-7E, 9E, 11Z, 13E-eicosatetraenoic acid) and lipoxin B4 (LXB4; 5S, 14R, 15S-trihydroxy-6E, 8Z, 10E, 12E-eicosatetraenoic acid) were the first lipid SPMs to be discovered (Chiang and Serhan 2017).
T29 4653-4812 Sentence denotes They are produced from the conversion of omega-6 (ω-6) arachidonic acid (AA) by lipoxygenase (LOX) through unicellular and transcellular biosynthesis pathways.
T30 4813-5050 Sentence denotes In transcellular biosynthesis, LXs are synthesized by12-LOX derived through platelet-leukocyte interaction while unicellular biosynthesis pathways involve a series of LOXs-15-lipoxygenase, 5-lipoxygenase, and epoxide hydrolase reactions.
T31 5051-5219 Sentence denotes In addition to the lipoxygenase-initiated biosynthesis, two distinct lipoxins biosynthesis pathways have been elucidated; aspirin-triggered and statin-triggered routes.
T32 5220-5471 Sentence denotes Aspirin induces the production of a lipoxin named “aspirin-triggered " (AT) 15-epi-LX through acetylation of serine residue of cyclooxygenase-2 (COX-2), acetylated COX-2 transforms AA into 15R-HETE, which serves as a substrate for 5-LOX (Chiang et al.
T33 5472-5478 Sentence denotes 2005).
T34 5479-5632 Sentence denotes Statins, widely used as potent cholesterol-lowering agents, have also been found to enhance the conversion of arachidonate to 15-epi-LX (Planaguma et al.
T35 5633-5639 Sentence denotes 2010).
T36 5640-5799 Sentence denotes Epi-lipoxins, trihydroxy metabolites of arachidonic acid, are 15R-epimers of their respective lipoxins, 15-epi-LXA4, LXA4, and 15-epi-LXB4, LXB4 (Romano et al.
T37 5800-5806 Sentence denotes 2015).
T38 5807-6054 Sentence denotes In vivo biosynthesis of LXA4 is triggered in an acute inflammatory process in which Polymorphonuclear neutrophil (PMN)’s interaction with PGE2 and PGD2 activates 15-lipoxygenase subsequently facilitating LXA4 biosynthesis (Claria and Serhan 1995).
T39 6055-6208 Sentence denotes In a murine peritonitis model, the maximum level of LXA4 was achieved within 2 hours and gradually decreased during the first 24 hours (Bannenberg et al.
T40 6209-6215 Sentence denotes 2005).
T41 6216-6321 Sentence denotes The formation of LXs is preserved across a wide range of animal species, from fish to humans (Levy 2005).
T42 6322-6373 Sentence denotes This indicates the physiological importance of LXs.
T43 6375-6411 Sentence denotes E-, D-, and T-series resolvins (Rvs)
T44 6412-6650 Sentence denotes Resolvin (Rv) is a pro-resolving mediator that is derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and clupanodonic acid (Duvall and Levy 2016; Serhan et al.
T45 6651-6657 Sentence denotes 2014).
T46 6658-6804 Sentence denotes Rvs are divided into several subclasses based on the unique aspects of their structure and/or the straight-chain PUFAs from which they are formed.
T47 6805-6863 Sentence denotes Resolvin Ds (RvDs) are metabolites of 22-carbon PUFA, DHA.
T48 6864-7214 Sentence denotes Resolvin Es (RvE) are metabolites of 20 carbons PUFA, EPA; Resolvin Dn-6DPA (RvDn-6DPA) is a DPA isomer, a metabolite of osbond acids; Resolvin Dn-3DPA (RvDn-3DPA) is a DPA isomer, a metabolite of clupanodonic acid; Resolvin Ts (RvT) is a metabolite of clupanodonic acid with 17R-hydroxyl residues, unlike RvDsn-3DPA (all have 17S-hydroxyl residues).
T49 7215-7360 Sentence denotes AT-RvDs, RvD isomers are synthesized by the aspirin-modified COX-2 enzyme to form 17 (R)-hydroxyl rather than the 17 (S)-hydroxyl residue of RvE.
T50 7361-7512 Sentence denotes Cytochrome P450 enzymes that have not yet been characterized may also form this 17 (R)-hydroxy intermediate and contribute to the production of AT-RvE.
T51 7513-7602 Sentence denotes All mentioned Rvs except RvDsn-6DPA are metabolites of omega-3 fatty acids (Serhan et al.
T52 7603-7631 Sentence denotes 2014; Duvall and Levy 2016).
T53 7633-7651 Sentence denotes E-series resolvins
T54 7652-7699 Sentence denotes RvE is a di- or tri-hydroxyl metabolite of EPA.
T55 7700-7773 Sentence denotes To date, four RvEs (RvE1, 18S-RvE1, RvE2, and RvE3) have been discovered.
T56 7774-7915 Sentence denotes COX-2, acetylated by aspirin in hypoxic endothelial cells, introduces oxygen groups into 18R-hydro (peroxy)-eicosapentaenoic acid (18R-HEPE).
T57 7916-8037 Sentence denotes Activated PMN uses 5-LOX to convert 18R-HEPE to 5S (6)-epoxy-18R-HEPE, which is further hydrolyzed to RvE1 (Serhan et al.
T58 8038-8044 Sentence denotes 2000).
T59 8045-8164 Sentence denotes RvE2 is produced by reduction of 18R HEPE products by 5-LOX to 5S-hydroperoxy, 18-hydroxy-EPE in whole blood (Oh et al.
T60 8165-8171 Sentence denotes 2012).
T61 8172-8285 Sentence denotes Unlike RvE1, RvE2 and RvE3 are biosynthesized from 18-HEPE via the 12/15-LOX pathway in eosinophils (Isobe et al.
T62 8286-8293 Sentence denotes 2012b).
T63 8294-8426 Sentence denotes Endogenous RvE1 has been shown to accumulate for between 48 and 72 hours, which is a delayed time point of inflammation (Hong et al.
T64 8427-8433 Sentence denotes 2008).
T65 8434-8601 Sentence denotes RvE2 appeared at the time point corresponding to initial PMN infiltration in rat peritoneal exudate stimulated by zymosan A and decreased within 24 hours (Isobe et al.
T66 8602-8609 Sentence denotes 2012a).
T67 8610-8699 Sentence denotes 18S-RvE1 is produced by 5-LOX and LTA4 hydrolase using 18S-HEPE as a substrate (Oh et al.
T68 8700-8706 Sentence denotes 2011).
T69 8708-8726 Sentence denotes D-series resolvins
T70 8727-8766 Sentence denotes RvD is a polyhydroxy metabolite of DHA.
T71 8767-8924 Sentence denotes To date, six RvDs with different positions of cis-trans isomers, as well as the number, position and chirality of the hydroxyl residues have been discovered.
T72 8925-9026 Sentence denotes D-series Rvs (RvD1-RvD6) are biosynthesized from DHA by the LOX in PMN and macrophages (Serhan et al.
T73 9027-9033 Sentence denotes 2002).
T74 9034-9123 Sentence denotes Hydrolysis of peroxide intermediates derived from two LOXs in DHA produces RvD1 and RvD2.
T75 9124-9215 Sentence denotes On the other hand, the reduction of the peroxide intermediates produces RvD5 (Serhan et al.
T76 9216-9222 Sentence denotes 2002).
T77 9223-9423 Sentence denotes In hypoxic endothelial cells in the presence of aspirin, COX-2 converts DHA to 13-hydroxy-DHA or 17R-hydroxy-DHA and activated PMN converts these products to AT-RvD1, AT-RvD2, and other AT-RvD-series.
T78 9424-9584 Sentence denotes RvD3 and RvD4 are produced through hydrolysis of 4S-hydroperoxy-17S-hydroxy-docosahexaenoic acid, whereas RvD6 is derived from peroxidase of the same precursor.
T79 9585-9845 Sentence denotes In a peritonitis model, the in vivo RvD3 levels after zymosan A challenge increases significantly up to 48 hours after inflammation initiation, while RvD1, RvD2, and RvD5 peak at the early stages of the inflammation termination phase (6–24 hours) (Dalli et al.
T80 9846-9853 Sentence denotes 2013b).
T81 9854-9955 Sentence denotes RvD3 appears to be produced by a subpopulation of macrophages with high 15-LOX activity (Dalli et al.
T82 9956-9963 Sentence denotes 2013b).
T83 9964-10225 Sentence denotes In vivo production of RvD4 in an Staphylococcus aureus injected the dorsal pouch infection model continues for more than 72 hours after sustained release, suggesting that RvD is produced continuously and is under different control from other Rvs (Winkler et al.
T84 10226-10232 Sentence denotes 2016).
T85 10233-10274 Sentence denotes RvD6 kinetics have not been reported yet.
T86 10276-10294 Sentence denotes Resolvin Ts (RvTs)
T87 10295-10445 Sentence denotes In human platelets, COX-2 pre-treated with aspirin or atorvastatin metabolizes omega-3s, DPA and clupanodonic acid (DPAn-3), to 13S-hydroperoxy forms.
T88 10446-10552 Sentence denotes Aspirin and atorvastatin change the activity of COX-2 from cyclooxygenase to hydroperoxide-forming enzyme.
T89 10553-10729 Sentence denotes The intermediates formed are transported to the nearby human neutrophils and perhaps by the activity of the ALOX5 enzyme they are metabolized into four polyhydroxy metabolites:
T90 10730-10889 Sentence denotes RvT1 (7,13R, 20-trihydroxy-DPAn-3); RvT2 (7, 8,13R-trihydroxy-DPAn-3); RvT3 (7,12,13R-trihydroxy-8Z, 10E, 14E, 16Z, 19Z-DPAn-3); RvT4 (7,13R-dihydroxy-DPAn-3).
T91 10890-11039 Sentence denotes These four RvTs are formed by human neutrophils and vascular endothelial cells and are also found in rodents and human infected tissues (Dalli et al.
T92 11040-11053 Sentence denotes 2013a, 2015).
T93 11054-11190 Sentence denotes Recently, the total synthesis of RvT1, RvT2, and its 13R-epimer RvT2, and RvT4 were successfully achieved (Rodriguez and Spur 2020a, b).
T94 11191-11306 Sentence denotes Therefore, it is expected that there will be many physiological and pharmacological research on RvTs in the future.
T95 11308-11316 Sentence denotes Maresins
T96 11317-11521 Sentence denotes Maresins (MaRs) are biosynthesized from DHA by macrophages through the action of 12-LOX, which catalyzes the oxygenation of DHA to 14-hydroperoxidocosahexaenoic acid (14-HpDHA) (Rodriguez and Spur 2020a).
T97 11522-11654 Sentence denotes This is followed by reduction to 13S, 14S-epoxy-maresin, which is further modified in human macrophages to produce MaR1 (Deng et al.
T98 11655-11759 Sentence denotes 2014) and conversion of 13S, 14S-epoxy-maresin by soluble epoxide hydrolase to produce MaR2 (Deng et al.
T99 11760-11766 Sentence denotes 2014).
T100 11767-11888 Sentence denotes Maresins, like the many other SPM members mentioned, have anti-inflammatory, protective and healing-promoting properties.
T101 11889-12137 Sentence denotes In a study using a murine model of respiratory distress syndrome, and initial in vivo production of MaR1was detected during platelet-neutrophil interactions, and its levels increased significantly within 2 hours and peaked at 24 hours (Dalli et al.
T102 12138-12145 Sentence denotes 2013c).
T103 12146-12269 Sentence denotes Measurement of 17-HDHA in tissue is used as a marker for the level of activation of the MaR production pathway (Wang et al.
T104 12270-12276 Sentence denotes 2015).
T105 12277-12454 Sentence denotes Maresin-like lipid mediators MaR-L1 and MaR-L2 are produced by white blood cells and platelets and rescue the reparative function of macrophages damaged by diabetes (Hong et al.
T106 12455-12461 Sentence denotes 2014).
T107 12462-12512 Sentence denotes Total synthesis of MaRs has not yet been reported.
T108 12514-12530 Sentence denotes Protectins (PDs)
T109 12531-12611 Sentence denotes Protectin D1 (PD1), also known as neuroprotectin D1 (NPD1), is derived from DHA.
T110 12612-12679 Sentence denotes DHA is a component of fish oil and the most important omega-3 PUFA.
T111 12680-12867 Sentence denotes Like other members of PUFA metabolites specialized pro-resolving mediators class, PD1 exerts potent anti-inflammatory and anti-apoptotic/neuroprotective biological activities (Hong et al.
T112 12868-12886 Sentence denotes 2003; Bazan 2007).
T113 12887-13036 Sentence denotes PD1 accumulates in the ipsilateral hemisphere of the brain after focal ischemia and has been shown to take part in wound healing and neuroprotection.
T114 13037-13156 Sentence denotes 15-LOX can acts 17S-HpDHA to produce the isomers of PD1, 10S, 17S-diHDHA (PDx), which also have pro-resolving activity.
T115 13157-13253 Sentence denotes PD1 production peaks at 12 hours in a zymosan A-induced rat peritonitis model (Bannenberg et al.
T116 13254-13260 Sentence denotes 2005).
T117 13261-13354 Sentence denotes Other PDs with similar activity include PDX; 20-hydroxy-PD1; and 10-epi-PD1 (Shinohara et al.
T118 13355-13384 Sentence denotes 2012; Balas and Durand 2016).
T119 13385-13458 Sentence denotes The activity of 17-epi-PD1, a PD1-like metabolite, has not been reported.
T120 13459-13602 Sentence denotes It should be noted that Neuroprotectin A and B, the bicyclohexapeptides, are structurally and mechanically different from PDs (Kobayashi et al.
T121 13603-13609 Sentence denotes 2001).
T122 13610-13695 Sentence denotes The total synthesis of PDX and PD1 methyl ester epimer was successful (Dayaker et al.
T123 13696-13716 Sentence denotes 2014; Sanceau et al.
T124 13717-13723 Sentence denotes 2019).
T125 13725-13739 Sentence denotes SPMs receptors
T126 13740-13803 Sentence denotes Herein, we briefly describe each known SPMs receptors (Fig. 2).
T127 13804-14028 Sentence denotes Previous studies have demonstrated that pro-resolving activities of SPMs occur through activation of one or more G protein-coupled receptors (GPCRs), suitable receptors for several types of SPMs have not yet been identified.
T128 14029-14231 Sentence denotes Four GPCRs have been reported as receptors for RvD1 and RvE1; however, it has not been determined whether other Rvs and PDs such as RvE2, RvE4, RvD2, RvD3, PDs, and MaRs act on these GPCRs (Arita et al.
T129 14232-14265 Sentence denotes 2005, 2007; Krishnamoorthy et al.
T130 14266-14272 Sentence denotes 2010).
T131 14273-14441 Sentence denotes For recent and specific physiological actions of these receptors and research data in KO mice, we would like to refer to other reviews and references there (Park et al.
T132 14442-14457 Sentence denotes 2020; Im 2012).
T133 14459-14478 Sentence denotes Chemerin receptor 1
T134 14479-14670 Sentence denotes Chemerin receptor 1 (chemerin1, ChemR23, or ERV1) is expressed on a wide range of immune cells, including monocytes, macrophages, natural killer cells, bone marrow cells, and dendritic cells.
T135 14671-14757 Sentence denotes Besides, ERV1 has been identified in adipocytes and endothelial cells (Luangsay et al.
T136 14758-14764 Sentence denotes 2009).
T137 14765-14871 Sentence denotes ERV1 was initially classified as an orphan GPCR with homology to the formyl peptide receptor (Gantz et al.
T138 14872-14936 Sentence denotes 1996) and the anaphylatoxin C3a and C5a receptors (Samson et al.
T139 14937-15048 Sentence denotes 1998) until recently when it was discovered to be a receptor for the chemotactic protein chemerin (Meder et al.
T140 15049-15055 Sentence denotes 2003).
T141 15056-15196 Sentence denotes In addition to chemerin, RvE1 was identified as a second endogenous agonist through a screening program against the GPCR panel (Arita et al.
T142 15197-15203 Sentence denotes 2007).
T143 15204-15372 Sentence denotes ERV1 (chemokine like receptor 1, also known as CMKLR1) is a receptor for RvE1, which has been shown to bind more strongly than chemerin (a peptide ligand) (Arita et al.
T144 15373-15394 Sentence denotes 2005; Wittamer et al.
T145 15395-15401 Sentence denotes 2004).
T146 15402-15557 Sentence denotes ERV1 overexpressing mice showed a large increase in phagocytosis upon decreased neutrophil inhibition and decreased neutrophil infiltration (Herrera et al.
T147 15558-15564 Sentence denotes 2015).
T148 15565-15667 Sentence denotes Also, RvE2 is a partial agonist compared to RvE1 in CHO-chemerin1 β-arrestin recruitment (Isobe et al.
T149 15668-15675 Sentence denotes 2012a).
T150 15676-15811 Sentence denotes However, since there is no additional information on this ligand, further investigation of potential ligand-receptor pairs is required.
T151 15813-15866 Sentence denotes N-formyl peptide receptor 2/LX A4 receptor (FPR2/ALX)
T152 15867-16022 Sentence denotes Originally FPR2 was classified as an FPR receptor due to its activation by the low-affinity endogenous agonist N-formyl methionyl peptide (fMLP) (Ye et al.
T153 16023-16029 Sentence denotes 1992).
T154 16030-16268 Sentence denotes The receptor was reclassified as FPR2/ALX, as LXA4 exhibited the highest affinity of all FPR2/ALX endogenous agonists through screening of various receptor ligands using radiolabelled [3H]-LXA4 and subsequent GTPase activity (Fiore et al.
T155 16269-16287 Sentence denotes 1994; Brink et al.
T156 16288-16294 Sentence denotes 2003).
T157 16295-16421 Sentence denotes Binding of LXA4 leads to the stimulation of monocyte chemotaxis, macrophage differentiation, and efferocytosis (Maderna et al.
T158 16422-16452 Sentence denotes 2010; Maddox and Serhan 1996).
T159 16453-16577 Sentence denotes LXA4 also reduces the adaptive immune response by reducing memory B cell antibody production and proliferation (Ramon et al.
T160 16578-16584 Sentence denotes 2014).
T161 16585-16755 Sentence denotes Endogenous and exogenous lipids, peptides, and proteins have been shown to bind and activate FPR2/ALX to produce inflammatory and anti-inflammatory effects (Takano et al.
T162 16756-16775 Sentence denotes 1997; Cooray et al.
T163 16776-16782 Sentence denotes 2013).
T164 16783-16942 Sentence denotes Both the LXs and Rvs families, including LXA4, AT-LXA4 (15-epi-LXA4), RvD1, AT-RvD1 (17-epi-RvD1), and Annexin A1 (ANXA1) activate receptors with high potency.
T165 16943-17082 Sentence denotes On the other hand, endogenous antagonists, including serum amyloid A (SAA) and cathelicidin (LL-37) have been identified (Bozinovski et al.
T166 17083-17099 Sentence denotes 2012; Wan et al.
T167 17100-17106 Sentence denotes 2011).
T168 17108-17113 Sentence denotes GPR18
T169 17114-17212 Sentence denotes GPR18 was discovered as a receptor for RvD2 through GPCR-β-arrestin-based screening (Chiang et al.
T170 17213-17281 Sentence denotes 2015), and the receptor was referred to as DRV2/GPR18 (Chiang et al.
T171 17282-17295 Sentence denotes 2017, 2019a).
T172 17296-17347 Sentence denotes Besides, several other ligands activate DRV2/GPR18.
T173 17348-17663 Sentence denotes These include endogenous ligands such as N-arachidonylglycine (NAGly), anandamide, a metabolite of the endocannabinoid anandamide, synthetic ligands such as abnormal-cannabidiol (Abn-CBD), and O-1918, a partial agonist, which can be used as a pharmacological tool to inhibit DRV2/GPR18 signalling (Offertaler et al.
T174 17664-17682 Sentence denotes 2003; Kohno et al.
T175 17683-17689 Sentence denotes 2006).
T176 17690-17767 Sentence denotes GPR18 is abundantly expressed in PMNs, monocytes and macrophages (Wang et al.
T177 17768-17774 Sentence denotes 2014).
T178 17775-18141 Sentence denotes In addition to the resolution of inflammation, while GPR18 has low structural similarity to the cannabinoid receptors CB1, CB2, and GPR55, it responds to endogenous and synthetic cannabinoid ligands including n-arachidonoyl ethanolamine (AEA), 2-arachidonoyl glycerol (2-AG), Δ9-tetrahydrocannabinol (Δ9-THC), and, arachidonoylcyclopropylamide (ACPA) (McHugh, 2012).
T179 18142-18405 Sentence denotes Also interestingly, GPR18 is structurally very similar to EBV-induced receptor 2 (EBI2), whose expression is increased more than 20 times in Epstein-Barr virus (EBV) infected cells, and is a GPCR receptor clustered together in the 13q32 (Rosenkilde et al., 2006).
T180 18407-18412 Sentence denotes GPR32
T181 18413-18539 Sentence denotes GPR32 is primarily expressed in human PMN, monocytes, adipose tissue and vascular endothelial cells (Sansbury and Spite 2016).
T182 18540-18768 Sentence denotes RvD1 was identified as a potential agonist due to the activation of GPR32, where [3H]-RvD1 binds to human leukocytes and significantly lowers TNF-α-stimulated NF-κB signalling in GPR32 overexpressing cells (Krishnamoorthy et al.
T183 18769-18775 Sentence denotes 2010).
T184 18776-18912 Sentence denotes Although RvD1 has a higher affinity for GPR32 than FPR2/ALX, its interaction with GPR32 has not been extensively studied (Norling et al.
T185 18913-18919 Sentence denotes 2012).
T186 18920-19035 Sentence denotes This could be since GPR32 exists as a pseudogene in rodents, which makes animal testing in principle inappropriate.
T187 19036-19230 Sentence denotes Treatment of inflammatory macrophages expressing GPR32 with RvD1 enhanced the pro-resolving phenotype to increase phagocytosis and decrease the secretion of inflammatory cytokines (Schmid et al.
T188 19231-19237 Sentence denotes 2016).
T189 19238-19362 Sentence denotes Also, GPR32 was also involved when during the inhibition of the EMT phenomenon of lung cancer cell lines by RvD1 (Lee et al.
T190 19363-19369 Sentence denotes 2013).
T191 19370-19509 Sentence denotes Additionally, RvD3, AT-RvD3, and RvD5 have all been shown to activate GPR32 in a recombinant system of β-arrestin recruitment (Dalli et al.
T192 19510-19530 Sentence denotes 2013b; Chiang et al.
T193 19531-19537 Sentence denotes 2012).
T194 19538-19610 Sentence denotes These facts suggest the potential redundancy of ligands acting on GPCRs.
T195 19612-19617 Sentence denotes GPR37
T196 19618-19788 Sentence denotes GPR37 or Parkin-related endothelin-like receptor (Pael-R) was originally discovered through genomic library screening to find new neuropeptide receptors (Marazziti et al.
T197 19789-19795 Sentence denotes 1997).
T198 19796-19946 Sentence denotes The GPR37 receptor is primarily expressed in the brain and is associated with neurological disorders such as Parkin’s disease and autism (Lopes et al.
T199 19947-19953 Sentence denotes 2015).
T200 19954-20107 Sentence denotes Mutations within GPR37 affect various autism spectrum disorders, regulation of dopamine reuptake and oligodendrocyte differentiation (Fujita-Jimbo et al.
T201 20108-20130 Sentence denotes 2012; Marazziti et al.
T202 20131-20148 Sentence denotes 2007; Yang et al.
T203 20149-20155 Sentence denotes 2016).
T204 20156-20354 Sentence denotes PD1 is considered as a ligand for GPR37 because it induced a significant increase in intracellular calcium in HEK293 cells overexpressing GPR37 and murine peritoneal-derived macrophages (Bang et al.
T205 20355-20361 Sentence denotes 2018).
T206 20362-20594 Sentence denotes Based on the fact that Gpr37-/- mice exhibited increased apoptosis and infarct size, it has recently been suggested that GPR37 is also involved in cell damage protection and inflammation after ischemic stroke (McCrary et al., 2019).
T207 20595-20811 Sentence denotes However, due to its clear role in the central nervous system (CNS), the development of a therapeutic agent targeting GPR37 requires a balance between the effect on the central nervous system and therapeutic benefits.
T208 20813-20829 Sentence denotes Leukotriene BLT1
T209 20830-21086 Sentence denotes BLT1 has also been shown to be a receptor for RvE1 although its clone, high-affinity leukotriene B4 (LTB4) is a potent lipid inflammatory chemoattractant, inducing T helper cell chemotaxis and early effector T cell recruitment through BLT1 (Yokomizo et al.
T210 21087-21105 Sentence denotes 1997; Arita et al.
T211 21106-21112 Sentence denotes 2007).
T212 21113-21331 Sentence denotes BLT1 shares 21% sequence identity with chemerin1; while this value is relatively low, selective BLT1 antagonist U-75,302 has been demonstrated to replace the binding of [3H]-RvE1 to the human PMN membrane (Arita et al.
T213 21332-21338 Sentence denotes 2007).
T214 21339-21521 Sentence denotes Besides, although RvE1 is 100 times less potent than LTB4, it inhibited adenylate cyclase activity and induced intracellular calcium mobilization in HEK293 cells overexpressing BLT1.
T215 21522-21721 Sentence denotes These data indicate the role of RvE1 in reducing BLT1-induced inflammation by RvE1 acting as a partial agonist that competes with LTB4-mediated NF-κB activation and calcium mobilization (Arita et al.
T216 21722-21728 Sentence denotes 2007).
T217 21729-21933 Sentence denotes Activation of BLT1 by RvE1 also serves as a feedback mechanism for other SPMs, including increased production of LXA4 in the FPR2/ALX-mediated resolution of allergic pulmonary inflammation (Haworth et al.
T218 21934-21940 Sentence denotes 2008).
T219 21941-22159 Sentence denotes RvE2 was identified as an additional BLT1 agonist, and the β-arrestin assay showed that RvE2 blocked LTB4-mediated β-arrestin signalling with similar efficacy to RvE1, indicating direct competition with LTB4 (Oh et al.
T220 22160-22166 Sentence denotes 2012).
T221 22167-22295 Sentence denotes Various pro-resolving roles of RvE2 have been proposed, including regulation of PMN infiltration and IL-10 production (Oh et al.
T222 22296-22302 Sentence denotes 2012).
T223 22303-22441 Sentence denotes However, while RvE1 promotes NADPH oxidase-mediated ROS production through the BLT1, RvE2 and RvE3 do not exhibit this effect (Unno et al.
T224 22442-22448 Sentence denotes 2018).
T225 22450-22487 Sentence denotes Activation of other receptors by SPMs
T226 22488-22558 Sentence denotes A few studies have reported the possibility of other GPCR involvement.
T227 22559-22667 Sentence denotes Among them, GPR101 mediates the pro-resolving effects of RvD5n-3 DPA in arthritis and infection (Flak et al.
T228 22668-22674 Sentence denotes 2020).
T229 22675-22767 Sentence denotes Besides, SPMs have been reported to activate non-GPCRs receptors, such as nuclear receptors.
T230 22768-22954 Sentence denotes In a dose-dependent manner, PD1 enhances PPARγ transcriptional activation reporter activity in human neuron-glia (HNG) cells co-transfected with hPPARγ-GAL4 and MH100-tk-Luc (Zhao et al.
T231 22955-22961 Sentence denotes 2011).
T232 22962-23079 Sentence denotes This suggests that PD1 is capable of enhancing the peroxisome proliferator-activated receptor gamma (PPARγ) (Fig. 2).
T233 23080-23178 Sentence denotes The transcriptional activity of PPARγ was significantly increased after treatment with 100 nM PD1.
T234 23179-23410 Sentence denotes RvD1 was also assumed to be a ligand for PPARγ and inhibited IκBα degradation and NF-κB p65 nuclear translocation in an LPS-induced lung injury model, which was partially reversed by the PPARγ inhibitor GW9662 (Fig. 2) (Liao et al.
T235 23411-23417 Sentence denotes 2012).
T236 23418-23533 Sentence denotes Recently, it has been reported that LXA4 binds to the nuclear aryl hydrocarbon receptor (AhR) (Fig. 2) (Asha et al.
T237 23534-23540 Sentence denotes 2020).
T238 23541-23603 Sentence denotes A GPCR that acts directly on MaR1 has not yet been identified.
T239 23604-23926 Sentence denotes However, MaR1 blocks TRPV1-mediated currents in neurons, acts as a ligand for the retinoid-associated orphan receptor α (RORα), and inhibits TLR4 signalling (Fig. 2) (Park 2015), Chiang et al. found that MaR1 can activate LGR6, a member of the glycoprotein hormone receptor subfamily of rhodopsin-like GPCRs (Chiang et al.
T240 23927-24070 Sentence denotes 2019b), which initiates cAMP, impedance changes, and stimulate an innate immune response against PMNs, monocytes and macrophages (Chiang et al.
T241 24071-24078 Sentence denotes 2019b).
T242 24080-24132 Sentence denotes Role of SPMs and Their Receptors in Virus Infections
T243 24133-24296 Sentence denotes Because viruses are obligate intracellular parasites, viruses must enter target cells and multiply using host cell machinery to produce progeny viruses (Ryu 2017).
T244 24297-24397 Sentence denotes The various stages involved in viral growth that occur inside cells are called the viral life cycle.
T245 24398-24489 Sentence denotes The viral life cycle can be divided into three stages: entry, genome replication, and exit.
T246 24490-24618 Sentence denotes Entry can be subdivided into attachment, penetration and uncoating, and exit can be subdivided into virion assembly and release.
T247 24619-24660 Sentence denotes Genome replication differs by virus type.
T248 24661-24846 Sentence denotes Many studies are showing that SPMs regulate the inflammatory response caused by viral infections, but studies on the effects of SPMs on the viral life cycle have been difficult to find.
T249 24847-24881 Sentence denotes There have a few reports recently.
T250 24882-25216 Sentence denotes For example, among SPMs, LXA4 modulates Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) life cycle through chromatin modulation and hedgehog signalling to destabilize the latency of herpes virus and decreases the expression of programmed death-ligand 1 (PD-L1) in Kaposi’s Sarcoma, thereby reducing immune evasion (Fig. 3) (Asha et al.
T251 25217-25223 Sentence denotes 2020).
T252 25224-25363 Sentence denotes On the other hand, there are not a few reports that the receptors mentioned above for SPMs act as receptors in virus infection (see below).
T253 25364-25560 Sentence denotes So, in this section, we will discuss the effect of SPMs on the virus and the viral infection-induced inflammation and mention how the receptors of SPMs affect the life cycle of the virus (Fig. 3).
T254 25562-25571 Sentence denotes Influenza
T255 25572-25716 Sentence denotes Influenza viruses are a well-studied model for understanding the role of inflammation resolution mediators and the mechanism of viral infection.
T256 25717-25803 Sentence denotes This is because different viruses elicit different host immune responses and outcomes.
T257 25804-26027 Sentence denotes From studies comparing more virulent influenza virus strains to less virulent strains, it has been reported that pro-resolving mediators have an inverse correlation with the biological activity of the virus (Cilloniz et al.
T258 26028-26034 Sentence denotes 2010).
T259 26035-26137 Sentence denotes The more toxic strains of influenza induced reduction of LXs, which increased the spread of the virus.
T260 26138-26288 Sentence denotes LXB4 recently improved IgG production in B cells from donors vaccinated against influenza virus, suggesting potential as a novel adjuvant. (Kim et al.
T261 26289-26295 Sentence denotes 2018).
T262 26296-26440 Sentence denotes Annexin is the most abundant host cell protein in the virion, and annexin A1 (ANXA1) contributes to influenza-induced toxicity (Tcherniuk et al.
T263 26441-26447 Sentence denotes 2016).
T264 26448-26659 Sentence denotes That is, during virus entry into the host cell, viral hemagglutinin (HA) not only binds sialic acid but also ANXA1 binds to FPR2, resulting in activation of ERK2 and increased viral replication (Tcherniuk et al.
T265 26660-26666 Sentence denotes 2016).
T266 26667-26700 Sentence denotes RvD1 and LXA4 also activate FPR2.
T267 26701-26873 Sentence denotes It is still unknown whether RvD1 and LXA4 compete with viral annexin at the receptors site leads to the prevention of viral infection or the promotion of viral replication.
T268 26874-26975 Sentence denotes However, it is reported that AT-RvD1 reduces inflammation caused by the viral infection. (Wang et al.
T269 26976-26982 Sentence denotes 2017).
T270 26983-27253 Sentence denotes Increased SAA in recurrent acute exacerbations of COPD caused by bacterial and virus coinfection acts as a functional agonist of FPR2/ALX, antagonizing the protective action of FPR2/ALX by AT-RvD1, promoting chemotaxis of neutrophils and prolonging survival (Wang et al.
T271 27254-27260 Sentence denotes 2018).
T272 27261-27375 Sentence denotes There are no reports of direct research on whether RvD1, the same family as AT-RvD1, inhibits the influenza virus.
T273 27376-27466 Sentence denotes However, it promotes inflammation and removal of bacteria caused by a bacterial infection.
T274 27467-27594 Sentence denotes For example, RvD1 relieves lung inflammation and promotes the elimination of untypeable Haemophilus influenza (Croasdell et al.
T275 27595-27601 Sentence denotes 2016).
T276 27602-27755 Sentence denotes ChemR23, a receptor for RvE1, relieves lung inflammation and enhances antiviral immunity in a mouse model of acute viral pneumonia (Bondue et al., 2011).
T277 27756-27869 Sentence denotes Therefore, it would be fascinating to study whether RvE1 is effective in pneumonia caused by the influenza virus.
T278 27870-27939 Sentence denotes PD1 has pivotal and multiple roles in regulating viral pathogenicity.
T279 27940-28013 Sentence denotes Influenza strains, such as the lethal H5N1, down-regulate PD1 (Tam et al.
T280 28014-28020 Sentence denotes 2013).
T281 28021-28135 Sentence denotes There is an inverse correlation between the level of PD1 and the level of pathogenicity of various virus isolates.
T282 28136-28237 Sentence denotes In addition to the host’s inflammatory response, PD1 has a direct antiviral action against influenza.
T283 28238-28420 Sentence denotes Both PD1 and its isomer PDX (LOX-mediated double oxygenation) limit viral replication by interfering with the viral RNA nuclear transport mechanism (Fig. 3) (Imai 2015; Morita et al.
T284 28421-28452 Sentence denotes 2013; Baillie and Digard 2013).
T285 28453-28662 Sentence denotes Treatment of infected mice with PD1 improves survival, even if administered 48 hours after the onset of infection when the current antiviral therapy is no longer significantly effective (Fig. 4) (Morita et al.
T286 28663-28678 Sentence denotes 2013; Ng et al.
T287 28679-28685 Sentence denotes 2010).
T288 28687-28707 Sentence denotes Herpes simplex virus
T289 28708-28957 Sentence denotes Herpesviruses 1 and 2 (HSV-1 and HSV-2), with the taxonomic names human alphaherpesvirus 1 and human alphaherpesvirus 2, are the most common causes of human viral infections among the members of the human Herpesviridae family (Chayavichitsilp et al.
T290 28958-28964 Sentence denotes 2009).
T291 28965-29304 Sentence denotes Herpes simplex virus (HSV) ocular infection represents another example in which local control of the virus stems from a robust inflammatory response with long-term consequences of chronic inflammation, including the possibility of final blindness due to interstitial keratitis that persists even after the viral infection has been cleared.
T292 29305-29599 Sentence denotes In animals with HSV, topical administration of RvE1 reduced the influx of CD4+ T cells (both TH1 cells and TH17 cells) and neutrophils, decreased production of inflammatory cytokines including IFNγ and IL-6, and increased levels of the anti-inflammatory cytokine IL-10 (Fig. 4) (Rajasagi et al.
T293 29600-29606 Sentence denotes 2011).
T294 29607-29661 Sentence denotes Overall, RvE1 significantly reduced stromal keratitis.
T295 29662-29730 Sentence denotes Similar results were demonstrated with PD1 (Fig. 4) (Rajasagi et al.
T296 29731-29737 Sentence denotes 2013).
T297 29738-30038 Sentence denotes Besides, AT-RvD1 treatment significantly reduced the degree of corneal angiogenesis and the severity of stromal keratitis lesions, and AT-RvD1 treated mice had fewer Th1 and Th17 cells in the infected cornea, as well as the reduced number of inflammatory cells, including neutrophils (Rajasagi et al.
T298 30039-30045 Sentence denotes 2017).
T299 30047-30127 Sentence denotes Respiratory syncytial virus, human immunodeficiency virus, and hepatitis C virus
T300 30128-30381 Sentence denotes Respiratory syncytial virus (RSV), also known as human respiratory cell fusion virus (HRSV) and human orthopneumovirus, is a virus that causes respiratory infections in which infected mucosal cells fuse to form a syncytium (Schweitzer and Justice 2020).
T301 30382-30511 Sentence denotes It is the leading cause of lower respiratory tract infections and hospital visits in infancy and childhood (Read and Bosco 2020).
T302 30512-30682 Sentence denotes RSV infection results in bronchiolitis, which is classically caused by activated macrophages and eventually resolved by alternatively activated macrophages (Shirey et al.
T303 30683-30689 Sentence denotes 2010).
T304 30690-30863 Sentence denotes The promotion of these two alternative macrophage fates appears to be related to RSV-induced COX-2 and LXA4 and RvE1-mediated protective measures (Fig. 4) (Richardson et al.
T305 30864-30883 Sentence denotes 2005; Shirey et al.
T306 30884-30890 Sentence denotes 2014).
T307 30891-31164 Sentence denotes Also, although it does not directly act on the virus, RvD1 inhibits inflammatory signal transduction by polyinosinic-polycytidylic acid, an analogue of RNAs derived from respiratory viruses such as RSV, and the action of RvD1 is mediated by FPR2/ALX and GPR32 (Hsiao et al.
T308 31165-31171 Sentence denotes 2014).
T309 31172-31334 Sentence denotes These reports suggest the critical role of SPMs and lipid mediator class shift in the host’s response to RSV in the initial control and final infection clearance.
T310 31335-31515 Sentence denotes Human immunodeficiency virus (HIV) is a lentivirus (a subgroup of retroviruses) and are classified into two based on the genetic characteristics and viral antigen, HIV-1 and HIV-2.
T311 31516-31632 Sentence denotes HIV infection may progress to acquired immunodeficiency syndrome (AIDS), a progressive failure of the immune system.
T312 31633-31751 Sentence denotes Over time, AIDS causes life-threatening opportunistic infections and a condition in which cancer thrives (Douek et al.
T313 31752-31771 Sentence denotes 2009; Powell et al.
T314 31772-31778 Sentence denotes 2016).
T315 31779-32092 Sentence denotes When co-cultured with HIV-1 infected mononuclear cells and human glial cells (astrocytoma, glial and primary human astrocyte), tumour necrosis factor alpha (TNF-α) and interleukin-1β are produced, and large amounts of LTB4, LTD4, LXA4, and PAF, were also found in media from this co-culture (Fig. 4) (Genis et al.
T316 32093-32099 Sentence denotes 1992).
T317 32100-32210 Sentence denotes So far, this is the only in vitro study to prove, that LXs are produced in direct response to viral infection.
T318 32211-32286 Sentence denotes However, the role of LXs in this infection model has not been investigated.
T319 32287-32512 Sentence denotes Synthetic peptides derived from human immunodeficiency virus type 1 gp120 activate the 7-transmembrane GPCR FPR2/ALX, down-regulating the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes (Deng et al.
T320 32513-32519 Sentence denotes 1999).
T321 32520-32610 Sentence denotes FPR2/ALX acts as an efficient core receptor for the primary isolate of HIV (Shimizu et al.
T322 32611-32617 Sentence denotes 2008).
T323 32618-32728 Sentence denotes Viral entries through the alternative core receptors (CoR) CCR3 and FPR2/ALX depend on the HIV type 1 subtype.
T324 32729-32874 Sentence denotes Viruses pseudotyped with subtype A and C Env proteins use the recently described alternative CoR FPR2 more efficiently than CCR3 (Nedellec et al.
T325 32875-32881 Sentence denotes 2009).
T326 32882-32917 Sentence denotes ChemR23 also acts as a CoR for HIV.
T327 32918-33057 Sentence denotes At this time, HIV-1 and HIV-2 appear to use the N-terminus and the second extracellular loop of ChemR23 during infection (Martensson et al.
T328 33058-33064 Sentence denotes 2006).
T329 33065-33192 Sentence denotes As mentioned above, research is needed to determine the role of SPMs that act as ligands for FPR2 and ChemR23 in HIV infection.
T330 33193-33339 Sentence denotes Hepatitis C virus (HCV) is a positive-sense single-stranded RNA virus of the family Flaviviridae with a small (55–65 nm size) envelope (Lee et al.
T331 33340-33346 Sentence denotes 2017).
T332 33347-33501 Sentence denotes The HCV is the cause of hepatitis C and some cancers such as liver cancer (hepatocellular carcinoma, abbreviated HCC) and lymphoma in humans (Ferri et al.
T333 33502-33530 Sentence denotes 2015; Rusyn and Lemon 2014).
T334 33531-33611 Sentence denotes To date, there appears to be no report on the effectiveness of SPMs against HCV.
T335 33612-33759 Sentence denotes However, HCV peptide (C5A), an amphiphilic α-helix peptide of HCV, is an activator of the N-formyl peptide receptor in human phagocytes (Lin et al.
T336 33760-33766 Sentence denotes 2011).
T337 33767-33857 Sentence denotes This suggests the possibility of interaction between RvD1 and LXA4, FPR families, and HCV.
T338 33858-33980 Sentence denotes Vitamin D metabolites inhibit HCV and upregulate GPR37 gene expression, which induces cellular autophagy (Gutierrez et al.
T339 33981-33987 Sentence denotes 2014).
T340 33988-34119 Sentence denotes PD1 was recently proposed as a new ligand for GPR37, and some studies suggest a possible relationship between PD1 and HCV (Fig. 4).
T341 34120-34270 Sentence denotes SAA also has antiviral effects against HCV, however, it induces chronic inflammation through FPR2/ALX, causing liver damage (Abouelasrar Salama et al.
T342 34271-34277 Sentence denotes 2019).
T343 34278-34443 Sentence denotes Although research has not been conducted yet, RvD1 and LXA4, which inhibit the action of SAA, are likely to suppress liver damage caused by SAA during HCV infection.
T344 34445-34455 Sentence denotes SARS-CoV-2
T345 34456-34742 Sentence denotes Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) refers to a coronavirus strain that causes 2019 coronavirus disease (COVID-19), a respiratory disease that is the cause of the COVID-19 pandemic (Coronaviridae Study Group of the International Committee on Taxonomy of, 2020).
T346 34743-34871 Sentence denotes SARS-CoV-2 is an RNA virus that infects the lungs and causes deaths through complications such as cytokine storms (Goldin et al.
T347 34872-34878 Sentence denotes 2020).
T348 34879-35057 Sentence denotes The anti-inflammatory action of mesenchymal stem cells is well known, and it is believed that these mesenchymal stem cells exhibit anti-inflammatory action through PGE2 and LXA4.
T349 35058-35240 Sentence denotes These lipids mediators alleviate the SARS-CoV-2 cytokine storm, while arachidonic acid, dihomo-gamma-linolenic acid, and gamma-linolenic acid inactivate enveloped viruses (Das 2020).
T350 35241-35375 Sentence denotes Obesity is a risk factor for SARS-CoV-2 infection, and a BMI of 30 kg/m2 increases the risk of infection by 61% (Bello-Chavolla et al.
T351 35376-35382 Sentence denotes 2020).
T352 35383-35531 Sentence denotes This is likely due to a deficiency of SPMs in obese patients, and this deficiency promotes adverse reactions during SARS-CoV-2 infection (Pal et al.
T353 35532-35538 Sentence denotes 2020).
T354 35539-35664 Sentence denotes LXA4, Elovanoid-N32 or RvD6 isomers reduced expression of angiotensin-converting enzyme 2 (ACE2), but NDP1 did not reduce it.
T355 35665-35835 Sentence denotes These lipids mediators also counteract the binding of the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein to the injured cornea (Figs. 3 and 4) (Pham et al.
T356 35836-35842 Sentence denotes 2020).
T357 35843-35968 Sentence denotes Elovanoid-N32 or RvD6 isomers also attenuated the expression of cytokines involved in a cytokine storm and hyperinflammation.
T358 35969-36199 Sentence denotes Based on previous study results that have demonstrated SPMs as potential therapeutic targets for SARS-CoV-2 infection, studies and review on the use of fish oil, an SPMs precursor, as an adjuvant are in progress. (Torrinhas et al.
T359 36200-36219 Sentence denotes 2020; Rogero et al.
T360 36220-36226 Sentence denotes 2020).
T361 36227-36499 Sentence denotes SPMs and soluble epoxide hydrolase inhibitors are currently in clinical trials for other inflammatory diseases and can be quickly converted and used for SARS-CoV-2 management through the removal of cellular debris and inhibition of inflammatory cytokines (Panigrahy et al.
T362 36500-36506 Sentence denotes 2020).
T363 36508-36519 Sentence denotes Conclusions
T364 36520-36609 Sentence denotes Recently, a new group of molecules, named SPMs that resolve inflammation were elucidated.
T365 36610-36732 Sentence denotes Further, in efforts to investigate and demonstrate their mechanism of action, their receptors are slowly being discovered.
T366 36733-36810 Sentence denotes As an additional milestone, SPMs were detected in several biological samples.
T367 36811-36984 Sentence denotes However, the investigation of the pharmacological principle based on GPCR for SPMs under various physiological and pathological conditions is insufficient (Psychogios et al.
T368 36985-37003 Sentence denotes 2011; Lukiw et al.
T369 37004-37010 Sentence denotes 2005).
T370 37011-37125 Sentence denotes Further research is needed on specific molecular targets of omega-3 fatty acids such as RvE2, RvD2, PDs, and MaRs.
T371 37126-37400 Sentence denotes The interaction between the host immune system and infectious viral attacks represents new opportunities for the utilization of SPMs. The use of SPMs is likely to help regulate abnormal viral-mediated inflammation and prevent complications such as SARS-CoV-2 cytokine storm.
T372 37401-37483 Sentence denotes Besides, SPMs play parts in restoring tissue homeostasis, including wound healing.
T373 37484-37589 Sentence denotes Therefore, they are very likely to have therapeutic effects against the sequelae of SARS-CoV-2 infection.
T374 37590-37680 Sentence denotes Both inflammation and resolution of inflammation are vital processes of the immune system.
T375 37681-37909 Sentence denotes Therefore, a balance between the need for a sufficient immune response to clear the infection and the rapid decline of immune response to prevent host damage presents a novel opportunity for therapeutic exploitation of the SPMs.
T376 37910-38015 Sentence denotes Further research is needed to identify opportunities to optimize this balance in human viral infectivity.
T377 38016-38195 Sentence denotes Among them, it will be exciting to study how the receptors of SPMs, which act as coreceptors during virus infection, play a role in virus infection and virus-induced inflammation.
T378 38196-38344 Sentence denotes Finally, although not mentioned in this review, the author would like to emphasize that SPMs are effective in treating bacterial infections as well.
T379 38345-38519 Sentence denotes In nutshell, SPMs shows excellent potential as novel therapeutic options for severe inflammation and tissue damage caused by viral infections, including SARS-CoV-2 infection.
T380 38520-38559 Sentence denotes Fig. 1 Inflammation-resolution process.
T381 38560-38649 Sentence denotes Modified from Fullerton and Gilroy (Fullerton and Gilroy 2016), and Lee et al. (Lee 2018)
T382 38650-38682 Sentence denotes Fig. 2 SPMS and their receptors.
T383 38683-38775 Sentence denotes Blue dotted lines mean activation of receptors, and red dotted lines inhibition of receptors
T384 38776-38823 Sentence denotes Fig. 3 Effects of SPMS on the virus life cycle.
T385 38824-38861 Sentence denotes Please refer to the text for details.
T386 38862-38913 Sentence denotes RTA: replication and transcription activator, KSHV:
T387 38914-38953 Sentence denotes Kaposi’s sarcoma-associated herpesvirus
T388 38954-39033 Sentence denotes Fig. 4 Effects of SPMS on the viruses and viral infection-induced inflammation.
T389 39034-39076 Sentence denotes Green lines mean direct antiviral effects.
T390 39077-39179 Sentence denotes Blue dotted lines mean indirect effects on virus and purple dotted lines possible effects (not proved)
T391 39181-39197 Sentence denotes Publisher's Note
T392 39198-39316 Sentence denotes Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T393 39318-39334 Sentence denotes Acknowledgements
T394 39335-39497 Sentence denotes This research was supported by National Research Foundation of Korea (NRF 2018R1E1A2A02057995, NRF-2018R1A5A 2023127, NRF-2020R1A2C3004973, NRF-2020M3E5E2038356).
T395 39499-39532 Sentence denotes Compliance with ethical standards
T396 39534-39554 Sentence denotes Conflict of interest
T397 39555-39574 Sentence denotes Nothing to declare.