Biomedical subjects

Song Hong

Publications and source records attributed to Song Hong.

At least 19 recordsLinked to original sources

PubMed2007

Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness.

Protectins are newly identified natural chemical mediators that counter leukocyte activation to promote resolution of inflammation. In this study, we provide the first evidence for protectin D1 (PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) formation from docosahexaenoic acid in human asthma in vivo and PD1 counterregulatory actions in allergic airway inflammation. PD1 and 17S-hydroxy-docosahexaenoic acid were present in exhaled breath condensates from healthy subjects. Of interest, levels of PD1 were significantly lower in exhaled breath condensates from subjects with asthma exacerbations. PD1 was also present in extracts of murine lungs from both control animals and those sensitized and aerosol challenged with allergen. When PD1 was administered before aeroallergen challenge, airway eosinophil and T lymphocyte recruitment were decreased, as were airway mucus, levels of specific proinflammatory mediators, including IL-13, cysteinyl leukotrienes, and PGD(2), and airway hyperresponsiveness to inhaled methacholine. Of interest, PD1 treatment after aeroallergen challenge markedly accelerated the resolution of airway inflammation. Together, these findings provide evidence for endogenous PD1 as a pivotal counterregulatory signal in allergic airway inflammation and point to new therapeutic strategies for modulating inflammation in asthmatic lung.

Animals↗

PubMed2007

Identification of endogenous resolvin E1 and other lipid mediators derived from eicosapentaenoic acid via electrospray low-energy tandem mass spectrometry: spectra and fragmentation mechanisms.

Resolvin E1 (RvE1, 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is a novel anti-inflammatory lipid mediator recently found in humans, mice, and fish in vivo. To identify endogenous RvE1 and other eicosapentaenoic acid (EPA)-derived lipid mediators using electrospray low-energy collision-induced dissociation tandem mass spectrometry (MS/MS), the MS/MS product ion spectra of these compounds were correlated with their structures, and the MS/MS fragmentation mechanisms were studied. Deuterium labeling confirmed the proposed correlations and the fragmentation mechanisms. beta-cleavage was observed for RvE1, and beta and gamma cleavages were seen for leukotriene B5; however, alpha-cleavage was more common. The positions and numbers of hydroxyls and double bonds of these lipid mediators can be deduced from the MS/MS spectra. The MS/MS fragmentation generating chain-cut ions involved beta-ene, gamma-ene, or alpha-H-beta-ene rearrangement, depending on the specific structure. The m/z value of a detected chain-cut ion from RvE1 or from an EPA-derived product is equal to the corresponding hypothetical homolytic segment (cc, cm, mc, or mm) with the addition or extraction of up to two hydrogen atoms (H) from hydroxyls or an alpha-carbon; namely, the m/z value of an alpha-cleavage-generated ion is equal to [cc+H], [cm-2H], [mc-H], or [mm]. Wideband activation increased the signal intensities of chain-cut ions, and therefore was better for trace analysis of RvE1 in biological samples. RvE1, LTB5, PGE3, and other EPA-derived lipid mediators were found in trout brain or head-kidney via this approach on the basis of MS/MS spectra and fragmentation mechanisms. Negative ion electrospray low-collision-energy MS/MS spectra provide adequate data to elucidate and identify the structures of RvE1 and other EPA-derived lipid mediators at levels below a few picomoles in trout samples.

Animals↗

PubMed2006

Resolvin D series and protectin D1 mitigate acute kidney injury.

Omega-3 fatty acid docosahexaenoic acid is converted to potent resolvins (Rv) and protectin D1 (PD1), two newly identified families of natural mediators of resolution of inflammation. We report that, in response to bilateral ischemia/reperfusion injury, mouse kidneys produce D series resolvins (RvDs) and PD1. Administration of RvDs or PD1 to mice before the ischemia resulted in a reduction in functional and morphological kidney injury. Initiation of RvDs and RvD1 administration 10 min after reperfusion also resulted in protection of the kidney as measured by serum creatinine 24 and 48 h later. Interstitial fibrosis after ischemia/reperfusion was reduced in mice treated with RvDs. Both RvDs and PD1 reduced the number of infiltrating leukocytes and blocked TLR-mediated activation of macrophages. Thus, the renal production of Rv and protectins, a previously unrecognized endogenous anti-inflammatory response, may play an important role in protection against and resolution of acute kidney injury. These data may also have therapeutic implications for potentiation of recovery from acute kidney injury.

Acute Disease↗

PubMed2006

Resolvin D1, protectin D1, and related docosahexaenoic acid-derived products: Analysis via electrospray/low energy tandem mass spectrometry based on spectra and fragmentation mechanisms.

Resolvin D1 (RvD1) and protectin D1 (Neuroprotectin D1, PD1/NPD1) are newly identified anti-inflammatory lipid mediators biosynthesized from docosahexaenoic acid (DHA). In this report, the spectra-structure correlations and fragmentation mechanisms were studied using electrospray low-energy collision-induced dissociation tandem mass spectrometry (MS/MS) for biogenic RvD1 and PD1, as well as mono-hydroxy-DHA and related hydroperoxy-DHA. The loss of H2O and CO2 in the spectra indicates the number of functional group(s). Chain-cut ions are the signature of the positions and numbers of functional groups and double bonds. The observed chain-cut ion is equivalent to a hypothetical homolytic-segment (cc, cm, mc, or mm) with addition or extraction of up to 2 protons (H). The alpha-cleavage ions are equivalent to: [cc + H], with H from the hydroxyl through a beta-ene or gamma-ene rearrangement; [cm - 2H], with 2H from hydroxyls of PD1 through a gamma-ene rearrangement, or 1H from the hydroxyl and the other H from the alpha-carbon of mono-HDHA through an alpha-H-beta-ene rearrangement; [mc - H], with H from hydroxyl through a beta-ene or gamma-ene rearrangement, or from the alpha-carbon through an alpha-H-beta-ene rearrangement; or [mm] through charge-direct fragmentations. The beta-ene or gamma-ene facilitates the H shift to gamma position and alpha-cleavage. Deuterium labeling confirmed the assignment of MS/MS ions and the fragmentation mechanisms. Based on the MS/MS spectra and fragmentation mechanisms, we identified RvD1, PD1, and mono-hydroxy-DHA products in human neutrophils and blood, trout head-kidney, and stroke-injury murine brain-tissue.

Chromatography, High Pressure Liquid↗

PubMed2006

Melanoma growth is reduced in fat-1 transgenic mice: impact of omega-6/omega-3 essential fatty acids.

An important nutritional question as to whether the ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids plays a role in tumorigenesis remains to be clarified in well qualified experimental models. The recently engineered fat-1 mice, which can convert n-6 to n-3 fatty acids and have a balanced ratio of n-6 to n-3 fatty acids in their tissues and organs independent of diet, allow carefully controlled studies to be performed in the absence of potential confounding factors of diet and therefore are a useful model for elucidating the role of n-6/n-3 fatty acid ratio in tumorigenesis. We implanted mouse melanoma B16 cells into transgenic and WT littermates and examined the incidence of tumor formation and tumor growth rate. The results showed a dramatic reduction of melanoma formation and growth in fat-1 transgenic mice. The level of n-3 fatty acids and their metabolite prostaglandin E(3) (PGE(3)) were much higher (but the n-6/n-3 ratio is much lower) in the tumor and surrounding tissues of fat-1 mice than that of WT animals. The phosphatase and tensin homologue deleted on the chromosome 10 (PTEN) gene was significantly up-regulated in the fat-1 mice. In vitro experiments showed that addition of the n-3 fatty acid eicosapentaenoic acid or PGE(3) inhibited the growth of B16 cell line and increased the expression of PTEN, which could be partially attenuated by inhibition of PGE(3) production, suggesting that PGE(3) may act as an antitumor mediator. These data demonstrate an anticancer (antimelanoma) effect of n-3 fatty acids through, at least in part, activation of PTEN pathway mediated by PGE(3).

Animals↗

PubMed2006

Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis.

Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are the precursors of potent lipid mediators and play an important role in regulation of inflammation. Generally, n-6 PUFA promote inflammation whereas n-3 PUFA have antiinflammatory properties, traditionally attributed to their ability to inhibit the formation of n-6 PUFA-derived proinflammatory eicosanoids. Newly discovered resolvins and protectins are potent antiinflammatory lipid mediators derived directly from n-3 PUFA with distinct pathways of action. However, the role of the n-3 PUFA tissue status in the formation of these antiinflammatory mediators has not been addressed. Here we show that an increased n-3 PUFA tissue status in transgenic mice that endogenously biosynthesize n-3 PUFA from n-6 PUFA leads to significant formation of antiinflammatory resolvins and effective reduction in inflammation and tissue injury in colitis. The endogenous increase in n-3 PUFA and related products did not decrease n-6 PUFA-derived lipid mediators such as leukotriene B4 and prostaglandin E2. The observed inflammation protection might result from decreased NF-kappaB activity and expression of TNFalpha, inducible NO synthase, and IL-1beta, with enhanced mucoprotection probably because of the higher expression of trefoil factor 3, Toll-interacting protein, and zonula occludens-1. These results thus establish the fat-1 transgenic mouse as a new experimental model for the study of n-3 PUFA-derived lipid mediators. They add insight into the molecular mechanisms of inflammation protection afforded by n-3 PUFA through formation of resolvins and protectins other than inhibition of n-6 PUFA-derived eicosanoid formation.

Animals↗

PubMed2006

Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions.

The resolvins (Rv) are lipid mediators derived from omega-3 polyunsaturated fatty acids that act within a local inflammatory milieu to stop leukocyte recruitment and promote resolution. Resolvin E1 (RvE1; (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an oxygenase product derived from omega-3 eicosapentaenoic acid that displays potent anti-inflammation/pro-resolution actions in vivo. Here, we determined whether oxidoreductase enzymes catalyze the conversion of RvE1 and assessed the biological activity of the RvE1 metabolite. With NAD+ as a cofactor, recombinant 15-hydroxyprostaglandin dehydrogenase acted as an 18-hydroxyl dehydrogenase to form 18-oxo-RvE1. In the murine lung, dehydrogenation of the hydroxyl group at carbon 18 position to form 18-oxo-RvE1 represented the major initial metabolic route for RvE1. At a concentration where RvE1 potently reduced polymorphonuclear leukocyte (PMN) recruitment in zymosan-induced peritonitis, 18-oxo-RvE1 was devoid of activity. In human neutrophils, carbon 20 hydroxylation of RvE1 was the main route of conversion. An RvE1 analog, i.e. 19-(p-fluorophenoxy)-RvE1, was synthesized that resisted rapid metabolic inactivation and proved to retain biological activity reducing PMN infiltration and pro-inflammatory cytokine/chemokine production in vivo. These results established the structure of a novel RvE1 initial metabolite, indicating that conversion of RvE1 to the oxo product represents a mode of RvE1 inactivation. Moreover, the designed RvE1 analog, which resisted further metabolism/inactivation, could be a useful tool to evaluate the actions of RvE1 in complex disease models.

Animals↗

PubMed2006

Lipid mediator informatics and proteomics in inflammation resolution.

Lipid mediator informatics is an emerging area denoted to the identification of bioactive lipid mediators (LMs) and their biosynthetic profiles and pathways. LM informatics and proteomics applied to inflammation, systems tissues research provides a powerful means of uncovering key biomarkers for novel processes in health and disease. By incorporating them with system biology analysis, we review here our initial steps toward elucidating relationships among a range of bimolecular classes and provide an appreciation of their roles and activities in the pathophysiology of disease. LM informatics employing liquid chromatography-ultraviolet-tandem mass spectrometry (LC-UV-MS/MS), gas chromatography-mass spectrometry (GC-MS), computer-based automated systems equipped with databases and novel searching algorithms, and enzyme-linked immunosorbent assay (ELISA) to evaluate and profile temporal and spatial production of mediators combined with proteomics at defined points during experimental inflammation and its resolution enable us to identify novel mediators in resolution. The automated system including databases and searching algorithms is crucial for prompt and accurate analysis of these lipid mediators biosynthesized from precursor polyunsaturated fatty acids such as eicosanoids, resolvins, and neuroprotectins, which play key roles in human physiology and many prevalent diseases, especially those related to inflammation. This review presents detailed protocols used in our lab for LM informatics and proteomics using LC-UV-MS/MS, GC-MS, ELISA, novel databases and searching algorithms, and 2-dimensional gel electrophoresis and LC-nanospray-MS/MS peptide mapping.

Algorithms↗

PubMed2006

Lipid mediator informatics-lipidomics: novel pathways in mapping resolution.

Lipidomics, the systematic decoding of lipid-based information in biosystems, is composed of identifying and profiling lipids and lipid-derived mediators. As currently practiced, lipidomics can be subdivided into architecture/membrane lipidomics and mediator lipidomics. The mapping of structural components and their relation to cell activation as well as generation of potent lipid mediators and networks involves a mass spectrometry-computational approach so that interrelationships and complex mediator networks important for cell homeostasis can be appreciated. Cell membranes are composed of a bilayer that contains phospholipids, fatty acids, integral membrane proteins, membrane-associated proteins, sphingolipids, and so on. The membrane composition of many cell types has been established. The components' organization and effect on cell function remains to be established, however, and is a quest for lipidomics. Here, we review liquid chromatography tandem mass spectrometry-based lipidomic analyses to address bioactive lipid mediators in signaling pathways and the roles of lipid-derived mediators in resolution of inflammation.

Animals↗

PubMed2006

Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes.

Protectin D1, neuroprotectin D1 when generated by neural cells, is a member of a new family of bioactive products generated from docosahexaenoic acid. The complete stereochemistry of protectin D1 (10,17S-docosatriene), namely, chirality of the carbon-10 alcohol and geometry of the conjugated triene, required for bioactivity remained to be assigned. To this end, protectin D1/neuroprotectin D1 (PD1) generated by human neutrophils during murine peritonitis and by neural tissues was separated from natural isomers and subjected to liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Comparisons with six 10,17-dihydroxydocosatrienes prepared by total organic and biogenic synthesis showed that PD1 from human cells carrying potent bioactivity is 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Additional isomers identified included trace amounts of Delta15-trans-PD1 (isomer III), 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid (isomer IV), and a double dioxygenation product 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid (isomer I), present in exudates. 18O2 labeling showed that 10S,17S-diHDHA (isomer I) carried 18O in the carbon-10 position alcohol, indicating sequential lipoxygenation, whereas PD1 formation proceeded via an epoxide. PD1 at 10 nM attenuated (approximately 50%) human neutrophil transmigration, whereas Delta15-trans-PD1 was essentially inactive. PD1 was a potent regulator of polymorphonuclear leukocyte (PMN) infiltration (approximately 40% at 1 ng/mouse) in peritonitis. The rank order at 1- to 10-ng dose was PD1 approximately PD1 methyl ester >> Delta15-trans-PD1 > 10S,17S-diHDHA (isomer I). 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid (isomer VI) proved > or = PD1 in blocking PMN infiltration, but was not a major product of leukocytes. PD1 also reduced PMN infiltration after initiation (2 h) of inflammation and was additive with resolvin E1. These results indicate that PD1 is a potent stereoselective anti-inflammatory molecule.

Animals↗

PubMed2006

Composite thin film by hydrogen-bonding assembly of polymer brush and poly(vinylpyrrolidone).

Based on hydrogen-bonding layer-by-layer (LBL) assembly in aqueous solution, poly(vinylpyrrolidone) (PVPON) and a spherical polymer brush with a poly(methylsilsesquioxane) (PSQ) core and poly(acrylic acid) (PAA) hair chains were used to fabricate composite multilayer thin films. Hydrogen bonding as the driving force was confirmed by FT-IR spectrometry. A simple method (Filmetric F20) was introduced to determine the thickness and refractive index of the films. The film thickness was found to be a linear function of the number of bilayers. The average increase in thickness per bilayer is 28.3 nm. The film morphology was characterized with scanning electron microscopy and atomic force microscopy. The images obtained from the two instruments show a great resemblance. The films were further calcined to get an inorganic film by removing the organic components, or treated with tetrabutylammonium fluoride (TBAF) to remove the PSQ core and get an organic film. The optical properties and morphological changes induced by these treatments were also studied.

Journal Article↗

PubMed2006

Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis.

The family of resolvins consists of omega-3 fatty acid-derived mediators, including E series resolvins generated from eicosapentaenoic acid (EPA), and carry potent anti-inflammatory properties. Here, we report the isolation, identification, and bioactions of resolvin E2 (RvE2), which is 5S,18-dihydroxy-eicosapentaenoic acid. RvE2 stopped zymosan-induced polymorphonuclear (PMN) leukocyte infiltration and displayed potent anti-inflammatory properties in murine peritonitis. We also demonstrate that human recombinant 5-lipoxygenase generates RvE2 from a common precursor of E series resolvins, namely, 18-hydroxyeicosapentaenoate (18-HEPE). Furthermore, the initial 5-hydroperoxide intermediate was also converted to a 5(6)-epoxide intermediate in RvE1 formation. These results demonstrate that RvE2, together with RvE1, may contribute to the beneficial actions of omega-3 fatty acids in human diseases. Moreover, they indicate that the 5-lipoxygenase in human leukocytes is a pivotal enzyme that can produce both pro- and anti-inflammatory chemical mediators.

Animals↗

PubMed2005

The docosatriene protectin D1 is produced by TH2 skewing and promotes human T cell apoptosis via lipid raft clustering.

Docosahexaenoic acid, a major omega-3 fatty acid in human brain, synapses, retina, and other neural tissues, displays beneficial actions in neuronal development, cancer, and inflammatory diseases by mechanisms that remain to be elucidated. In this study we found, using lipid mediator informatics employing liquid chromatography-tandem mass spectrometry, that (10,17S)-docosatriene/neuroprotectin D1, now termed protectin D1 (PD1), is generated from docosahexaenoic acid by T helper type 2-skewed peripheral blood mononuclear cells in a lipoxygenase-dependent manner. PD1 blocked T cell migration in vivo, inhibited tumor necrosis factor alpha and interferon-gamma secretion, and promoted apoptosis mediated by raft clustering. These results demonstrated novel anti-inflammatory roles for PD1 in regulating events associated with inflammation and resolution.

Animals↗

PubMed2005

Rainbow trout (Oncorhynchus mykiss) brain cells biosynthesize novel docosahexaenoic acid-derived resolvins and protectins-Mediator lipidomic analysis.

Docosahexaenoic acid (DHA; C22:6 n-3) is an abundant fatty acid in fish phospholipids. In the present study, we employed liquid chromatography-ultraviolet spectrometry-tandem mass spectrometry and dissociated rainbow trout (Oncorhynchus mykiss) brain cells to determine whether fish utilize endogenous DHA to produce the recently uncovered novel lipid mediators termed the resolvins and protectins, generated by mammalian cells [Serhan CN, Hong S, Gronert K, et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 2002; 196:1025-37; Hong S, Gronert K, Devchand P, Moussignac R-L, Serhan, CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. J Biol Chem 2003;278:14677-87]. Trout brain cells biosynthesize a range of recently identified di- and tri-hydroxy-containing bioactive products from endogenous sources of DHA when challenged in vitro. We identified neuroprotectin D1, resolvin D5, resolvin D1 and resolvin D2 from trout brain cells. Each compound was identified on the basis of its characteristic physical chemical properties that included MS, MS-MS, UV spectra and chromatographic behavior. The monohydroxy products from DHA, signatures of DHA conversion by lipoxygenases, were also identified. These included both 14S-hydroxy-docosahexaenoic acid and 17S-hydroxy-docosahexaenoic acid. The biosynthesis of these novel bioactive lipid mediators, namely resolvins and protectins, by fish cells provides the first evidence for the conservation of these structures from fish to humans as chemical signals in diverse biological systems.

Animals↗

PubMed2005

Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis.

Resolvin E1 (RvE1; 5S,12R,18R-trihydroxyeicosapentaenoic acid) is an antiinflammatory lipid mediator derived from omega-3 fatty acid eicosapentaenoic acid (EPA). At the local site of inflammation, aspirin treatment enhances EPA conversion to 18R-oxygenated products, including RvE1, which carry potent antiinflammatory signals. Here, we obtained evidence for reduced leukocyte infiltration in a mouse peritonitis model, where the administration of EPA and aspirin initiated the generation of RvE1 in the exudates. Similar results were obtained with the administration of synthetic RvE1, which blocked leukocyte infiltration. RvE1 also protected against the development of 2,4,6-trinitrobenzene sulfonic acid-induced colitis. The beneficial effect was reflected by increased survival rates, sustained body weight, improvement of histologic scores, reduced serum anti-2,4,6-trinitrobenzene sulfonic acid IgG, decreased leukocyte infiltration, and proinflammatory gene expression, including IL-12 p40, TNF-alpha, and inducible nitric oxide synthase. Thus, the endogenous lipid mediator RvE1 counter-regulates leukocyte-mediated tissue injury and proinflammatory gene expression. These findings show an endogenous mechanism that may underlie the beneficial actions of omega-3 EPA and provide targeted approaches for the treatment of intestinal inflammation.

Animals↗

PubMed2005

Molecular circuits of resolution: formation and actions of resolvins and protectins.

The cellular events underlying the resolution of acute inflammation are not known in molecular terms. To identify anti-inflammatory and proresolving circuits, we investigated the temporal and differential changes in self-resolving murine exudates using mass spectrometry-based proteomics and lipidomics. Key resolution components were defined as resolution indices including Psi(max), the maximal neutrophil numbers that are present during the inflammatory response; T(max), the time when Psi(max) occurs; and the resolution interval (R(i)) from T(max) to T(50) when neutrophil numbers reach half Psi(max). The onset of resolution was at approximately 12 h with proteomic analysis showing both haptoglobin and S100A9 levels were maximal and other exudate proteins were dynamically regulated. Eicosanoids and polyunsaturated fatty acids first appeared within 4 h. Interestingly, the docosahexaenoic acid-derived anti-inflammatory lipid mediator 10,17S-docosatriene was generated during the R(i). Administration of aspirin-triggered lipoxin A(4) analog, resolvin E1, or 10,17S-docosatriene each either activated and/or accelerated resolution. For example, aspirin-triggered lipoxin A(4) analog reduced Psi(max), resolvin E1 decreased both Psi(max) and T(max), whereas 10,17S-docosatriene reduced Psi(max), T(max), and shortened R(i). Also, aspirin-triggered lipoxin A(4) analog markedly inhibited proinflammatory cytokines and chemokines at 4 h (20-50% inhibition), whereas resolvin E1 and 10,17S-docosatriene's inhibitory actions were maximal at 12 h (30-80% inhibition). Moreover, aspirin-triggered lipoxin A(4) analog evoked release of the antiphlogistic cytokine TGF-beta. These results characterize the first molecular resolution circuits and their major components activated by specific novel lipid mediators (i.e., resolvin E1 and 10,17S-docosatriene) to promote resolution.

Animals↗

PubMed2005

Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1.

The essential fatty acid eicosapentaenoic acid (EPA) present in fish oils displays beneficial effects in a range of human disorders associated with inflammation including cardiovascular disease. Resolvin E1 (RvE1), a new bioactive oxygenated product of EPA, was identified in human plasma and prepared by total organic synthesis. Results of bioaction and physical matching studies indicate that the complete structure of RvE1 is 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA. At nanomolar levels, RvE1 dramatically reduced dermal inflammation, peritonitis, dendritic cell (DC) migration, and interleukin (IL) 12 production. We screened receptors and identified one, denoted earlier as ChemR23, that mediates RvE1 signal to attenuate nuclear factor-kappaB. Specific binding of RvE1 to this receptor was confirmed using synthetic [(3)H]-labeled RvE1. Treatment of DCs with small interference RNA specific for ChemR23 sharply reduced RvE1 regulation of IL-12. These results demonstrate novel counterregulatory responses in inflammation initiated via RvE1 receptor activation that provide the first evidence for EPA-derived potent endogenous agonists of antiinflammation.

Amino Acid Sequence↗

PubMed2005

Mediator-lipidomics: databases and search algorithms for PUFA-derived mediators.

Lipid mediators (LMs) derived from PUFAs play important roles in health and disease. Databases and search algorithms are crucial, but currently unavailable, for accurate and prompt analysis of LMs via liquid chromatography-ultraviolet-tandem mass spectrometry (LC-UV-MS/MS). A novel algorithm and databases, cognoscitive-contrast-angle algorithm and databases (COCAD), were developed for the identification of LMs based on the integration of standard MS/MS spectra with chromatograms and UV spectra. Segment naming and empirical fragmentation rules were introduced to determine MS/MS ion identities, along with ion intensities used by COCAD in matching the unknown to those of authentic standards. The structures of potential LMs without synthetic and/or authentic products as standards were identified by developing theoretical databases and algorithms based on virtual LC-UV-MS/MS spectra and chromatograms. The performance of these databases and algorithms was tested by identifying LMs in murine tissues. These results indicate that COCAD has many advantages for profiling and identification of LMs compared with the conventional dot-product algorithm.

Algorithms↗