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Nicolas G. Bazan - One of the best experts on this subject based on the ideXlab platform.

  • Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection.
    Molecular aspects of medicine, 2018
    Co-Authors: Nicolas G. Bazan
    Abstract:

    The functional significance of the selective enrichment of the omega-3 essential fatty acid docosahexaenoic acid (DHA; 22C and 6 double bonds) in cellular membrane phospholipids of the nervous system is being clarified by defining its specific roles on membrane protein function and by the uncovering of the bioactive mediators, Docosanoids and elovanoids (ELVs). Here, we describe the preferential uptake and DHA metabolism in photoreceptors and brain as well as the significance of the Adiponectin receptor 1 in DHA retention and photoreceptor cell (PRC) survival. We now know that this integral membrane protein is engaged in DHA retention as a necessary event for the function of PRCs and retinal pigment epithelial (RPE) cells. We present an overview of how a) NPD1 selectively mediates preconditioning rescue of RPE and PR cells; b) NPD1 restores aberrant neuronal networks in experimental epileptogenesis; c) the decreased ability to biosynthesize NPD1 in memory hippocampal areas of early stages of Alzheimer's disease takes place; d) NPD1 protection of dopaminergic circuits in an in vitro model using neurotoxins; and e) bioactivity elicited by DHA and NPD1 activate a neuroprotective gene-expression program that includes the expression of Bcl-2 family members affected by Aβ42, DHA, or NPD1. In addition, we highlight ELOVL4 (ELOngation of Very Long chain fatty acids-4), specifically the neurological and ophthalmological consequences of its mutations, and their role in providing precursors for the biosynthesis of ELVs. Then we outline evidence of ELVs ability to protect RPE cells, which sustain PRC integrity. In the last section, we present a summary of the protective bioactivity of Docosanoids and ELVs in experimental ischemic stroke. The identification of early mechanisms of neural cell survival mediated by DHA-synthesized ELVs and Docosanoids contributes to the understanding of cell function, pro-homeostatic cellular modulation, inflammatory responses, and innate immunity, opening avenues for prevention and therapeutic applications in neurotrauma, stroke and neurodegenerative diseases.

  • Retinal Pigment Epithelium and Photoreceptor Preconditioning Protection Requires Docosanoid Signaling
    Cellular and Molecular Neurobiology, 2018
    Co-Authors: Eric J. Knott, William C Gordon, Khanh Do, Nicolas G. Bazan
    Abstract:

    Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are necessary for functional cell integrity. Preconditioning (PC), as we define it, is an acquired protection or resilience by a cell, tissue, or organ to a lethal stimulus enabled by a previous sublethal stressor or stimulus. In this study, we provide evidence that the omega-3 fatty acid docosahexaenoic acid (DHA) and its derivatives, the Docosanoids 17-hydroxy docosahexaenoic acid (17-HDHA) and neuroprotectin D1 (NPD1), facilitate cell survival in both in vitro and in vivo models of retinal PC. We also demonstrate that PC requires the enzyme 15-lipoxygenase-1 (15-LOX-1), which synthesizes 17-HDHA and NPD1, and that this is specific to docosanoid signaling despite the concomitant release of the omega-6 arachidonic acid and eicosanoid synthesis. These findings advocate that DHA and Docosanoids are protective enablers of PC in photoreceptor and retinal pigment epithelial cells.

  • elovanoids are novel cell specific lipid mediators necessary for neuroprotective signaling for photoreceptor cell integrity
    Scientific Reports, 2017
    Co-Authors: Bokkyoo Jun, Rong Yang, William C Gordon, Pranab K Mukherjee, Aram Asatryan, Marieaudrey Ines Kautzmann, Jessica Heap, Surjyadipta Bhattacharjee, Nicos A Petasis, Nicolas G. Bazan
    Abstract:

    Docosahexaenoic acid (DHA, 22:6 n-3) is abundant in the retina and is enzymatically converted into pro-homeostatic Docosanoids. The DHA- or eicosapentaenoic acid (EPA)-derived 26 carbon fatty acid is a substrate of elongase ELOVL4, which is expressed in photoreceptor cells and generates very long chain (≥C28) polyunsaturated fatty acids including n-3 (VLC-PUFAs,n-3). While ELOVL4 mutations are linked to vision loss and neuronal dysfunctions, the roles of VLC-PUFAs remain unknown. Here we report a novel class of lipid mediators biosynthesized in human retinal pigment epithelial (RPE) cells that are oxygenated derivatives of VLC-PUFAs,n-3; we termed these mediators elovanoids (ELV). ELVs have structures reminiscent of Docosanoids but with different physicochemical properties and alternatively-regulated biosynthetic pathways. The structures, stereochemistry, and bioactivity of ELVs were determined using synthetic materials produced by stereo-controlled chemical synthesis. ELVs enhance expression of pro-survival proteins in cells undergoing uncompensated oxidative stress. Our findings unveil a novel autocrine/paracrine pro-homeostatic RPE cell signaling that aims to sustain photoreceptor cell integrity and reveal potential therapeutic targets for retinal degenerations.

  • Thematic Minireview Series: Inflammatory transcription confronts homeostatic disruptions
    The Journal of biological chemistry, 2017
    Co-Authors: Nicolas G. Bazan, George M. Carman
    Abstract:

    In this Thematic Minireview Series, three stimulating articles are presented: one on long non-coding RNAs, another on the ligand-activated transcription factor aryl hydrocarbon receptor, and the third on how Docosanoids modulate transcriptionally modulated homeostasis and ultimately cell survival in the retina and brain.

  • Molecular mechanisms of signaling via the docosanoid neuroprotectin D1 for cellular homeostasis and neuroprotection.
    The Journal of biological chemistry, 2017
    Co-Authors: Aram Asatryan, Nicolas G. Bazan
    Abstract:

    Docosahexaenoic acid, enriched in the brain and retina, generates Docosanoids in response to disruptions of cellular homeostasis. Docosanoids include neuroprotectin D1 (NPD1), which is decreased in the CA1 hippocampal area of patients with early-stage Alzheimer's disease (AD). We summarize here how NPD1 elicits neuroprotection by up-regulating c-REL, a nuclear factor (NF)-κB subtype that, in turn, enhances expression of BIRC3 (baculoviral inhibitor of apoptosis repeat-containing protein 3) in the retina and in experimental stroke, leading to neuroprotection. Elucidating the mechanisms of action of Docosanoids will contribute to managing diseases, including stroke, AD, age-related macular degeneration, traumatic brain injury, Parkinson's disease, and other neurodegenerations.

Eric J. Knott - One of the best experts on this subject based on the ideXlab platform.

  • Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke
    Brain circulation, 2020
    Co-Authors: Ludmila Belayev, Eric J. Knott, Pranab K Mukherjee, Andre Obenaus, Larissa Khoutorova, Madigan M Reid, Cassia R Roque, Lawrence Nguyen, Jeong Bin Lee, Nicos A Petasis
    Abstract:

    OBJECTIVE: Acute ischemic stroke triggers complex neurovascular, neuroinflammatory, and synaptic alterations. This study explores whether blocking pro-inflammatory platelet-activating factor receptor (PAF-R) plus selected Docosanoids after middle cerebral artery occlusion (MCAo) would lead to neurological recovery. The following small molecules were investigated: (a) LAU-0901, a PAF-R antagonist that blocks pro-inflammatory signaling; and (b) derivatives of docosahexaenoic acid (DHA), neuroprotectin D1 (NPD1), and aspirin-triggered NPD1 (AT-NPD1), which activates cell survival pathways and are exert potent anti-inflammatory activity in the brain. MATERIALS AND METHODS: Sprague-Dawley rats received 2 h MCAo and LAU-0901 (30 or 60 mg/kg, 2 h after stroke), NPD1, and AT-NPD1 (333 μg/kg), DHA (5 mg/kg), and their combination were administered intravenous at 3 h after stroke. Behavior testing and ex vivo magnetic resonance imaging were conducted on day 3 or 14 to assess lesion characteristics and lipidomic analysis on day 1. Series 1 (LAU-0901 + NPD1, 14d), Series 2 (LAU-0901 + AT-NPD1, 3d), and Series 3 (LAU-0901 + DHA, 1d). RESULTS: All combinatory groups improved behavior compared to NPD1, AT-NPD1, or DHA treatments alone. Total lesion volumes were reduced with LAU-0901 + NPD1 by 62% and LAU-0901 + AT-NPD1 by 90% treatments versus vehicle groups. LAU-0901 and LAU-0901 + DHA increased the production of vasoactive lipid mediators (prostaglandins: PGE2, PGF2-α, 6-keto-PGF1-α, and PGD2) as well an inflammatory regulating mediator hydroxyoctadecadienoic acid. In contrast, LAU-0901 and LAU-0901 + DHA decreased the production of 12-hydroxyeicosatetraenoic acid, a pro-inflammatory mediator. CONCLUSION: Combination therapy with LAU-0901 and selected Docosanoids is more effective than the single therapy, affording synergistic neuroprotection, with restored pro-homeostatic lipid mediators and improved neurological recovery. Altogether, our findings support the combinatory therapy as the basis for future therapeutics for ischemic stroke.

  • Retinal Pigment Epithelium and Photoreceptor Preconditioning Protection Requires Docosanoid Signaling
    Cellular and Molecular Neurobiology, 2018
    Co-Authors: Eric J. Knott, William C Gordon, Khanh Do, Nicolas G. Bazan
    Abstract:

    Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are necessary for functional cell integrity. Preconditioning (PC), as we define it, is an acquired protection or resilience by a cell, tissue, or organ to a lethal stimulus enabled by a previous sublethal stressor or stimulus. In this study, we provide evidence that the omega-3 fatty acid docosahexaenoic acid (DHA) and its derivatives, the Docosanoids 17-hydroxy docosahexaenoic acid (17-HDHA) and neuroprotectin D1 (NPD1), facilitate cell survival in both in vitro and in vivo models of retinal PC. We also demonstrate that PC requires the enzyme 15-lipoxygenase-1 (15-LOX-1), which synthesizes 17-HDHA and NPD1, and that this is specific to docosanoid signaling despite the concomitant release of the omega-6 arachidonic acid and eicosanoid synthesis. These findings advocate that DHA and Docosanoids are protective enablers of PC in photoreceptor and retinal pigment epithelial cells.

  • Endogenous Signaling by Omega-3 Docosahexaenoic Acid-derived Mediators Sustains Homeostatic Synaptic and Circuitry Integrity
    Molecular Neurobiology, 2011
    Co-Authors: Nicolas G. Bazan, Alberto E. Musto, Eric J. Knott
    Abstract:

    The harmony and function of the complex brain circuits and synapses are sustained mainly by excitatory and inhibitory neurotransmission, neurotrophins, gene regulation, and factors, many of which are incompletely understood. A common feature of brain circuit components, such as dendrites, synaptic membranes, and other membranes of the nervous system, is that they are richly endowed in docosahexaenoic acid (DHA), the main member of the omega-3 essential fatty acid family. DHA is avidly retained and concentrated in the nervous system and known to play a role in neuroprotection, memory, and vision. Only recently has it become apparent why the surprisingly rapid increases in free (unesterified) DHA pool size take place at the onset of seizures or brain injury. This phenomenon began to be clarified by the discovery of neuroprotectin D1 (NPD1), the first-uncovered bioactive docosanoid formed from free DHA through 15-lipoxygenase-1 (15-LOX-1). NPD1 synthesis includes, as agonists, oxidative stress and neurotrophins. The evolving concept is that DHA-derived Docosanoids set in motion endogenous signaling to sustain homeostatic synaptic and circuit integrity. NPD1 is anti-inflammatory, displays inflammatory resolving activities, and induces cell survival, which is in contrast to the pro-inflammatory actions of the many of omega-6 fatty acid family members. We highlight here studies relevant to the ability of DHA to sustain neuronal function and protect synapses and circuits in the context of DHA signalolipidomics. DHA signalolipidomics comprises the integration of the cellular/tissue mechanism of DHA uptake, its distribution among cellular compartments, the organization and function of membrane domains containing DHA phospholipids, and the precise cellular and molecular events revealed by the uncovering of signaling pathways regulated by Docosanoids endowed with prohomeostatic and cell survival bioactivity. Therefore, this approach offers emerging targets for prevention, pharmaceutical intervention, and clinical translation involving DHA-mediated signaling.

  • Endogenous Signaling by Omega-3 Docosahexaenoic Acid-derived Mediators Sustains Homeostatic Synaptic and Circuitry Integrity
    2011
    Co-Authors: Nicolas G. Bazan, Alberto E. Musto, Eric J. Knott
    Abstract:

    Abstract The harmony and function of the complex brain circuits and synapses are sustained mainly by excitatory and inhibitory neurotransmission, neurotrophins, gene regulation, and factors, many of which are incompletely understood. A common feature of brain circuit components, such as dendrites, synaptic membranes, and other membranes of the nervous system, is that they are richly endowed in docosahexaenoic acid (DHA), the main member of the omega-3 essential fatty acid family. DHA is avidly retained and concentrated in the nervous system and known to play a role in neuroprotection, memory, and vision. Only recently has it become apparent why the surprisingly rapid increases in free (unesterified) DHA pool size take place at the onset of seizures or brain injury. This phenomenon began to be clarified by the discovery of neuroprotectin D1 (NPD1), the first-uncovered bioactive docosanoid formed from free DHA through 15lipoxygenase-1 (15-LOX-1). NPD1 synthesis includes, as agonists, oxidative stress and neurotrophins. The evolving concept is that DHA-derived Docosanoids set in motion endogenous signaling to sustain homeostatic synaptic and circuit integrity. NPD1 is anti-inflammatory, displays inflammatory resolving activities, and induces cell survival, which is in contrast to the pro-inflammatory actions of the many of omega-6 fatty acid family members. We highlight here studies relevant to the ability of DHA t

Charles N. Serhan - One of the best experts on this subject based on the ideXlab platform.

  • 2002. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals
    2013
    Co-Authors: Charles N. Serhan, Song Hong, Karsten Gronert, Sean P Colgan, Gudrun Mirick, Pallavi R. Devch, Roselaure Moussignac
    Abstract:

    Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R-containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17R-hydroxy-containing di- and tri-hydroxy-Docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17R-hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17R-HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA–derived 17R-hydroxy-DHA into two sets of novel diand trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC50 �50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40–80 % leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17R-hydroxy series of Docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status. Key words: endothelial cells • leukocytes • docosahexaenoic acid • cyclooxygenase-2 • resolutio

  • Novel eicosanoid and docosanoid mediators: resolvins, docosatrienes, and neuroprotectins
    Current opinion in clinical nutrition and metabolic care, 2005
    Co-Authors: Charles N. Serhan
    Abstract:

    Purpose of review It is well known that arachidonic acid is the precursor to potent mediators. Many clinical studies suggest that omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid have beneficial actions in human diseases. The molecular basis of these actions remains of interest. Recent findings These demonstrate that eicosapentaenoic acid and docosahexaenoic acid are precursors to potent (nM range) bioactive mediators that possess both anti-inflammatory and protective properties. These mediators were coined resolvins, docosatrienes, and protectins as general classes, since each possesses unique chemical structures that are features of the new chemical classes and are biosynthesized by new pathways. Resolvins, discovered first, were identified during the resolution phase of acute inflammation; hence the term resolution interaction products, because they are also biosynthesized by human cells via cell–cell interactions. Docosatrienes contain conjugated triene structures generated from docosahexaenoic acid as a defining feature. The protectins comprise docosatrienes and resolvins of the D series that are both neuroprotective and anti-inflammatory. Aspirin impacts on these new pathways by triggering formation of their epimers (i.e. R isomers). Summary In view of the many beneficial actions attributed to omega-3 dietary supplementation, identification of novel potent mediators from omega-3 that are both anti-inflammatory and protective may have wide implications.

  • novel Docosanoids inhibit brain ischemia reperfusion mediated leukocyte infiltration and pro inflammatory gene expression
    Journal of Biological Chemistry, 2003
    Co-Authors: Victor L Marcheselli, Nan Chiang, Alberto E. Musto, Walter J. Lukiw, Song Hong, Karsten Gronert, Xiao Hua Tian, Mattie Hardy, Juan M Gimenez, Charles N. Serhan
    Abstract:

    Abstract Ischemic stroke triggers lipid peroxidation and neuronal injury. Docosahexaenoic acid released from membrane phospholipids during brain ischemia is a major source of lipid peroxides. Leukocyte infiltration and pro-inflammatory gene expression also contribute to stroke damage. In this study using lipidomic analysis, we have identified stereospecific messengers from docosahexaenoate-oxygenation pathways in a mouse stroke model. Aspirin, widely used to prevent cerebrovascular disease, activates an additional pathway, which includes the 17R-resolvins. The newly discovered brain messenger 10,17S-docosatriene potently inhibited leukocyte infiltration, NFκB, and cyclooxygenase-2 induction in experimental stroke and elicited neuroprotection. In addition, in neural cells in culture, this lipid messenger also inhibited both interleukin 1-β-induced NFκB activation and cyclooxygenase-2 expression. Thus, the specific novel bioactive Docosanoids generated in vivo counteract leukocyte-mediated injury as well as pro-inflammatory gene induction. These results challenge the view that docosahexaenoate only participates in brain damage and demonstrate that this fatty acid is also the endogenous precursor to a neuroprotective signaling response to ischemia-reperfusion.

  • novel docosatrienes and 17s resolvins generated from docosahexaenoic acid in murine brain human blood and glial cells autacoids in anti inflammation
    Journal of Biological Chemistry, 2003
    Co-Authors: Song Hong, Karsten Gronert, Pallavi R Devchand, Roselaure Moussignac, Charles N. Serhan
    Abstract:

    Abstract Docosahexaenoic acid (DHA, C22:6) is highly enriched in brain, synapses, and retina and is a major ω-3 fatty acid. Deficiencies in this essential fatty acid are reportedly associated with neuronal function, cancer, and inflammation. Here, using new lipidomic analyses employing high performance liquid chromatography coupled with a photodiode-array detector and a tandem mass spectrometer, a novel series of endogenous mediators was identified in blood, leukocytes, brain, and glial cells as 17S-hydroxy-containing Docosanoids denoted as docosatrienes (the main bioactive member of the series was 10,17S-docosatriene) and 17S series resolvins. These novel mediators were biosynthesized via epoxide-containing intermediates and proved potent (pico- to nanomolar range) regulators of both leukocytes reducing infiltration in vivo and glial cells blocking their cytokine production. These results indicate that DHA is the precursor to potent protective mediators generated via enzymatic oxygenations to novel docosatrienes and 17Sseries resolvins that each regulate events of interest in inflammation and resolution.

  • resolvins a family of bioactive products of omega 3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals
    Journal of Experimental Medicine, 2002
    Co-Authors: Charles N. Serhan, Song Hong, Karsten Gronert, Sean P Colgan, Pallavi R Devchand, Gudrun Mirick, Roselaure Moussignac
    Abstract:

    Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R- containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17 R -hydroxy-containing di- and tri-hydroxy-Docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17 R -hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17 R -HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA‐derived 17 R -hydroxy-DHA into two sets of novel diand trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC 50 � 50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40‐80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17 R -hydroxy series of Docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status.

Yale Impact Team - One of the best experts on this subject based on the ideXlab platform.

  • cutting edge severe sars cov 2 infection in humans is defined by a shift in the serum lipidome resulting in dysregulation of eicosanoid immune mediators
    Journal of Immunology, 2021
    Co-Authors: Benjamin Schwarz, Lokesh Sharma, Lydia M Roberts, Xiaohua Peng, Santos Bermejo, Ian Leighton, Arnau Casanovasmassana, Maksym Minasyan, Shelli Farhadian, Yale Impact Team
    Abstract:

    The COVID-19 pandemic has affected more than 20 million people worldwide, with mortality exceeding 800,000 patients. Risk factors associated with severe disease and mortality include advanced age, hypertension, diabetes, and obesity. Each of these risk factors pathologically disrupts the lipidome, including immunomodulatory eicosanoid and docosanoid lipid mediators (LMs). We hypothesized that dysregulation of LMs may be a defining feature of the severity of COVID-19. By examining LMs and polyunsaturated fatty acid precursor lipids in serum from hospitalized COVID-19 patients, we demonstrate that moderate and severe disease are separated by specific differences in abundance of immune-regulatory and proinflammatory LMs. This difference in LM balance corresponded with decreased LM products of ALOX12 and COX2 and an increase LMs products of ALOX5 and cytochrome p450. Given the important immune-regulatory role of LMs, these data provide mechanistic insight into an immuno-lipidomic imbalance in severe COVID-19.

  • Severe SARS-CoV-2 infection is defined by a shift in the serum lipidome resulting in dysregulation of eicosanoid lipid immune mediators
    2020
    Co-Authors: Benjamin Schwarz, Lokesh Sharma, Xiaohua Peng, Santos Bermejo, Ian Leighton, Shelli Farhadian, Lydia Roberts, Arnau Casanovas-massana, Yale Impact Team
    Abstract:

    Abstract The COVID-19 pandemic has affected more than 10 million people worldwide with mortality exceeding3 half a million patients. Risk factors associated with severe disease and mortality include advanced age,4 hypertension, diabetes, and obesity.1 Clear mechanistic understanding of how these comorbidities5 converge to enable severe infection is lacking. Notably each of these risk factors pathologically disrupts6 the lipidome and this disruption may be a unifying feature of severe COVID-19.1-7 Here we provide the first in depth interrogation of lipidomic changes, including structural-lipids as well as the eicosanoids and Docosanoids lipid mediators (LMs), that mark COVID-19 disease severity. Our data reveal that progression from moderate to severe disease is marked by a loss of specific immune regulatory LMs and increased pro-inflammatory species. Given the important immune regulatory role of LMs, these data provide mechanistic insight into the immune balance in COVID-19 and potential targets for therapy with currently approved pharmaceuticals.8

  • severe sars cov 2 infection in humans is defined by a shift in the serum lipidome resulting in dysregulation of eicosanoid immune mediators
    medRxiv, 2020
    Co-Authors: Benjamin Schwarz, Lokesh Sharma, Lydia M Roberts, Xiaohua Peng, Santos Bermejo, Ian Leighton, Shelli Farhadian, Yale Impact Team, Arnau Casanovas Massana, Charles Dela S Cruz
    Abstract:

    The COVID-19 pandemic has affected more than 10 million people worldwide with mortality exceeding half a million patients. Risk factors associated with severe disease and mortality include advanced age,hypertension, diabetes, and obesity. Clear mechanistic understanding of how these comorbidities converge to enable severe infection is lacking. Notably each of these risk factors pathologically disrupts the lipidome and this disruption may be a unifying feature of severe COVID-19. Here we provide the first in depth interrogation of lipidomic changes, including structural-lipids as well as the eicosanoids and Docosanoids lipid mediators (LMs), that mark COVID-19 disease severity. Our data reveal that progression from moderate to severe disease is marked by a loss of specific immune regulatory LMs and increased pro-inflammatory species. Given the important immune regulatory role of LMs, these data provide mechanistic insight into the immune balance in COVID-19 and potential targets for therapy with currently approved pharmaceuticals.

Edward A. Dennis - One of the best experts on this subject based on the ideXlab platform.

  • plasma eicosanoids as noninvasive biomarkers of liver fibrosis in patients with nonalcoholic steatohepatitis
    Therapeutic Advances in Gastroenterology, 2020
    Co-Authors: Cyrielle Caussy, Edward A. Dennis, Jenchieh Chuang, Andrew N Billin, Tao Hu, Ya Wang, Mani G Subramanian, Stephen C Djedjos, Robert P Myers, Rohit Loomba
    Abstract:

    Background:Eicosanoid and related docosanoid polyunsaturated fatty acids (PUFAs) and their oxygenated derivatives have been proposed as noninvasive lipidomic biomarkers of nonalcoholic steatohepati...

  • Eicosanoid storm in infection and inflammation
    Nature Reviews Immunology, 2015
    Co-Authors: Edward A. Dennis, Paul C. Norris
    Abstract:

    Controlled immune responses to infection and injury involve complex molecular signalling networks with coordinated and often opposing actions. Eicosanoids and related bioactive lipid mediators derived from polyunsaturated fatty acids constitute a major bioactive lipid network that is among the most complex and challenging pathways to map in a physiological context. Eicosanoid signalling, similar to cytokine signalling and inflammasome formation, has primarily been viewed as a pro-inflammatory component of the innate immune response; however, recent advances in lipidomics have helped to elucidate unique eicosanoids and related Docosanoids with anti-inflammatory and pro-resolution functions. This has advanced our overall understanding of the inflammatory response and its therapeutic implications. The induction of a pro-inflammatory and anti-inflammatory eicosanoid storm through the activation of inflammatory receptors by infectious agents is reviewed here. Infection and injury cause controlled immune and inflammatory responses involving complex molecular signalling networks that lead to the production of bioactive lipid mediators. Eicosanoids are bioactive lipid mediators derived from oxygenated polyunsaturated fatty acids. Similar to cytokine signalling and inflammasome formation, eicosanoid signalling has been viewed primarily as a pro-inflammatory component of innate immunity. Recent advances in lipidomics technologies have helped to elucidate unique eicosanoids and related Docosanoids with anti-inflammatory and pro-resolution functions that are a key component of the inflammatory response. Receptor activation initiated by Toll-like receptors (TLRs), purinergic receptors and other signalling pathways induced by infectious agents generates both pro-inflammatory and anti-inflammatory metabolites resulting in an eicosanoid storm. Lipidomics has advanced our overall understanding of the inflammatory response and its therapeutic implications, and has suggested new pharmacological approaches. Eicosanoids are bioactive signalling lipids that regulate numerous homeostatic and inflammatory processes. Here, the authors review our current understanding of cellular eicosanoid metabolism and the physiological functions of pro-inflammatory and pro-resolving eicosanoids in infection and inflammation.

  • eicosanoid storm in infection and inflammation
    Nature Reviews Immunology, 2015
    Co-Authors: Edward A. Dennis, Paul C. Norris
    Abstract:

    Controlled immune responses to infection and injury involve complex molecular signalling networks with coordinated and often opposing actions. Eicosanoids and related bioactive lipid mediators derived from polyunsaturated fatty acids constitute a major bioactive lipid network that is among the most complex and challenging pathways to map in a physiological context. Eicosanoid signalling, similar to cytokine signalling and inflammasome formation, has primarily been viewed as a pro-inflammatory component of the innate immune response; however, recent advances in lipidomics have helped to elucidate unique eicosanoids and related Docosanoids with anti-inflammatory and pro-resolution functions. This has advanced our overall understanding of the inflammatory response and its therapeutic implications. The induction of a pro-inflammatory and anti-inflammatory eicosanoid storm through the activation of inflammatory receptors by infectious agents is reviewed here.

  • Targeted lipidomic strategies for oxygenated metabolites of polyunsaturated fatty acids
    Biochimica et biophysica acta, 2014
    Co-Authors: Giuseppe Astarita, Alexandra C. Kendall, Edward A. Dennis, Anna Nicolaou
    Abstract:

    Oxidation of polyunsaturated fatty acids (PUFA) through enzymatic or non-enzymatic free radical-mediated reactions can yield an array of lipid metabolites including eicosanoids, octadecanoids, Docosanoids and related species. In mammals, these oxygenated PUFA mediators play prominent roles in the physiological and pathological regulation of many key biological processes in the cardiovascular, renal, reproductive and other systems including their pivotal contribution to inflammation. Mass spectrometry-based technology platforms have revolutionized our ability to analyze the complex mixture of lipid mediators found in biological samples, with increased numbers of metabolites that can be simultaneously quantified from a single sample in few analytical steps. The recent development of high-sensitivity and high-throughput analytical tools for lipid mediators affords a broader view of these oxygenated PUFA species, and facilitates research into their role in health and disease. In this review, we illustrate current analytical approaches for a high-throughput lipidomic analysis of eicosanoids and related mediators in biological samples. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance."