Synthesis of Resolvin E3, a Proresolving Lipid Mediator, and Its Deoxy Derivatives: Identification of 18-Deoxy-resolvin E3 as a Potent Anti-Inflammatory Agent

Fukuda, Hayato; Ikeda, Hiroyuki; Muromoto, Ryuta; Hirashima, Koki; Ishimura, Kohei; Fujiwara, Koichi; Aoki‐Saito, Haruka; Hisada, Takeshi; Watanabe, Mizuki; Ishihara, Jun; Matsuda, Tadashi; Shuto, Satoshi

doi:10.1021/acs.joc.0c01701

Cited by 13 publications

(20 citation statements)

References 27 publications

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“…Also, 18-HEPE, a precursor of the E-series resolvins, inhibits macrophage-mediated pro-inflammatory activation of cardiac fibroblasts and prevents overload-induced maladaptive cardiac remodeling in vivo , demonstrating its potent actions in cardiac tissue ( 16 ). This is further illustrated by the recent discovery of the potent bioactivity of 18-deoxy-resolvin E3 (18-deoxy-RvE3), which stops neutrophil infiltration and resolves peritonitis in mice ( 79 ). Of interest, recent results demonstrated that RvE3 is reduced in severe compared to moderate COVID-19 patients ( 77 ), highlighting the significance of SPMs in human disease.…”

Section: Discussionmentioning

confidence: 99%

A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution

et al. 2021

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The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.

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Section: Discussionmentioning

confidence: 99%

A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution

et al. 2021

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“…This results in decreased immune cell infiltration into the airways and improved lung function parameters [ 57 ]. Following this discovery, novel highly potent (in fg dose range) deoxy-resolvin E3 derivates were synthesized and characterized [ 58 ]. Interestingly, eosinophils isolated from healthy individuals were discovered to generate high levels of protectin D1 through the action of 15-LOX.…”

Section: Eicosanoids and Eosinophilsmentioning

confidence: 99%

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Knuplez

Sturm

Marsche

2021

IJMS

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Eosinophils are important effector cells involved in allergic inflammation. When stimulated, eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of phospholipids and thus the production of reactive lipid mediators. Eosinophils express high levels of secreted phospholipase A2 compared to other leukocytes, indicating their direct involvement in the production of lipid mediators during allergic inflammation. On the other side, eosinophils have also been recognized as crucial mediators with regulatory and homeostatic roles in local immunity and repair. Thus, targeting the complex network of lipid mediators offer a unique opportunity to target the over-activation and ‘pro-inflammatory’ phenotype of eosinophils without compromising the survival and functions of tissue-resident and homeostatic eosinophils. Here we provide a comprehensive overview of the critical role of phospholipase-derived lipid mediators in modulating eosinophil activity in health and disease. We focus on lysophospholipids, polyunsaturated fatty acids, and eicosanoids with exciting new perspectives for future drug development.

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“…RvE1 induces periodontal regeneration in pre-clinical periodontitis models ( 12 – 14 , 59 , 60 ), promotes regenerative properties of periodontal ligament (PDL) stem cells ( 61 ), and regulates osteoclasts as well as osteoblasts favorably for bone preservation ( 62 – 64 ). RvE3 demonstrates potent resolution properties by limiting neutrophil infiltration in the peritonitis model and inhibiting neutrophil chemotaxis ( 65 – 67 ). RvD1 inhibits osteoclast differentiation and reduces bone destruction in an arthritis preclinical model ( 68 ), inhibits production of pro-inflammatory cytokines from gingival fibroblasts ( 69 ) and enhances PDL fibroblast proliferation as well as wound closure ( 70 ).…”

Section: Discussionmentioning

confidence: 99%

Subgingival Microbiome and Specialized Pro-Resolving Lipid Mediator Pathway Profiles Are Correlated in Periodontal Inflammation

Lee

Zhu

et al. 2021

Front. Immunol.

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Failure of resolution pathways in periodontitis is reflected in levels of specialized pro-resolving lipid mediators (SPMs) and SPM pathway markers but their relationship with the subgingival microbiome is unclear. This study aimed to analyze and integrate lipid mediator level, SPM receptor gene expression and subgingival microbiome data in subjects with periodontitis vs. healthy controls. The study included 13 periodontally healthy and 15 periodontitis subjects that were evaluated prior to or after non-surgical periodontal therapy. Samples of gingival tissue and subgingival plaque were collected prior to and 8 weeks after non-surgical treatment; only once in the healthy group. Metabololipidomic analysis was performed to measure levels of SPMs and other relevant lipid mediators in gingiva. qRT-PCR assessed relative gene expression (2-ΔΔCT) of known SPM receptors. 16S rRNA sequencing evaluated the relative abundance of bacterial species in subgingival plaque. Correlations between lipid mediator levels, receptor gene expression and bacterial abundance were analyzed using the Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) and Sparse Partial Least Squares (SPLS) methods. Profiles of lipid mediators, receptor genes and the subgingival microbiome were distinct in the three groups. The strongest correlation existed between lipid mediator profile and subgingival microbiome profile. Multiple lipid mediators and bacterial species were highly correlated (correlation coefficient ≥0.6) in different periodontal conditions. Comparing individual correlated lipid mediators and bacterial species in periodontitis before treatment to healthy controls revealed that one bacterial species, Corynebacterium durum, and five lipid mediators, 5(S)6(R)-DiHETE, 15(S)-HEPE, 7-HDHA, 13-HDHA and 14-HDHA, were identified in both conditions. Comparing individual correlated lipid mediators and bacterial species in periodontitis before treatment to after treatment revealed that one bacterial species, Anaeroglobus geminatus, and four lipid mediators, 5(S)12(S)-DiHETE, RvD1, Maresin 1 and LTB4, were identified in both conditions. Four Selenomonas species were highly correlated with RvD1, RvE3, 5(S)12(S)-DiHETE and proinflammatory mediators in the periodontitis after treatment group. Profiles of lipid mediators, receptor gene and subgingival microbiome are associated with periodontal inflammation and correlated with each other, suggesting inflammation mediated by lipid mediators influences microbial composition in periodontitis. The role of correlated individual lipid mediators and bacterial species in periodontal inflammation have to be further studied.

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Synthesis of Resolvin E3, a Proresolving Lipid Mediator, and Its Deoxy Derivatives: Identification of 18-Deoxy-resolvin E3 as a Potent Anti-Inflammatory Agent

Cited by 13 publications

References 27 publications

A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution

A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Subgingival Microbiome and Specialized Pro-Resolving Lipid Mediator Pathway Profiles Are Correlated in Periodontal Inflammation

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