Resolvin Research Articles

Resolvin E1 heals injured cardiomyocytes: Therapeutic implications and H-FABP as a readout for cardiovascular disease & systemic inflammation

The purpose of this study is to investigate heart-fatty acid binding protein (H-FABP) leakage from cardiomyocytes as a quantitative measure of cell membrane damage and to test healing by Resolvin E1 (RVE1) as a potential therapeutic for patients with inflammatory diseases (cardiovascular disease and comorbidities) with high morbidity and mortality. Our quantitative ELISA assays demonstrated H-FABP as a sensitive and reliable biomarker for measuring cardiomyocyte damage induced by lipopolysaccharide (LPS) and healing by RvE1, a specialized pro-resolving mediator (SPM) derived from the Omega-3 fatty acid, eicosapentaenoic acid (EPA), a dietary nutrient that balances inflammation to restore homeostasis. RvE1 reduced leakage of H-FABP by up to 86%, which supports our hypothesis that inflammation as a mechanism of injury can be targeted for therapy. H-FABP as a blood biomarker was tested in 40 patients admitted to Boston Medical Center for respiratory distress, (20 patients with and 20 patients without COVID infection). High levels of H-FABP correlated with clinically diagnosed CVD, diabetes, and end-stage renal disease (ESRD) in both patient groups. The level of H-FABP indicates not only CVD damage but is a valuable measure for patients with increased inflammation disease comorbidities.

Eosinophil Phenotypes Are Functionally Regulated by Resolvin D2 during Allergic Lung Inflammation.

Eosinophils (Eos) reside in multiple organs during homeostasis and respond rapidly to an inflammatory challenge. Although Eos share chemical staining properties, they also demonstrate phenotypic and functional plasticity that is not fully understood. Here, we used a murine model of allergic lung inflammation to characterize Eos subsets and determine their spatiotemporal and functional regulation during inflammation and its resolution in response to resolvin D2 (RvD2), a potent specialized proresolving mediator. Two Eos subsets were identified by CD101 expression with distinct anatomic localization and transcriptional signatures at baseline and during inflammation. CD101low Eos were predominantly located in a lung vascular niche and responded to allergen challenge by moving into the lung interstitium. CD101high Eos were predominantly located in bronchoalveolar lavage (BAL) and extravascular lung, only present during inflammation, and had transcriptional evidence for cell activation. RvD2 reduced total Eos numbers and changed their phenotype and activation by at least two distinct mechanisms: decreasing interleukin 5-dependent recruitment of CD101low Eos and decreasing conversion of CD101low Eos to CD101high Eos. Collectively, these findings indicate that Eos are a heterogeneous pool of cells with distinct activation states and spatiotemporal regulation during resolution of inflammation and that RvD2 is a potent proresolving mediator for Eos recruitment and activation.

Periodontal and cardiovascular therapies modify specialized pro-resolving lipid mediator (sPRLM) (LPXA4, PD1, RvE1, RvD1, and MaR1)-mediated pathway: the first pilot clinical study.

Cardiovascular disease (CVD) and periodontal disease have a common pathogenesis with inflammation and resolution steps. Although the relationships among periodontal disease, CVD, and specialized pro-resolving lipid mediator (sPRLM)s are well known, there is no study about the combined effects of cardiovascular and periodontal treatments on sPRLM levels. It was aimed to evaluate the effects of periodontal and cardiovascular therapies on sPRLMs (lipoxin A4, protectin (PD)1, resolvin (Rv) E1, RvD1, and maresin (MaR)1) in patients with CVD and periodontal disease. This observational study consisted of fifty-five patients with CVD and mild or moderate periodontitis. The clinical periodontal parameters (plaque index, gingival index, probing pocket depth, percentage of bleeding on probing, and clinical attachment level) and blood and unstimulated total saliva samples were obtained at baseline, at 3months (following only cardiovascular therapy), and at 6months (following cardiovascular and periodontal therapies). The blood count and serum levels of cardiometabolic biomarkers (white blood cell, neutrophil/lymphocyte, serum total cholesterol (TC), triglyceride, and low and high-density lipoprotein (HDL) levels) were evaluated. sPRLMs were evaluated by ELISA. There were significant decreases in body mass index, clinical periodontal parameters, WBC, LDL, PD1, and RvD1 at 6months compared to baseline. The decreases in TC/HDL, RvE1, and MaR1 levels were significant at 3 and 6months compared to baseline (p < 0.05). The combination of cardiovascular and periodontal treatments leads to significant reductions in clinical periodontal and cardiometabolic parameters and sPRLMs. Our report, which is the first in their field, suggested that cardiovascular and periodontal therapies provide an important contribution via decreasing the periodontal and atherosclerotic inflammation modulating sPRLMs. This finding will be a big step toward increasing the quality of life in these patients by drawing attention to importance of public health associated with oral hygiene, periodontal health, and systemic phase of periodontal treatment.

Resolvin D1 Attenuates Inflammation and Pelvic Pain Associated with EAP by Inhibiting Oxidative Stress and NLRP3 Inflammasome Activation via the Nrf2/HO-1 Pathway.

Resolvin D1 (RvD1), a member of the specialized pro-resolving lipid mediators family, has a potent anti-inflammatory effect and alleviates tissue damage. The purpose of the current research was to study the effect of RvD1 on CP/CPPS and the underlying mechanisms using a mouse model of experimental autoimmune prostatitis (EAP) mice. The EAP mouse model was successfully established, and was used to test the therapeutic effect of RvD1. Hematoxylin-eosin staining and dihydroethidium staining were used to evaluate the histological changes and oxidative stress levels of prostate tissues. Chronic pelvic pain was assessed by applying von Frey filaments to the lower abdomen. The superoxide dismutase enzyme and malondialdehyde levels were detected using enzyme-linked immunosorbent assay (ELISA). The levels of inflammation-related cytokines, including IL-1β, IL-6, and TNF-α were detected by ELISA. RvD1 treatment ameliorated prostatic inflammation and the pelvic pain of EAP mice. RvD1 treatment could inhibit activation of the NLRP3 inflammasome and oxidative stress. RvD1 treatment could activate Nrf2/HO-1 signaling in mice with EAP. Blockade of Nrf2/HO-1 signaling abolished the RvD1-mediated inhibition of oxidative stress, NLRP3 inflammasome activation and the anti-inflammatory effect of RvD1 in EAP. RvD1 treatment can reduce inflammatory cell infiltration in prostate tissue and attenuate pelvic pain associated with EAP by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway. These results provide new insights that RvD1 has the potential as an effective agent in the treatment of EAP.

Resolvin D1 prevents injurious neutrophil swarming in transplanted lungs

Neutrophils are the primary cell type involved in lung ischemia-reperfusion injury (IRI), which remains a frequent and morbid complication after organ transplantation. Endogenous lipid mediators that become activated during acute inflammation-resolution have gained increasing recognition for their protective role(s) in promoting the restoration of homeostasis, but their influence on early immune responses following transplantation remains to be uncovered. Resolvin D1, 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid (RvD1), is a potent stereoselective mediator that exhibits proresolving and anti-inflammatory actions in the setting of tissue injury. Here, using metabololipidomics, we demonstrate that endogenous proresolving mediators including RvD1 are increased in human and murine lung grafts immediately following transplantation. In mouse grafts, we observe lipid mediator class switching early after reperfusion. We use intravital two-photon microscopy to reveal that RvD1 treatment significantly limits early neutrophil infiltration and swarming, thereby ameliorating early graft dysfunction in transplanted syngeneic lungs subjected to severe IRI. Through integrated analysis of single-cell RNA sequencing data of donor and recipient immune cells from lung grafts, we identify transcriptomic changes induced by RvD1. These results support a role for RvD1 as a potent modality for preventing early neutrophil-mediated tissue damage after lung IRI that may be therapeutic in the clinics.

Disturbed Plasma Lipidomic Profiles in Females with Diffuse Large B-Cell Lymphoma: A Pilot Study.

Lipidome dysregulation is a hallmark of cancer and inflammation. The global plasma lipidome and sub-lipidome of inflammatory pathways have not been reported in diffuse large B-cell lymphoma (DLBCL). In a pilot study of plasma lipid variation in female DLBCL patients and BMI-matched disease-free controls, we performed targeted lipidomics using LC-MRM to quantify lipid mediators of inflammation and immunity, and those known or hypothesised to be involved in cancer progression: sphingolipids, resolvin D1, arachidonic acid (AA)-derived oxylipins, such as hydroxyeicosatetraenoic acids (HETEs) and dihydroxyeicosatrienoic acids, along with their membrane structural precursors. We report on the role of the eicosanoids in the separation of DLBCL from controls, along with lysophosphatidylinositol LPI 20:4, implying notable changes in lipid metabolic and/or signalling pathways, particularly pertaining to AA lipoxygenase pathway and glycerophospholipid remodelling in the cell membrane. We suggest here the set of S1P, SM 36:1, SM 34:1 and PI 34:1 as DLBCL lipid signatures which could serve as a basis for the prospective validation in larger DLBCL cohorts. Additionally, untargeted lipidomics indicates a substantial change in the overall lipid metabolism in DLBCL. The plasma lipid profiling of DLBCL patients helps to better understand the specific lipid dysregulations and pathways in this cancer.

Specialized Pro-resolving Mediator Improves Vascular Relaxation via Formyl Peptide Receptor-2.

The resolution of inflammation is an active phenomenon important for switching off inflammatory processes once the harmful stimuli are removed and facilitate the return to homeostasis. Specialized pro-resolving mediators (SPMs), such as lipoxin A4, resolvin D1, and resolvin E1, derived from ω-3 or ω-6 polyunsaturated fatty acids, are crucial for the resolution of inflammation. We hypothesized that SPMs are decreased in hypertension which contributes to the acetylcholine-induced contraction in resistance arteries, which are well known to be mediated by leukotrienes and prostaglandins. Moreover, treatment with SPMs will decrease this contraction via formyl peptide receptor-2 (FPR-2) in resistance arteries from spontaneously hypertensive rats (SHR). We performed a comprehensive eicosanoid lipid panel analysis, and our data showed for the first time that precursors of SPMs are decreased in SHR, limiting the production of SPMs and resolution of inflammation in vivo. This phenomenon was associated with an increase in lipid peroxidation in resistance arteries. Although SPMs did not abolish acetylcholine-induced contraction, these lipid mediators improved endothelial function in arteries from SHR via FPR-2 activation at nanomolar concentrations. SPMs also buffered TNF-α-induced reactive oxygen species generation in endothelial cells from C57Bl/6 mice. We suggest that FPR-2 and SPMs could be revealed as a new target or therapeutic agent to improve vascular function in arteries from hypertensive rats.

The Anti-Aggregative Potential of Resolvin E1 on Human Platelets.

Resolvin E1 is a metabolite of eicosapentaenoic acid (EPA) which is one of the omega-3 polyunsaturated fatty acids (omega-3 PUFAs). The antiplatelet properties of omega-3 PUFAs are well known, but the effect of resolvin E1 on platelets via the collagen receptors is extremely poorly reported. We investigated the effect of resolvin E1 on collagen-induced platelet aggregation, activation, and reactivity, and also platelet membrane fluidity. The ultimate and statistically significant results showed that resolvin E1 may inhibit platelet reactivity due to the reduction of collagen-induced platelet aggregation in platelet-rich plasma and isolated platelets, but not in whole blood. Also, resolvin E1 significantly reduced P-selectin exposure on collagen-stimulated platelets. Moreover, we demonstrated that resolvin E1 can maintain platelet membrane structure (without increasing membrane fluidity). The association between platelet reactivity and membrane fluidity, including resolvin E1 and collagen receptors requires further research. However, the goal of this study was to shed light on the molecular mechanisms behind the anti-aggregative effects of resolvin E1 on platelets, which are still not fully clarified. We also indicate an innovative research direction focused on further analysis and then use of omega-3 PUFAs metabolites as antiplatelet compounds for future applications in the treatment and prevention of cardiovascular diseases.

ALX/FPR2 Activation by Stereoisomers of D1 Resolvins Elucidating with Molecular Dynamics Simulation.

Chronic inflammation contributes to several diseases, but its resolution is driven by specialized pro-resolving mediators (SPM) such as resolvin D1 (RvD1) and its epimer aspirin-triggered resolvin D1 (AT-RvD1), both biosynthesized from ω-3 fatty docosahexaenoic acid (DHA). RvD1 and AT-RvD1 have anti-inflammatory and pro-resolution potentials, and their effects could be mediated by formyl peptide receptor type 2 receptor ALX/FPR2, a G-protein-coupled receptor (GPCR). In this work, we performed 44 μs of molecular dynamics simulations with two complexes: FPR2@AT-RvD1 and FPR2@RvD1. Our results show the following: (i) in the AT-RvD1 simulations, the ALX/FPR2 receptor remained in the active state in 62% of the frames, while in the RVD1 simulations, the receptor remained in the active state in 74% of the frames; (ii) two residues, R201 and R205, of ALX/FPR2 appear, establishing interactions with both resolvins in all simulations (22 in total); (iii) RvD1 hydrogen bonds with R201 and R205 presented higher frequency than AT-RvD1; and (iv) residues R201 and R205 are the two receptor hotspots, demonstrated by the binding free calculations. Such results show that the ALX/FPR2 receptor remained in the active state for longer in the FPR2@RvD1 simulations than in the FPR2@AT-RvD1 simulations.

Polyunsaturated Fatty Acid-Derived Lipid Mediators as Potential Biomarkers for Leprosy Among Individuals with Asymptomatic Mycobacterium leprae Infection.

Intra-household contacts (HCs) of leprosy patients are at increased risk of infection by Mycobacterium leprae and about ∼5-10% will develop active disease. A prognostic tool to identify HCs with the greatest risk of progressing to active disease would enhance early leprosy diagnosis and optimize prophylactic intervention. Previous metabolomics studies suggest that host lipid mediators derived from ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) are potential biomarkers for leprosy. In this study, we investigated retrospective sera of leprosy HCs by liquid chromatography-mass spectrometry and enzyme-linked immunoassay to determine whether circulating levels of ω-3 and ω-6 PUFA metabolites were altered in HCs that developed leprosy (HCDL) in comparison to those that did not (HCNDL). Sera were collected from HCs at the time of index case diagnosis and before clinical signs/symptoms of leprosy. Our findings showed that HCDL sera exhibited a distinct metabolic profile in comparison to HCDNL. Specifically, arachidonic acid, leukotriene B4, 11-hydroxyeicosatetraenoic acid, prostaglandin D2, and lipoxin A4 were elevated in HCDL. In contrast, prostaglandin E2 levels were reduced in HCDL. The ω-3 PUFAs, docosahexaenoic acid, eicosapentaenoic acid, and the docosahexaenoic acid-derived resolvin D1 and maresin-1 were also elevated in HCDL individuals compared to HCNDL. Principal component analyses provided further evidence that lipid mediators could serve as an early biomarker for progression to active leprosy. A logistic model identified resolvin D1 and D2, and prostaglandin D2 as having the greatest potential for early detection of HCs that will manifest leprosy.

Anti-Inflammatory and Pro-Resolving Actions of the N-Terminal Peptides Ac2-26, Ac2-12, and Ac9-25 of Annexin A1 on Conjunctival Goblet Cell Function

Annexin A1 (AnxA1) is the main mediator of the anti-inflammatory actions of glucocorticoids. AnxA1 functions as a pro-resolving mediator in cultured rat conjunctival goblet cells to ensure tissue homeostasis through stimulation of intracellular [Ca2+] ([Ca2+]i) and mucin secretion. AnxA1 has several N-terminal peptides with anti-inflammatory properties of their own, including Ac2-26, Ac2-12, and Ac9-25. The increase in [Ca2+]i caused by AnxA1 and its N-terminal peptides in goblet cells was measured to determine which formyl peptide receptors the compounds use and the action of the peptides on histaminestimulation. Changes in [Ca2+]i were determined by using a fluorescent Ca2+ indicator. AnxA1 and its peptides each activated formyl peptide receptors in goblet cells. AnxA1 and Ac2-26 at 10-12 mol/L and Ac2-12 at 10-9 M inhibited the histamine-stimulated increase in [Ca2+]i, as did resolvin D1 and lipoxin A4 at 10-12 mol/L, whereas Ac9-25 did not. AnxA1 and Ac2-26 counter-regulated the H1 receptor through the p42/p44 mitogen-activated proteinkinase/extracellular regulated kinase 1/2, β-adrenergic receptor kinase, and protein kinase C pathways, whereas Ac2-12 counter-regulated only through β-adrenergic receptor kinase. In conclusion, the N-terminal peptides Ac2-26 and Ac2-12, but not Ac9-25, share multiple functions with the full-length AnxA1 in goblet cells, including inhibition of histamine-stimulated increase in [Ca2+]i and counter-regulation of the H1receptor. These actions suggest a potential pharmaceutical application of the AnxA1 N-terminal peptides Ac2-26 and Ac2-12 in homeostasis and ocular inflammatory diseases.

Co-Administration of Resolvin D1 and Peripheral Nerve-Derived Stem Cell Spheroids as a Therapeutic Strategy in a Rat Model of Spinal Cord Injury.

Spinal cord injury (SCI), primarily caused by trauma, leads to permanent and lasting loss of motor, sensory, and autonomic functions. Current therapeutic strategies are focused on mitigating secondary injury, a crucial aspect of SCI pathophysiology. Among these strategies, stem cell therapy has shown considerable therapeutic potential. This study builds on our previous work, which demonstrated the functional recovery and neuronal regeneration capabilities of peripheral nerve-derived stem cell (PNSC) spheroids, which are akin to neural crest stem cells, in SCI models. However, the limited anti-inflammatory capacity of PNSC spheroids necessitates a combined therapeutic approach. As a result, we investigated the potential of co-administering resolvin D1 (RvD1), known for its anti-inflammatory and neuroprotective properties, with PNSC spheroids. In vitro analysis confirmed RvD1's anti-inflammatory activity and its inhibitory effect on pro-inflammatory cytokines. In vivo studies involving a rat SCI model demonstrated that combined therapy of RvD1 and PNSC spheroids outperformed monotherapies, exhibiting enhanced neuronal regeneration and anti-inflammatory effects as validated through behavior tests, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry. Thus, our findings suggest that the combined application of RvD1 and PNSC spheroids may represent a novel therapeutic approach for SCI management.

Differential effects of resolvin D1 and resolvin E1 on cementoblast function.

Resolvins are endogenous mediators of the resolution of inflammation. They are derived from omega-3 polyunsaturated fatty acid precursors. Resolvin D1 (RvD1) and Resolvin E1 (RvE1) are the best-characterized members for actively promoting periodontal regeneration in experimental animal models. Here, we evaluated the efficacy of RvD1 and RvE1 on cementoblasts, the key cells involved in dental cementum regeneration and the attachment of the tooth to the alveolar bone. Immortalized mouse cementoblasts (OCCM-30) were treated with different concentrations (0.1-1000ng/mL) of RvD1 and RvE1. Cell proliferation was measured using an electrical impedance-based real-time cell analyzer. Mineralization was evaluated with von Kossa staining. The mRNA expression of mineralized tissue-associated markers of bone sialoprotein (BSP), Type I collagen (COL I), osteocalcin (OCN), osteopontin (OPN), runt-related transcription factor 2 (RunX2), alkaline phosphatase (ALP), osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (NF-κB) (RANK), receptor activator of NF-κB ligand (RANKL), and extracellular matrix-degrading enzymes [matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-9, and their tissue inhibitors (TIMP-1, TIMP-2)], RvE1 receptor (ChemR23) and RvD1 receptor (ALX/PFR2), cytokines (tumor necrosis factor-alpha {TNF-α}, interleukin {IL}-1β, IL-6, IL-8, IL-10, IL-17), oxidative stress enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPX), and cyclooxygenase-2 (Cox-2)] were analyzed using quantitative polymerase chain reaction (qPCR). Both RvD1 and RvE1 (10-100ng/mL) significantly increased the proliferation of cementoblasts and mineralized nodules at all concentrations (p<0.05). RvE1 increased BSP, RunX2, and ALP compared with the RvD1 dose and time-dependently, while RvD1 and RvE1 differentially regulated COL-I. RvE1 increased OPG mRNA expression, whereas RANK-RANKL mRNA expression decreased by RvE1. MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 expressions were reduced by RvE1 compared with RvD1. Treatment of cementoblasts with RvD1 and RvE1 differentially affected cytokine and oxidative stress enzymes while significantly increasing their receptor expressions (ChemR23 and ALX/PFR2). RvD1 and RvE1 regulate proliferation, mineralization, and gene expression in cementoblasts using similar pathways while differentially affecting tissue degradation, suggesting a targeted therapeutic approach for cementum turnover during periodontal regeneration.

Prognostic significance of serum resolvin D1 levels in patients with acute supratentorial intracerebral hemorrhage: A prospective longitudinal cohort study

ObjectiveResolvin D1 (RvD1) has anti-inflammatory properties and may be neuroprotective. This study was designed to assess usability of serum RvD1 as a prognostic biomarker after intracerebral hemorrhage (ICH). MethodsIn this prospective, observational study of 135 patients and 135 controls, serum RvD1 levels were measured. Its relations to severity, early neurologic deterioration (END) and poststroke 6-month worse outcome (modified Rankin Scale scores of 3–6) were determined via multivariate analysis. Predictive effectiveness was evaluated based on area under receiver operating characteristic curve (AUC). ResultsPatients had markedly lower serum RvD1 levels than controls (median, 0.69 ng/ml versus 2.15 ng/ml). Serum RvD1 levels were independently correlated with the National Institutes of Health Stroke Scale (NIHSS) [β, −0.036; 95 % confidence interval (CI), −0.060--0.013; VIF, 2.633; t = -3.025; P = 0.003] and hematoma volume (β, −0.019; 95 % CI, −0.056--0.009; VIF, 1.688; t = -2.703; P = 0.008). Serum RvD1 levels substantially discriminated risks of END and worse outcome with AUCs at 0.762 (95 % CI, 0.681–0.831) and 0.783 (95 % CI, 0.704–0.850) respectively. A RvD1 cut-off value of 0.85 ng/ml was effective in predicting END with a sensitivity of 95.0 % and specificity of 48.4 % and its levels <0.77 ng/ml distinguished patients at risk of worse outcome with a sensitivity of 84.5 % and specificity of 63.6 %. Under restricted cubic spline, serum RvD1 levels were linearly related to risk of END and worse outcome (both P > 0.05). Serum RvD1 levels and NIHSS scores independently predicted END with odds ratio (OR) values of 0.082 (95 % CI, 0.010–0.687) and 1.280 (95 % CI, 1.084–1.513) respectively. Serum RvD1 levels (OR, 0.075; 95 % CI, 0.011–0.521), hematoma volume (OR, 1.084; 95 % CI, 1.035–1.135) and NIHSS scores (OR, 1.240; 95 % CI, 1.060–1.452) were independently associated with worse outcome. END prediction model containing serum RvD1 levels and NIHSS scores, and prognostic prediction model containing serum RvD1 levels, hematoma volumes and NIHSS scores displayed efficient predictive ability with AUCs at 0.828 (95 % CI, 0.754–0.888) and 0.873 (95 % CI, 0.805–0.924) respectively. Such two models were visually shown via building two nomograms. Using Hosmer-Lemeshow test, calibration curve and decision curve, the models were comparatively stable and had clinical benefit. ConclusionThere is a dramatical declination of serum RvD1 levels after ICH, which is tightly related to stroke severity and is independently predictive of poor clinical outcome, implying that serum RvD1 may be of clinical significance as a prognostic marker of ICH.

#2524 RESOLVIN D1 ATTENUATES SEPSIS INDUCED ACUTE KIDNEY INJURY TARGETING MITOCHONDRIA AND NF-κB SIGNALING PATHWAY

Abstract Background and Aims Acute kidney injury is a highly common and multifactorial renal disease resulting in significant morbidity and mortality, especially sepsis-induced acute kidney injury. There is no effective therapy available to treat or prevent sepsis-induced acute kidney injury. One of the specialized pro-resolving mediators, Resolvin D1 exhibits special anti-inflammatory effects in several inflammatory disease models, but there is little evidence about the effect and mechanism of Resolvin D1 in sepsis-induced acute kidney injury. To explore the renal protective role of RvD1 in SI-AKI and to further explore the inherent pathophysiological mechanism, especially the role of mitochondrial function and NF-κB signaling pathway, in vitro and in vivo experiments were conducted. Method We conducted experiments to explore the effect and mechanism of Resolvin D1 in sepsis-induced acute kidney injury. In vitro, human proximal tubular epithelial cells were used to test the apoptosis ratio, cell viability and reactive oxygen species level. In vivo, C57BL/6 mice were injected with lipopolysaccharide to establish a sepsis-induced acute kidney injury model. Renal function and structure, apoptosis ratio of kidney cells, mitochondrial structure and function and related protein and gene levels were assessed. Results In vitro, the resolvin D1-treated group showed higher cell viability and lower reactive oxygen species levels and apoptosis ratios than the LPS group. In vivo, Resolvin D1 can not only improve renal function and mitochondrial function but also reduce the apoptosis ratio, while mediating mitochondrial dynamics and inhibiting NF-κB pathway. Conclusion Resolvin D1 has a good renoprotective effect by maintaining mitochondrial dynamics and inhibiting the NF-κB pathway. This provides an important basis for us to further develop the clinical therapeutic value of RvD1 in acute renal injury in sepsis.

Infectious neutrophil deployment is regulated by resolvin D4

AbstractNeutrophils reside in the bone marrow (BM), ready for deployment to sites of injury/infection, initiating inflammation and its resolution. Here, we report that distal infections signal to the BM via resolvins to regulate granulopoiesis and BM neutrophil deployment. Emergency granulopoiesis during peritonitis evoked changes in BM resolvin D1 (RvD1) and BM RvD4. We found that leukotriene B4 stimulates neutrophil deployment. RvD1 and RvD4 each limited neutrophilic infiltration to infections, and differently regulated BM myeloid populations: RvD1 increased reparative monocytes, and RvD4 regulated granulocytes. RvD4 disengaged emergency granulopoiesis, prevented excess BM neutrophil deployment, and acted on granulocyte progenitors. RvD4 also stimulated exudate neutrophil, monocyte, and macrophage phagocytosis, and enhanced bacterial clearance. This mediator accelerated both neutrophil apoptosis and clearance by macrophages, thus expediting the resolution phase of inflammation. RvD4 stimulated phosphorylation of ERK1/2 and STAT3 in human BM-aspirate–derived granulocytes. RvD4 in the 1 to 100 nM range stimulated whole-blood neutrophil phagocytosis of Escherichia coli. RvD4 increased BM macrophage efferocytosis of neutrophils. Together, these results demonstrate the novel functions of resolvins in granulopoiesis and neutrophil deployment, contributing to the resolution of infectious inflammation.

NPD1 Plus RvD1 Mediated Ischemic Stroke Penumbra Protection Increases Expression of Pro-homeostatic Microglial and Astrocyte Genes.

Neuroprotection to attenuate or block the ischemic cascade and salvage neuronal damage has been extensively explored for treating ischemic stroke. However, despite increasing knowledge of the physiologic, mechanistic, and imaging characterizations of the ischemic penumbra, no effective neuroprotective therapy has been found.This study focuses on the neuroprotective bioactivity of docosanoid mediators: Neuroprotectin D1 (NPD1), Resolvin D1 (RvD1), and their combination in experimental stroke. Molecular targets of NPD1 and RvD1 are defined by following dose-response and therapeutic window. We demonstrated that treatment with NPD1, RvD1, and combination therapy provides high-grade neurobehavioral recovery and decreases ischemic core and penumbra volumes even when administered up to 6h after stroke. The expression of the following genes was salient: (a) Cd163, an anti-inflammatory stroke-associated gene, was the most differentially expressed gene by NPD1+RvD1, displaying more than a 123-fold upregulation in the ipsilesional penumbra (Lisi et al., Neurosci Lett 645:106-112, 2017); (b) 100-fold upregulation takes place in astrocyte gene PTX3, a key regulator of neurogenesis and angiogenesis after cerebral ischemia (. Rodriguez-Grande et al., J Neuroinflammation 12:15, 2015); and (c) Tmem119 and P2y12, two markers of homeostatic microglia, were found to be enhanced by ten- and fivefold, respectively (Walker et al. Int J Mol Sci 21:678, 2020). Overall, we uncovered that protection after middle cerebral artery occlusion (MCAo) by the lipid mediators elicits expression of microglia and astrocyte-specific genes (Tmem119, Fcrls, Osmr, Msr1, Cd68, Cd163, Amigo2, Thbs1, and Tm4sf1) likely participating in enhancing homeostatic microglia, modulating neuroinflammation, promoting DAMP clearance, activating NPC differentiation and maturation, synapse integrity and contributing to cell survival.

Influences of resolvin D1 and D2 on the risk of type 2 diabetes mellitus: a Chinese community-based cohort study.

Although cellular and animal studies have reported that resolvin D1 (RvD1) and resolvin D2 (RvD2) are mechanisms involved in the development of type 2 diabetes mellitus (T2DM), the impact of RvD1 and RvD2 on the risk of T2DM at a population level remains unclear. We included 2755 non-diabetic adults from a community-based cohort in China and followed them for seven years. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of RvD1 and RvD2 with T2DM probability. Time-dependent receiver operator characteristics (ROC) curve was used to evaluate the predictive performance of RvD1 and RvD2 for the risk of T2DM based on the Chinese CDC T2DM prediction model (CDRS). A total of 172 incident T2DM cases were identified. Multivariate-adjusted HRs (95% CI) for T2DM across quartiles of RvD1 levels (Q1, Q2, Q3 and Q4) were 1.00, 1.64 (1.03-2.63), 1.80 (1.13-2.86) and 1.61 (1.01-2.57), respectively. Additionally, body mass index (BMI) showed a significant effect modification in the association of RvD1 with incident T2DM (P interaction = 0.026). After multivariate adjustment, the HR (95% CI) for T2DM in the fourth compared with the first quartile of RvD2 was 1.94 (95% CI: 1.24-3.03). Time-dependent ROC analysis showed that the area under time-dependent ROC curves of the "CDRS+RvD1+RvD2" model for the 3-, 5- and 7-year risk of T2DM were 0.842, 0.835 and 0.828, respectively. Higher RvD1 and RvD2 levels are associated with a higher risk of T2DM at the population level.

Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke

Neutrophil aggregation and clearance are important factors affecting neuroinflammatory injury during acute ischemic stroke. Emerging evidence suggests that energy metabolism is essential for microglial functions, especially microglial phagocytosis, which determines the degree of brain injury. Here, we demonstrate that Resolvin D1 (RvD1), a lipid mediator derived from docosahexaenic acid (DHA), promotes the phagocytosis of neutrophils by microglia, thereby reducing neutrophil accumulation in the brain and alleviating neuroinflammation in the ischemic brain. Further studies reveal that RvD1 reprograms energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS), providing sufficient energy for microglial phagocytosis. Moreover, RvD1 enhances microglial glutamine uptake and stimulates glutaminolysis to support OXPHOS to boost ATP production depending on adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Overall, our results reveal that RvD1 reprograms energy metabolism to promote the microglial phagocytosis of neutrophils after ischemic stroke. These findings may guide perspectives for stroke therapy from modulating microglial immunometabolism.

Resolvin E1 ameliorates diabetes‐related cognitive impairment via ChemR23

AbstractBackgroundDiabetes mellitus (DM) is an independent risk factor for cognitive dysfunction. The resolvin E1 (RvE1)/ChemR23 axis is involved in the progression and complications of DM. However, the impact of the RvE1/ChemR23 axis on diabetes‐related cognitive impairment remains unclear.MethodAging‐related behavioral changes in db/db diabetic mice and age‐matched nondiabetic controls were assessed, and changes of ChemR23 in the hippocampus were studied.ResultThe results showed that db/db mice exhibited age dependent learning and memory impairments in the Morris water maze test, along with reduced expression of ChemR23 in the hippocampus compared with age‐matched wild‐type mice. Moreover, neuronal damage, oxidative stress, and neuroinflammation were also observed in db/db mice. A moderate dose of RvE1 for 4 weeks elicited a significant reduction in memory loss, along with reduced neuronal damage, alleviation of oxidative stress, and attenuated neuroinflammation in diabetic mice but not in ChemR23‐knockout diabetic mice.ConclusionCollectively, our study suggested that RvE1 could ameliorate DM‐related cognitive dysfunction by reducing oxidative stress and neuroinflammation in a ChemR23‐dependent manner.