Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia

Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

Effect of chiropractic manipulation on disrupted epithelium barrier and its mechanism of specialized pro-resolving mediators in a spleen-deficiency murine model

OBJECTIVE: To investigate the influence of spleen deficiency on the epithelial barrier of jejunum and lungs in a rat model of spleen-deficiency and the effect and potential specialized pro-resolving mediators (SPMs) mechanism of chiropractic manipulation. METHODS: Three-week-old male Sprague-Dawley rats were divided randomly into normal control group (n = 6), spleen-deficiency group (n = 5) and chiropractic group (n = 6). Spleen-deficiency model was induced in spleen-deficiency group and chiropractic group. Moreover, chiropractic manipulation was performed in chiropractic group. Four weeks later, systemic Th1/Th2 balance was evaluated by the ratio of plasma interferon (IFN)-γ/interleukin (IL)-4 levels by enzyme-linked immunosorbent assay (ELISA). Epithelial barrier integrity were assessed by the observation of morphological changes by hematoxylin-eosin staining and zonula occludens (ZO)-1 gene expressions by quantitative real time polymerase chain reaction in jejunum and lungs. Plasma resolvin D1 (RvD1) and lipoxin A4 (LXA4) levels were measures by ELISA for endogenous SPMs production. The levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) in jejunum and lungs were also measured by HPLC-MS/ MS. RESULTS: Comparing with normal control group, spleen-deficiency group showed disrupted mucosa in jejunum, inflammatory condition in lungs, significantly decreased ratio of plasma IFN-γ/IL-4 levels and lower expressions of ZO-1 mRNA in both jejunum and lung tissues. Comparing with spleen-deficiency group, chiropractic group had less disrupted mucosa in jejunum and inflammatory condition in lungs, significantly increased systemic ratio of IFN-γ/IL-4 and expressions of ZO-1 mRNA in both jejunum and lung tissues. Chiropractic group had significantly enhanced plasma levels of RvD1 and LXA4, but had no significantly higher levels of DHA and AA in jejunum and lungs when comparing with spleen-deficiency group. CONCLUSION: Spleen deficiency caused systemic Th1/Th2 imbalance towards Th2 polarization and epithelial barrier disruption in jejunum and lungs.Chiropractic manipulation helped enhance endogenous SPMs production, which might be one of the action mechanism of chiropractic manipulation on the improvement of epithelial barrier disruption.

Specialized Pro-resolving Mediators Regulate Alveolar Fluid Clearance during Acute Respiratory Distress Syndrome

Objective：Acute respiratory distress syndrome （ARDS） is an acute and lethal clinical syndrome that is characterized by the injury of alveolar epithelium, which impairs active fluid transport in the lung, and impedes the reabsorption of edema fluid from the alveolar space. This review aimed to discuss the role of pro-resolving mediators on the regulation of alveolar fluid clearance （AFC） in ARDS.Data Sources：Articles published up to September 2017 were selected from the PubMed, with the keywords of ＂alveolar fluid clearance＂ or ＂lung edema＂ or ＂acute lung injury＂ or ＂acute respiratory distress syndrome＂ , and ＂specialized pro-resolving mediators＂ or ＂lipoxin＂ or ＂resolvin＂ or ＂protectin＂ or ＂maresin＂ or ＂alveolar epithelial cells＂ or ＂aspirin-triggered lipid mediators＂ or ＂carbon monoxide and heme oxygenase＂ or ＂annexin A1＂ .Study Selection：We included all relevant articles published up to September 2017, with no limitation of study design.Results：Specialized pro-resolving mediators （SPMs）, as the proinflammatory mediators, not only upregulated epithelial sodium channel, Na,K-ATPase, cystic fibrosis transmembrane conductance regulator （CFTR）, and aquaporins levels, but also improved Na,K-ATPase activity to promote AFC in ARDS. In addition to the direct effects on ion channels and pumps of the alveolar epithelium, the SPMs also inhibited the inflammatory cytokine expression and improved the alveolar epithelial cell repair to enhance the AFC in ARDS.Conclusions：The present review discusses a novel mechanism for pulmonary edema fluid reabsorption. SPMs might provide new opportunities to design ＂reabsorption-targeted＂ therapies with high degrees of precision in controlling ALI/ARDS.

Targeting the resolution pathway of inflammation using Ac2–26 peptide-loaded PEGylated lipid nanoparticles for the remission of rheumatoid arthritis

Rheumatoid arthritis(RA)is a common autoimmune disease characterized by joint inflammation and immune dysfunction.Although various therapeutic approaches have been utilized for the treatment of RA in clinical applications,the low responsiveness of RA patients and undesired systemic toxicity are still unresolved problems.Targeting the resolution pathway of inflammation with pro-resolving mediators would evoke the protective actions of patient for combating the inflammation.Ac2–26,a 25-amino acid peptide derived from Annexin A(a pro-resolving mediator),has shown good efficacy in the treatment of inflammatory disorders.However,the low bioavailability of Ac2–26 peptides hinders their efficacy in vivo.In this paper,we formed PEGylated lipid nanoparticles(LDNPs)by the co-assembly of l-ascorbyl palmitate(L-AP)and N-(carbonyl methoxypolyethylene glycol-2000)-1,2-distearoyl-sn–glycero-3-phosphoethanolamine(DSPE-PEG 2 k)to encapsulate and deliver Ac2–26 peptides to the arthritic rats.They showed good stability and biocompatibility.After being intravenously administrated,Ac2–26 peptide-loaded PEGylated lipid nanoparticles(ADNPs)showed the prolonged in vivo circulation time and enhanced accumulation in inflamed sites.In vivo therapeutic evaluations revealed that ADNPs could attenuate synovial inflammation and improve joint pathology.Therefore,the pro-resolving therapeutic strategy using ADNPs is effective in RA treatment.

New translational and experimental insights into the role of proresolving lipid mediators in inflammatory bowel disease

The resolution of inflammation is an active process,guided by specialized proresolution lipid mediators(SPMs).These mediators originate from polyunsaturated fatty acids,such as omega-3.Sufficient evidence suggests that the beneficial effects attributed to omega-3 are,at least in part,the result of the immunomodulatory action of the SPMs,which act systemically by overcoming inflammation and repairing tissue damage,without suppressing the immune response.Recent studies suggest that an imbalance in the synthesis and/or activity of these compounds may be associated with the pathogenesis of several inflammatory conditions,such as inflammatory bowel disease(IBD).Thus,this review highlights the advances made in recent years with regard to the endogenous synthesis and the biological role of lipoxins,resolvins,protectins,and maresins,as well as their precursors,in the regulation of inflammation;and provides an update on the participation of these mediators in the development and evolution of IBD and the therapeutic approaches that these immunomodulating substances are involved in this context.