Maresin 1 Research Articles

Maresin 1 regulates insulin signaling in human adipocytes as well as in adipose tissue and muscle of lean and obese mice.

Maresin 1 (MaR1) is a DHA-derived pro-resolving lipid mediator. The present study aimed to characterize the ability of MaR1 to prevent the alterations induced by TNF-α on insulin actions in glucose uptake and Akt phosphorylation in cultured human adipocytes from overweight/obese subjects, as well as to investigate the effects of MaR1 acute and chronic administration on Akt phosphorylation in absence/presence of insulin in white adipose tissue (WAT) and skeletal muscle from lean and diet-induced obese (DIO) mice. MaR1 (0.1nM) prevented the inhibitory effect of TNF-α on insulin-stimulated 2-Deoxy-D-glucose uptake and Akt phosphorylation in human adipocytes. Acute treatment with MaR1 (50μg/kg, 3h, i.p.) induced Akt phosphorylation in WAT and skeletal muscle of lean mice. However, MaR1 did not further increase the stimulatory effect of insulin on Akt activation. Interestingly, intragastric chronic treatment with MaR1 (50μg/kg, 10days) in DIO mice reduced the hyperglycemia induced by the high fat diet (HFD) and improved systemic insulin sensitivity. In parallel, MaR1 partially restored the impaired insulin response in skeletal muscle of DIO mice and reversed HFD-induced lower Akt phosphorylation in WAT in non-insulin-stimulated DIO mice while did not restore the defective Akt activation in response to acute insulin observed in DIO mice. Our results suggest that MaR1 attenuates the impaired insulin signaling and glucose uptake induced by proinflammatory cytokines. Moreover, the current data support that MaR1 treatment could be useful to reduce the hyperglycemia and the insulin resistance associated to obesity, at least in part by improving Akt signaling.

Abstract 14951: Maresin 1 Induces Cardiomyocyte Hypertrophy Through RORα/IGF-1/PI3K/Akt Pathway

Myocardial inflammation is a critical event for the onset and progression of the heart failure. Maresin 1 (MaR1) was originally identified as a macrophage lipid mediator that exhibits anti-inflammatory and pro-resolving activities. Though it is widely accepted that macrophages positively and negatively regulate myocardial inflammation through cytokines and growth factors, the biological functions of lipid mediators, such as MaR1, in cardiomyocytes remain to be addressed. This study explored the functional roles of MaR1 in cardiomyocytes. Neonatal rat cardiomyocytes (NRCMs) were stimulated with MaR1 for 48 hours. Immunofluorescent staining with anti-sarcomeric α-actinin antibody revealed that MaR1 (50 nM) induced a significant increase in cardiomyocyte surface area (1760.34±66.86μm 2 vs. 960.83±29.46μm 2 ). Quantitative RT-PCR analyses revealed that the treatment with MaR1 upregulated the expression of IGF-1 mRNA (2.9±0.6 folds), accompanied by the enhanced level of total and phosphorylated Akt. Interestingly, MaR1 did not influence the expression of BNP and skeletal actin significantly, suggesting that MaR1 induced physiological hypertrophy. Since MaR1 is a ligand of RORα, we examined the effects of RORα blockade (SR3335) and found that this compound inhibited the increase of cardiomyocyte surface area by abrogating MaR1-mediated activation of IGF-1/PI3K/Akt pathway. Importantly, treatment with wortmannin or NVP-AEW541, inhibitors for PI3K or IGF-1 receptor, respectively, suppressed MaR1-induced cardiomyocyte hypertrophy, indicating that IGF-1/PI3K/Akt pathway is essential for MaR1-induced hypertrophy. In conclusion, MaR1 is a novel lipid mediator that induces physiological cardiomyocyte hypertrophy by activating RORα/IGF-1/PI3K/Akt pathway. Thus, MaR1 could coordinate the resolving process and tissue recovery in myocardial inflammation.

Maresin-1 and Resolvin E1 Promote Regenerative Properties of Periodontal Ligament Stem Cells Under Inflammatory Conditions.

Maresin-1 (MaR1) and Resolvin E1 (RvE1) are specialized pro-resolving lipid mediators (SPMs) that regulate inflammatory processes. We have previously demonstrated the hard and soft tissue regenerative capacity of RvE1 in an in vivo model of the periodontal disease characterized by inflammatory tissue destruction. Regeneration of periodontal tissues requires a well-orchestrated process mediated by periodontal ligament stem cells. However, limited data are available on how SPMs can regulate the regenerative properties of human periodontal ligament stem cells (hPDLSCs) under inflammatory conditions. Thus, we measured the impact of MaR1 and RvE1 in an in vitro model of hPDLSC under stimulation with IL-1β and TNF-α by evaluating pluripotency, migration, viability/cell death, periodontal ligament markers (α-smooth muscle actin, tenomodulin, and periostin), cementogenic-osteogenic differentiation, and phosphoproteomic perturbations. The data showed that the pro-inflammatory milieu suppresses pluripotency, viability, and migration of hPDLSCs; MaR1 and RvE1 both restored regenerative capacity by increasing hPDLSC viability, accelerating wound healing/migration, and up-regulating periodontal ligament markers and cementogenic-osteogenic differentiation. Protein phosphorylation perturbations were associated with the SPM-induced regenerative capacity of hPDLSCs. Together, these results demonstrate that MaR1 and RvE1 restore or improve the regenerative properties of highly specialized stem cells when inflammation is present and offer opportunities for direct pharmacologic treatment of lost tissue integrity.

Maresin 1 Attenuates Radicular Pain Through the Inhibition of NLRP3 Inflammasome-Induced Pyroptosis via NF-κB Signaling.

BackgroundThe exposure of the nucleus pulposus (NP) causes an immune and inflammatory response, which is intrinsically linked to the pathogenesis of radicular pain. As a newly discovered pro-resolving lipid mediator, maresin 1 (MaR1) could exert powerful inflammatory resolution, neuroprotection, and analgesic activities. In the present research, the analgesic effect of MaR1 was observed. Then, the potential mechanism by which MaR1 attenuated radicular pain was also analyzed in a rat model.MethodsIntrathecal administration of MaR1 (10 or 100 ng) was successively performed in a rat with non-compressive lumbar disk herniation for three postoperative days. Mechanical and thermal thresholds were determined to assess pain-related behavior from days 1 to 7 (n = 8/group). On day 7, the tissues of spinal dorsal horns from different groups were gathered to evaluate expression levels of inflammatory cytokines (IL-1β, IL-18, and TNF-α), the NLRP3 inflammasome and pyroptosis indicators (GSDMD, ASC, NLRP3, and Caspase-1), together with NF-κB/p65 activation (n = 6/group). TUNEL and PI staining were performed to further examine the process of pyroptosis.ResultsAfter intrathecal administration in the rat model, MaR1 exhibited potent analgesic effect dose-dependently. MaR1 significantly prompted the resolution of the increased inflammatory cytokine levels, reversed the up-regulated expression of the inflammasome and pyroptosis indicators, and reduced the cell death and the positive activation of NF-κB/p65 resulting from the NP application on the L5 dorsal root ganglion.ConclusionThis study indicated that the activation of NLRP3 inflammasome and pyroptosis played a significant role in the inflammatory reaction of radicular pain. Also, MaR1 could effectively down-regulate the inflammatory response and attenuate pain by inhibiting NLRP3 inflammasome-induced pyroptosis via NF-κB signaling.

Maresin1 Promotes M2 Macrophage Polarization Through Peroxisome Proliferator–Activated Receptor-γ Activation to Expedite Resolution of Acute Lung Injury

BackgroundAcute lung injury (ALI), manifested by progressive hypoxemia and respiratory distress, is associated with high morbidity and mortality, which lacks the effective therapies in clinics. Our previous studies demonstrated that maresin1 (MaR1), a specialized proresolving mediator, could effectively mitigate the inflammation of lipopolysaccharide (LPS)-induced ALI. However, whether MaR1 impacts the macrophage polarization to alleviate ALI remains unclear. Our study explored the effects and underlying mechanisms of MaR1 on the macrophage phenotypes in ALI. Material and methodsMale BALB/c mice were subjected to endotracheal instillation of LPS to induce ALI and then intravenously injected with MaR1 or normal saline. Intraperitoneal administration of peroxisome proliferator–activated receptor-γ (PPAR-γ) inhibitor GW9662 was given 30 mins before MaR1. We measured the pathohistologic changes, pulmonary edema, inflammatory cytokines, and the flow cytometry of macrophage phenotypes. ResultsOur results illustrated that MaR1 ameliorated lung injury and increased monocyte or macrophage recruitment and the release of anti-inflammatory cytokines. The flow cytometry showed that MaR1 promoted polarization of CD11c−CD206+ (M2) macrophages and inhibited polarization of CD11c+CD206- (M1) macrophages. Besides, the western blotting revealed that MaR1 increased the expression of PPAR-γ. The pretreatment with PPAR-γ antagonist GW9662 could significantly suppress the polarization of M2 macrophages and antagonize the protective effects of MaR1 on LPS-stimulated ALI. ConclusionsMaR1 was able to promote M2 macrophage polarization by reversing LPS-mediated PPAR-γ inhibition, thereby expediting the recovery of LPS-stimulated ALI.

Maresin 1 resolves aged-associated macrophage inflammation to improve bone regeneration.

Inflammaging is associated with poor tissue regeneration observed in advanced age. Specifically, protracted inflammation after acute injury has been associated with decreased bone fracture healing and increased rates of nonunion in elderly patients. Here, we investigated the efficacy of using Maresin 1 (MaR1), an omega-3 fatty acid-derived pro-resolving agent, to resolve inflammation after tibial fracture injury and subsequently improving aged bone healing. Aged (24-month-old mice) underwent tibial fracture surgery and were either treated with vehicle or MaR1 3 days after injury. Fracture calluses were harvested 7 days, 14 days, 21 days, and 28 days after injury to investigate inflammatory response, cartilage development, bone deposition, and mechanical integrity, respectively. Healing bones from MaR1-treated mice displayed decreased cartilage formation and increased bone deposition which resulted in increased structural stiffness and increased force to fracture in the later stages of repair. In the early stages, MaR1 treatment decreased the number of pro-inflammatory macrophages within the fracture callus and decreased the level of inflammatory biomarkers in circulation. In tissue culture models, MaR1 treatment of bone marrow-derived macrophages from aged mice protected cells form a pro-inflammatory phenotype and induced an anti-inflammatory fate. Furthermore, the secretome of MaR1-treated bone marrow-derived macrophages was identified as osteoinductive, enhancing osteoblast differentiation of bone marrow stromal cells. Our findings here identify resolution of inflammation, and MaR1 itself, to be a point of intervention to improve aged bone healing.

Alzheimer's Disease and Specialized Pro-Resolving Lipid Mediators: Do MaR1, RvD1, and NPD1 Show Promise for Prevention and Treatment?

Alzheimer’s disease (AD) is a common neurodegenerative disease and a major contributor to progressive cognitive impairment in an aging society. As the pathophysiology of AD involves chronic neuroinflammation, the resolution of inflammation and the group of lipid mediators that actively regulate it—i.e., specialized pro-resolving lipid mediators (SPMs)—attracted attention in recent years as therapeutic targets. This review focuses on the following three specific SPMs and summarizes their relationships to AD, as they were shown to effectively address and reduce the risk of AD-related neuroinflammation: maresin 1 (MaR1), resolvin D1 (RvD1), and neuroprotectin D1 (NPD1). These three SPMs are metabolites of docosahexaenoic acid (DHA), which is contained in fish oils and is thus easily available to the public. They are expected to become incorporated into promising avenues for preventing and treating AD in the future.

Role and Mechanism of Maresin-1 in Acute Lung Injury Induced by Trauma-Hemorrhagic Shock.

BackgroundIt is reported that trauma hemorrhagic shock (THS) could resulted in organ injury and is related to a high mortality rate. Maresin-1 (MaR1), a derived medium through biosynthesis, is involved in inflammatory responses. However, the mechanism of MaR1 against acute lung injury needs to be further understood. This report aimed to explore whether MaR1 had a protective effect on lung injury.Material/MethodsWe constructed a THS-induced acute lung damage rat model and then treated the rats with MaR1. We determined Evan’s blue dye (EBD) lung permeability, lung permeability index, wet/dry (W/D) weight ratio, nitric oxide (NO) concentration and inducible nitric oxide synthase (iNOS) expression in lung tissue samples. The inflammation-related cytokines levels in the bronchoalveolar lavage fluid (BALF) and serum of rats were determined by enzyme-linked immunosorbent assay (ELISA). Finally, the TLR4/p38MAPK/NF-κB pathway was analyzed by quantitative real-time polymerase chain reaction and western blot assay.ResultsThe increased EBD ratio, lung permeability index and W/D weight ratio, NO concentration and iNOS levels were suppressed by MaR1 treatment. THS-induced over-production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in BALF and serum was suppressed by MaR1. Besides, the TLR4/p38MAPK/NF-κB pathway activation in THS-induced rats were inhibited by MaR1 treatment.ConclusionsOur study showed that MaR1 could effectively alleviated THS-induced lung injury via inhibiting the excitation of the TLR4/p38MAPK/NF-κB pathway in THS-induced rats, suggesting that MaR1 might be a novel agent for lung damage treatment.

Effects of Maresin 1 (MaR1) on Colonic Inflammation and Gut Dysbiosis in Diet-Induced Obese Mice

The aim of this study was to characterize the effects of Maresin 1 (MaR1), a DHA-derived pro-resolving lipid mediator, on obesity-related colonic inflammation and gut dysbiosis in diet-induced obese (DIO) mice. In colonic mucosa of DIO mice, the MaR1 treatment decreased the expression of inflammatory genes, such as Tnf-α and Il-1β. As expected, the DIO mice exhibited significant changes in gut microbiota composition at the phylum, genus, and species levels, with a trend to a higher Firmicutes/Bacteroidetes ratio. Deferribacteres and Synergistetes also increased in the DIO animals. In contrast, these animals exhibited a significant decrease in the content of Cyanobacteria and Actinobacteria. Treatment with MaR1 was not able to reverse the dysbiosis caused by obesity on the most abundant phyla. However, the MaR1 treatment increased the content of P. xylanivorans, which have been considered to be a promising probiotic with healthy effects on gut inflammation. Finally, a positive association was found between the Deferribacteres and Il-1β expression, suggesting that the increase in Deferribacteres observed in obesity could contribute to the overexpression of inflammatory cytokines in the colonic mucosa. In conclusion, MaR1 administration ameliorates the inflammatory state in the colonic mucosa and partially compensates changes on gut microbiota caused by obesity.

Maresin-1 suppresses IL-1β-induced MMP-13 secretion by activating the PI3K/AKT pathway and inhibiting the NF-κB pathway in synovioblasts of an osteoarthritis rat model with treadmill exercise

ABSTRACT Aim: Maresin-1 is a metabolite of docosahexaenoic acid (DHA) that has potential anti-inflammatory effects. To explore whether maresin-1 changes and has a therapeutic effect in osteoarthritis (OA) model rats undergoing treadmill exercise, we examined endogenous maresin-1 in a single-session treadmill experiment and OA model rats were treated with maresin-1, moreover, we examined the effects of maresin-1 on IL-1β induced rat fibroblast-like synoviocytes (FLSs) and possible mechanisms. Methods: In single-session treadmill experiment, 48 rats were randomly divided into 3 groups and performed three different intensities of exercise (15.2 m/min, 0°; 19.3 m/min, 5°; 26.8 m/min, 10°) for 60 min. Intra-articular lavage fluid (IALF) samples were harvested after 0, 2, and 4 h from each group (n = 4) and maresin-1 levels were evaluated by ELISA. Another 30 rats were treated with monosodium iodoacetate (MIA) to induce osteoarthritis and exogenous maresin-1 (MaR-1) and were divided into three groups (n = 10, OA: MIA, OAM: MIA+MaR1, and CG: control group). The level of injury was evaluated by OARSI and Mankin scores, and the levels of type II collagen and MMP13 were evaluated by immunohistochemistry. FLSs were obtained from the knee joint of SD rats, and the expression of MMP13 and activation of the PI3k/Akt and NF-κB p65 pathways in IL-1β-induced FLSs were evaluated by western blotting. Results: Maresin-1 levels were increased in IALF at 4 h after exercise, and type II collagen increased in cartilage and MMP13 decreased in the synovium after treatment with maresin-1 in MIA-induced osteoarthritis. The results of vitro experiment showed decreased MMP13, activation of the PI3k/Akt pathway, and suppression of the NF-κB p65 pathway upon treatment with maresin-1 in IL-1β-induced FLSs. Conclusions: The changes in maresin-1 in IALF, as seen in our single-section treadmill exercise, provides an explanation for the therapeutic effect of appropriate-strength treadmill exercise on osteoarthritis, and our experiments confirmed the therapeutic effect of maresin-1 both in vivo and in vitro.

Maresin 1, a specialized proresolving mediator, stimulates intracellular [Ca2+ ] and secretion in conjunctival goblet cells.

Mucin secretion from conjunctival goblet cells forms the tear film mucin layer and requires regulation to function properly. Maresin 1 (MaR1) is a specialized proresolving mediator produced during the resolution of inflammation. We determined if MaR1 stimulates mucin secretion and signaling pathways used. Cultured rat conjunctival goblet cells were used to measure the increase in intracellular Ca2+ ([Ca2+ ]i ) concentration and mucin secretion. MaR1-increased [Ca2+ ]i and secretion were blocked by inhibitors of phospholipase C, protein kinase C, Ca2+ /calmodulin-dependent protein kinase II, and extracellular-regulated kinase 1/2. MaR1 added before addition of histamine counterregulated histamine-stimulated increase in [Ca2+ ]i and secretion. We conclude that MaR1 likely has two actions in conjunctival goblet cells: first, maintaining optimal tear film mucin levels by increasing [Ca2+ ]i and stimulating mucin secretion in health and, second, attenuating the increase in [Ca2+ ]i and overproduction of mucin secretion by counterregulating the effect of histamine as occurs in ocular allergy.

A Novel Mechanism of Specialized Proresolving Lipid Mediators Mitigating Radicular Pain: The Negative Interaction with NLRP3 Inflammasome.

Inhibition of immune and inflammatory reaction induced by the expose of nucleus pulposus (NP) could effectively ameliorate neuropathic pain in the lumbar disc herniation. Maresin1 (MaR1), as a macrophage-derived mediator of inflammation resolution, displayed potent anti-inflammatory action. In the present study, we attempted to elucidate the impact of MaR1 on radicular pain and the interaction with NLRP3 inflammasome. We established a rat model of non-compressive lumbar disc herniation and different administration (MaR1 or Caspase-1 inhibitor) was given to them. The paw withdrawal latency (PWL) and paw withdrawal thresholds (PWTs) were observed to assess pain behaviors. The spinal cord horns were collected and the levels of IL-1β and IL-18 were measured by ELISA. The mRNA and protein expression levels of NLRP3 inflammasome components were tested by RT-PCR, western blot and immunohistochemistry. The endogenous MaR1 levels of the spinal cord were analyzed using LC-MS/MS. The application of NP in the models lead to mechanical and thermal hypersensitivity, increased IL-1β and IL-18 levels and expressions of NLRP3 inflammasome components, which were reversed markedly by administration of MaR1. Caspase-1 inhibition also improved mechanical hypersensitivity, decreased the expressions of inflammatory cytokines and restrained the activation of inflammasome. Meanwhile, Caspase-1 inhibitor promoted the endogenous MaR1 synthesis, which was hindered in the pain models. Altogether, our study indicated that the negative interaction between MaR1 and NLRP3 inflammasome mediated the inflammatory response in spinal dorsal horn, which involved in the pathogenesis of radicular pain.

Maresin 1 Promotes Wound Healing and Socket Bone Regeneration for Alveolar Ridge Preservation

Tooth extraction results in alveolar bone resorption and is accompanied by postoperative swelling and pain. Maresin 1 (MaR1) is a proresolving lipid mediator produced by macrophages during the resolution phase of inflammation, bridging healing and tissue regeneration. The aim of this study was to examine the effects of MaR1 on tooth extraction socket wound healing in a preclinical rat model. The maxillary right first molars of Sprague-Dawley rats were extracted, and gelatin scaffolds were placed into the sockets with or without MaR1. Topical application was also given twice a week until complete socket wound closure up to 14 d. Immediate postoperative pain was assessed by 3 scores. Histology and microcomputed tomography were used to assess socket bone fill and alveolar ridge dimensional changes at selected dates. The assessments of coded specimens were performed by masked, calibrated examiners. Local application of MaR1 potently accelerated extraction socket healing. Macroscopic and histologic analysis revealed a reduced soft tissue wound opening and more rapid re-epithelialization with MaR1 delivery versus vehicle on socket healing. Under micro–computed tomography analysis, MaR1 (especially at 0.05 μg/μL) stimulated greater socket bone fill at day 10 as compared with the vehicle-treated animals, resulting in less buccal plate resorption and a wider alveolar ridge by day 21. Interestingly, an increased ratio of CD206+:CD68+ macrophages was identified in the sockets with MaR1 application under immunohistochemistry and immunofluorescence analysis. As compared with the vehicle therapy, local delivery of MaR1 reduced immediate postoperative surrogate pain score panels. In summary, MaR1 accelerated extraction wound healing, promoted socket bone fill, preserved alveolar ridge bone, and reduced postoperative pain in vivo with a rodent preclinical model. Local administration of MaR1 offers clinical potential to accelerate extraction socket wound healing for more predictable dental implant reconstruction.

Imbalance of proresolving lipid mediators in persistent allodynia dissociated from signs of clinical arthritis.

Rheumatoid arthritis-associated pain is poorly managed, often persisting when joint inflammation is pharmacologically controlled. Comparably, in the mouse K/BxN serum-transfer model of inflammatory arthritis, hind paw nociceptive hypersensitivity occurs with ankle joint swelling (5 days after immunisation) persisting after swelling has resolved (25 days after immunisation). In this study, lipid mediator (LM) profiling of lumbar dorsal root ganglia (DRG), the site of sensory neuron cell bodies innervating the ankle joints, 5 days and 25 days after serum transfer demonstrated a shift in specialised proresolving LM profiles. Persistent nociception without joint swelling was associated with low concentrations of the specialised proresolving LM Maresin 1 (MaR1) and high macrophage numbers in DRG. MaR1 application to cultured DRG neurons inhibited both capsaicin-induced increase of intracellular calcium ions and release of calcitonin gene-related peptide in a dose-dependent manner. Furthermore, in peritoneal macrophages challenged with lipopolysaccharide, MaR1 reduced proinflammatory cytokine expression. Systemic MaR1 administration caused sustained reversal of nociceptive hypersensitivity and reduced inflammatory macrophage numbers in DRG. Unlike gabapentin, which was used as positive control, systemic MaR1 did not display acute antihyperalgesic action. Therefore, these data suggest that MaR1 effects observed after K/BxN serum transfer relate to modulation of macrophage recruitment, more likely than to direct actions on sensory neurons. Our study highlights that, in DRG, aberrant proresolution mechanisms play a key role in arthritis joint pain dissociated from joint swelling, opening novel approaches for rheumatoid arthritis pain treatment.

Characterization of the local and systemic temporal changes to the lipid mediator and cytokine cascades following osteotomy and polytrauma

Abstract Polytrauma (PT) inducesglobal changes to inflammatory signaling, contributing to delayed fracturehealing. In a rat model of PT encompassing burn, blunt trauma, and osteotomy, we characterized the local and systemic temporal changes to the lipid mediator(LM) cascade, circulating white blood cells (WBCs), and local levels of growthfactors (GF)s and cytokines. Male rats received either a non-critical 3mmfemoral osteotomy (OST) or PT trauma procedures and were survived for 6, 24,48, 72, 96, 168, or 240hrs and blood, plasma, and fractured femurs werecollected. Whole femurs were homogenized to extract LMs, protein, and RNA, while blood and plasma were used for WBC and LM analysis, respectively. At the fracture site, prostaglandin (PG) E2 was significantly higher in OST at 24 and 72hrs, levels of PGF2α were higher in OST at 24hrs, while resolvin (Rv) D1 was higher in PTat 6hrs post injury. There were no differences in the expression ofcyclooxygenase-2 (COX-2), or lipoxygenase-5 (LOX-5) and LOX-15. In plasma, there were no significant differences in PG levels at any time. Plasma RvE1 was elevated in PT immediately following injury while maresin 1 (MaR1) was significantly lower in PT at 168hrs. Total WBCs and lymphocytes (103cells/uL) were lower in PT overall and significantly so at 72 and 96hrs, respectively. Additionally, the percent of neutrophils in PT was significantlyelevated and percent lymphocytes was decreased at 48 and 168hrs compared toOST. Protein analysis of the fracture site found early elevation of cytokines(IL-1β, IL-13, IL-6) and GFs in PT at 48 and 72hrs. These results indicate thatchanges to circulating LM and WBCs may provide predictive measures of non-unionand therapeutic targets to improve fracture healing.

Decreased Plasma Maresin 1 Concentration Is Associated with Diabetic Foot Ulcer.

Aims To assess the maresin 1 (MaR1) contents in type 2 diabetic patients with or without diabetic foot ulcer and to analyze the association of MaR1 concentrations with several metabolism-related parameters. Methods Plasma MaR1 concentrations were analyzed in 96 subjects with normal glucose tolerant (NC, n = 43), type 2 diabetes (T2DM, n = 40), or diabetic foot ulcer (DFU, n = 13). The intravenous glucose tolerance test (IVGTT) and biochemical parameters were measured in all participants. Results Plasma MaR1 concentrations were significant decreased in type 2 diabetes patient with or without DFU compared with NC (both P < 0.001) and were lowest in DFU patients among these 3 groups. (DFU vs. T2DM, P < 0.05). Plasma MaR1 concentrations were negatively correlated with BMI, waist circumference (Wc), waist hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), LDL-c, FPG, 2hPG, HbA1c, and homeostasis model assessment for insulin resistance (HOMA-IR) (all P < 0.05) and were positively correlated with HDL-c, acute insulin response (AIR), area under the curve of the first-phase (0-10 min) insulin secretion (AUC), and homeostasis model assessment for beta-cell function (HOMA-β) (all P < 0.05). After adjusting for age and sex, Wc, WHR, TG, FPG, 2hPG, HbA1c, HOMA-IR, AIR, AUC, and HOMA-β remain statistically significant (all P < 0.05). Conclusions Plasma MaR1 concentration were decreased in T2DM with or without DFUs and were the lowest in DFU patients. The decreased plasma MaR1 strongly associated with obesity, impaired glucose and lipid metabolism, reduced first-phase of glucose-stimulated insulin secretion, and enhanced insulin resistance.

Maresin1 Decreased Microglial Chemotaxis and Ameliorated Inflammation Induced by Amyloid-β42 in Neuron-Microglia Co-Culture Models.

Inflammation resolution is regulated by specialized pro-resolving lipid mediators (SPMs) and the levels of SPMs are found decreased in Alzheimer's disease (AD) brain. We have previously found that one of the SPMs, Maresin1 (MaR1), improved neuronal survival and increase microglial phagocytosis of amyloid-β 1-42 (Aβ42); however, the mechanisms underlying the protective mechanism remain further investigation. We aim to investigate the effects of MaR1 on microglial chemotaxis and activation in this study. Both indirect and direct primary neuron and microglia co-culture system was used in this study. Our results showed MaR1 downregulated the increased microglial chemotaxis induced by Aβ42. The microglial inactivation marker CD200R was downregulated by Aβ42 and upregulated by MaR1. Pro-inflammatory cytokines secretion such as tumor necrosis factor (TNF)-α were increased by Aβ42 and these changes were revised by MaR1 treatment. In addition, the levels of chemokine monocyte chemoattractant protein (MCP)-1 were increased while the levels of anti-inflammatory factor IL-10 secretion were decreased by Aβ42, and these changes were abolished by MaR1 treatment. Moreover, by proteomics analysis, we identified cell signaling pathways affected by MaR1 were not only limited to inflammation-related pathways such as P38, but also in pathways involved in cell survival, autophagy, axon formation, and apoptosis, including PI3K/AKT, mTOR, ERK, caspase3, Cdc42, and p75NTR. In conclusion, MaR1 promoted inflammation resolution by inhibiting chemotaxis and regulating activation of microglia. MaR1 played a neuroprotective role by affecting cell signaling pathways involving inflammation, cell survival, autophagy, axon formation, and apoptosis inhibition.

Maresin 1, a Proresolving Lipid Mediator, Ameliorates Liver Ischemia-Reperfusion Injury and Stimulates Hepatocyte Proliferation in Sprague-Dawley Rats

Maresin-1 (MaR1) is a specialized pro-resolving mediator, derived from omega-3 fatty acids, whose functions are to decrease the pro-inflammatory and oxidative mediators, and also to stimulate cell division. We investigated the hepatoprotective actions of MaR1 in a rat model of liver ischemia-reperfusion (IR) injury. MaR1 (4 ng/gr body weight) was administered prior to ischemia (1 h) and reperfusion (3 h), and controls received isovolumetric vehicle solution. To analyze liver function, transaminases levels and tissue architecture were assayed, and serum cytokines TNF-α, IL-6, and IL-10, mitotic activity index, and differential levels of NF-κB and Nrf-2 transcription factors, were analyzed. Transaminase, TNF-α levels, and cytoarchitecture were normalized with the administration of MaR1 and associated with changes in NF-κB. IL-6, mitotic activity index, and nuclear translocation of Nrf-2 increased in the MaR1-IR group, which would be associated with hepatoprotection and cell proliferation. Taken together, these results suggest that MaR1 alleviated IR liver injury, facilitated by the activation of hepatocyte cell division, increased IL-6 cytokine levels, and the nuclear localization of Nrf-2, with a decrease of NF-κB activity. All of them were related to an improvement of liver injury parameters. These results open the possibility of MaR1 as a potential therapeutic tool in IR and other hepatic pathologies.

Maresin 1 mitigates concanavalin A-induced acute liver injury in mice by inhibiting ROS-mediated activation of NF-κB signaling

The liver is the most important metabolic and detoxifying organ in the human body, and liver damage can seriously affect bodily function and potentially be life threatening. Accumulating evidence suggests that maresin 1 (MaR1) exhibits protective and anti-inflammatory effects in some diseases, such as pneumonia and colitis; however, its role in acute hepatitis remains unclear. Here, we established a concanavalin A (ConA)-induced acute liver-injury mouse model to determine whether MaR1 administration can attenuate liver damage. Our results indicate that MaR1 confers protective effects against ConA-induced acute liver injury, improves liver function and survival, and reduces histopathological damage. Additionally, MaR1 attenuated the inflammatory response and reduced hepatocyte apoptosis while increasing mouse macrophage apoptosis and markedly decreasing levels of reactive oxygen species (ROS) in macrophages. We also found that MaR1 significantly inhibited ConA-induced activation of the nuclear factor-kappaB (NF-κB) pathway. This work will contribute to a better understanding of acute liver injury (ALI) and advancement towards its treatment.

Maresin 1 alleviates dextran sulfate sodium-induced ulcerative colitis by regulating NRF2 and TLR4/NF-kB signaling pathway

ObjectiveUlcerative colitis (UC) is one of the most common gastrointestinal diseases, characterized as a chronic, relapsing inflammation that causes damage to the colonic mucosa. Maresin 1 (MaR1), a specialized proresolving mediator, has powerful anti-inflammatory activity that prevents the occurrence of various inflammatory diseases. The aim of this study was to explore the role and potential mechanism of MaR1 in DSS-induced ulcerative colitis. MethodsIn the present study, we established dextran sulfate sodium (DSS)-induced ulcerative colitis rat model in vivo. Rats with colitis received tail vein injection of MaR1, with or without intraperitoneal injection of ML385. The changes of body weight, colon length, disease activity index (DAI), colonic histopathology, inflammatory cytokines, the activity of myeloperoxidase (MPO) and reactive oxygen species (ROS), and infiltration of macrophages expressing F4/80 were analyzed for the evaluation of colitis severity. In addition, protein expressions were detected using western blot. ResultsMaR1 significantly reduced inflammatory cytokines production, and restored body weight, DAI and colonic histopathology. Besides, MaR1 improved the expression of tight junction (TJ) proteins and reduced the infiltration of neutrophil and macrophages, as well as a decreased activity of MPO and ROS. Meanwhile, MaR1 activated Nrf2 signaling and decreased toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB) activation. Furthermore, ML385, an inhibitor of Nrf2, significantly reversed the protective effect of MaR1. ConclusionMaR1 play a protective role in DSS-induced colitis by activating Nrf2 signaling and inactivating Nrf2-mediated TLR4/NF-κB signaling pathway, which mediate proinflammatory mediators and intestinal TJ proteins in rats, providing novel insights into the therapeutic strategy of colitis.