Maresins: Specialized Proresolving Lipid Mediators and Their Potential Role in Inflammatory-Related Diseases

Acute inflammatory responses are host-protective and normally self-limited; these responses can maintain cell homeostasis and promote defense against various infections and damage factors. However, when improperly managed or inappropriately activated, acute inflammation can lead to persistent and uncontrolled chronic inflammation, which is associated with many other chronic diseases including cardiovascular disease and metabolic disease. Recently, studies have shown that resolution of acute inflammation is a biosynthetically active process. Specialized proresolving lipid mediators (SPMs) known as resolvins and protectins are autacoids that resolve inflammation. A new family of anti-inflammatory and proresolving lipid mediators have recently been reported, known as maresins, which are biosynthesized from docosahexaenoic acid (DHA) by macrophages, have a conjugated double-bond system, and display strong anti-inflammatory and proresolving activity. Here, we review the biological actions, pathways, and mechanisms of maresins, which may play pivotal roles in the resolution of inflammation.

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New Perspectives on Aspirin and the Endogenous Control of Acute Inflammatory Resolution

The Scientific World JOURNAL ◽

10.1100/tsw.2006.192 ◽

2006 ◽

Vol 6 ◽

pp. 1048-1065 ◽

Cited By ~ 16

Author(s):

Thea Morris ◽

Melanie Stables ◽

Derek W. Gilroy

Keyword(s):

Mode Of Action ◽

Acute Inflammation ◽

Lipid Mediators ◽

The Other ◽

Endogenous Control ◽

Protective Properties ◽

Traditional Mode ◽

Inflammatory Drugs ◽

Cox 2 ◽

Anti Inflammatory

Aspirin is unique among the nonsteroidal anti-inflammatory drugs in that it has both anti-inflammatory as well as cardio-protective properties. The cardio-protective properties arise form its judicious inhibition of platelet-derived thromboxane A2over prostacyclin, while its anti-inflammatory effects of aspirin stem from its well-established inhibition of prostaglandin (PG) synthesis within inflamed tissues. Thus aspirin and the other NSAIDs have popularised the notion of inhibiting PG biosynthesis as a common anti-inflammatory strategy based on the erroneous premise that all eicosanoids are generally detrimental to inflammation. However, our fascination with aspirin has shown a more affable side to lipid mediators based on our increasing interest in the endogenous control of acute inflammation and in factors that mediate its resolution. Epi-lipoxins (epi-LXs), for instance, are produced from aspirins acetylation of inducible cyclooxygenase 2 (COX-2) and together with Resolvins represent an increasingly important family of immuno-regulatory and potentially cardio-protective lipid mediators. Aspirin is beginning to teach us what nature knew all along that not all lipid mediators are bad. It seems that while some eicosanoids are pathogenic in a variety of diseases, others are unarguable protective. In this review we will re-count aspirins colorful history, discuss its traditional mode of action and the controversies associated therewith, as well as highlight some of the new pathways in inflammation and the cardiovascular systems that aspirin has recently revealed.

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n-3 Fatty acids, inflammation and immunity: new mechanisms to explain old actions

Proceedings of The Nutrition Society ◽

10.1017/s0029665113001031 ◽

2013 ◽

Vol 72 (3) ◽

pp. 326-336 ◽

Cited By ~ 202

Author(s):

Philip C. Calder

Keyword(s):

Fatty Acids ◽

Inflammatory Responses ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Mechanisms Of Action ◽

Lipid Mediators ◽

Functional Responses ◽

New Family ◽

Epa And Dha ◽

Novel Interactions

Numerous effects of n-3 fatty acids EPA and DHA on functional responses of cells involved in inflammation and immunity have been described. Fatty acid-induced modifications in membrane order and in the availability of substrates for eicosanoid synthesis are long-standing mechanisms that are considered important in explaining the effects observed. More recently, effects on signal transduction pathways and on gene expression profiles have been identified. Over the last 10 years or so, significant advances in understanding the mechanisms of action of n-3 fatty acids have been made. These include the identification of new actions of lipid mediators that were already described and of novel interactions among those mediators and the description of an entirely new family of lipid mediators, resolvins and protectins that have anti-inflammatory actions and are critical to the resolution of inflammation. It is also recognised that EPA and DHA can inhibit activation of the prototypical inflammatory transcription factor NF-κB. Recent studies suggest three alternative mechanisms by which n-3 fatty acids might have this effect. Within T-cells, as well as other cells of relevance to immune and inflammatory responses, EPA and DHA act to disrupt very early events involving formation of the structures termed lipid rafts which bring together various proteins to form an effective signalling platform. In summary, recent research has identified a number of new mechanisms of action that help to explain previously identified effects of n-3 fatty acids on inflammation and immunity.

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Abstract 702: Walnut Treatment Reduces Specific Pro-inflammatory Lipid Mediators While Increasing Anti-inflammatory Ones: An RCT subanalysis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.702 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Gregory C Shearer ◽

John W Newman ◽

Roberta R Holt ◽

Carl L Keen ◽

Robert M Hackman

Keyword(s):

Fatty Acids ◽

Heart Disease ◽

Fatty Acid ◽

Inflammatory Responses ◽

Plasma Lipid ◽

Lipid Mediators ◽

Lipid Mediator ◽

Plasma Fatty Acid ◽

Anti Inflammatory ◽

Active Dose

Background: Lipid mediators are transported in plasma, inducing pro- or anti-inflammatory responses in target tissues. Each daily nut serving is associated with 30% reduction in risk for cardiovascular or ischemic heart disease. Walnuts are an abundant source of bioactives and of precursors to lipid mediator synthesis: linoleic (LA) and alpha-linolenic (aLA) acids. How walnuts impact plasma lipid mediators either by providing more substrate or more specifically via other bioactives is unknown. Objective: Measure lipid mediators from the cyclooxygenase (COX), lipoxygenase (LOX), cytochrome p450 (CYP), and auto-oxidative pathways in plasma from subjects consuming large and small amounts of walnuts. Design: 40 hypercholesterolemic, postmenopausal females were randomly assigned to a null dose (5g/d) or an active dose (40 g/d) of walnuts for 4 weeks. In a subset of 20 subjects, plasma lipid mediators synthesized from LA, aLA and other polyunsaturated fatty acids were measured by LC/MS/MS at baseline and final visits. Differences are reported as mean, 95% CIs. Results: Walnuts did not alter the compositional abundance of any plasma fatty acid except aLA, which was increased 1.46 fold [1.83, 1.16], p=0.003. Walnuts did modify plasma lipid mediator composition: specific pro-inflammatory COX metabolites, PGD2 and PGJ2/delta-12-PGJ2 were reduced by -72% [-43, -86] and -55% [-9, -77] respectively. LOX metabolites were almost uniformly depressed: the immediate mid-chain alcohols of LA (HODEs), dgLA (HETrEs), AA (HETEs), EPA (HEPEs) and DHA (HDoHEs) were reduced by 50-75% (p≤0.007), but aLA (HOTEs) were not. Metabolites of 5-LOX further downstream were also reduced: 5-KETE by 79% [-91, -50], and 6-trans-LTB4 by -89% [-76, -95]. Conversely, anti-inflammatory CYP-epoxides of LA (EpOME) and aLA (EpODE) were increased 82% [3, 223] and 143% [37, 331]. Epoxides of eicosanoids and docosanoids were unchanged (AA EpETrEs or EETs; EPA EpETEs; DHA EpDPEs). Conclusion: Walnut feeding reduces plasma pro-inflammatory COX and LOX metabolites while increasing some anti-inflammatory CYP metabolites. The effect occurs largely without changes in fatty acids, suggesting a molecular mechanism independent of simple changes in precursor abundance.

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The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19124058 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4058 ◽

Cited By ~ 2

Author(s):

Stella Bernardi ◽

Annalisa Marcuzzi ◽

Elisa Piscianz ◽

Alberto Tommasini ◽

Bruno Fabris

Keyword(s):

Lipid Metabolism ◽

Acute Inflammation ◽

Metabolic Diseases ◽

Inflammatory Responses ◽

Organ Damage ◽

Lipid Lowering ◽

Peripheral Tissues ◽

Obesity Epidemic ◽

Nutritional Environment ◽

Anti Inflammatory

Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response—and interleukins—had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed.

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Unraveling the Complex Relationship Triad between Lipids, Obesity, and Inflammation

Mediators of Inflammation ◽

10.1155/2014/502749 ◽

2014 ◽

Vol 2014 ◽

pp. 1-16 ◽

Cited By ~ 32

Author(s):

Shahida A. Khan ◽

Ashraf Ali ◽

Sarah A. Khan ◽

Solafa A. Zahran ◽

Ghazi Damanhouri ◽

...

Keyword(s):

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Lipid Mediators ◽

Peroxisome Proliferator ◽

Omega 3 ◽

Mortality And Morbidity ◽

Increased Risk ◽

Omega 6 ◽

Anti Inflammatory ◽

Peroxisome Proliferator Activated Receptors

Obesity today stands at the intersection between inflammation and metabolic disorders causing an aberration of immune activity, and resulting in increased risk for diabetes, atherosclerosis, fatty liver, and pulmonary inflammation to name a few. Increases in mortality and morbidity in obesity related inflammation have initiated studies to explore different lipid mediated molecular pathways of attempting resolution that uncover newer therapeutic opportunities of anti-inflammatory components. Majorly the thromboxanes, prostaglandins, leukotrienes, lipoxins, and so forth form the group of lipid mediators influencing inflammation. Of special mention are the omega-6 and omega-3 fatty acids that regulate inflammatory mediators of interest in hepatocytes and adipocytes via the cyclooxygenase and lipoxygenase pathways. They also exhibit profound effects on eicosanoid production. The inflammatory cyclooxygenase pathway arising from arachidonic acid is a critical step in the progression of inflammatory responses. New oxygenated products of omega-3 metabolism, namely, resolvins and protectins, behave as endogenous mediators exhibiting powerful anti-inflammatory and immune-regulatory actions via the peroxisome proliferator-activated receptors (PPARs) and G protein coupled receptors (GPCRs). In this review we attempt to discuss the complex pathways and links between obesity and inflammation particularly in relation to different lipid mediators.

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Xuebijing Protects Rats from Sepsis Challenged withAcinetobacter baumanniiby Promoting Annexin A1 Expression and Inhibiting Proinflammatory Cytokines Secretion

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/804940 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 16

Author(s):

Xian-Di He ◽

Yan Wang ◽

Qiong Wu ◽

Hua-Xue Wang ◽

Zhen-Dong Chen ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Potential Role ◽

Inflammatory Responses ◽

Treatment Time ◽

Control Group ◽

Annexin A1 ◽

Male Wistar Rats ◽

Anti Inflammatory ◽

Underlying Mechanisms ◽

Necrosis Factor

Xuebijing (XBJ) injection is a herbal medicine that has been widely used in the treatment of sepsis in China; however, its role in the development and progression ofAcinetobacter baumanniisepsis and the underlying mechanisms remain uninvestigated. In the present study, fifty-four male Wistar rats were randomly assigned to normal-control group, sepsis-control group, and sepsis + XBJ group, each containing three subgroups of different treatment time periods (6, 12, and 24 hrs following injection, resp.). The sepsis model was established by intraperitoneal injection ofA. baumanniiATCC 19606. For XBJ treatment, 4 mL/kg XBJ was administrated simultaneously by intravenous injection through caudal vein every 12 hrs. All animals demonstrated ill state, obvious intestinal dysfunction, histopathological lung damages, and overactive inflammatory responses afterA. baumanniiinfection, and these events could be partially reversed by XBJ treatment from the beginning of infection. XBJ induced an increase in the expression of anti-inflammatory mediator annexin A1; however, two proinflammatory cytokines, interleukin-8 (IL-8) and tumor necrosis factor-α(TNF-α), were decreased at the each monitored time point. These findings suggested that XBJ via its cytokine-mediated anti-inflammatory effects might have a potential role in preventing the progression ofA. baumanniiinfection to sepsis by early administration.

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Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice

Molecules ◽

10.3390/molecules25092181 ◽

2020 ◽

Vol 25 (9) ◽

pp. 2181 ◽

Cited By ~ 2

Author(s):

Lindaiane Bezerra Rodrigues Dantas ◽

Ana Letícia Moreira Silva ◽

Cícero Pedro da Silva Júnior ◽

Isabel Sousa Alcântara ◽

Maria Rayane Correia de Oliveira ◽

...

Keyword(s):

Chronic Inflammation ◽

Acute Inflammation ◽

Inflammatory Responses ◽

In Silico Analysis ◽

Histamine Receptor ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory ◽

Acute And Chronic Inflammation ◽

The Impact

Nootkatone (NTK) is a sesquiterpenoid found in essential oils of many species of Citrus (Rutaceae). Considering previous reports demonstrating that NTK inhibited inflammatory signaling pathways, this study aimed to investigate the effects of this compound in mice models of acute and chronic inflammation. Murine models of paw edema induced by carrageenan, dextran, histamine, and arachidonic acid, as well as carrageenan-induced peritonitis and pleurisy, were used to evaluate the effects of NTK on acute inflammation. A murine model of granuloma induced by cotton pellets was used to access the impact of NTK treatment on chronic inflammation. In the acute inflammation models, NTK demonstrated antiedematogenic effects and inhibited leukocyte recruitment, which was associated with decreased vascular permeability, inhibition of myeloperoxidase (MPO), interleukin (IL)1-β, and tumor necrosis factor (TNF)-α production. In silico analysis suggest that NTZ anti-inflammatory effects may also occur due to inhibition of cyclooxygenase (COX)-2 activity and antagonism of the histamine receptor type 1 (H1). These mechanisms might have contributed to the reduction of granuloma weight and protein concentration in the homogenates, observed in the chronic inflammation model. In conclusion, NTK exerted anti-inflammatory effects that are associated with inhibition of IL1-β and TNF-α production, possibly due to inhibition of COX-2 activity and antagonism of the H1 receptor. However, further studies are required to characterize the effects of this compound on chronic inflammation.

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Reduction of paw edema and liver oxidative stress in carrageenan-induced acute inflammation by Lobaria pulmonaria and Parmelia caperata, lichen species, in mice

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000620 ◽

2019 ◽

pp. 1-9

Author(s):

Samira Salem ◽

Essaid Leghouchi ◽

Rachid Soulimani ◽

Jaouad Bouayed

Keyword(s):

Time Course ◽

Acute Inflammation ◽

Lichen Species ◽

Paw Edema ◽

Sod Activity ◽

Edema Formation ◽

Lobaria Pulmonaria ◽

Anti Inflammatory ◽

Endogenous Antioxidant ◽

Inflammatory Effect

Abstract. Paw edema volume reduction is a useful marker in determining the anti-inflammatory effect of drugs and plant extracts in carrageenan-induced acute inflammation. In this study, the anti-inflammatory effect of Lobaria pulmonaria (LP) and Parmelia caperata (PC), two lichen species, was examined in carrageenan-induced mouse paw edema test. Compared to the controls in carrageenan-induced inflammation (n = 5/group), our results showed that pretreatment by single oral doses with PC extract (50–500 mg/kg) gives better results than LP extract (50–500 mg/kg) in terms of anti-edematous activity, as after 4 h of carrageenan subplantar injection, paw edema formation was inhibited at 82–99% by PC while at 35–49% by LP. The higher anti-inflammatory effect of PC, at all doses, was also observed on the time-course of carrageenan-induced paw edema, displaying profile closely similar to that obtained with diclofenac (25 mg/kg), an anti-inflammatory drug reference (all p < 0.001). Both LP and PC, at all doses, significantly ameliorated liver catalase (CAT) activity (all p < 0.05). However, superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity and glutathione (GSH) levels were found increased in liver of PC- compared to LP-carrageenan-injected mice. Our findings demonstrated on one hand higher preventive effects of PC compared to LP in a mouse carrageenan-induced inflammatory model and suggested, on the other hand, that anti-inflammatory effects elicited by the two lichens were closely associated with the amelioration in the endogenous antioxidant status of liver.

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