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The role of chemical mediators in the acute inflammatory response. At the site of tissue injury or bacterial invasion, both exogenous and endogenous chemical mediators are liberated. Classic endogenous mediators such as prostaglandins and leukotrienes dilate vasculatures, enhance permeability of capillaries, increase blood flow, and stimulate the recruitment of neutrophils (PMNs) to form inflammatory exudate. Novel chemical mediators are produced in the evolution and resolution of the exudate that regulate tissue responses (see text for details). The black arrow denotes leukocyte traffic from venules and the dashed arrow denotes exogenous, i.e., bacterial components and chemoattractants.
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Endogenous mechanisms for successful resolution of an acute inflammatory response and the local return to homeostasis are of interest because excessive inflammation underlies many human diseases. In this review, we provide an update and overview of functional metabolomics that identified a new bioactive metabolome of docosahexaenoic acid (DHA). Sys...
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... In addition to its role in maintaining neuronal membranes, DHA enhances synaptic plasticity, promotes the degradation of beta amyloid (Aβ), and facilitates the resolution of inflammation [1,2,[40][41][42][43][44]. Many of the effects of DHA on inflammation are mediated by its bioactive lipid metabolites or docosanoids, including D-series resolvins, maresins, and neuroprotectins, collectively referred to as specialized pro-resolving mediators (SPMs) [45][46][47][48][49][50][51]. These SPMs are capable of mitigating glial cell activation and inflammatory signaling [45,52]. ...
... Other neuroprotective structurally related agents exhibiting similar activity are PDX (10R, 17S-dihydroxy-4Z, 7Z, 11E, 13Z, 15E, 19Z-DHA); 20-hydroxy-PD1 (10R, 17S, 20trihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-DHA); and 10-epi-PD1 (10R, 17S-Dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-DHA) [60,61]. The beneficial effect of these anti-inflammatory mediators was reported by Sheets et al. [62], who demonstrated both a laser-induced choroidal neurovascularisation attenuation and microglia cells elongating in mouse eyes treated with NPD1. ...
Cancer is a process involving cell mutation, increased proliferation, invasion, and metastasis. Over the years, this condition has represented one of the most concerning health problems worldwide due to its significant morbidity and mortality. At present, the incidence of cancer continues to grow exponentially. Thus, it is imperative to open new avenues in cancer research to understand the molecular changes driving DNA transformation, cell-to-cell interaction derangements, and immune system surveillance decay. In this regard, evidence supports the relationship between chronic inflammation and cancer. In light of this, a group of bioactive lipids derived from polyunsaturated fatty acids (PUFAs) may have a position as novel anti-inflammatory molecules known as the specialized pro-resolving mediators (SPMs), a group of pro-resolutive inflammation agents that could improve the anti-tumor immunity. These molecules have the potential role of chemopreventive and therapeutic agents for various cancer types, and their effects have been documented in the scientific literature. Thus, this review objective centers around understanding the effect of SPMs on carcinogenesis and their potential therapeutic effect.
... A novel protectin-synthesis pathway, called aspirin-triggered PD1, utilizes aspirin-triggered cyclooxygenase-2 to synthesize epimeric 17 R-hydroxyperoxide from docosahexaenoic acid [168,169]. It has shown a positive interaction with CB2 and peroxisome proliferator-activated receptor family receptors [164,170]. ...
... Protectins reduce polymorphonuclear neutrophil transmigration through endothelial cells and enhance the clearance (efferocytosis) of apoptotic polymorphonuclear neutrophils by human macrophages [170]. ...
It is commonly believed that the inactivation of inflammation is mainly due to the decay or cessation of inducers. In reality, in connection with the development of atherosclerosis, spontaneous decay of inducers is not observed. It is now known that lipid mediators originating from polyunsaturated fatty acids (PUFAs), which are important constituents of all cell membranes, can act in the inflamed tissue and bring it to resolution. In fact, PUFAs, such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are precursors to both pro-inflammatory and anti-inflammatory compounds. In this review, we describe the lipid mediators of vascular inflammation and resolution, and their biochemical activity. In addition, we highlight data from the literature that often show a worsening of atherosclerotic disease in subjects deficient in lipid mediators of inflammation resolution, and we also report on the anti-proteasic and anti-thrombotic properties of these same lipid mediators. It should be noted that despite promising data observed in both animal and in vitro studies, contradictory clinical results have been observed for omega-3 PUFAs. Many further studies will be required in order to clarify the observed conflicts, although lifestyle habits such as smoking or other biochemical factors may often influence the normal synthesis of lipid mediators of inflammation resolution.
... However, the sum of the two fatty acids was almost unchanged (2.87 EPA plus DHA instead of 3 g, as in the first trial). In our opinion, the increase in the dose of DHA was very appropriate, since not only EPA, but also DHA may be endogenously converted to several metabolic derivatives showing powerful pro-resolving activities [156]. The aims of this second trial include the evaluation of metabolic bioactive derivatives of EPA and DHA, as well as cytokines, in untreated and treated patient blood and wound fluid. ...
Long-chain Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) are widely recognized as powerful negative regulators of acute inflammation. However, the precise role exerted by these dietary compounds during the healing process is still largely unknown, and there is increasing interest in understanding their specific effects on the implicated cells/molecular factors. Particular attention is being focused also on their potential clinical application in chronic pathologies characterized by delayed and impaired healing, such as diabetes and vascular diseases in lower limbs. On these bases, we firstly summarized the current knowledge on wound healing (WH) in skin, both in normal conditions and in the setting of these two pathologies, with particular attention to the cellular and molecular mechanisms involved. Then, we critically reviewed the outcomes of recent research papers investigating the activity exerted by Omega-3 PUFAs and their bioactive metabolites in the regulation of WH in patients with diabetes or venous insufficiency and showing chronic recalcitrant ulcers. We especially focused on recent studies investigating the mechanisms through which these compounds may act. Considerations on the optimal dietary doses are also reported, and, finally, possible future perspectives in this area are suggested.
... Resolvins play an important role in inflammation, vascular biology, and platelet aggregation [99,100]. DHA-derived oxylipins can also be synthesized by COX [101,102] and cytochrome P450 epoxygenase. DHA derived epoxy-fatty acids [93] are known to decrease platelet aggregation and thromboxane A2 synthesis [95,103]. ...
Cardiovascular disease remains a leading cause of mortality worldwide. Unresolved inflammation plays a critical role in cardiovascular diseases development. Specialized Pro-Resolving Mediators (SPMs), derived from long chain polyunsaturated fatty acids (LCPUFAs), enhances the host defense, by resolving the inflammation and tissue repair. In addition, SPMs also have anti-inflammatory properties. These physiological effects depend on the availability of LCPUFAs precursors and cellular metabolic balance. Most of the studies have focused on the impact of SPMs in adult cardiovascular health and diseases. In this review, we discuss LCPUFAs metabolism, SPMs, and their potential effect on cardiovascular health and diseases primarily focusing in neonates. A better understanding of the role of these SPMs in cardiovascular health and diseases in neonates could lead to the development of novel therapeutic approaches in cardiovascular dysfunction.
... Inflamed human endothelial cells used both EPA and DHA to release lipid-derived intermediates that are metabolized by leukocytes or glial cells to bioactive series E (RvE1) and series D (RvD1, PD1) metabolites [42]. Ethanolamide esters of DHA and EPA are also metabolized by neutrophils and brain tissues to active products that interact with CB1/2R receptors [43]. Activation of CB2 receptors on the immune cells by these cannabinoid ligands generally leads to the inhibition of CD14/TLR4 (Tol-like Receptor-4) inflammatory signaling pathway that drives pro-inflammatory T-helper-1 (TH1) immune response by increased interleukins (IL-1b, IL-6, IL-8) and tumor necrosis factor -α (TNF-α) production in macrophages [38]. ...
The endocannabinoid system (ECS) consists of endogenous cannabinoids, their receptors, and metabolic enzymes that play a critical homeostatic role in modulating polyunsaturated omega fatty acid (PUFA) signaling to maintain a balanced inflammatory and redox state. Whole food-based diets and dietary interventions linked to PUFAs of animal (fish, calamari, krill) or plant (hemp, flax, walnut, algae) origin, as well as full-spectrum hemp oils, are increasingly used to support the ECS tone, promote healthy metabolism, improve risk factors associated with cardiovascular disorders, encourage brain health and emotional well-being, and ameliorate inflammation. While hemp cannabinoids of THC and CBD groups show distinct but complementary actions through a variety of cannabinoid (CB1 and CB2), adenosine (A2A), and vanilloid (TRPV1) receptors, they also modulate PUFA metabolism within a wide variety of specialized lipid mediators that promote or resolve inflammation and oxidative stress. Clinical evidence reviewed in this study links PUFAs and cannabinoids to changes in ECS tone, immune function, metabolic and oxidative stress adaptation, and overall maintenance of a well-balanced systemic function of the body. Understanding how the body coordinates signals from the exogenous and endogenous ECS modulators is critical for discerning the underlying molecular mechanisms of the ECS tone in healthy and disease states. Nutritional and lifestyle interventions represent promising approaches to address chronic metabolic and inflammatory disorders that may overlap in the population at risk. Further investigation and validation of dietary interventions that modulate the ECS are required in order to devise clinically successful second-generation management strategies.
... Other PDs with similar activity include PDX; 20-hydroxy-PD1; and 10-epi-PD1 (Shinohara et al. 2012;Balas and Durand 2016). The activity of 17-epi-PD1, a PD1-like metabolite, has not been reported. ...
Unexpected viral infections outbreaks, significantly affect human health, leading to increased mortality and life disruption. Among them is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged as a deadly pandemic, calling for intense research efforts on its pathogenicity mechanism and development of therapeutic strategies. In the SARS-CoV-2 cytokine storm, systemic inflammation has been associated with severe illness and mortality. Recent studies have demonstrated special pro-resolving lipids mediators (SPMs) lipoxins, resolvins, maresins, and protectins as potential therapeutic options for abnormal viral-triggered inflammation. Pro-resolving lipids mediators have shown great promise for the treatment of Herpes simplex virus, respiratory syncytial virus, human immunodeficiency virus, and hepatitis C virus. Based on this, studies are being conducted on their therapeutic effects in SARS-CoV-2 infection. In this review, we discussed SPMs and reviewed evidence from recent studies on SPMs as therapeutic options for viral infections, including SARS-CoV2. Based on our analysis of the previous study, we argue that SPMs are a potential treatment for SARS-CoV-2 infection and other viral infections. We expect further research on how SPMs modulate viral-triggered inflammation through G-protein-coupled receptors (GPCRs), and chemical stability and druggability of SPMs.
... Like other members of the specialized pro-resolving mediators, NPD1 exerts potent anti-inflammatory and anti-apoptotic/neuroprotective biological activities[75,76]. Other neuroprotective agents with similar activity exist: PDX (10R, 17S-dihydroxy-4Z, 7Z, 11E, 13Z, 15E, 19Z-docosahexaenoic acid); 20-hydroxy-PD1 (10R, 17S, 20-trihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-docosahexaenoic acid); 10-epi-PD1 (10R, 17S-Dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-docosahexaenoic acid)[77,78]. The activity of the neuroprotectin-like metabolite 17-epi-PD1 (10R, 17R-dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-docosahexaenoic acid) has not yet been reported. ...
Heart disease is the number one mortality disease in the world. In particular, cardiac fibrosis is considered as a major factor causing myocardial infarction and heart failure. In particular, oxidative stress is a major cause of heart fibrosis. In order to control such oxidative stress, the importance of nuclear factor erythropoietin 2 related factor 2 (NRF2) has recently been highlighted. In this review, we will discuss the activation of NRF2 by docosahexanoic acid (DHA), eicosapentaenoic acid (EPA), and the specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated lipids, including DHA and EPA. Additionally, we will discuss their effects on cardiac fibrosis via NRF2 activation.
... In an enzymatic assay with 15-LOX and DHEA they showed that 17-HDHEA was produced as a specific 15-LOX metabolite. In addition, four major 15-LOX derived metabolites, 7,17-diHDHEA, 4,17-diHDHEA 10,17-diHDHEA and 15-HEDPE, were identified in brain tissue [77,105], of which 10,17-diHDHEA and 15-HEDPEA significantly reduced leukocyte chemotaxis. In addition, 10,17-diHDHEA was observed to block platelet-activator factor (PAF)-stimulated platelet-leukocyte aggregation and to stop PMN chemotaxis. ...
... Both 10,17-diHDHEA and 15-HEDPEA were found to activate CB2 receptors. Concluding, both 10,17-diHDHEA and 15-HEDPEA are biologically active anti-inflammatory compounds derived from DHEA [77,105] (Fig. 5, Table 1). ...
Notwithstanding the ongoing debate on their full potential in health and disease, there is general consensus that n-3 PUFAs play important physiological roles. Increasing dietary n-3 PUFA intake results in increased DHA and EPA content in cell membranes as well as an increase in n-3 derived oxylipin and -endocannabinoid concentrations, like fatty acid amides and glycerol-esters. These shifts are believed to (partly) explain the pharmacological and anti-inflammatory effects of n-3 PUFAs. Recent studies discovered that n-3 PUFA-derived endocannabinoids can be further metabolized by the oxidative enzymes CYP-450, LOX and COX, similar to the n-6 derived endocannabinoids. Interestingly, these oxidized n-3 PUFA derived endocannabinoids of eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA) have higher anti-inflammatory and anti-proliferative potential than their precursors. In this review, an overview of recently discovered n-3 PUFA derived endocannabinoids and their metabolites is provided. In addition, the use of chemical probes will be presented as a promising technique to study the n-3 PUFA and n-3 PUFA metabolism within the field of lipid biochemistry.
... In macrophages, DHEA lowers production of MCP-1, NO, and eicosanoids (227,228). Furthermore, oxidation of DHEA yields anti-inflammatory derivatives (229)(230)(231). eCBs bind to the cannabinoid receptors, CB1 and CB2, which are expressed by neurons and glia (232,233). ...
Overstimulation of the pro-inflammatory pathways within brain areas responsible for sympathetic outflow is well evidenced as a primary contributing factor to the establishment and maintenance of neurogenic hypertension. However, the precise mechanisms and stimuli responsible for promoting a pro-inflammatory state are not fully elucidated. Recent work has unveiled novel compounds derived from omega-3 polyunsaturated fatty acids (ω-3 PUFAs), termed specialized pro-resolving mediators (SPMs), which actively regulate the resolution of inflammation. Failure or dysregulation of the resolution process has been linked to a variety of chronic inflammatory and neurodegenerative diseases. Given the pathologic role of neuroinflammation in the hypertensive state, SPMs and their associated pathways may provide a link between hypertension and the long-standing association of dietary ω-3 PUFAs with cardioprotection. Herein, we review recent progress in understanding the RAS-driven pathophysiology of neurogenic hypertension, particularly in regards to the chronic low-grade neuroinflammatory response. In addition, we examine the potential for an impaired resolution of inflammation process in the context of hypertension.
