Arachidonic acid and lipoxin A4 as possible endogenous anti-diabetic molecules.

In both type 1 and type 2 diabetes mellitus, increased production of pro-inflammatory cytokines and reactive oxygen species (ROS) occurs that induce apoptosis of ß cells and cause peripheral insulin resistance respectively though the degree of their increased production is higher in type 1 and less in type 2 diabetes mellitus. Despite this, the exact mechanism(s) that lead to increased production of pro-inflammatory cytokines: interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and ROS is not known. Studies showed that plasma concentrations of arachidonic acid (AA) and lipoxin A4 (LXA4) are low in alloxan-induced type 1 diabetes mellitus in experimental animals and patients with type 2 diabetes mellitus. Prior administration of AA, eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively) and transgenic animals that produce increased amounts of EPA and DHA acids were protected from chemical-induced diabetes mellitus that was associated with enhanced formation of LXA4 and resolvins, while protectin D1 ameliorated peripheral insulin resistance. AA, LXA4, resolvins and protectins inhibit IL-6 and TNF-α production and suppress ROS generation. Thus, AA and lipoxins, resolvins and protectins may function as endogenous anti-diabetic molecules implying that their administration could be useful in the prevention and management of both types of diabetes mellitus.

Lipoxin A4 may function as an endogenous anti-arrhythmic molecule.

Cardiac arrhythmias cause significant morbidity and mortality in patients with coronary heart disease, hypertension, and congestive cardiac failure and in the elderly. Inflammation, oxidative injury, altered myocyte metabolism, extracellular matrix remodeling and fibrosis initiate and perpetuate cardiac arrhythmias, especially atrial fibrillation. Enhanced myeloperoxidase (MPO) activity by infiltrating activated leukocytes could bind to myocardial cells and cause fibrosis resulting in the initiation and progression of arrhythmias. Supplementation of eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively) suppresses arrhythmias. EPA and DHA form precursors to anti-inflammatory lipid molecules: lipoxins, resolvins, protectins and maresins that are known to suppress inflammation, have anti-fibrotic actions and inhibit MPO activity. Hence, it is likely that leukocyte and/or myocardial deficiency of EPA and DHA and consequent reduced formation of lipoxins, resolvins, protectins and maresins enhance inflammation and MPO activity that leads to myocardial damage and fibrosis and initiation and progression of cardiac arrhythmias. Based on these evidences, I propose that lipoxins, resolvins and protectins function as endogenous anti-arrhythmic molecules and their stable synthetic analogs could be useful in the management of cardiac arrhythmias.

Mediators and receptors in the resolution of inflammation: drug targeting opportunities.

The active resolution of inflammation is recognized as offering new opportunities to generate novel anti-inflammatory agents. The emerging appreciation of the importance of active resolution in regulation of inflammation also creates an imperative to examine developing and existing agents for their potential to influence these pathways. This themed issue of the British Journal of Pharmacology contains papers that discuss the roles of annexin-1, lipoxins and related lipid products of fish oils as well as other mechanisms involved in active resolution and their receptor targets.

Role of lipoxins and resolvins as anti-inflammatory and proresolving mediators in colon cancer.

Recently, lipoxins (LXs) and resolvins (Rvs) have become the topic of intense interest because of expanding views of their action, particularly in chronic disorders where unresolved inflammation is a key factor leading to colon carcinogenesis. Rvs are biosynthesized from omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) via cyclooxygenase-2/lipoxygenase (COX-2/LOX) pathways; Rvs are shown to dramatically reduce dermal inflammation, peritonitis, dendritic cell migration, and interleukin production. This explains that dietary supplementation of omega-3 fatty acids generates potent local endogenous mediators that control inflammation. LXs are biosynthesized from COX-2/LOX pathways. Metabolites of 15-LOX-1 and 2 are anti-tumorigenic; similarly, 15-epi-LXA(4) synthesized during COX-2 acetylation by low doses of aspirin too possesses anti-tumorigenic effects. Acetylating nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin, switches COX-2 from forming PGE(2) (promoting tumorigenesis) to 15-epi-LXA(4) (antitumorigenesis). LXs and Rvs are endogenously generated during the spontaneous resolution phase. These newly identified LXs and Rvs have proved to be potent regulators of both leukocytes and cytokine productions, thereby regulating the events of interest in inflammation and resolution. In light of existing knowledge on interconnected pathways of pro-inflammatory mediators (leukotrienes, chemokines (IL8, SDF-1 alpha, MIP-1 alpha, MCP-1,2 etc), and cytokines (IL3, IL6, IL12, IL-1 beta, GM-CSF, B94, TNF-alpha etc)), the anti-inflammatory properties of pro-resolving mediators in preventing chronic inflammation which leads to carcinogenesis needs further understanding. In this review, we explore the mechanisms that trigger formation of LXs and Rvs, to highlight the relative importance of LXs and Rvs in carcinogenesis in relation to pro-inflammatory mediators.

Anticancer actions of omega-3 fatty acids--current state and future perspectives.

Omega-3 fatty acids (omega3-FA) were shown to attenuate growth and induce apoptosis in a variety of human cancer cell lines derived from colonic, pancreatic, prostate, and breast cancer. In addition, recent findings indicate that omega3-FA act synergistically with chemotherapeutic agents and may also be used to enhance tumour radiosensitivity. The mechanisms underlying the anti-tumour effects of omega3-FA are complex. Incorporation of omega3-FA in biological membranes alters the profile of lipid mediators generated during inflammatory reactions. Furthermore, omega3-FA act as ligands of nuclear peroxisome proliferator-activated receptors that attenuate transcription of NF-kappaB-dependent genes. Thereby, the cyclooxygenase-2/prostaglandin E(2)-dependent production of pro-angiogenic vascular endothelial growth factor and levels of anti-apoptotic bcl-2 and bcl-X(L) are decreased. Eicosanoid-independent pro-apoptotic pathways include enhanced lipid peroxidation, modulation of mitochondrial calcium homeostasis and enhanced production of reactive oxygen species as well as activation of p53. This review article will give a comprehensive overview over the pleiotropic actions of omega3-FA and will discuss the potential of omega3-FA and derivatives like conjugated eicosapentaenoic acid as important nutritional adjuvant therapeutics in the management of various human cancer diseases and the impact of nutritional omega-3 FA on cancer prevention.

Resolvin E1 as a novel agent for the treatment of asthma.

BACKGROUND: Asthma is characterized by airway hyperresponsiveness and chronic airway inflammation. Inflammatory cells, including eosinophils and lymphocytes, infiltrate peribronchial tissue in patients with asthma. Resolvin E1 (RvE1) is an anti-inflammatory lipid mediator derived from the omega-3 fatty acid, eicosapentaenoic acid, and has been shown to be involved in resolving inflammation. Although little is known about the actions of RvE1 in the resolution of inflammation due to asthma, recent studies in a mouse model have shown the possibilities of RvE1 in asthma. OBJECTIVE/METHODS: We review the current understanding of the mechanism of RvE1 action in connection with asthma pathogenesis and treatment. RESULTS/CONCLUSION: Findings provide evidence for the use of RvE1 as a pivotal counter-regulatory signal in allergic inflammation and offer the possibility of novel multi-pronged therapeutic approaches for human asthma.

Controlling the resolution of acute inflammation: a new genus of dual anti-inflammatory and proresolving mediators.

A well-integrated host inflammatory response is essential in maintaining health and fighting disease. It is important to achieve a complete understanding of the cellular and molecular events that govern the resolution of acute inflammation. Because novel lipid-derived mediators, called resolvins and protectins in animal models, control the duration and magnitude of inflammation, the mapping of these resolution circuits may provide new ways of understanding the molecular basis of many inflammatory diseases. This article provides an overview of recent studies on resolvin and protectin biosynthesis and of advances in understanding the actions of these novel anti-inflammatory and proresolving lipid mediators. These new families of lipid-derived mediators were originally isolated from experimental murine models of acute inflammation identified during the natural spontaneous resolution phase. They are biosynthesized from omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) and possess potent anti-inflammatory, proresolving, and antifibrotic actions in vivo. Taken together, these findings suggest that defective resolution mechanisms may underlie the inflammatory phenotypes that are believed to characterize many common human diseases. The new families of endogenous proresolving and anti-inflammatory agonists constitute a new genus of anti-inflammatories.

New endogenous anti-inflammatory and proresolving lipid mediators: implications for rheumatic diseases.

Prostaglandins and leukotrienes are lipid mediators that carry out pivotal roles in host defense and acute inflammation. Failure to completely resolve an acute inflammatory response can lead to chronic inflammation, scarring, and eventual loss of tissue function. Until recently, it was thought that tissue resolution of acute inflammation was a passive event. However, it is now known than lipoxins, which--like prostaglandins and leukotrienes--are also derived from arachidonic acid, are active anti-inflammatory and proresolution mediators, acting in part by reducing neutrophil entry to the inflammation site and stimulating the uptake of apoptotic polymorphonuclear leukocytes by macrophages. Novel families of locally acting and locally generated mediators derived from omega-3 polyunsaturated fatty acids have also been identified as biosynthetically active components in the resolution phase of inflammation. The new families of chemical mediators are termed 'resolvins' and 'protectins' because individual members of each family are stereospecific in controlling the duration and magnitude of inflammation in animal models. Possible deficiencies in the biosynthesis of lipoxins, resolvins, and protectins, and/or their signal transduction, might underlie some aspects of pathogenesis in chronic inflammatory diseases.

New perspectives on aspirin and the endogenous control of acute inflammatory resolution.

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 A2 over 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 aspirin's 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 aspirin's 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.

Novel omega -- 3-derived local mediators in anti-inflammation and resolution.

The integrated inflammatory response of the host is essential in health and disease. Hence, it is important to achieve a more complete understanding of the local cellular and molecular events that govern the formation and actions of local mediators that can serve as endogenous local mediators of resolution. Because these compounds in experimental animal models of inflammation can control the duration and magnitude of inflammation, knowledge of their formation and actions may provide new avenues for appreciating the molecular basis of many inflammatory diseases. The first of these endogenous local counterregulators recognized were the lipoxins, which are trihydroxytetraene-containing mediators generated from arachidonic acid during cell-cell interactions via transcellular biosynthesis. Because this circuit of lipoxin formation appears to be of physiological relevance in resolution, therapeutic modalities targeting this and related systems should allow for the development of novel therapeutic agents (i.e., agonists of the important cellular and physiological responses required for timely resolution). This review offers a general overview of recent advances from studies by the author and colleagues on the biosynthesis and bioactions of the novel anti-inflammatory lipid mediators, resolvins, docosatrienes, and neuroprotectins as well as their endogenous aspirin-triggered epimeric counterparts. These previously unappreciated families of lipid-derived mediators were originally isolated from experimental murine models of acute inflammation captured during the natural spontaneous resolution phase. They possess anti-inflammatory, pro-resolving, and protective properties. Inappropriate resolution mechanism(s) may underlie our current appreciation of the inflammatory phenotype(s) that characterizes many prevalent human diseases where inflammation is now acknowledged to play an important role in the disease process. Moreover, these new pathways give opportunities to appreciate the complex roles of neutrophils in the generation of potent host protective lipid mediators that may be harnessed for the design of novel treatments for a wide range of diseases where inflammation contributes to the pathophysiology of the disorder.