Retinoic Acid: The Autacoid for All Seasons.

All-trans-retinoic acid (RA), a metabolite of vitamin A (retinol), exerts profuse actions that enable multiple aspects of reproduction, embryonic development and post-natal regulation of energy metabolism, glucoregulatory control, organ function, and of the skeletal, immune, nervous and cardiovascular systems, as well as cell proliferation vs [...].

Resolution-promoting autacoids demonstrate promising cardioprotective effects against heart diseases.

Chronic heart diseases have in common an unresolved inflammatory status. In atherosclerosis, myocarditis, myocardial infarction, or atrial fibrillation, mounting evidence suggests that unresolved inflammation contributes to the chronicity, aggravation, and morbidity of the disease. Following cardiac injury or infection, acute inflammation is a normal and required process to repair damaged tissues or eliminate pathogens and promote restoration of normal functions and structures. However, if acute inflammation is not followed by resolution, a chronic and deleterious inflammatory status may occur, characterized by the persistence of inflammatory biomarkers, promoting aggravation of myocardial pathogenesis, abnormal structural remodeling, development of cardiac fibrosis, and loss of function. Although traditional antiinflammatory strategies, including the use of COX-inhibitors, to inhibit the production of inflammation promotors failed to promote homeostasis, mounting evidence suggests that activation of specific endogenous autacoids may promote resolution and perpetuate cardioprotective effects. The recent discovery of the active mechanism of resolution suggests that proresolving signals and cellular processes may help to terminate inflammation and combat the development of its chronic profile in cardiac diseases. This review discussed (I) the preclinical and clinical evidence of inflammation-resolution in cardiac disorders including atrial fibrillation; (II) how and why many traditional antiinflammatory treatments failed to prevent or cure cardiac inflammation and fibrosis; and (III) whether new therapeutic strategies may interact with the resolution machinery to have cardioprotective effects. RvD D-series resolving, RvE E-series resolving, LXA4 lipoxin A4, MaR1 maresin-1.

Randomized clinical trials of oral vitamin D supplementation in need of a paradigm change: The vitamin D autacoid paradigm.

Epidemiological studies highlight the negative correlation between vitamin D levels and the incidence of many non-skeletal diseases including inflammatory diseases, cancer, and metabolic and neurological disorders. However, most randomized controlled trials (RCTs) with oral vitamin D supplementation give mixed results or are inconclusive. It has been said that "discovery commences with the awareness of anomaly". The "anomaly" between our preclinical and clinical data provides the opportunity to propose an alternative paradigm to the vitamin D endocrine system: the vitamin D autacoid paradigm. In the vitamin D autacoid paradigm, the extra-skeletal effects of vitamin D depend on the tissue reserves of vitamin D metabolites. These vitamin D autacoid systems are inducible oscillatory ecosystems in which 1,25D is produced, acts and is inactivated locally. In the vitamin D autacoid paradigm, attaining adequacy of vitamin D in the systemic circulation is necessary but not sufficient; we must also ensure the repletion of the tissue stores. The co-existence of two different vitamin D systems, endocrine and autacoid, with different functions and regulations leads to "significant shifts in the criteria determining the legitimacy both of problems and of proposed solutions". With respect to our clinical trials of vitamin D supplementation for unconventional effects, the proposed solution is administering and quantifying vitamin D metabolites directly to the target tissue.

Treatment patterns among adults with ADHD receiving long-acting therapy.

OBJECTIVES: To evaluate the treatment patterns among commercially insured adults in the United States with attention-deficit/hyperactivity disorder (ADHD) who received long-acting (LA) combination therapy (CT) or monotherapy for ADHD. STUDY DESIGN: Retrospective observational study. METHODS: Adults with at least 1 ADHD diagnosis and at least 1 LA ADHD medication were identified from the MarketScan claims database (April 1, 2009, to March 31, 2014). The index date was randomly selected among LA medication initiation dates (index treatment). CT was identified if a different ADHD medication was filled within 30 days of the index date and the 2 medications overlapped by 30 days or more; otherwise, the treatment was considered monotherapy. Adherence was measured using proportion of days covered (PDC) during the 1 year post index date and was defined as a PDC of 0.8 or greater. Persistence was defined as time to discontinuation (TTD) (ie, ≥30-day supply gap). Adherence and persistence were compared between CT and monotherapy using multivariable logistic and Cox models, respectively, adjusting for baseline characteristics. RESULTS: Of 225,600 eligible patients, 7.3% received LA CT and 92.7% received LA monotherapy (mean age, 29 vs 31 years, respectively). Patients receiving LA CT had significantly lower adherence than those receiving LA monotherapy (mean PDC, 0.33 vs 0.41; adherence rate, 7% vs 16%, respectively; adjusted odds ratio, 0.38; P <.001). They also demonstrated significantly lower persistence than patients receiving LA monotherapy (median TTD, 59 vs 79 days, respectively; adjusted hazard ratio, 1.32; P <.001). CONCLUSIONS: Among US adults with ADHD treated with LA medications, LA CT was associated with significantly lower adherence and persistence compared with LA monotherapy.

Resolvins and aliamides: lipid autacoids in ophthalmology - what promise do they hold?

Resolvins are a novel class of lipid-derived endogenous molecules (autacoids) with potent immunomodulating properties, which regulate the resolution phase of an active immune response. These modulating factors are locally produced, influencing the function of cells and/or tissues, which are produced on demand and subsequently metabolized in the same cells and/or tissues. This review is focused on certain lipid autacoids with putative relevance for ophthalmology in general and for dry eye more specifically. We also briefly investigate the concept of aliamides and the role of palmitoylethanolamide in ophthalmology, and analyze in more detail the putative role and the preclinical and clinical development of resolvins as emerging treatments for dry eye and related disorders, with a focus on one of the lead resolvin derivatives - RX-10045.

Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids: Implications for idiopathic pain syndromes?

BACKGROUND: Chronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes. RESULTS: Increasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues. CONCLUSIONS: The present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes.

Kinin release from human kininogen by 10 aspartic proteases produced by pathogenic yeast Candida albicans.

BACKGROUND: Candida albicans yeast produces 10 distinct secreted aspartic proteases (Saps), which are some of the most important virulence factors of this pathogenic fungus. One of the suggested roles of Saps is their deregulating effect on various proteolytic cascades that constitute the major homeostatic systems in human hosts, including blood coagulation, fibrinolysis, and kallikrein-kinin systems. This study compared the characteristics of the action of all 10 Saps on human kininogens, which results in generating proinflammatory bradykinin-related peptides (kinins). RESULTS: Recombinant forms of Saps, heterologously overexpressed in Pichia pastoris were applied. Except for Sap7 and Sap10, all Saps effectively cleaved the kininogens, with the highest hydrolytic activity toward the low-molecular-mass form (LK). Sap1-6 and 8 produced a biologically active kinin-Met-Lys-bradykinin-and Sap3 was exceptional in terms of the kinin-releasing yield (>60% LK at pH 5.0 after 24 hours). Des-Arg(1)-bradykinin was released from LK by Sap9 at a comparably high yield, but this peptide was assumed to be biologically inactive because it was unable to interact with cellular B2-type kinin receptors. However, the collaborative actions of Sap9 and Sap1, -2, -4-6, and -8 on LK rerouted kininogen cleavage toward the high-yield release of the biologically active Met-Lys-bradykinin. CONCLUSIONS: Our present results, together with the available data on the expression of individual SAP genes in candidal infection models, suggest a biological potential of Saps to produce kinins at the infection foci. The kinin release during candidiasis can involve predominant and complementary contributions of two different Sap3- and Sap9-dependent mechanisms.

The terms 'autacoid', 'hormone' and 'chalone' and how they have shifted with time.

The increase of knowledge in a particular field (endocrinology) can be understood if one follows how certain key concepts were constructed and transformed over time. To explore such construction and transformation (shifts in meaning), we studied the use of the concepts 'autacoid' and 'chalone' in a period of one century (1916-2016), since the introduction of these concepts by the British professor of physiology Sir Sharpey-Schäfer. We could identify that the use of 'autacoid' shifted from a very broad category encompassing both stimulating and inhibiting hormones, in the period 1916-1960, to a much more specific use of the term for locally produced bioactive molecules, from the 1960s onwards. Histamine was the first compound seen as an 'autacoid', followed by prostaglandins, ATP, ADP and bradykinin, and from 1993 onwards, compounds such as 'palmitoylethanolamide' were also classified as 'autacoids'. For 'chalone', a comparable shift was noticed around the 1960s, when the concept suddenly changed from the category of inhibiting hormones into a substance that is produced within a tissue, inhibiting mitosis of the cells of that tissue. For both concept shifts, we could not find any argument. Around 1980, authors started to relate autacoids to various promising indications in the field of inflammation and immune modulation. The Nobel laureate Rita Levi-Montalcini gave an extra dimension to the concept autacoid in 1993, and introduced a new class of compounds modulating mast cells, the ALIAmides (from Autacoid Local Inflammation Antagonist), of which palmitoylethanolamide was the prototype. Our exploration demonstrates that biomedical concepts can be constructed and defined differently as time goes by, while concept transformations seem to emerge without arguments.

Aging delays resolution of acute inflammation in mice: reprogramming the host response with novel nano-proresolving medicines.

Aging is associated with an overt inflammatory phenotype and physiological decline. Specialized proresolving lipid mediators (SPMs) are endogenous autacoids that actively promote resolution of inflammation. In this study, we investigated resolution of acute inflammation in aging and the roles of SPMs. Using a self-resolving peritonitis and resolution indices coupled with lipid mediator metabololipidomics, we found that aged mice had both delayed resolution and reduced SPMs. The SPM precursor docosahexaenoic acid accelerated resolution via increased SPMs and promoted human monocyte reprogramming. In aged mice, novel nano-proresolving medicines carrying aspirin-triggered resolvins D1 and D3 reduced inflammation by promoting efferocytosis. These findings provide evidence for age-dependent resolution pathways in acute inflammation and novel means to activate resolution.

Combined contribution of endothelial relaxing autacoides in the rat femoral artery response to CPCA: an adenosine A2 receptor agonist.

We examined the contribution of endothelial relaxing factors and potassium channels in actions of CPCA, potent adenosine A(2) receptor agonist, on isolated intact male rat femoral artery (FA). CPCA produced concentration-dependent relaxation of FA, which was notably, but not completely, reduced after endothelial denudation. DPCPX, A(1) receptor antagonist, had no significant effect, while SCH 58261 (A(2A) receptor antagonist) notably reduced CPCA-evoked effect. Pharmacological inhibition of nitric oxide synthase or cyclooxygenase comparably reduced CPCA-evoked action, still in a lesser degree than after denudation. In the presence of buffer with high K(+) (100 mM), CPCA-produced relaxations were almost abolished. TEA (nonselective K(Ca) blocker), glibenclamide (K(ATP) blocker), Ba(++) (K(IR) blocker), or ouabain (Na(+)/K(+)-ATPase inhibitor) did not change CPCA-induced relaxation. Concentration-response curve for CPCA was significantly shifted to the right after the incubation of apamin (SK channel blocker). CPCA produced concentration-dependent relaxation of FA that was partly dependent on endothelial cells. Endothelium-related portion of CPCA-elicited effect was mediated by combined action of endothelial NO, prostacyclin, and EDHF after activation of endothelial A(2A) receptors. Small conductance K(Ca) channels were involved in this action.

Characterization of local vascular effects of the nitric oxide inhibitor NG-monomethyl-L-arginine on dorsal hand veins.

Infusion of NG-monomethyl-L-arginine (L-NMMA; 6.4 µmol/min) into hand veins can cause a 20% increase in vein size in specific subjects. This study explored potential underlying mechanisms in healthy male participants. Ten healthy male participants received in phenylephrine (PE)-preconstricted veins a dose-response curve (DRC) to L-NMMA (0.2-6.4 µmol/min) without and with coinfusion of the endothelium-dependent dilator histamine, a DRC to L-arginine with and without coinfusion of L-NMMA, a DRC to NG-monomethyl-D-arginine (D-NMMA), and a DRC to L-NMMA in prostaglandin F(2α)-(PGF(2α))-preconstricted veins. Participants were classified as L-NMMA responders (R) and nonresponders (NR). Infusion of L-NMMA resulted in a maximum venodilation of 38% ± 11% (R) versus 10% ± 5% (NR; P = .005). In PGF(2α)-preconstricted veins, L-NMMA caused venodilation to 26% ± 34% (NS) in responders. Results suggest that endothelial nitric oxide synthase-mediated formation of nitric oxide (NO) from L-NMMA in doses >3.2 µmol/min and continuous PE-induced α-adrenergic stimulation resulting in release of very small amounts of NO from L-NMMA contribute to the observed L-NMMA-induced increase in vein size. Venous reactivity to L-NMMA resulting in a phenotype as R or NR is most likely genetically predetermined, which requires further study.

Antimicrobial aspects of inflammatory resolution in the mucosa: a role for proresolving mediators.

Mucosal surfaces function as selectively permeable barriers between the host and the outside world. Given their close proximity to microbial Ags, mucosal surfaces have evolved sophisticated mechanisms for maintaining homeostasis and preventing excessive acute inflammatory reactions. The role attributed to epithelial cells was historically limited to serving as a selective barrier; in recent years, numerous findings implicate an active role of the epithelium with proresolving mediators in the maintenance of immunological equilibrium. In this brief review, we highlight new evidence that the epithelium actively contributes to coordination and resolution of inflammation, principally through the generation of anti-inflammatory and proresolution lipid mediators. These autacoids, derived from ω-6 and ω-3 polyunsaturated fatty acids, are implicated in the initiation, progression, and resolution of acute inflammation and display specific, epithelial-directed actions focused on mucosal homeostasis. We also summarize present knowledge of mechanisms for resolution via regulation of epithelial-derived antimicrobial peptides in response to proresolving lipid mediators.

Autacoid 14S,21R-dihydroxy-docosahexaenoic acid counteracts diabetic impairment of macrophage prohealing functions.

Impaired macrophage functions imposed by diabetic complications and the suppressed formation of 14S,21R-dihydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA) in wounds contribute significantly to deficient wound healing in diabetics, but how are macrophage functions and 14S,21R-diHDHA formation associated? We studied 14S,21R-diHDHA generation from macrophages using liquid chromatography/mass spectrometry. The role in macrophage-mediated wound healing functions was determined using a murine splinted excisional wound healing model and in vitro assays. 14S,21R-diHDHA acts as a macrophage-generated autacoid, and its attenuated formation in macrophages of diabetic db/db mice was accompanied by impairment of macrophage prohealing functions. 14S,21R-diHDHA restored db/db macrophage-impaired prohealing functions by promoting wound re-epithelialization, formulation of granulation tissue, and vascularization. Additionally, 12/15-lipoxygenase-deficient macrophages, which are unable to produce 14S,21R-diHDHA, exhibited impaired prohealing functions, which also were restored by 14S,21R-diHDHA treatment. The molecular mechanism for 14S,21R-diHDHA-induced recovery of impaired prohealing functions of db/db macrophages involves enhancing their secretion of vascular endothelial growth factor and platelet-derived growth factor BB, decreasing hyperglycemia-induced generation of reactive oxygen species, and increasing IL-10 expression under inflammatory stimulation. Taken together, these results indicate that deficiency of 14S,21R-diHDHA formation by diabetic macrophages contributes to their impaired prohealing functions. Our findings provide mechanistic insights into wound healing in diabetics and suggest the possibility of using autologous macrophages/monocytes, treated with 14S,21R-diHDHA, or related compounds, to promote diabetes-impaired wound healing.

Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution.

Inflammation when unchecked is associated with many prevalent disorders such as the classic inflammatory diseases arthritis and periodontal disease, as well as the more recent additions that include diabetes and cardiovascular maladies. Hence mechanisms to curtail the inflammatory response and promote catabasis are of immense interest. In recent years, evidence has prompted a paradigm shift whereby the resolution of acute inflammation is a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are a novel genus of SPMs (specialized proresolving mediators) that comprise novel families of mediators including lipoxins, resolvins, protectins and maresins. SPMs have distinct structures and act via specific G-protein seven transmembrane receptors that signal intracellular events on selective cellular targets activating proresolving programmes while countering pro-inflammatory signals. An appreciation of these endogenous pathways and mediators that control timely resolution opened a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. In the present review, we provide an overview of the biosynthesis and actions of resolvin E1, underscoring its protective role in vascular systems and regulating platelet responses. We also give an overview of newly described resolution circuitry whereby resolvins govern miRNAs (microRNAs), and transcription factors that counter-regulate pro-inflammatory chemokines, cytokines and lipid mediators.