Aspirin-triggered Lipoxin Research Articles

The effect of low-dose aspirin on aspirin triggered lipoxin, interleukin 1 beta, and prostaglandin E2 levels in periapical fluid: a double-blind randomized clinical trial

BackgroundThe role of pro-resolving mediators in inflammation is a new concern in research. The effect of low-dose aspirin on production of a special kind of these mediators named aspirin triggered lipoxin (ATL) has been studied on different tissues. This randomized clinical trial evaluated the effect of low-dose aspirin on ATL and pro-inflammatory mediators’ level in periapical fluid of necrotic teeth with large lesions.MethodsTwenty-four patients with necrotic pulp and periapical lesion were randomly assigned to low-dose aspirin and placebo groups. In the first appointment, canals were shaped up to F3 size and #40 K-file and cleaned with 10 milliliters 2.5% sodium hypochlorite and 17% Ethylenediaminetetraacetic acid. Periapical fluid was sampled by a paper cone. The tooth was temporized without any intracanal medication. Tablets were administered for 7 days, then the teeth were re-opened and the sampling were repeated. Interleukin-1 beta (IL-1β), prostaglandin E2 (PGE2) and ATL were analyzed by enzyme-linked immunosorbent assay. Data were analyzed with paired t-test using SPSS statistical software, version 21 (α = 0.05).ResultsA significant reduction in PGE2 and IL-1β was noted in the aspirin-treated group while an increase in ATL was observed (P < 0.001). There was no significant difference in the mediator scores before and after in the placebo-treated group (P > 0.05).ConclusionLow-dose aspirin can influence the inflammatory process by reducing pro-inflammatory mediators such as PGE2 and IL-1β, as well as increasing the pro-resolving mediators such as ATL.Trial registrationIRCT20191211045702N1.

Modulation of the activation of endothelial nitric oxide synthase and nitrosative stress biomarkers by aspirin triggered lipoxins: A possible mechanism of action of aspirin in the antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by the clinical manifestation of vascular thrombosis (VT) or pregnancy morbidity (PM) and antiphospholipid antibodies (aPL) that can modify the nitric oxide production. Low-dose aspirin is used in the prevention and treatment of diverse alterations of pregnancy. One of the mechanisms of action of aspirin is to induce the production of aspirin-triggered-lipoxins (ATL). The aim of this study was to evaluate the modulatory effect of ATL over the activation of endothelial nitric oxide synthase (eNOS) and nitrosative stress biomarkers induced by aPL. We used polyclonal IgG and sera from women with aPL and PM/VT or VT only, and from women with PM only and positive for non-criteria aPL (SN-OAPS). In these sera, biomarkers of nitrosative stress (nitrites and nitrotyrosine) were measured. The protein expression of nitrotyrosine and the phosphorylation of eNOS (at Ser1177) were estimated in human umbilical vein endothelial cells (HUVECs) stimulated with polyclonal IgG with or without ATL. Women with SN-OAPS showed increased circulating levels of nitrites and nitrotyrosine. Likewise, polyclonal IgG from either SN-OAPS or VT patients stimulated nitrotyrosine expression in HUVECs. ATL decreased the nitrotyrosine expression induced by polyclonal IgG from the SN-OAPS group. ATL also recovered the reduced eNOS phosphorylation at Ser1177 in HUVECs stimulated with polyclonal IgG from women with PM/VT or SN-OAPS. Increased nitrosative stress present in serum of women with SN-OAPS is associated with IgG-mediated impaired endothelial NO synthesis in endothelial cells. ATL prevent these cellular changes.

Aspirin modulates production of pro-inflammatory and pro-resolving mediators in endothelial cells.

Endothelial cells synthesize biochemical signals to coordinate a response to insults, resolve inflammation and restore barrier integrity. Vascular cells release a variety of vasoactive bioactive lipid metabolites during the inflammatory response and produce pro-resolving mediators (e.g., Lipoxin A4, LXA4) in cooperation with leukocytes and platelets to bring a halt to inflammation. Aspirin, used in a variety of cardiovascular and pro-thrombotic disorders (e.g., atherosclerosis, angina, preeclampsia), potently inhibits proinflammatory eicosanoid formation. Moreover, aspirin stimulates the synthesis of pro-resolving lipid mediators (SPM), so-called Aspirin-Triggered Lipoxins (ATL). We demonstrate that cytokines stimulated a time- and dose-dependent increase in PGI2 (6-ketoPGF1α) and PGE2 formation that is blocked by aspirin. Eicosanoid production was caused by cytokine-induced expression of cyclooxygenase-2 (COX-2). We also detected increased production of pro-resolving LXA4 in cytokine-stimulated endothelial cells. The R-enantiomer of LXA4, 15-epi-LXA4, was enhanced by aspirin, but only in the presence of cytokine challenge, indicating dependence on COX-2 expression. In contrast to previous reports, we detected arachidonate 5-lipoxygenase (ALOX5) mRNA expression and its cognate protein (5-lipoxygenase, 5-LOX), suggesting that endothelial cells possess the enzymatic machinery necessary to synthesize both pro-inflammatory and pro-resolving lipid mediators independent of added leukocytes or platelets. Finally, we observed that, endothelial cells produced LTB4 in the absence of leukocytes. These results indicate that endothelial cells produce both pro-inflammatory and pro-resolving lipid mediators in the absence of other cell types and aspirin exerts pleiotropic actions influencing both COX and LOX pathways.

Cell-free fetal DNA impairs trophoblast migration in a TLR9-dependent manner and can be reversed by hydroxychloroquine

Growing evidence suggests a relationship between elevated circulating placental-derived cell-free fetal DNA (cffDNA) and preeclampsia. Hypomethylation of CpG motifs, a hallmark of cffDNA, allows it to activate Toll-like receptor 9 (TLR9). Using an in vitro human first trimester extravillous trophoblast cell model, we sought to determine if trophoblast-derived cffDNA and ODN 2216, a synthetic unmethylated CpG oligodeoxynucleotide, directly impacted spontaneous trophoblast migration. The role of the DNA sensors TLR9, AIM2, and cGAS was assessed using the inhibitor A151. To test whether any effects could be reversed by therapeutic agents, trophoblasts were treated with or without cffDNA or ODN 2216 with or without aspirin (ASA; a known cGAS inhibitor), aspirin-triggered lipoxin (ATL), or hydroxychloroquine (HCQ; a known TLR9 inhibitor). Trophoblast-derived cffDNA and ODN 2216 reduced trophoblast migration without affecting cell viability. Reduced trophoblast migration in response to cffDNA or ODN 2216 was reversed by A151. cffDNA inhibition of trophoblast migration was reversed by HCQ, while ASA or ATL had no effect. In contrast ODN 2216 inhibition of trophoblast migration was reversed by ASA, ATL and HCQ. Our findings suggest that cffDNA can exert a local effect on placental function by impairing trophoblast migration through activation of innate immune DNA sensors. HCQ, a known TLR9 inhibitor, reversed the effects of cffDNA on trophoblast migration. Greater insights into the molecular underpinnings of how cffDNA impacts placentation can aid in our understanding of the pathogenesis of preeclampsia, and in the development of novel therapeutic approaches for preeclampsia therapy.

Cell-free fetal DNA impairs trophoblast migration in a TLR9-dependent manner and is reversed by hydroxychloroquine

Growing evidence suggests a relationship between elevated circulating cell-free fetal DNA (cffDNA) and preeclampsia. Hypomethylation of CpG motifs is a hallmark of cffDNA, allowing it to activate Toll-like receptor 9 (TLR9). Since TLR9 is expressed by the trophoblast, we hypothesize that placental-derived cffDNA accumulates at the maternal-fetal interface and limits trophoblast migration. We investigated this and if available therapeutics would have an impact. A human first trimester extravillous trophoblast cell line (Sw.71) was cultured in serum-free media after which cffDNA was isolated. Trophoblast cells were treated with media, cffDNA (375ng/ml), or as a positive control ODN 2216 (1M), a synthetic TLR9 agonist. For some experiments, cells were pretreated with A151 (5M), an antagonist of the DNA sensors TLR9, AIM2, and cGAS, prior to exposure to cffDNA or ODN 2216. Trophoblast cells were also treated with cffDNA or ODN 2216 together with aspirin (ASA, 10g/ml), aspirin-triggered lipoxin (ATL, 100nM), or hydroxychloroquine (HCQ, 1g/ml). After 48hrs, cell viability and cell migration were measured using the CellTiter assay and a two-chamber colorimetric assay. cffDNA and ODN 2216 significantly reduced trophoblast migration by 36.9 4.3% and 47.2 3.2%, respectively (p< 0.05), without affecting cell viability. Reduced cell migration in response to cffDNA or ODN 2216 was significantly reversed by A151 (p< 0.05). cffDNA inhibition of migration was significantly reversed by HCQ, but not ASA or ATL. ODN 2216 inhibition of migration was reversed by HCQ, ASA and ATL (p< 0.05). Our findings suggest that cffDNA exerts a local effect on placental function by limiting trophoblast migration through activation of DNA sensors. HCQ, which can inhibit TLR9 and cGAS, reverses this, while ASA, which can inhibit cGAS, does not. Thus, cffDNA inhibits trophoblast migration via TLR9. Further research can aid our understanding of the pathogenesis of preeclampsia to improve perinatal outcomes.

Aspirin-triggered lipoxins in high-risk pregnancy: A dose-effect comparison

Aspirin-triggered lipoxins in high-risk pregnancy: A dose-effect comparison

Specialized Proresolving Lipid Meditators Agonistic to Formyl Peptide Receptor Type 2 Attenuate Ischemia-reperfusion Injury in Rat Lung.

Lung ischemia-reperfusion injury (IRI) is a form of acute lung injury characterized by nonspecific alveolar damage and lung edema due to robust inflammation. Little is known about the roles of specialized proresolving lipid mediators (SPMs) in lung IRI. Therefore, we aimed to evaluate the dynamic changes in endogenous SPMs during the initiation and resolution of lung IRI and to determine the effects of SPM supplementation on lung IRI. We used a rat left hilar clamp model with 90 min of ischemia, followed by reperfusion. Dynamic changes in endogenous SPMs were evaluated using liquid chromatography-tandem mass spectrometry. Endogenous SPMs in the left lung showed a decreasing trend after 1 h of reperfusion. Oxygenation improved between 3 and 7 d following reperfusion; however, the level of endogenous SPMs remained low compared with that in the naïve lung. Among SPM receptors, only formyl peptide receptor type 2 (ALX/FPR2) gene expression in the left lung was increased 3 h after reperfusion, and the inflammatory cells were immunohistochemically positive for ALX/FPR2. Administration of aspirin-triggered (AT) resolvin D1 (AT-RvD1) and AT lipoxin A4 (AT-LXA4), which are agonistic to ALX/FPR2, immediately after reperfusion improved lung function, reduced inflammatory cytokine levels, attenuated lung edema, and decreased neutrophil infiltration 3 h after reperfusion. The effects of AT-RvD1 and AT-LXA4 were not observed after pretreatment with the ALX/FPR2 antagonist. The level of intrapulmonary endogenous SPMs decreased during lung IRI process and the administration of AT-RvD1 and AT-LXA4 prevented the exacerbation of lung injury via ALX/FPR2.

NAP1051, a Lipoxin A4 Biomimetic Analogue, Demonstrates Antitumor Activity Against the Tumor Microenvironment.

Resolving tumor-associated inflammation in the tumor microenvironment (TME) may promote antitumor effects. Lipoxin A4 (LXA4) is a short-lived endogenous bioactive lipid with potent anti-inflammatory and pro-resolving properties. Here, a biomimetic of LXA4, NAP1051, was shown to have LXA4-like in vitro properties and antitumor activity in colorectal cancer xenograft models. NAP1051 inhibited neutrophil chemotaxis toward fMLP and dose-dependently promoted dTHP-1 efferocytosis which was equipotent to aspirin-triggered lipoxin A4 (ATLA). In dTHP-1 cells, NAP1051 induced strong phosphorylation on ERK1/2 and AKT similar to formyl peptide receptor 2 (FPR2/ALX) agonists. In two mouse xenograft colorectal cancer models, NAP1051 significantly inhibited tumor growth when given orally at 4.8 to 5 mg/kg/day. Flow cytometric analyses showed that NAP1051 reduced splenic and intratumoral neutrophil and myeloid-derived suppressor cell populations, which correlated to the antitumor effect. In addition, NAP1051 reduced NETosis in the TME while stimulating T-cell recruitment. Overall, these results show that NAP1051 possesses key lipoxin-like properties and has antitumor activity against colorectal cancer via modulation of neutrophils and NETosis in the TME.

Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways.

Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflammation (RoI). The importance of specialized pro-resolving lipid mediators (SPMs) in RoI has been highlighted. Among them, lipoxins (LXA4) and aspirin-triggered lipoxin A4 (AT-LXA4) mediate beneficial responses through the activation of N-formyl peptide receptor-2 (FPR2). We aimed to shed more light on the time-dependent protective and anti-inflammatory impact of the endogenous SPMs, LXA4, and AT-LXA4, and of a new synthetic FPR2 agonist MR-39, in lipopolysaccharide (LPS)-exposed rat microglial cells. Our results showed that LXA4, AT-LXA4, and MR-39 exhibit a protective and pro-resolving potential in LPS-stimulated microglia, even if marked differences were apparent regarding the time dependency and efficacy of inhibiting particular biomarkers. The LXA4 action was found mainly after 3 h of LPS stimulation, and the AT-LXA4 effect was varied in time, while MR-39′s effect was mainly observed after 24 h of stimulation by endotoxin. MR-39 was the only FPR2 ligand that attenuated LPS-evoked changes in the mitochondrial membrane potential and diminished the ROS and NO release. Moreover, the LPS-induced alterations in the microglial phenotype were modulated by LXA4, AT-LXA4, and MR-39. The anti-inflammatory effect of MR-39 on the IL-1β release was mediated through FPR2. All tested ligands inhibited TNF-α production, while AT-LXA4 and MR-39 also diminished IL-6 levels in LPS-stimulated microglia. The favorable action of LXA4 and MR-39 was mediated through the inhibition of ERK1/2 phosphorylation. AT-LXA4 and MR39 diminished the phosphorylation of the transcription factor NF-κB, while AT-LXA4 also affected p38 kinase phosphorylation. Our results suggest that new pro-resolving synthetic mediators can represent an attractive treatment option for the enhancement of RoI, and that FPR2 can provide a perspective as a target in immune-related brain disorders.

30 Viral and bacterial signatures impair trophoblast migration which is reversed by aspirin, aspirin-triggered-lipoxin and hydroxychloroquine

While the etiology of preeclampsia remains elusive, an inflammatory response at the maternal-fetal interface is thought to play a role. Growing evidence suggests a relationship between maternal infection and risk of preeclampsia. Thus, infection may contribute to the pathogenesis by affecting trophoblast function. These cells express Toll-like receptors (TLRs) and Nod-like receptors (NLRs), which mediate infection-induced inflammation. We hypothesize that in addition to inducing inflammation via TLRs and NLRs, infections may limit trophoblast migration leading to a preeclampsia-like phenotype, and this may be reversed by potential therapeutics. A human first trimester trophoblast cell line (Sw.71) was treated with or without bacterial or viral signatures known to activate TLRs and NLRs (Table 1). For some experiments, cells were also treated with the therapeutics aspirin (ASA; 10ug/ml), aspirin-triggered lipoxin (ATL; 100nM), or hydroxychloroquine (HCQ; 1ug/ml). Cell viability was measured using the CellTiter assay. Cell migration was quantified using a two-chamber colorimetric assay. Cell viability was not altered by any infectious triggers with the exception of viral dsRNA which reduced viability by 50.4±4.7% (p<0.05). This was not tested further. Compared to media, viral ssRNA and bacterial CpG ODN significantly reduced trophoblast migration by 48.7±7.2% and 52.5±4.1%, respectively (p<0.05). Bacterial LPS, PGN, flagellin, iE-DAP and MDP did not alter cell migration. Compared to viral ssRNA alone, ASA, ATL and HCQ independently increased trophoblast migration by 1.6±0.3, 2.0±0.3 and 2.0±0.4-fold, respectively (p<0.05). Similarly, compared to CpG ODN alone, ASA, ATL and HCQ independently increased trophoblast migration by 1.6±0.1, 1.5±0.1 and 1.6±0.2-fold, respectively (p<0.05). Our findings suggest that viral ssRNA and bacterial CpG ODN may impair trophoblast migration leading to a preeclampsia-like phenotype. Further research is needed to understand the mechanisms by which ASA, ATL, and HCQ may reverse these effects and improve perinatal outcomes.

The 15-Epilipoxin-A4 Pathway with Prophylactic Aspirin in Preventing Preeclampsia: A Longitudinal Cohort Study.

The benefit of aspirin in preventing preeclampsia is increasingly recognized; however, its mechanism of action remains unclear. Nonobstetric studies have described an anti-inflammatory effect of aspirin through the 15-epilipoxin-A4 pathway (aspirin-triggered lipoxin [ATL]). However, the anti-inflammatory mechanism of aspirin in the prevention of preeclampsia remains unknown. To examine (1) the difference in longitudinal endogenous lipoxin-A4 (En-Lipoxin-A4) concentration in low-risk (LR) and high-risk (HR) pregnancies, and (2) the effect of aspirin on endogenous ATL concentration and the associated effect on cytokine profile of HR women. Plasma from 220 HR women was collected at 12, 16, 20, 24, 28, 32, and 36 weeks of gestation. Adherence to aspirin was biochemically verified. Plasma En-Lipoxin-A4 and ATL concentrations were analyzed using liquid chromatography mass spectrometry, and cytokines, interleukin (IL)-10, tumor necrosis factor-α, interferon-γ, IL-8, and IL-1β, with the high-sensitivity multibead Luminex® assay. HR women have up to 70% lower plasma concentration of En-Lipoxin-A4 (P < 0.001) than LR women. HR women with adequate aspirin adherence (HR-AA) (n = 82) had higher plasma concentration of ATL (P < .001), lower concentration of IL-8 from 16 to 36 weeks of gestation (P < .001), and increased IL-10 concentration from 16 to 28 weeks of gestation (P = .03) compared with high-risk women who were not on aspirin (HR-NA). HR-AA who did not develop preeclampsia had higher plasma En-lipoxin-A4 (P < .001), ATL (P = .02), and IL-10 concentrations (P < .001) with lower IL-8 concentration (P = .004) than HR women who developed preeclampsia. Plasma concentration of En-Lipoxin-A4 is lower in HR women than in LR controls. Adequate adherence with aspirin results in an increase in ATL and IL-10 with reduced IL-8 plasma concentration. This study suggests a potential anti-inflammatory role of aspirin through the ATL pathway with prophylactic aspirin in HR pregnant women.

The Novel Aspirin as Breakthrough Drug for COVID-19: A Narrative Review

Introduction: Aspirin has justifiably been called the first miracle drug. In this article, we highlight the history of Aspirin, a novel mechanism of action, and its use in cardiovascular and other diseases. Also included is a brief statement of emerging new applications. Objective: We highlight principal mechanisms by which Aspirin inhibits acute inflammation and alters platelet-biology; therefore, hypothesized that Aspirin might prove highly beneficial as a novel therapeutic drug for combating severe acute inflammation and thrombosis associated with the cytokine storm in COVID -19 patients. The communiqué also suggests possible strategies for maximizing the gain of Aspirin as a wonder-drug of the future. Discussion: Interestingly, some fascinating studies demonstrated Aspirin's superior benefits with dangerous side effects. Aspirin inhibits COX-1 (cyclooxygenase-1). Its impact on COX-2 is more delicate because it “turns off” COX-2's production of prostaglandins but “switches on” the enzymatic ability to produce novel protective lipid mediators. The established mechanism of action of Aspirin is the inhibition of prostaglandin synthesis. However, further evidence showed that aspirin-elicited nitric oxide exerts anti-inflammatory effects in the microcirculation by inhibiting leukocyte– endothelium interactions. Interestingly, aspirin-triggered lipoxin formation may provide a novel mechanism underlying Aspirin's clinical benefits. Interestingly, Aspirin reduces the risk of a cardiovascular event by about 30 percent. Also, Aspirin has been associated with a reduced risk of colorectal cancer, and possibly a few other digestive tract cancers. Conclusion: The current emerging interest is to conduct further study to provide evidence for Aspirin as the novel therapeutic drug for combating severe acute inflammation and thrombosis associated with the cytokine storm in COVID-19 patients. Besides, the most wanted is The RECOVERY II (Randomized Evaluation of COVID-19 Therapy II) trial to be established as a randomized clinical trial to test the effectiveness of low-dose Aspirin as an anti-inflammatory and antithrombotic treatment in COVID-19 patients.

Antiplatelet Therapy for Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a common and devastating syndrome that contributes to serious morbidities and mortality in critically ill patients. No known pharmacologic therapy is beneficial in the treatment of ARDS, and the only effective management is through a protective lung strategy. Platelets play a crucial role in the pathogenesis of ARDS, and antiplatelet therapy may be a potential medication for ARDS. In this review, we introduce the overall pathogenesis of ARDS, and then focus on platelet-related mechanisms underlying the development of ARDS, including platelet adhesion to the injured vessel wall, platelet-leukocyte-endothelium interactions, platelet-related lipid mediators, and neutrophil extracellular traps. We further summarize antiplatelet therapy, including aspirin, glycoprotein IIb/IIIa receptor antagonists, and P2Y12 inhibitors for ARDS in experimental and clinical studies and a meta-analysis. Novel aspirin-derived agents, aspirin-triggered lipoxin, and aspirin-triggered resolvin D1 are also described here. In this narrative review, we summarize the current knowledge of the role of platelets in the pathogenesis of ARDS, and the potential benefits of antiplatelet therapy for the prevention and treatment of ARDS.

Aspirin-Triggered Lipoxin Protects Lipopolysaccharide-Induced Acute Kidney Injury via the TLR4/MyD88/NF-κB Pathway.

The protective effect of aspirin-triggered lipoxin (ATL) on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and its possible mechanisms were explored. To induce acute renal injury, mice were treated with LPS. Concentration of serum creatinine (SCr) and blood urea nitrogen (BUN) was detected, and inflammatory cytokines and AKI biomarkers were determined by ELISA. The relative protein expression levels of TLR4/myeloid differentiation factor 88 (MyD88)/NF-κB signal pathway was assessed by Western blot. Mice subjected to LPS (4 mg/kg) treatment exhibited AKI demonstrated by markedly increased SCr and BUN levels compared with controls (P <0.01). Treatment with ATL decreased SCr and BUN levels after LPS injection (P <0.01). AKI biomarkers, such as urine NGAL, KIM-1, netrin-1, and L-FABP levels, increased by LPS and were inhibited by ATL (P <0.01). ATL also reduced LPS-induced secretion of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, and IL-8 (P <0.01). Furthermore, mice pretreated with ATL before exposure to LPS showed a reduction in TLR, MyD88, and p65 phosphorylation (P <0.01), which are the key factors of the TLR/MyD88/NF-κB signaling pathway. These results indicated that ATL had protective effects on renal function and showed amelioration of LPS-induced kidney injury. The mechanisms underlying the protective effects of ATL can be considered are related to attenuation of the TLR4/MyD88/NF-κB signaling pathway.

763: Aspirin-triggered Lipoxin A4 is diminished in obese pregnant women at risk for developing preeclampsia

763: Aspirin-triggered Lipoxin A4 is diminished in obese pregnant women at risk for developing preeclampsia

Role of aspirin-triggered lipoxin A4, aspirin, and salicylic acid in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia.

Oxidative stress and inflammation are key events leading to pre-eclampsia, involved in several maternal deaths. Low doses of acetylsalicylic acid (ASA) are used in the prevention and treatment of pre-eclampsia. The synthesis of aspirin-triggered lipoxin (ATL) by cyclooxygenase-2 acetylation is an alternative mechanism of ASA, which could explain the effectiveness of ASA treatments. The aim of this study was to evaluate the role of ASA, salicylates, and ATL in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia. Plasma from 14 women with pre-eclampsia and 17 normotensive pregnant women was probed for inducing oxidative and inflammatory responses on endothelial cells and U937 promonocytes. The role of ATL, ASA, and salicylic acid (SA) on these events was evaluated. Plasma from women with pre-eclampsia induced TBARS and nitrotyrosine production on endothelial and U937 cells. Pre-treatment with both ATL and ASA decreased the TBARS production, while ATL decreased the nitrotyrosine. Pre-eclamptic plasma augmented the translocation of NF-kB on U937 cells, which decreased by a high dose of ASA and SA. Finally, the pre-eclamptic plasma increased the adhesion of leukocytes-PMN and monocytes-to endothelium, and we were able to determine a state of resolution of inflammation, since ATL decreased the PMN adhesion, and conversely, it increased the monocytes adhesion to endothelium. Together, these results suggest that ATL could explain the beneficial actions of ASA and support further research on mechanisms, real efficacy, and rational use of ASA in pre-eclampsia.

Aspirin-triggered lipoxins modulate phosphorylation of endothelial nitric oxide synthase and protein nitration of endothelial cells stimulated with polyclonal IgG from patients with antiphospholipid syndrome

Aspirin-triggered lipoxins modulate phosphorylation of endothelial nitric oxide synthase and protein nitration of endothelial cells stimulated with polyclonal IgG from patients with antiphospholipid syndrome

Recent research progress on the mechanism of lipoxins promoting phagocytosis

Lipoxins (LXs) are endogenous lipid mediators that play a role on anti-inflammatory action, regulating immune response, and repairing damaged cells. It was also known as brake signal of inflammatory response. Researches revealed that LXs and aspirin-triggered lipoxin A4 (ATL) promote the macrophage cells and microglia cell phagocytose cell debris and apoptotic cells by different ways while it regulates anti-inflammation effect and stabilize internal milieu. We reviewed the research progresses in the study of LXs and phagocytosis and summarized their roles as four mechanisms: ① Changing cell polarity and rebuild cellular structure. ② Up-regulation of specific scavenger receptors. ③ Activating M2 phagocytes. ④ Inhibition the apoptosis of phagocytes. Microglia and its phagocytosis function play vital roles in brain diseases, thus studying LXs may provide new therapeutic strategies. Key words: Lipoxin; Inflammatory; Phagocytosis

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity.

Effect of systemic long-term, low-dose aspirin on periodontal status and soluble CD14 in gingival crevicular fluid: a case-control study.

In the present study, we evaluated the effect of systemic long-term, low-dose aspirin on the periodontal status and gingival crevicular fluid (GCF) concentrations of aspirin-triggered lipoxins (ATL) and soluble CD14 (sCD14). The study group consisted of 45 patients who were on long-term, low-dose aspirin therapy, and the control group included patients not on aspirin therapy. Mean bleeding index, plaque index (PI), probing depth (PD), and clinical attachment loss (CAL) were recorded. GCF samples were analyzed for concentrations of ATL, and sCD14 using enzyme-linked immunosorbent assay method. The means of PI, PD, and CAL were higher for the control group compared to the study group. The mean concentration of ATL was significantly higher for the study group (49.13±37.39ng/mL). The mean concentration of sCD14 was higher in the control group (5.75±3.91μg/mL). There was a negative correlation in the study group between concentrations of ATL with PD (r=-0.54) and CAL (r=-0.123). There was a positive correlation between sCD14 and CAL (r=0.047) in the study group. A negative correlation was also observed between concentrations of sCD14 and ATL (r=-0.134) in the study group. The results indicate better periodontal status among long-term aspirin users compared to non-aspirin users.