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Background: Diabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A4 (LXA4), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought. Thus, we aimed to determine whether LXA4 therapeutic treatment attenuates diabetes-induced cardiac pathology. Methods: Six-week-old male apolipoprotein E-deficient (ApoE−/−) mice were followed for 16 weeks after injection of streptozotocin (STZ, 55 mg/kg/day, i.p. for 5 days) to induce type-1 diabetes (T1DM). Treatment with LXA4 (5 μg/kg, i.p.) or vehicle (0.02% ethanol, i.p.) was administered twice weekly for the final 6 weeks. One week before endpoint, echocardiography was performed within a subset of mice from each group. At the end of the study, mice were euthanized with sodium pentobarbital (100 mg/kg i.p.) and hearts were collected for ex vivo analysis, including histological assessment, gene expression profiling by real-time PCR and protein level measurement by western blot. Results: As expected diabetic mice showed a significant elevation in plasma glycated hemoglobin (HbA1c) and glucose levels, along with reduced body weight. Vehicle-treated diabetic mice exhibited increased cardiac inflammation, macrophage content, and an elevated ratio of M1-like to M2-like macrophage markers. In addition, myocardial fibrosis, cardiomyocytes apoptosis and hypertrophy (at the genetic level) were evident, with echocardiography revealing early signs of left ventricular (LV) diastolic dysfunction. Treatment with LXA4 ameliorated diabetes-induced cardiac inflammation, pro-inflammatory macrophage polarization and cardiac remodeling (especially myocardial fibrosis and cardiomyocytes apoptosis), with ultimate improvement in cardiac function. Of note, this improvement was independent of glucose control. Conclusions: These findings demonstrated that LXA4 treatment attenuated the extent of cardiac inflammation in diabetic hearts, resulting in limited cardiac remodeling and improved LV diastolic function. This supports further exploration of LXA4-based therapy for the management of diabetic heart disease. The recent development of stable LXA4 mimetics holds potential as a novel strategy to treat cardiac dysfunction in diabetes, paving the way for innovative and more effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract Background Diabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A4 (LXA4), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought. Thus, we aimed to determine whether LXA4 therapeutic treatment attenuates diabetes-induced cardiac pathology. Methods Six-week-old male apolipoprotein E-deficient (ApoE−/−) mice were followed for 16 weeks after injection of streptozotocin (STZ, 55 mg/kg/day, i.p. for 5 days) to induce type-1 diabetes (T1DM). Treatment with LXA4 (5 μg/kg, i.p.) or vehicle (0.02% ethanol, i.p.) was administered twice weekly for the final 6 weeks. One week before endpoint, echocardiography was performed within a subset of mice from each group. At the end of the study, mice were euthanized with sodium pentobarbital (100 mg/kg i.p.) and hearts were collected for ex vivo analysis, including histological assessment, gene expression profiling by real-time PCR and protein level measurement by western blot. Results As expected diabetic mice showed a significant elevation in plasma glycated hemoglobin (HbA1c) and glucose levels, along with reduced body weight. Vehicle-treated diabetic mice exhibited increased cardiac inflammation, macrophage content, and an elevated ratio of M1-like to M2-like macrophage markers. In addition, myocardial fibrosis, cardiomyocytes apoptosis and hypertrophy (at the genetic level) were evident, with echocardiography revealing early signs of left ventricular (LV) diastolic dysfunction. Treatment with LXA4 ameliorated diabetes-induced cardiac inflammation, pro-inflammatory macrophage polarization and cardiac remodeling (especially myocardial fibrosis and cardiomyocytes apoptosis), with ultimate improvement in cardiac function. Of note, this improvement was independent of glucose control. Conclusions These findings demonstrated that LXA4 treatment attenuated the extent of cardiac inflammation in diabetic hearts, resulting in limited cardiac remodeling and improved LV diastolic function. This supports further exploration of LXA4-based therapy for the management of diabetic heart disease. The recent development of stable LXA4 mimetics holds potential as a novel strategy to treat cardiac dysfunction in diabetes, paving the way for innovative and more effective therapeutic strategies. Graphical Abstract

Abstract It is hypothesized that COVID-19, post-COVID and post-mRNA COVID-19 (and other related) vaccine manifestations including “long haul syndrome” are due to deficiency of essential fatty acids (EFAs) and dysregulation of their metabolism. This proposal is based on the observation that EFAs and their metabolites can modulate the swift immunostimulatory response of SARS-CoV-2 and similar enveloped viruses, suppress inappropriate cytokine release, possess cytoprotective action, modulate serotonin and bradykinin production and other neurotransmitters, inhibit NF-kB activation, regulate cGAS-STING pathway, modulate gut microbiota, inhibit platelet activation, regulate macrophage and leukocyte function, enhance wound healing and facilitate tissue regeneration and restore homeostasis. This implies that administration of EFAs could be of benefit in the prevention and management of COVID-19 and its associated complications.

Abstract Background Persistent airway inflammation is a central feature of bronchiectasis. Arachidonate 15-lipoxygenase (ALOX-15) controls production of endogenous lipid mediators, including lipoxins that regulate airway inflammation. Mutations at various positions in ALOX-15 gene can influence airway disease development. We investigated association between ALOX-15,c.-292 C > T gene polymorphism and bronchiectasis unrelated to cystic fibrosis in Egyptian children. Also, lipoxin A4 (LXA4) level in bronchoalveolar lavage (BAL) was studied in relation to polymorphism genotypes and disease phenotypes determined by clinical, pulmonary functions, and radiological severity parameters. Methods This was an exploratory study that included 60 participants. Thirty children with non-cystic fibrosis bronchiectasis (NCFB) were compared with 30 age and sex-matched controls. ALOX-15,c.-292 C > T polymorphism was genotyped using TaqMan-based Real-time PCR. LXA4 was measured in BAL using ELISA method. Results There was no significant difference between patients and controls regarding ALOX-15,c.-292 C > T polymorphism genotypes and alleles (OR = 1.75; 95% CI (0.53–5.7), P = 0.35) (OR = 1; 95% CI (0.48-2), p = 1). BAL LXA4 level was significantly lower in patients, median (IQR) of 576.9 (147.6–1510) ng/ml compared to controls, median (IQR) of 1675 (536.8–2542) (p = 0.002). Patients with severe bronchiectasis had a significantly lower LXA4 level (p T polymorphism might be a protective genetic factor against bronchiectasis development and/or progression due to enhanced LXA4 production.

Osteoarthritis (OA) represents a chronic joint disorder, predominantly exhibiting cartilage degeneration, synovial inflammation, and deterioration of joint function. The pathological progression involves critical roles of inflammatory reactions and an over-release of inflammatory cytokines. lipoxin A4 (LXA4), a lipid mediator with pronounced anti-inflammatory characteristics, exhibits intrinsic anti-inflammatory and immunomodulatory effects in the onset of OA. Recent studies have unveiled that physical activity, serving as a non-drug therapeutic strategy for OA, notably modulates LXA4 levels and inflammatory reactions. LXA4 is capable of suppressing NF-kB and p38-MAPK signaling, mitigating inflammation and pain associated with OA. Physical activity activates 12-lipoxygenase (12-LOX) and lipid oxidation pathways, bolsters LXA4 synthesis, and further, diminish levels of inflammatory cytokines by interaction with synovial fibroblasts, macrophages, and neutrophils. The intensity and frequency of exercise also impart an impact in LXA4 levels and the therapeutic efficacy for OA. Moderate to high-intensity exercise notably excels in elevating LXA4 levels and inhibits inflammatory factors. However, high-intensity exercise may exert negative effects on cartilage. At present, the optimal exercise regimen involves 20-30 minutes per session, 2-3 sessions daily, with a 4-hour interval, exhibiting outstanding result in diminishing enzymes related to cartilage breakdown and optimizing cartilage tissue structure. [ABSTRACT FROM AUTHOR]

Lipoxin A（4 LXA4）is a natural pro ⁃catabolic molecule produced by endogenous fatty acids that is known as the“brake signal”of inflammatory factors. It has a powerful anti⁃inflammatory effect，but its metabolism is fast，and LXA4 analogues are relatively more stable and also have certain anti⁃inflammatory effects. The star cell in the fight against inflammation，the macrophage，is a vital component of our natural immunological barrier and plays a crucial role in inflammation reduction，as does LXA4. LXA4 and its analogs are intricately related to macrophages in the anti⁃inflammatory process. The interactions between the two in the inflammatory response are examined in order to generate novel ideas for treating a variety of inflammation⁃related disorders. [ABSTRACT FROM AUTHOR]

Neurogenic inflammation plays a significant role in the pathogenesis of migraines. This study aimed to investigate the serum levels of prostaglandin E2 (PGE2), lipoxin A4 (LXA4), and other inflammatory biomarkers (C-reactive protein, fibrinogen) in migraine patients. In total, 53 migraine patients and 53 healthy controls were evaluated. Blood serum samples were collected during both attack and interictal periods and compared with the control group. In both the attack and interictal periods, PGE2 and LXA4 values were significantly lower in migraine patients compared to the control group (p < 0.001). Additionally, PGE2 values during the attack period were significantly higher than those during the interictal period (p = 0.016). Patients experiencing migraine attacks lasting ≥ 12 h had significantly lower serum PGE2 and LXA4 levels compared to those with attacks lasting < 12 h (p = 0.028 and p = 0.009, respectively). In ROC analysis, cut-off values of 332.7 pg/mL for PGE2 and 27.2 ng/mL for LXA4 were determined with 70–80% sensitivity and specificity. In conclusion, PGE2 and LXA4 levels are significantly lower in migraine patients during both interictal and attack periods. Additionally, the levels of LXA4 and PGE2 decrease more with the prolongation of migraine attack duration. Our findings provide a basis for future treatment planning. [ABSTRACT FROM AUTHOR]

Background: Our previous studies have shown that lipoxin A4 (LXA4) can serve as a potential biomarker for assessing the efficacy of exercise therapy in knee osteoarthritis (KOA), and fibroblast-like synoviocytes (FLSs) may play a crucial role in KOA pain as well as in the progression of the pathology. Objective: By analyzing the GSE29746 dataset and collecting synovial samples from patients with different Kellgren–Lawrence (KL) grades for validation, we focused on exploring the potential effect of LXA4 on ferroptosis in FLSs through the ESR2/LPAR3/Nrf2 axis to alleviate pain and pathological advancement in KOA. Methods: The association between FLSs ferroptosis and chondrocyte matrix degradation was explored by cell co-culture. We overexpressed and knocked down LPAR3 in vitro to explore its potential mechanism in FLSs. A rat model of monosodium iodoacetate (MIA)-induced KOA was constructed and intervened with moderate-intensity treadmill exercise and intraperitoneal injection of PHTPP to investigate the effects of the LXA4 intracellular receptor ESR2 on exercise therapy. Results: ESR2, LPAR3, and GPX4 levels in the synovium decreased with increasing KL grade. After LXA4 intervention in the co-culture system, GPX4, LPAR3, and ESR2 were upregulated in FLSs, collagen II was upregulated in chondrocytes, and MMP3 and ADAM9 were downregulated. LPAR3 overexpression upregulated the expression of GPX4, Nrf2, and SOD1 in FLSs, while downregulating the expression of MMP13 and MMP3; LPAR3 knockdown reversed these changes. Moderate-intensity platform training improved the behavioral manifestations of pain in KOA rats, whereas PHTPP treatment partially reversed the improvement in synovial and cartilage pathologies induced by platform training. Conclusion: LXA4 inhibited FLSs ferroptosis by activating the ESR2/LPAR3/Nrf2 axis, thereby alleviating the pain and pathological progression of KOA. This study brings a new target for the treatment of KOA and also leads to a deeper understanding of the potential mechanisms of exercise therapy for KOA.

In this study, our objective was to explore the association between gestational diabetes mellitus (GDM) and second trimester maternal plasma levels of lipoxin A4 (LXA4), along with proinflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α), and the anti-angiogenic factor vascular endothelial growth factor receptor 1 (VEGFR-1) in pregnant women. The study included a cohort of 30 pregnant women with GDM and a control group of 30 normoglycaemic pregnant women matched for age, body mass index, and gestational age. Plasma samples were collected and analysed by enzyme-linked immunosorbent assay to assess specific biomarkers. The GDM group had significantly lower levels of LXA4 and higher levels of TNF-α and VEGFR-1 compared to the control group (p = 0.038, p = 0.025, and p = 0.002, respectively). A statistically significant decrease in the LXA4/TNF-α ratio was observed in the GDM group (p = 0.004). The results suggest that each unit decrease in the LXA4/TNF-α ratio is associated with a 1.280-fold increase in the risk of GDM. These findings suggest a potential diagnostic role for the LXA4/TNFα ratio as a marker for women with GDM. This work provides new insights into the pathogenesis of GDM and highlights the important interplay between inflammation and metabolic dysregulation.

Feng Hu,1,2,&ast; Zilu Qu,1,2,&ast; Kai Chen,1,2 Ping Zhang,1 Bei Wang,1 Ruili Jiang,1 Yuyue Zuo,1 Ping Xia,1,&ast; Hongxiang Chen3,4,&ast; 1Department of Dermatology, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Hubei Province & Key Laboratory of Skin Infection and Immunity, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, People’s Republic of China; 4Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongxiang Chen, Huazhong University of Science and Technology Union Shenzhen Hospital, No. 89, Taoyuan Road, Nanshan District, Shenzhen, 518052, People’s Republic of China, Tel +86 13871022932, Email hongxiangchen@hotmail.com Ping Xia, Email alicexiaping@gmail.comIntroduction: As a mediator of inflammation resolution, lipoxin A4 (LXA4) mainly plays an anti-inflammatory role and promotes inflammation resolution. LXA4 plays an inhibiting inflammatory role in a variety of diseases, tissues and cells, including keratinocytes. Psoriasis is a chronic inflammatory skin disease mediated by dysregulation of inflammation of immune cells and keratinocytes. However, the expression and role of LXA4 in psoriasis-like mouse models are still unclear.Methods: Imiquimod (IMQ) topical treatment of dorsal skin induces psoriasis-like dermatitis in BALB/c mice, pretreated intraperitoneally with or without LXA4 prior to IMQ application. Severity of dorsal lesions is assessed by using a modified human scoring system and histopathology. The concentration of LXA4 and the expression of ALOX15 (a key gene in LXA4 metabolic synthesis) in lesional skins were detected by ELISA and Western blot. Quantitative PCR and ELISA were conducted to detect the mRNA and secretion levels of inflammatory cytokines. The proportion of IL-17A-producing γδT cells in skin and skin draining cervical lymph nodes and helper (Th) 17 cells in spleens was evaluated by flow cytometry. Western blotting was used to analyze the expressions of p-STAT3 and TRAF6.Results: The concentration of LXA4 and the expression of ALOX15 were decreased in IMQ-induced lesional skin. LXA4 significantly relieved psoriasis-like lesions in IMQ-induced mouse models. Furthermore, LXA4 decreased IMQ-induced systemic inflammation, including reduced the proportion of IL-17A-producing gdT cells in skin and skin draining cervical lymph nodes and Th17 cells in spleens, the secretion and expression of CCL20, IL-17A, IL-1β, and TNF-α in skin and serum. LXA4 markedly inhibited IMQ-induced expression of TRAF6 and p-STAT3.Conclusion: LXA4 significantly ameliorates IMQ-induced psoriasis-like inflammation, and LXA4 can be used as a target for psoriasis treatment.Keywords: lipoxin A4, psoriasiform dermatitis, imiquimod, γδT cells, Th17, inflammation

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To investigate the predictive value of serum lipoxin A4 (LXA4) combined with matrix metalloproteinase-9 (MMP-9) on multiple organ dysfunction syndrome (MODS) in patients with sepsis. 140 patients with sepsis who were treated in The Second Affiliated Hospital of Air Force Medical University of PLA from January 2020 to January 2023 were selected as study subjects. The patients were divided into MODS group (n=41) and non MODS group (n=99) according to whether MODS occurred within 28 days after admission. The levels of serum LXA4 and MMP-9 were detected and compared between two groups. The influencing factors of MODS in patients with sepsis were analyzed by univariate and multivariate Logistic regression models. The predictive value of serum LXA4 and MMP-9 for MODS in patients with sepsis were analyzed by receiver operating characteristic (ROC) curve. Among the 140 patients with sepsis included in this study, 41 patients developed MODS within 28 days of admission, with an incidence of 29.29% (41/140). The serum LXA4 level in MODS group was lower than that in non MODS group, and the serum MMP-9 level was higher than that in non MODS group(P<0.05). The results of univariate analysis showed that: MODS in patients with sepsis was related to complicated hypertension, sepsis course, shock, age, diabetes, bacterial infection, APACHE II score, disease severity, SOFA score, hypocalcemia, PCT (P<0.05). Multivariate Logistic regression analysis showed that, older, higher MMP-9, longer duration of sepsis, lower LXA4, higher APACHE II score, higher PCT, higher SOFA score, shock, diabetes, hypocalcemia, hypertension, critical disease, bacterial infection were risk factors for MODS in patients with sepsis (P<0.05). The area under the curve (AUC) of serum LXA4, MMP-9 alone and combined detection in predicting MODS in patients with sepsis was 0.815, 0.821 and 0.898 respectively, and the efficacy of combined detection was better than that of single detection. The serum LXA4 decrease and MMP-9 increase in MODS patients with sepsis, the combine detection of the two has a good predictive value for sepsis complicate with MODS. Age, shock, sepsis course, hypocalcemia, APACHE II score, disease severity, SOFA score, bacterial infection, diabetes, PCT, LXA4, MMP-9, hypertension are influencing factors of MODS in patients with sepsis. [ABSTRACT FROM AUTHOR]

COVID-19 is caused by SARS-CoV-2 infection. Epithelial and T, NK, and other immunocytes release bioactive lipids especially arachidonic acid (AA) in response to microbial infections to inactivate them and upregulate the immune system. COVID-19 (coronavirus) and other enveloped viruses including severe acute respiratory syndrome (SARS-CoV-1 of 2002-2003) and Middle East respiratory syndrome (MERS; 2012-ongoing) and hepatitis B and C (HBV and HCV) can be inactivated by AA, g-linolenic acid (GLA, dihomo- GLA (DGLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), which are precursors to several eicosanoids. Prostaglandin E1, lipoxin A4, resolvins, protectins and maresins enhance phagocytosis of macrophages and leukocytes to clear debris from the site(s) of infection and injury, enhance microbial clearance and wound healing to restore homeostasis. Bioactive lipids modulate the generation of M1 and M2 macrophages and the activity of other immunocytes. Mesenchymal and adipose tissue-derived stem cells secrete LXA4 and other bioactive lipids to bring about their beneficial actions in COVID-19. Bioactive lipids regulate vasomotor tone, inflammation, thrombosis, immune response, inactivate enveloped viruses, regulate T cell proliferation and secretion of cytokines, stem cell survival, proliferation and differentiation, and leukocyte and macrophage functions, JAK kinase activity and neutrophil extracellular traps and thus, have a critical role in COVID-19. [ABSTRACT FROM AUTHOR]

Background: Lipoxin A4 (LXA4) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO2) arthritis, a model of prosthesis-induced joint inflammation and pain. Methods: Mice were stimulated with TiO2 (3mg) in the knee joint followed by LXA4 (0.1, 1, or 10ng/animal) or vehicle (ethanol 3.2% in saline) administration. Pain-like behavior, inflammation, and dosages were performed to assess the effects of LXA4 in vivo. Results: LXA4 reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA4 reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFkB) activation in recruited macrophages. LXA4 improved antioxidant parameters [reduced glutathione (GSH) and 2,2-azino-bis 3-ethylbenzothiazoline-6- sulfonate (ABTS) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and Nrf2 protein expression], reducing reactive oxygen species (ROS) fluorescent detection induced by TiO2 in synovial fluid leukocytes. We observed an increase of lipoxin receptor (ALX/FPR2) in transient receptor potential cation channel subfamily V member 1 (TRPV1)+ DRG nociceptive neurons upon TiO2 inflammation. LXA4 reduced TiO2-induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFkB, indicating reduction of neuronal activation. LXA4 down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons. Conclusion: LXA4 might target recruited leukocytes and primary afferent nociceptive neurons to exert analgesic and anti-inflammatory activities in a model resembling what is observed in patients with prosthesis inflammation. [ABSTRACT FROM AUTHOR]

Preterm premature rupture of membranes (pPROM) is a common pregnancy disease closely related to inflammation. The formyl peptide receptor 2 (FPR2), a member of the G protein-coupled receptor family involved in defense responses, inflammation, and disturbances in glucose and lipid metabolism, is associated with pregnancy diseases. Lipoxin A4 (LXA4) can activate FPR2 and inhibit the inflammatory signals. Exosomes derived from mesenchymal stem cells are good materials for anti-inflammatory and tissue repair. This study aims to investigate the anti-inflammatory and tissue repair effects of the combined application of exosomes derived from human umbilical cord mesenchymal stem cells and FPR2 agonist LXA4. In this study, LPS was used to establish the inflammation model of pregnant mice and HTR8 cells, and LXA4 and exosome treatment were carried out to observe the fetal membranes' tissue repair. The scanning and transmission electron microscopy of fetal membrane tissue indicated that the structure of pPROM tissue was disordered, and the cell gap was significantly increased. The results of the inflammatory mice model suggested that LPS can cause damage to the fetal membrane structure. LXA4 combined with exosome treatment can inhibit the production of MMP2 and MMP9, and promote neovascularization by inhibiting the p38 MAPK/Nuclear factor kB p65 (NFkB) pathway in the inflammation model of HTR8 cells and pregnant mice, thus helping to control inflammation and tissue repair. [ABSTRACT FROM AUTHOR]

Introduction: Depression is frequent among older adults and is a risk factor for dementia. Identifying molecular links between depression and dementia is necessary to shed light on shared disease mechanisms. Reduced brain‐derived neurotrophic factor (BDNF) and neuroinflammation are implicated in the pathophysiology of depression and dementia. The exercise‐induced hormone, irisin, increases BDNF and improves cognition in animal models of Alzheimer's disease. Lipoxin A4 is a lipid mediator with anti‐inflammatory activity. However, the roles of irisin and lipoxin A4 in depression remain to be determined. Methods: In the present study, blood and CSF were collected from 61 elderly subjects, including individuals with and without cognitive impairment. Screening for symptoms of depression was performed using the 15‐item Geriatric Depression Scale (GDS‐15). Results: CSF irisin and lipoxin A4 were positively correlated and reduced, along with a trend of BDNF reduction, in elderly individuals with depression, similar to previous observations in patients with dementia. Discussion: Our findings provide novel insight into shared molecular signatures connecting depression and dementia. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the anti-inflammatory and anti-angiogenic effects of the bioactive lipid mediator LXA4 on a rat model of severe corneal alkali injury. Methods: To induce a corneal alkali injury in the right eyes of anesthetized Sprague Dawley rats. They were injured with a Φ 4 mm filter paper disc soaked in 1 N NaOH placed on the center of the cornea. After injury, the rats were treated topically with LXA4 (65 ng/20 μL) or vehicle three times a day for 14 days. Corneal opacity, neovascularization (NV), and hyphema were recorded and evaluated in a blind manner. Pro-inflammatory cytokine expression and genes involved in cornel repair were assayed by RNA sequencing and capillary Western blot. Cornea cell infiltration and monocytes isolated from the blood were analyzed by immunofluorescence and by flow cytometry. Results: Topical treatment with LXA4 for two weeks significantly reduced corneal opacity, NV, and hyphema compared to the vehicle treatment. RNA-seq and Western blot results showed that LXA4 decreased the gene and protein expression of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and pro-angiogenic mediators matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGFA). It also induces genes involved in keratinization and ErbB signaling and downregulates immune pathways to stimulate wound healing. Flow cytometry and immunohistochemistry showed significantly less infiltration of neutrophils in the corneas treated with LXA4 compared to vehicle treatment. It also revealed that LXA4 treatment increases the proportion of type 2 macrophages (M2) compared to M1 in blood-isolated monocytes. Conclusions: LXA4 decreases corneal inflammation and NV induced by a strong alkali burn. Its mechanism of action includes inhibition of inflammatory leukocyte infiltration, reduction in cytokine release, suppression of angiogenic factors, and promotion of corneal repair gene expression and macrophage polarization in blood from alkali burn corneas. LXA4 has potential as a therapeutic candidate for severe corneal chemical injuries. [ABSTRACT FROM AUTHOR]

Neurogenic inflammation plays a significant role in the pathogenesis of migraines. This study aimed to investigate the serum levels of prostaglandin E2 (PGE2), lipoxin A4 (LXA4), and other inflammatory biomarkers (C-reactive protein, fibrinogen) in migraine patients. In total, 53 migraine patients and 53 healthy controls were evaluated. Blood serum samples were collected during both attack and interictal periods and compared with the control group. In both the attack and interictal periods, PGE2 and LXA4 values were significantly lower in migraine patients compared to the control group (p < 0.001). Additionally, PGE2 values during the attack period were significantly higher than those during the interictal period (p = 0.016). Patients experiencing migraine attacks lasting ≥ 12 h had significantly lower serum PGE2 and LXA4 levels compared to those with attacks lasting < 12 h (p = 0.028 and p = 0.009, respectively). In ROC analysis, cut-off values of 332.7 pg/mL for PGE2 and 27.2 ng/mL for LXA4 were determined with 70–80% sensitivity and specificity. In conclusion, PGE2 and LXA4 levels are significantly lower in migraine patients during both interictal and attack periods. Additionally, the levels of LXA4 and PGE2 decrease more with the prolongation of migraine attack duration. Our findings provide a basis for future treatment planning.

Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A4 (LXA4), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15+/+ and Alox12/15-/- mice, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA4 significantly lowered transaminase levels only in Alox12/15-/- mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA4 injection attenuated selected parameters of disease progression in Alox12/15-/- mice, its beneficial impact on immunity was also apparent in Alox12/15+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.

Abstract Syntaxin regulates pancreatic β cell mass and participates in insulin secretion by regulating insulin exocytosis. In addition, syntaxin 4 reduces IFNγ and TNF-α signaling via NF-ĸB in islet β-cells that facilitates plasma glucose sensing and appropriate insulin secretion. Arachidonic acid (AA) has potent anti-inflammatory actions and prevents the cytotoxic actions of alloxan and streptozotocin (STZ) against pancreatic β cells and thus, prevents the development of type 1 diabetes mellitus (induced by alloxan and STZ) and by virtue of its anti-inflammatory actions protects against the development of type 2 diabetes mellitus (DM) induced by STZ in experimental animals that are models of type 1 and type 2 DM in humans. AA has been shown to interact with syntaxin and thus, potentiate exocytosis. AA enhances cell membrane fluidity, increases the expression of GLUT and insulin receptors, and brings about its anti-inflammatory actions at least in part by enhancing the formation of its metabolite lipoxin A4 (LXA4). Prostaglandin E2 (PGE2), the pro-inflammatory metabolite of AA, activates ventromedial hypothalamus (VMH) neurons of the hypothalamus and inhibits insulin secretion leading to reduced glucose tolerance and decreases insulin sensitivity in the skeletal muscle and liver. This adverse action of PGE2 on insulin release and action can be attributed to its (PGE2) pro-inflammatory action and inhibitory action on vagal tone (vagus nerve and its principal neurotransmitter acetylcholine has potent anti-inflammatory actions). High fat diet fed animals have hypothalamic inflammation due to chronic elevation of PGE2. Patients with type 2 DM show low plasma concentrations of AA and LXA4 and elevated levels of PGE2. Administration of AA enhances LXA4 formation without altering or reducing PGE2 levels and thus, tilts the balance more towards anti-inflammatory events. These results suggest that administration of AA is useful in the prevention and management of DM by enhancing the action of syntaxin, increasing cell membrane fluidity, and reducing VMH inflammation. Docosahexaenoic acid (DHA) has actions like AA: it increases cell membrane fluidity; has anti-inflammatory actions by enhancing the formation of its anti-inflammatory metabolites resolvins, protectins and maresins; interacts with syntaxin and enhance exocytosis in general and of insulin. But the DHA content of cell membrane is lower compared to AA and its content in brain is significant. Hence, it is likely DHA is important in neurotransmitters secretion and regulating hypothalamic inflammation. It is likely that a combination of AA and DHA can prevent DM.

BackgroundLipoxin A4 (LXA4) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO2) arthritis, a model of prosthesis-induced joint inflammation and pain.MethodsMice were stimulated with TiO2 (3mg) in the knee joint followed by LXA4 (0.1, 1, or 10ng/animal) or vehicle (ethanol 3.2% in saline) administration. Pain-like behavior, inflammation, and dosages were performed to assess the effects of LXA4in vivo.ResultsLXA4 reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA4 reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFκB) activation in recruited macrophages. LXA4 improved antioxidant parameters [reduced glutathione (GSH) and 2,2-azino-bis 3-ethylbenzothiazoline-6-sulfonate (ABTS) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and Nrf2 protein expression], reducing reactive oxygen species (ROS) fluorescent detection induced by TiO2 in synovial fluid leukocytes. We observed an increase of lipoxin receptor (ALX/FPR2) in transient receptor potential cation channel subfamily V member 1 (TRPV1)+ DRG nociceptive neurons upon TiO2 inflammation. LXA4 reduced TiO2‐induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFκB, indicating reduction of neuronal activation. LXA4 down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons.ConclusionLXA4 might target recruited leukocytes and primary afferent nociceptive neurons to exert analgesic and anti-inflammatory activities in a model resembling what is observed in patients with prosthesis inflammation.

Particulate matter in the air exacerbates airway inflammation (AI) in asthma; moreover, prenatal exposure to concentrated urban air particles (CAPs) and diesel exhaust particles (DEPs) predisposes the offspring to asthma and worsens the resolution of AI in response to allergens. We previously tested the hypothesis that such exposure impairs the pathways of specialized proresolving mediators that are critical for resolution and found declined Lipoxin A4 (LxA4) and Resolvin E2 (RvE2) levels in the "at-risk" pups of exposed mothers. Here, we hypothesized that supplementation with synthetic LxA4 or RvE2 via the airway can ameliorate AI after allergen exposure, which has not been tested in models with environmental toxicant triggers. BALB/c newborns with an asthma predisposition resultant from prenatal exposure to CAPs and DEPs were treated once daily for 3 days with 750 ng/mouse of LxA4 or 300 ng/mouse of RvE2 through intranasal instillation, and they were tested with the intentionally low-dose ovalbumin protocol that elicits asthma in the offspring of particle-exposed mothers but not control mothers, mimicking the enigmatic maternal transmission of asthma seen in humans. LxA4 and RvE2 ameliorated the asthma phenotype and improved AI resolution, which was seen as declining airway eosinophilia, lung tissue infiltration, and proallergic cytokine levels. [ABSTRACT FROM AUTHOR]

Background: Endometriosis is a benign gynecological disease with the feature of estrogen dependence and inflammation. The function of autophagy and the correlation with inflammation were not yet revealed. Methods: Autophagosomes were detected by transmission electron microscopy. Gene Expression Omnibus (GEO) database was referred to analyze the expression of autophagy‐related genes. Quantification of mRNA and protein expression was examined by qRT‐PCR and Western Blot. Immunohistochemistry was performed to explore the expression of proteins in tissues. The mouse model of endometriosis was performed to analyze the autophagic activity and effect of LXA4. Results: The expression of autophagy‐related genes in endometriotic lesions were unusually changed. The number of autophagosomes and LC3B‐II expression was diminished, and p62 was increased in ectopic lesions from both patients and mice. Interleukin 1β (IL1β) attenuated the expression of LC3B and promoted the level p62. The autophagy activator MG‐132 upregulated the expression of LC3B and reduced IL1β, IL6, and p62. LXA4 reversed the inhibitory effect of IL1β on the expression of LC3B and p62, and blocking the receptor of LXA4 AhR (aryl hydrocarbon receptor) resulted in the incapacitation of LXA4 to influence the effect of IL1β. LXA4 depressed the phosphorylation of AKT and mTOR to against IL1β, and blocking AhR negatively regulated the effect of LXA4 on AKT/mTOR pathway. LXA4 reduced the ectopic lesions and the expression of IL1β and p62, but enhanced LC3B‐II in endometriotic mouse models. Conclusion: In endometriosis, increased inflammation of ectopic lesions prominently depresses autophagy. LXA4 could regulate autophagy by suppressing inflammatory response through AhR/AKT/mTOR pathway. [ABSTRACT FROM AUTHOR]

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Prolonged dexamethasone (DEX) administration causes skeletal muscle atrophy through induction of both oxidative stress and mitochondrial dysfunction. Lipoxin A4 (LXA4) is a recognized antioxidant but its effect against DEX-induced muscle atrophy has not been studied yet. This study aimed to assess the potential ameliorating effect of LXA4 on DEX-induced muscle atrophy and investigate the possible involvement of the mitochondrial dynamics pathway and the redox state in this effect. Forty male rats were divided into four groups; normal control, LXA4-treated, DEX-treated, and LXA4 plus DEX-treated. At the end of the experiment, LXA4 counteracted the effect of DEX on different parameters including muscle weight, muscle strength, serum creatine kinase activity, malondialdehyde and protein carbonyl contents, Na/K-ATPase and citrate synthase activities, mitochondrial transmembrane potential, mitochondrial transcription factor (TFAM), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2). These findings signify the promising therapeutic effect of LXA4 against DEX-induced skeletal muscle atrophy and indicate the possible involvement of LXA4-induced mitochondrial activation in addition to its well-known antioxidant effects. [ABSTRACT FROM AUTHOR]

Background: Several cellular and animal studies have suggested that lipoxin A4 (LXA4) has a protective effect on type 2 diabetes mellitus (T2DM) development. However, little is known about whether LXA4 influences T2DM development at the population level. Methods: We included 2755 non-diabetic participants from a cohort study in China who were followed for about seven years. Cox proportional hazards modelwas used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association between LXA4 and incident T2DM. Mediation models were used to examine how serum lipids as mediators impact the association between LXA4 and T2DM. Results: In total, 172 newly diagnosed T2DM cases were identified. Multivariateadjusted HR for T2DM in the fourth compared with the first quartile of LXA4 was 0.62 (95% CI: 0.40-0.96). When used the optimal cutoff value determined by the receiver operating characteristic curve, the results showed participants with LXA4 > 2.84 ng/mL had a decreased T2DM risk compared to those with LXA4 ≤ 2.84 ng/mL (HR: 0.63, 95% CI: 0.45-0.89). The effect of LXA4 on incident T2DM was significantly modified by gender (P-interaction = 0.024) and family history of diabetes (P-interaction = 0.025). Additionally, the association between LXA4 and incident T2DM was partially suppressed by the TyG and TG/HDL-c ratio, with a suppression proportion of 22.2% and 16.0%, respectively. Conclusions: Higher LXA4 levels are significantly associated with a lower risk of T2DM development. The present findings would be helpful in understanding the effect of LXA4 on T2DM development at the population level. [ABSTRACT FROM AUTHOR]

Heme oxygenase-1 (HO-1) is a protective protein in oxidative stress response. LXA4 is an "inflammatory braking signal" that is widely studied at present. The purpose of this study was to elucidate that LXA4 can protect cells by inducing HO-1 in human pulmonary microvascular endothelial cells (HPMECs) as in vitro model to explain acute lung injury after severe acute pancreatitis. This study was performed in two parts: (1) To investigate the mechanisms of lipoxin A4-induced HO-1 expression in vitro , the study subjects were divided into four groups: a control group, LXA4 group (50 ng/mL LXA4), inhibitor group (50 ng/mL LXA4 + 20 μM LY294002 or 50 ng/mL LXA4 + 2 nmol/mL Bis II), and agonist group (50 ng/mL insulin-like growth factor 1, PMA). Western blotting was used to detect the expression of p-Akt, Akt, protein kinase C (PKC), p-Nrf2, Nrf2, and Keap1, and the location of Nrf2 was detected using immunofluorescence. The activation of antioxidant responsive element induced by Nrf2 was detected using Electrophoretic Mobility Shift Assay and (2) to investigate the cytoprotection of HO-1 induced by LXA4 in vitro , the subjects were divided into four groups: a control group, tumor necrosis factor α (TNF-α) group (50 ng/mL), LXA4 group (50 ng/mL TNF-α + 50 ng/mL LXA4), and Zinc protoporphyrin IX group (pretreated with 0.5 μM Zinc protoporphyrin IXfor 12 h, followed by 50 ng/mL TNF-α + 50 ng/mL LXA4). BCECF/AM-labeled THP-1 cells were used to analyze the adhesion of HPMECs, and a mitochondrial membrane potential assay kit with JC-1 was used to analyze the apoptosis of HPMECs. In part one, (1) LXA4 upregulated the expression of HO-1 in a dose-dependent manner and (2) LXA4 activated the PI3K/Akt and PKC pathways and modulated the phosphorylation and subsequent depolymerization of Nrf2 from Keap1, promoting the translocation of Nrf2 to the nucleus. In part two, (1) LXA4 reversed the changes in mitochondrial membrane potential to alleviate apoptosis in HPMECs and (2) LXA4 attenuated the adhesion of HPMECs induced by TNF-α. LXA4 can activate the PI3K/Akt and PKC pathways and induce the phosphorylation of Nrf2, resulting in the upregulation of HO-1. In addition, LXA4 alleviates adhesion and protects mitochondrial function by upregulating the expression of HO-1, which exerts cytoprotection in severe acute pancreatitis–induced lung injury. [ABSTRACT FROM AUTHOR]

Background: Lipoxin A4 (LXA4) is a specialized pro-resolving mediator involved in the resolution phase of inflammation that is crucial for the return of tissues to homeostasis, healing, and regenerative processes. LXA4 can modify the microenvironment via its receptor, formyl peptide receptor 2 (FPR2) and thus modulate the inflammatory response. However, the effect of exogeneous LXA4 application on polarized macrophages remains unstudied. The objective of this study was to assess the effect of LXA4 on macrophage activity and on the phenotype modulation of polarized M1 and M2 macrophages derived from THP-1 monocytes. Methods and results: Once differentiated, human macrophages were incubated with interleukin 4 (IL-4) and IL-13 to obtain M2-polarized macrophages or with interferon gamma and lipopolysaccharide for classical macrophage activation. The mRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1-derived macrophages. LXA4 (0–100 nM) did not affect the viability of M1 and M2 macrophages or the phagocytic activity of these cells. Gene expression of FPR2, referred as a receptor for the LXA4, was higher in M1 compared with M2, and was not modified by the LXA4 at the doses used. Moreover, LXA4 exhibited anti-inflammatory properties illustrated by the decreasing in the gene expression of pro-inflammatory cytokines (IL-6, tumor necrosis factor alpha, IL-1β) in M1 and by the increase in the expression of anti-inflammatory cytokines (IL-10) in M2 macrophages. Conclusions: These results provide new insights regarding the potential of LXA4 to regulate the polarization state of macrophages. [ABSTRACT FROM AUTHOR]

We discuss the fascinating pharmacology of formylpeptide receptor 2 (FPR2; often referred to as FPR2/ALX since it binds lipoxin A4 ). Initially identified as a low-affinity 'relative' of FPR1, FPR2 presents complex and diverse biology. For instance, it is activated by several classes of agonists (from peptides to proteins and lipid mediators) and displays diverse expression patterns on myeloid cells as well as epithelial cells and endothelial cells, to name a few. Over the last decade, the pharmacology of FPR2 has progressed from being considered a weak chemotactic receptor to a master-regulator of the resolution of inflammation, the second phase of the acute inflammatory response. We propose that exploitation of the biology of FPR2 offers innovative ways to rectify chronic inflammatory states and represents a viable avenue to develop novel therapies. Recent elucidation of FPR2 structure will facilitate development of the anti-inflammatory and pro-resolving drugs of next decade. [ABSTRACT FROM AUTHOR]

Background: A growing body of research suggests that oxidative stress and neuroinflammation are early pathogenic features of neurodegenerative disorders. In recent years, the vitagene system has emerged as a potential target, as it has been shown to have a high neuroprotective power. Therefore, the discovery of molecules capable of activating this system may represent a new therapeutic target to limit the deleterious consequences induced by oxidative stress and neuroinflammation, such as neurodegeneration. Lipoxins are derived from arachidonic acid, and their role in the resolution of systemic inflammation is well established; however, they have become increasingly involved in the regulation of neuroinflammatory and neurodegenerative processes. Our study aimed at activating the NF-E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) redox system and increasing lipoxin A4 for the modulation of antioxidant stress and neuroinflammation through the action of two fungi in a rotenone-induced Parkinson's model. Methods: During the experiment, mice received Hericium erinaceus, Coriolus versicolor or a combination of the two (200 mg/kg, orally) concomitantly with rotenone (5 mg/kg, orally) for 28 days. Results: The results obtained highlighted the ability of these two fungi and, in particular, their ability through their association to act on neuroinflammation through the nuclear factor-kB pathway and on oxidative stress through the Nrf2 pathway. This prevented dopaminergic neurons from undergoing apoptosis and prevented the alteration of typical Parkinson's disease (PD) markers and α-synuclein accumulation. The action of Hericium erinaceus and Coriolus versicolor was also able to limit the motor and non-motor alterations characteristic of PD. Conclusions: Since these two mushrooms are subject to fewer regulations than traditional drugs, they could represent a promising nutraceutical choice for preventing PD. [ABSTRACT FROM AUTHOR]

Syntaxin regulates pancreatic β cell mass and participates in insulin secretion by regulating insulin exocytosis. In addition, syntaxin 4 reduces IFNγ and TNF-α signaling via NF-ĸB in islet β-cells that facilitates plasma glucose sensing and appropriate insulin secretion. Arachidonic acid (AA) has potent anti-inflammatory actions and prevents the cytotoxic actions of alloxan and streptozotocin (STZ) against pancreatic β cells and thus, prevents the development of type 1 diabetes mellitus (induced by alloxan and STZ) and by virtue of its anti-inflammatory actions protects against the development of type 2 diabetes mellitus (DM) induced by STZ in experimental animals that are models of type 1 and type 2 DM in humans. AA has been shown to interact with syntaxin and thus, potentiate exocytosis. AA enhances cell membrane fluidity, increases the expression of GLUT and insulin receptors, and brings about its anti-inflammatory actions at least in part by enhancing the formation of its metabolite lipoxin A4 (LXA4). Prostaglandin E2 (PGE2), the pro-inflammatory metabolite of AA, activates ventromedial hypothalamus (VMH) neurons of the hypothalamus and inhibits insulin secretion leading to reduced glucose tolerance and decreases insulin sensitivity in the skeletal muscle and liver. This adverse action of PGE2 on insulin release and action can be attributed to its (PGE2) pro-inflammatory action and inhibitory action on vagal tone (vagus nerve and its principal neurotransmitter acetylcholine has potent anti-inflammatory actions). High fat diet fed animals have hypothalamic inflammation due to chronic elevation of PGE2. Patients with type 2 DM show low plasma concentrations of AA and LXA4 and elevated levels of PGE2. Administration of AA enhances LXA4 formation without altering or reducing PGE2 levels and thus, tilts the balance more towards anti-inflammatory events. These results suggest that administration of AA is useful in the prevention and management of DM by enhancing the action of syntaxin, increasing cell membrane fluidity, and reducing VMH inflammation. Docosahexaenoic acid (DHA) has actions like AA: it increases cell membrane fluidity; has anti-inflammatory actions by enhancing the formation of its anti-inflammatory metabolites resolvins, protectins and maresins; interacts with syntaxin and enhance exocytosis in general and of insulin. But the DHA content of cell membrane is lower compared to AA and its content in brain is significant. Hence, it is likely DHA is important in neurotransmitters secretion and regulating hypothalamic inflammation. It is likely that a combination of AA and DHA can prevent DM. [ABSTRACT FROM AUTHOR]

Background: Rhinitis is a prevalent chronic inflammatory illness of the nasal mucosa. Arachidonic acid-derived lipoxin A4 (LXA4) has long been recognized to exert crucial antiinflammatory and pro-resolving effects on inflammatory responses through a specific receptor named LXA4 receptor/formyl peptide receptor-2 (ALX/FPR2). This study aimed to determine the serum level of LXA4 and the relative mRNA expression level of FPR2 in peripheral blood cells of patients with rhinitis (allergic and nonallergic) compared to healthy individuals. Materials And Methods: The study groups consisted of 37 patients with Allergic Rhinitis (AR), 16 patients with Nonallergic Rhinitis (NAR), and 20 sex- and age-matched healthy individuals. The measurement of LXA4 serum level was performed by the Enzyme-Linked Immunosorbent Assay (ELISA) technique, and the analysis of FPR2 mRNA expression level was performed by quantitative real-time PCR method. Results: The serum concentrations of LXA4 decreased in AR and NAR patients compared to healthy controls; however, this difference was not statistically significant (P>0.05). Besides, the mRNA expression level of FPR2 in peripheral blood cells of patients with nonallergic rhinitis was significantly lower than that in allergic rhinitis (P

Ferroptosis is an iron‐dependent programmed cell death, which participates in the pathogenesis of spinal cord injury (SCI). Our previous study has revealed that Lipoxin A4 (LXA4) exerts a protective role in SCI. Here, we investigated whether LXA4 can protect SCI through inhibiting neuronal ferroptosis. We treated primary spinal cord neurons with Erastin (ferroptosis activator) to induce ferroptosis. Erastin treatment reduced cell viability and enhanced cell death of primary spinal cord neurons, which was rescued by ferrostatin‐1 (ferroptosis inhibitor). Moreover, Erastin repressed glutathione peroxidase 4 (GPX4) expression and the levels of glutathione and cysteine in primary spinal cord neurons. Erastin also enhanced the expression of ferroptosis biomarkers (PTGS2 and ACSL4) and the levels of reactive oxygen species (ROS) in primary spinal cord neurons. The influence conferred by Erastin was effectively abolished by LXA4 treatment. Furthermore, LXA4 enhanced the protein expression of p‐AKT, nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) and haem‐oxygenase‐1 (HO‐1) in primary spinal cord neurons. LXA4‐mediated inhibition of ferroptosis of primary spinal cord neurons was prohibited by LY294002 (AKT inhibitor), brusatol (Nrf2 inhibitor) or zinc protoporphyrin (HO‐1 inhibitor). In conclusion, this work demonstrated that LXA4 exerted a neuroprotective effect in Erastin‐induced ferroptosis of primary spinal cord neurons by activating the Akt/Nrf2/HO‐1 signaling pathway. Thus, this work provides novel insights into the mechanisms of action of LXA4 in ferroptosis of primary spinal cord neurons and indicates that LXA4 may be a potential therapeutic agent for SCI.

Purpose: To investigate the anti-inflammatory and anti-angiogenic effects of the bioactive lipid mediator LXA4 on a rat model of severe corneal alkali injury. Methods: To induce a corneal alkali injury in the right eyes of anesthetized Sprague Dawley rats. They were injured with a Φ 4 mm filter paper disc soaked in 1 N NaOH placed on the center of the cornea. After injury, the rats were treated topically with LXA4 (65 ng/20 μL) or vehicle three times a day for 14 days. Corneal opacity, neovascularization (NV), and hyphema were recorded and evaluated in a blind manner. Pro-inflammatory cytokine expression and genes involved in cornel repair were assayed by RNA sequencing and capillary Western blot. Cornea cell infiltration and monocytes isolated from the blood were analyzed by immunofluorescence and by flow cytometry. Results: Topical treatment with LXA4 for two weeks significantly reduced corneal opacity, NV, and hyphema compared to the vehicle treatment. RNA-seq and Western blot results showed that LXA4 decreased the gene and protein expression of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and pro-angiogenic mediators matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGFA). It also induces genes involved in keratinization and ErbB signaling and downregulates immune pathways to stimulate wound healing. Flow cytometry and immunohistochemistry showed significantly less infiltration of neutrophils in the corneas treated with LXA4 compared to vehicle treatment. It also revealed that LXA4 treatment increases the proportion of type 2 macrophages (M2) compared to M1 in blood-isolated monocytes. Conclusions: LXA4 decreases corneal inflammation and NV induced by a strong alkali burn. Its mechanism of action includes inhibition of inflammatory leukocyte infiltration, reduction in cytokine release, suppression of angiogenic factors, and promotion of corneal repair gene expression and macrophage polarization in blood from alkali burn corneas. LXA4 has potential as a therapeutic candidate for severe corneal chemical injuries.

Radiation is pro-inflammatory in nature in view of its ability to induce the generation of reactive oxygen species (ROS), cytokines, chemokines, and growth factors with associated inflammatory cells. Cells are efficient in repairing radiation-induced DNA damage; however, exactly how this happens is not clear. In the present study, GLA reduced DNA damage (as evidenced by micronuclei formation) and enhanced metabolic viability, which led to an increase in the number of surviving RAW 264.7 cells in vitro by reducing ROS generation, and restoring the activities of desaturases, COX-1, COX-2, and 5-LOX enzymes, TNF-α/TGF-β, NF-kB/IkB, and Bcl-2/Bax ratios, and iNOS, AIM-2, and caspases 1 and 3, to near normal. These in vitro beneficial actions were confirmed by in vivo studies, which revealed that the survival of female C57BL/6J mice exposed to lethal radiation (survival~20%) is significantly enhanced (to ~80%) by GLA treatment by restoring altered levels of duodenal HMGB1, IL-6, TNF-α, and IL-10 concentrations, as well as the expression of NF-kB, IkB, Bcl-2, Bax, delta-6-desaturase, COX-2, and 5-LOX genes, and pro- and anti-oxidant enzymes (SOD, catalase, glutathione), to near normal. These in vitro and in vivo studies suggest that GLA protects cells/tissues from lethal doses of radiation by producing appropriate changes in inflammation and its resolution in a timely fashion. [ABSTRACT FROM AUTHOR]

Hong-Xia Mei, Yang Ye, Hao-Ran Xu, Shu-Yang Xiang, Qian Yang, Hong-Yu Ma, Sheng-Wei Jin, Qian Wang Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of ChinaCorrespondence: Sheng-Wei Jin; Qian WangDepartment of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou, Zhejiang Province, 325027, People’s Republic of ChinaTel +86-577-88002806Fax +86-577-88832693Email jinshengwei69@163.com; wqian84@163.comIntroduction: Alveolar macrophages that regulate the inflammatory response in lungs are the main target cell for the treatment of inflammatory pulmonary pathologies, such as acute respiratory distress syndrome (ARDS). Yolk sac derived alveolar resident macrophages play an important role in the pulmonary inflammatory response. With regards to anti-inflammatory actions, lipoxin A4 (LXA4) has been identified as an inflammatory “braking signal”.Methods: In vivo, LXA4 (0.1 μg/mouse) was injected intraperitoneally after intratracheal (1 mg/kg) lipopolysaccharide (LPS) administration; flow cytometry was used to measure peripheral blood monocyte derived recruited macrophage and neutrophil numbers; resident alveolar macrophage was depleted by liposome clodronate; CXCL2, CCL2, MMP9 level was detected by RT-PCR and ELISA. In vitro, sorted resident macrophages (1× 106) were cultured with LPS (1 μg/mL) and LXA4 (100 nmol/mL) with or without BOC-2 (10 μM) for 24 h to gain a better understanding of the mechanisms of LXA4.Results: LXA4 inhibited tumor necrosis factor-a (TNF-a) and interleukin-1β (IL-1β) production induced by LPS. LXA4 also mediated LPS-induced macrophage recruitment and showed that this was dependent on CCL2 secretion and release by resident macrophages. LXA4 protects lung tissue by inhibiting neutrophil recruitment, partly through the CXCL2/MMP-9 signaling pathway. CXCL2 and MMP-9 are mainly expressed by resident macrophages and neutrophils, respectively. Finally, LXA4’s beneficial effects were abrogated by BOC-2, an LXA4 receptor inhibitor.Conclusion: These results suggest that LXA4 may be a promising therapy for preventing and treating ARDS.Keywords: resident macrophage, recruited macrophage, neutrophil, lipoxin A4, lipopolysaccharide

COVID-19 is caused by SARS-CoV-2 infection. Epithelial and T, NK, and other immunocytes release bioactive lipids especially arachidonic acid (AA) in response to microbial infections to inactivate them and upregulate the immune system. COVID-19 (coronavirus) and other enveloped viruses including severe acute respiratory syndrome (SARS-CoV-1 of 2002-2003) and Middle East respiratory syndrome (MERS; 2012-ongoing) and hepatitis B and C (HBV and HCV) can be inactivated by AA, g-linolenic acid (GLA, dihomo-GLA (DGLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), which are precursors to several eicosanoids. Prostaglandin E1, lipoxin A4, resolvins, protectins and maresins enhance phagocytosis of macrophages and leukocytes to clear debris from the site(s) of infection and injury, enhance microbial clearance and wound healing to restore homeostasis. Bioactive lipids modulate the generation of M1 and M2 macrophages and the activity of other immunocytes. Mesenchymal and adipose tissue-derived stem cells secrete LXA4 and other bioactive lipids to bring about their beneficial actions in COVID-19. Bioactive lipids regulate vasomotor tone, inflammation, thrombosis, immune response, inactivate enveloped viruses, regulate T cell proliferation and secretion of cytokines, stem cell survival, proliferation and differentiation, and leukocyte and macrophage functions, JAK kinase activity and neutrophil extracellular traps and thus, have a critical role in COVID-19.

AbstractBackground Lung ischaemia reperfusion injury (LIRI) is the major cause of primary lung dysfunction after lung transplantation. Lipoxin A4 inhibits the oxidative stress and inflammation. This study aimed to evaluate the potential protective effect of lipoxin A4 on LIRI in rats.Methods SD (Sprague-Dawley) rats were randomised into the sham, LIRI and LA4 groups. Rats in the sham group received anaesthesia, thoracotomy and intravenous injection of saline, while those in the LIRI or LA4 group received left lung transplantation and intravenous injection of saline or lipoxin A4, respectively. After 24 h of reperfusion, the PaO2/FiO2 (Partial pressure of O2 to fraction inspiratory O2), wet/dry weight ratios and protein levels in lungs were measured to assess the alveolar capillary permeability. The oxidative stress response and inflammation were examined. The histological and apoptosis analyses of lung tissues were performed via HE staining (Haematoxylin-eosin staining) and TUNEL assay, respectively. The effects of lipoxin A4 on the endothelial viability and tube formation of hypoxaemia and reoxygenation-challenged rat pulmonary microvascular endothelium cells were determined.Results Lipoxin A4 significantly ameliorated the alveolar capillary permeability, reduced the oxidative stress and inflammation in transplanted lungs. The histological injury and apoptosis of lung tissues were also alleviated by lipoxin A4. In vitro lipoxin A4 treatment promoted the endothelial tube formation and improved the endothelial viability.Conclusion Lipoxin A4 protects LIRI after lung transplantation in rats, and its therapeutic effect is associated with the properties of anti-inflammation, anti-oxidation, and endothelium protection.Key messages:Lung transplantation is a treatment approach for the patients with lung disease.LIRI is the major cause of postoperative primary lung dysfunction.Lipoxins A4 exhibits strong anti-inflammatory properties.

Parturition is the physiological process of newborn birth; more and more evidences show that parturition is closely related to the occurrence and resolution of inflammation. However, the inflammatory media and the mechanism are not very clear during parturition. Here, we investigate the inflammatory event during human parturition and in mouse model. We found that the pro-inflammatory cytokines (IL-6, IL-8, and IL-1β) and cells (neutrophil and macrophage) are decreased in pregnant women in labor and in mouse labor model. Mechanistically, increased stress stimulates the high-level adrenaline production in labor. Then, adrenaline upregulates the expression of 12/15-LOX (lipoxygenase) to produce more lipoxin A4 (LXA4), which is an inflammation inhibitor. Thus, LXA4 promotes the elimination of inflammation during labor to protect the body from excessive inflammatory damages. In addition, using BOC-2, the inhibitor of LXA4 receptor could reboot the pro-inflammatory cytokines. Our study indicates that LXA4 is induced by adrenaline in labor and appropriate interference of this pathway may be a potential strategy to regulate the inflammatory process in parturition. [ABSTRACT FROM AUTHOR]

Lipoxin A4 (LXA4) has been shown to have anti-inflammatory activity, but its underlying molecular mechanisms are not clear. Herein, we investigated the potential role of LXA4 in macrophage polarization and elucidated its possible molecular mechanism. The RAW264.7 macrophage cell line was pretreated with LXA4 with or without lipopolysaccharides (LPSs) and interleukin-4 (IL-4). In cultured macrophages, LXA4 inhibited LPS-induced inflammatory polarization, thereby decreasing the release of proinflammatory cell factors (IL-1β, IL-6, TNF-α) and increasing the release of anti-inflammatory cytokines (IL-4 and IL-10). Notably, the inhibitory effect of LXA4 on inflammatory macrophage polarization was related to the downregulation of p-NF-κB p65 and IRF5 activity, which reduced the LPS-induced phenotypic and functional polarization of M1 macrophages via the FPR2/IRF5 signaling pathway. Moreover, LXA4 also induced the IL-4-induced polarization of M2 macrophages by promoting the FPR2/IRF4 signaling pathway. Therefore, LXA4 regulates M1/M2 polarization of macrophages via the FPR2–IRF pathway. [ABSTRACT FROM AUTHOR]

• Leukotriene B4, lipoxin A4 and resolvin D1 levels vary throughout gestation. • Women with PE show high resolvin D1 levels at 12–19 weeks of pregnancy. • Women with PE show a low resolvin D1/leukotriene B4 ratio at 30–34 weeks. • Imbalanced levels of lipid mediators may underlie preeclampsia development. We carried out a longitudinal study to compare leukotriene B4 (LTB4), lipoxin A4 (LXA4), and resolvin D1 (RvD1) levels in pregnant women with risk factors for PE — who did (N = 11) or did not develop (N = 17) this clinical condition. For both groups, plasma levels of the lipid mediators were measured using immunoassays at 12–19, 20–29, and 30–34 weeks of gestation. LTB4 tended to be upregulated throughout gestation in women who developed PE. Moreover, this increase was significant at 30–34 weeks. Although LXA4 levels also tended to be higher in the PE group, this difference was not significant for the evaluated gestational periods. Pregnant women with PE had lower RvD1 levels and a low RvD1/LTB4 ratio at 30–34 weeks, compared to those in the normotensive pregnant women. Contrarily, RvD1 levels increased at weeks 12–19 in pregnant women who developed PE. Particularly, LXA4 and RvD1 levels were higher at 30–34 weeks than those at 20–29 weeks considering both groups of women. We observed an interaction between the gestational outcome and the gestational period in case of RvD1. The imbalance among LTB4, LXA4, and RvD1 levels in these preeclamptic women is consistent with the excessive inflammation that underlies the pathogenesis of PE. Although our data highlight the potential for the use of these lipid mediators as clinical markers for PE development, future longitudinal studies must be carried out to confirm these findings. [ABSTRACT FROM AUTHOR]

Lung ischaemia reperfusion injury (LIRI) is the major cause of primary lung dysfunction after lung transplantation. Lipoxin A4 inhibits the oxidative stress and inflammation. This study aimed to evaluate the potential protective effect of lipoxin A4 on LIRI in rats. SD (Sprague-Dawley) rats were randomised into the sham, LIRI and LA4 groups. Rats in the sham group received anaesthesia, thoracotomy and intravenous injection of saline, while those in the LIRI or LA4 group received left lung transplantation and intravenous injection of saline or lipoxin A4, respectively. After 24 h of reperfusion, the PaO2/FiO2 (Partial pressure of O2 to fraction inspiratory O2), wet/dry weight ratios and protein levels in lungs were measured to assess the alveolar capillary permeability. The oxidative stress response and inflammation were examined. The histological and apoptosis analyses of lung tissues were performed via HE staining (Haematoxylin-eosin staining) and TUNEL assay, respectively. The effects of lipoxin A4 on the endothelial viability and tube formation of hypoxaemia and reoxygenation-challenged rat pulmonary microvascular endothelium cells were determined. Lipoxin A4 significantly ameliorated the alveolar capillary permeability, reduced the oxidative stress and inflammation in transplanted lungs. The histological injury and apoptosis of lung tissues were also alleviated by lipoxin A4. In vitro lipoxin A4 treatment promoted the endothelial tube formation and improved the endothelial viability. Lipoxin A4 protects LIRI after lung transplantation in rats, and its therapeutic effect is associated with the properties of anti-inflammation, anti-oxidation, and endothelium protection. Lung transplantation is a treatment approach for the patients with lung disease. LIRI is the major cause of postoperative primary lung dysfunction. Lipoxins A4 exhibits strong anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Recently, it has been irrefutably discovered that brown adipocytes dissipate energy as heat and protect against obesity. Researchers make great efforts to explore approaches for its activation. Lipoxin A4 (LXA4) has been proven to reverse adipose tissue inflammation and improve insulin resistance, but its function on brown adipocyte differentiation has been poorly understood, which therefore to be investigated in the present study. Mouse embryonic fibroblasts (MEFs) were induced and differentiated to model brown adipocytes, and treated with LXA4 at 0, 1, 5, and 10 nM for 0–14 d. Afterwards, Oil Red O staining detected lipid droplets. In differentiated MEFs with or without LXA4 (10 nM) treatment, western blot and quantitative real-time polymerase chain reaction (qRT-PCR) assessed adipocyte browning marker uncoupling protein 1 (UCP-1), and brown adipogenesis markers peroxisome proliferator–activated receptor gamma (PPARγ), peroxisome proliferator–activated receptor gamma coactivator 1-alpha (PGC1α), cyclooxygenase-2 (COX-2), and positive regulation domain containing 16 (PRDM16) as well as lipogenic genes of stearoyl-CoA desaturase 1 (SCD1), fatty acid synthase (FASN), glucose transporter type 4 (GLUT4), and carbohydrate response element binding protein (ChREBP). The induced differentiation of MEFs toward brown adipocytes was successful. LXA4 promoted intracellular accumulation of lipid droplets of induced cells and increased UCP-1 expression in a dose- or time-dependent manner. Under the administration of LXA4, brown adipogenesis markers and lipogenic genes were further upregulated. LXA4 made a contribution to induce differentiation of MEFs to brown adipocytes, which could be regarded a new drug target for obesity management. [ABSTRACT FROM AUTHOR]