Eicosanoid signaling in neuroinflammation associated with Alzheimer's disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition affecting a substantial portion of the global population. It is marked by a complex interplay of factors, including the accumulation of amyloid plaques and tau tangles within the brain, leading to neuroinflammation and neuronal damage. Recent studies have underscored the role of free lipids and their derivatives in the initiation and progression of AD. Eicosanoids, metabolites of polyunsaturated fatty acids like arachidonic acid (AA), emerge as key players in this scenario. Remarkably, eicosanoids can either promote or inhibit the development of AD, and this multifaceted role is determined by how eicosanoid signaling influences the immune responses within the brain. However, the precise molecular mechanisms dictating the dual role of eicosanoids in AD remain elusive. In this comprehensive review, we explore the intricate involvement of eicosanoids in neuronal function and dysfunction. Furthermore, we assess the therapeutic potential of targeting eicosanoid signaling pathways as a viable strategy for mitigating or halting the progression of AD.

The beneficial effect of sulforaphane on platelet responsiveness during caloric load: a single-intake, double-blind, placebo-controlled, crossover trial in healthy participants.

Background and aims: As our understanding of platelet activation in response to infections and/or inflammatory conditions is growing, it is becoming clearer that safe, yet efficacious, platelet-targeted phytochemicals could improve public health beyond the field of cardiovascular diseases. The phytonutrient sulforaphane shows promise for clinical use due to its effect on inflammatory pathways, favorable pharmacokinetic profile, and high bioavailability. The potential of sulforaphane to improve platelet functionality in impaired metabolic processes has however hardly been studied in humans. This study investigated the effects of broccoli sprout consumption, as a source of sulforaphane, on urinary 11-dehydro-thromboxane B2 (TXB2), a stable thromboxane metabolite used to monitor eicosanoid biosynthesis and response to antithrombotic therapy, in healthy participants exposed to caloric overload. Methods: In this double-blind, placebo-controlled, crossover trial 12 healthy participants were administered 16g of broccoli sprouts, or pea sprouts (placebo) followed by the standardized high-caloric drink PhenFlex given to challenge healthy homeostasis. Urine samples were collected during the study visits and analyzed for 11-dehydro-TXB2, sulforaphane and its metabolites. Genotyping was performed using Illumina GSA v3.0 DTCBooster. Results: Administration of broccoli sprouts before the caloric load reduced urinary 11-dehydro-TXB2 levels by 50% (p = 0.018). The amount of sulforaphane excreted in the urine during the study visits correlated negatively with 11-dehydro-TXB2 (rs = -0.377, p = 0.025). Participants carrying the polymorphic variant NAD(P)H dehydrogenase quinone 1 (NQO1*2) showed decreased excretion of sulforaphane (p = 0.035). Conclusion: Sulforaphane was shown to be effective in targeting platelet responsiveness after a single intake. Our results indicate an inverse causal relationship between sulforaphane and 11-dehydro-TXB2, which is unaffected by the concomitant intake of the metabolic challenge. 11-Dehydro-TXB2 shows promise as a non-invasive, sensitive, and suitable biomarker to investigate the effects of phytonutrients on platelet aggregation within hours. Clinical trial registration: [https://clinicaltrials.gov/], identifier [NCT05146804].

Vascular Inflammatory Markers as Predictors of Peripheral Arterial Disease Patients' Quality-of-Life Changes after Endovascular Treatment.

The association between chronic inflammation and depression, anxiety, anhedonia, and quality of life (QoL) has been recently emphasized. However, the pathophysiology of this relationship remains unsolved. This study aims to assess the dependence between vascular inflammation represented by eicosanoid concentration and quality of life in patients with peripheral arterial disease (PAD). A total of 175 patients undergoing endovascular treatment due to lower limbs ischemia were covered with eight years of observation after the endovascular procedure, including ankle-brachial index (ABI), color Doppler ultrasound examination, urinary leukotriene E4 (LTE4), thromboxane B2 (TXB2) and 5-Hydroxyeicosatetraenoic acid (5-HETE) measurement and quality-of-life assessment with VascuQol-6. The baseline concentrations of LTE4 and TXB2 reversely correlated with preoperative VascuQol-6 and were predictive of the postoperative values of VascuQol-6 at each follow-up. At every follow-up timepoint, the results of VascuQol-6 reflected the LTE4 and TXB2 concentrations. Higher concentrations of LTE4 and TXB2 were correlated with lower life quality during the next follow-up meeting. Changes in VascuQol-6 at eight years vs. preoperative values were reversely related to the preoperative concentrations of LTE4 and TXB2. This is the first study to confirm that changes in life quality in PAD patients undergoing endovascular treatment are highly dependent on eicosanoid-based vascular inflammation.

Loss of Endothelial Cytochrome P450 Reductase Induces Vascular Dysfunction in Mice.

BACKGROUND: POR (cytochrome P450 reductase) provides electrons for the catalytic activity of the CYP (cytochrome P450) monooxygenases. CYPs are dual-function enzymes as they generate protective vasoactive mediators derived from polyunsaturated fatty acids but also reactive oxygen species. It is not known in which conditions the endothelial POR/CYP system is beneficial versus deleterious. Here, the activity of all CYP enzymes was eliminated in the vascular endothelium to examine its impact on vascular function. METHODS: An endothelial-specific, tamoxifen-inducible POR knockout mouse (ecPOR-/-) was generated. Vascular function was studied by organ chamber experiments. eNOS (endothelial nitric oxide synthase) activity was accessed by heavy arginine/citrulline LC-MS/MS detection and phosphorylation of serine1177 in aortic rings. CYP-derived epoxyeicosatrienoic acids and prostanoids were measured by LC-MS/MS. Gene expression of aorta and endothelial cells was profiled by RNA sequencing. Blood pressure was measured by telemetry. RESULTS: Acetylcholine-induced endothelium-dependent relaxation was attenuated in isolated vessels of ecPOR-/- as compared with control mice. Additionally, ecPOR-/- mice had attenuated eNOS activity and eNOS/AKT phosphorylation. POR deletion reduced endothelial stores of CYP-derived epoxyeicosatrienoic acids but increased vascular prostanoids. This phenomenon was paralleled by the induction of genes implicated in eicosanoid generation. In response to Ang II (angiotensin II) infusion, blood pressure increased significantly more in ecPOR-/- mice. Importantly, the cyclooxygenase inhibitor Naproxen selectively lowered the Ang II-induced hypertension in ecPOR-/- mice. CONCLUSIONS: POR expression in endothelial cells maintains eNOS activity and its loss results in an overactivation of the vasoconstrictor prostanoid system. Through these mechanisms, loss of endothelial POR induces vascular dysfunction and hypertension.

Macrophage 12(S)-HETE Enhances Angiotensin II-Induced Contraction by a BLT2 (Leukotriene B4 Type-2 Receptor) and TP (Thromboxane Receptor)-Mediated Mechanism in Murine Arteries.

12/15-LO (12/15-lipoxygenase), encoded by Alox15 gene, metabolizes arachidonic acid to 12(S)-HETE (12-hydroxyeicosatetraenoic acid). Macrophages are the major source of 12/15-LO among immune cells, and 12/15-LO plays a crucial role in development of hypertension. Global Alox15- or macrophage-deficient mice are resistant to Ang II (angiotensin II)-induced hypertension. This study tests the hypothesis that macrophage 12(S)-HETE contributes to Ang II-mediated arterial constriction and thus to development of Ang II-induced hypertension. Ang II constricted isolated abdominal aortic and mesenteric arterial rings. 12(S)-HETE (100 nmol/L) alone was without effect; however, it significantly enhanced Ang II-induced constriction. The presence of wild-type macrophages also enhanced the Ang II-induced constriction, while Alox15-/- macrophages did not. Using this model, pretreatment of aortic rings with inhibitors, receptor agonists/antagonists, or removal of the endothelium, systematically uncovered an endothelium-mediated, Ang II receptor-2-mediated and superoxide-mediated enhancing effect of 12(S)-HETE on Ang II constrictions. The role of superoxide was confirmed using aortas from p47phox-/- mice where 12(S)-HETE failed to enhance constriction to Ang II. In cultured arterial endothelial cells, 12(S)-HETE increased the production of superoxide, and 12(S)-HETE or Ang II increased the production of an isothromboxane-like metabolite. A TP (thromboxane receptor) antagonist inhibited 12(S)-HETE enhancement of Ang II constriction. Both Ang II-induced hypertension and the enhancing effect of 12(S)-HETE on Ang II contractions were eliminated by a BLT2 (leukotriene B4 receptor-2) antagonist. These results outline a mechanism where the macrophage 12/15-LO pathway enhances the action of Ang II. 12(S)-HETE, acting on the BLT2, contributes to the hypertensive action of Ang II in part by promoting endothelial synthesis of a superoxide-derived TP agonist.

Roles of Thromboxane Receptor Signaling in Enhancement of Lipopolysaccharide-Induced Lymphangiogenesis and Lymphatic Drainage Function in Diaphragm.

[Figure: see text].

Effect of natural polyphenols on thromboxane levels in children with Crohn's disease.

OBJECTIVES: The aim of this study was to investigate the relationship between thromboxane levels and oxidative stress in children with Crohn´s disease (CD), and examine the effect of natural polyphenolic compounds on thromboxane levels. METHODS: This study involved 14 children suffering from CD and 15 healthy controls. Patients were receiving the polyphenolic extract Pycnogenol for 10 weeks. Plasma levels of the static and dynamic forms of thromboxane B2 as well as their metabolite 11-dehydro thromboxane B2 in urine were determined. RESULTS: In comparison to controls, CD patients had significantly higher levels of the static and dynamic forms of thromboxane B2. Pycnogenol decreased the level of the dynamic form of thromboxane B2 after 10 weeks of administration. CONCLUSIONS: Paediatric Crohn's disease is associated with higher thromboxane levels. Our results indicate that Pycnogenol administration reduces thromboxane levels, which may positively influence some clinical symptoms of CD such as thromboembolic episodes (Tab. 3, Ref. 49).

Quantitative metabolic profiling of urinary eicosanoids for clinical phenotyping.

The eicosanoids are a family of lipid mediators of pain and inflammation involved in multiple pathologies, including asthma, hypertension, cancer, atherosclerosis, and neurodegenerative diseases. These signaling mediators act locally, but are rapidly metabolized and transported to the systemic circulation as a mixture of primary and secondary metabolites. Accordingly, urine has become a useful readily accessible biofluid for monitoring the endogenous synthesis of these molecules. Herein, we present the validation of a rapid, repeatable, and precise method for the extraction and quantification of 32 eicosanoid urinary metabolites by LC-MS/MS. For 12 out of 17 deconjugated glucuronide eicosanoids, there was no improvement in recovered signal. These metabolites cover the major synthetic pathways, including prostaglandins, leukotrienes, and isoprostanes. The method linearity was >0.99 for all metabolites analyzed, the limit of detection ranged from 0.05-5 ng/ml, and the average extraction recoveries were >90%. All analytes were stable for at least three freeze/thaw cycles. The method was formatted for large-scale analysis of clinical cohorts, and the long-term repeatability was demonstrated over 15 months of acquisition, evidencing high precision (CV <15%, except for tetranorPGEM and 2,3-dinor-11ß-PGF2α, which were <30%). The presented method is suitable for focused mechanistic studies as well as large-scale clinical and epidemiological studies that require repeatable methods capable of producing data that can be concatenated across multiple cohorts.

Metabolites of prostaglandin synthases as potential biomarkers of Lyme disease severity and symptom resolution.

BACKGROUND: Lyme disease or Lyme borreliosis (LB) is the commonest vector-borne disease in the North America. It is an inflammatory disease caused by the bacterium Borrelia burgdorferi. The role of the inflammatory processes mediated by prostaglandins (PGs), thromboxanes and leukotrienes (LTs) in LB severity and symptoms resolution is yet to be elucidated. OBJECTIVES: We aim to systematically review and evaluate the role of PGs and related lipid mediators in the induction and resolution of inflammation in LB. METHODS: We conducted a comprehensive search in PubMed, Ovid MEDLINE(R), Embase and Embase Classic to identify cell-culture, animal and human studies reporting the changes in PGs and related lipid mediators of inflammation during the course of LB. RESULTS: We identified 18 studies to be included into this systematic review. The selected reports consisted of seven cell-culture studies, seven animal studies, and four human studies (from three patient populations). Results from cell-culture and animal studies suggest that PGs and other lipid mediators of inflammation are elevated in LB and may contribute to disease development. The limited number of human studies showed that subjects with Lyme meningitis, Lyme arthritis (LA) and antibiotic-refractory LA had increased levels of an array of PGs and lipid mediators (e.g., LTB4, 8-isoPGF2α, and phospholipases A2 activity). Levels of these markers were significantly reduced following the treatment with antibiotics or non-steroidal anti-inflammatory drugs. CONCLUSION: Dysregulation of prostaglandins and related lipid mediators may play a role in the etiology of LB and persistence of inflammation that may lead to long-term complications. Further investigation into the precise levels of a wide range of PGs and related factors is critical as it may propose novel markers that can be used for early diagnosis.

Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: the influence of LCPUFA on neural development, aging, and neurodegeneration.

Many clinical and animal studies demonstrate the importance of long-chain polyunsaturated fatty acids (LCPUFA) in neural development and neurodegeneration. This review will focus on involvement of LCPUFA from genesis to senescence. The LCPUFA docosahexaenoic acid and arachidonic acid are important components of neuronal membranes, while eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid also affect cardiovascular health and inflammation. In neural development, LCPUFA deficiency can lead to severe disorders like schizophrenia and attention deficit hyperactivity disorder. Perinatal LCPUFA supplementation demonstrated beneficial effects in neural development in humans and rodents resulting in improved cognition and sensorimotor integration. In normal aging, the effect of LCPUFA on prevention of cognitive impairment will be discussed. LCPUFA are important for neuronal membrane integrity and function, and also contribute in prevention of brain hypoperfusion. Cerebral perfusion can be compromised as result of obesity, cerebrovascular disease, hypertension, or diabetes mellitus type 2. Last, we will focus on the role of LCPUFA in most common neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. These disorders are characterized by impaired cognition and connectivity and both clinical and animal supplementation studies have shown the potential of LCPUFA to decrease neurodegeneration and inflammation. This review shows that LCPUFA are essential throughout life.

Molecular and pharmacological characterization of zebrafish 'contractile' and 'inhibitory' prostanoid receptors.

Prostanoids comprising prostaglandins (PGs) and thromboxanes (TXs) have been shown to play physiological and pathological roles in zebrafish. However, the molecular basis of zebrafish prostanoid receptors has not been established. Here, we demonstrate that there exist at least five 'contractile' (Ca(2+)-mobilizing) and one 'inhibitory' (Gi-coupled) prostanoid receptors in zebrafish; five 'contractile' receptors consisting of two PGE2 receptors (EP1a and EP1b), two PGF2α receptors (FP1 and FP2), and one TXA2 receptor TP, and one 'inhibitory' receptor, the PGE2 receptor EP3. [(3)H]PGE2 specifically bound to the membranes of cells expressing zebrafish EP1a, EP1b and EP3 with a Kd of 4.8, 1.8 and 13.6nM, respectively, and [(3)H]PGF2α specifically bound to the membranes of cells expressing zebrafish FP1 and FP2, with a Kd of 6.5 and 1.6nM, respectively. U-46619, a stable agonist for human and mouse TP receptors, significantly increased the specific binding of [(35)S]GTPγS to membranes expressing the zebrafish TP receptor. Upon agonist stimulation, all six receptors showed an increase in intracellular Ca(2+) levels, although the increase was very weak in EP1b, and pertussis toxin abolished only the EP3-mediated response. Zebrafish EP3 receptor also suppressed forskolin-induced cAMP formation in a pertussis toxin-sensitive manner. In association with the low structural conservation with mammalian receptors, most agonists and antagonists specific for mammalian EP1, EP3 and TP failed to work on each corresponding zebrafish receptor. This work provides further insights into the diverse prostanoid actions mediated by their receptors in zebrafish.

Randomized placebo-controlled intervention with n-3 LC-PUFA-supplemented yoghurt: effects on circulating eicosanoids and cardiovascular risk factors.

BACKGROUND & AIMS: The study examined the value of n-3 LC-PUFA-enriched yogurt as means of improving cardiovascular health. DESIGN: Fifty three mildly hypertriacylglycerolemic subjects (TAG ≥ 1.7 mmol/L) participated in a randomized, placebo-controlled, double-blind, parallel designed study. The subjects consumed 1) control yoghurt; 2) yoghurt enriched with 0.8 g n-3 LC-PUFA/d; or 3) yoghurt enriched with 3 g n-3 LC-PUFA/d for a period of 10 wks. Blood samples were taken at the beginning and the end of the study period. RESULTS: Following daily intake of 3 g n-3 LC-PUFA for 10 weeks, n-3 LC-PUFA levels increased significantly in plasma and red blood cells (RBC) with concomitant increase in the EPA-derived mediators (PGE3, 12-, 15-, 18-HEPE) in plasma whilst cardiovascular risk factors such as HDL, TAG, AA/EPA ratio, and n-3 index were improved (P < 0.05); the decrease of TAG and increase in HDL were associated with the CD36 genotype. CONCLUSION: The observed increase of n-3 LC-PUFA in RBC and plasma lipids due to intake of n-3 LC-PUFA enriched yoghurt resulted in a reduction of cardiovascular risk factors and inflammatory mediators showing that daily consumption of n-3 PUFA enriched yoghurt can be an effective way of supplementing the daily diet and improving cardiovascular health.

Effects of cigarette smoking on hemodynamics and hypoxic pulmonary vasoconstriction in rats: role of prostaglandins and leukotrienes / 中国病理生理杂志

The changes of hemodynamics and hypoxic pulmonary vasoconstriction (HPV) inducedby cigarette smoking and the role of prostaglandins(PGs) and leukotrienes (LTs) were studied in rats. During smoking, systemic and pulmonary vascular resistance (SVR and PVR) increased 47% and 39%, respectively. The level of TXB_2 rose by 144% in plasma and 69% in lung tissue. HPV increased two-fold after smoking (△PVR increased from 55% to 102%). LTs receptor antagonist, LY-171883, prevented the smoking-in duced increase of SVR and PVR and augmentation of HPV. Cyclooxygenase inhibitor, in domethacin, prevented partly increase of PVR but not HPV induced by smoking. Our results suggest that smoking leads to pulmonary and systemic vasoconstriction and augmentation of HPV mediated by LTs, the increase of PVR during smoking is also mediated by TXA_2, This study also found that LY-171883 inhibited HPV by 72%, the result indictates that LTs mediate HPV in Wistar rats.

The Role of Thromboxane and Prostacyclin in Pulmonary Vasoconstriction under Hypoxia and Air-embolism in Conscious Goats / 第三军医大学学报

Sixteen adult goats were divided into 2 groups and were experimented in conscious conditions.The first group received air infusion (0.05ml/mm/kg) into the right ventricle for 4 hours under normal oxygen tension at sea level.The second group received combined injury of hypoxia and air embolism.The animals were put into a simulated altitude of 4 000 meters for one hour then were given air infusion as in group one.Then the changes of the mean pulmonary arterial pressure(Ppa) and pulmonary vascular resistance (PVR) were observed in the animals of both groups.The arterial plasma level of thrornboxane B2(TXB2) and 6-keto-PGF1a,the stable metabolites of thromboxane A2 and prostacyclin,were determined with radio-immunoassay.The leucocytes in the peripheral arterial blood were counted.It was found that in the early stage of hypoxia or air-embolism of the pulmonary vessels,the constriction of pulmonary vessels was related to the synthesis and release of thrornboxne A2; on the basis of increased tension of the pulmonary vessels induced by acute hypoxia,the infusion of air into the right ventricle could further increase the PVR but the amplitude of increment was markedly smaller than that induced by air-embolism alone.Introduction of air under hypo-xic condition would result in a transcient increase of prostacyclin release,but the release of prostacyclin would soon go down to the prehypoxic level

An Experimental Study of Pathogenesis of Acute Lung Injury Induced by Complement Activation in Conscious Goat, Roles of Leukocytes and Prostaglandins / 第三军医大学学报

The roles of leukocytes and prostaglandins in mediating alterations of pulmonary hemodynainics and lung fluid exchange after intravenous autologous zymo-san-activated plasma (ZAP) challenge is investigated in 14 conscious goats with chronic lung-lymph-fistula. In the control group, ZAP infusion causes the mean pulmonary arterial pressure (Ppa) markedly elevate, lung lymph flow (QI) and the lymph-to-plasma protein concentration ratio (L/P) increase. There is a significant correlation between Ppa and the content of plasma TXB2. In antiPMNs serum-induced leukopenia group, the extent of increment in Pp a is not as obvious as the normal goats, and no marked change is observed in QI, L/P and content of TXB2. These results indicate: l.TXA2 releases from leukocytes may affect lung fluid exchange during ZAP infusion; 2. leukocytes may play an important role in ZAP-induced lung injury.

Changes of Thromboxane and Prostacyclin in Severe Body Surface Burn Patients Complicated with Inhalation Injury / 第三军医大学学报

Forty-one burn patients were divided into inhalation injury and non-inhalation injury groups.It was found that in the inhalation injury group,TXB2 level and TXB2/G-keto-PGF1? ratio in plasma and lung tissue were significantly elevated,circulatory platelet aggregate ratio markedly decreased,and blood viscosity greatly increased.Histopathologically,congestion,edema,hemorrhage and thrombosis were seen in lung tissue.The changes of TXB2 level and TXB2/6-keto-PGF1?ratio were parallel to the clinical course of the development of respiratory failure in the patients with body surface burns complicated with inhalation injury.It is believed that the imbalance of TXA2/PGI2 is one of the factors of respiratory failure in severe body surface burns complicated with inhalation injury.