Prostaglandin Metabolites Research Articles

The Altered Lipid Composition and Key Lipid Metabolic Enzymes in Thiacloprid-Resistant Myzus persicae, with Special Attention Paid to the Function of MpTHEM6a

Neonicotinoid resistance is increasingly prevalent in the agricultural pest Myzus persicae. Lipids play a critical role in insect defense systems, but their contribution to insect neonicotinoid resistance is disregarded. We conducted metabolomics and transcriptomics studies on M. persicae thiacloprid-resistant (THG-R) and -susceptible (FFJ-S) populations. A total of 149 lipid metabolites were identified, with 90 upregulated and 59 downregulated in THG-R compared to in FFJ-S. Metabolites in the arachidonic acid (AA) pathway substantially varied between THG-R and FFJ-S. For example, arachidonic acid, (±)11-HETE, and prostaglandin B1 were significantly upregulated, while prostaglandin A1, tetranor-PGDM, 8,15-diHETE, and (±)11(12)-EET were significantly decreased in THG-R. Transcriptomics profiles and qPCR indicated that lipid metabolic enzymes, including fatty acid synthase (FAS), the elongase of very-long-chain fatty acids (ELO), fatty acid desaturase (FAD), and phospholipase (PL) genes, were not overexpressed in THG-R. Among the twelve thioesterase genes, only MpTHEM6a was significantly upregulated in THG-R. Knocking down the expression of MpTHEM6a in THG-R significantly increased the toxicity of the three neonicotinoids, reduced the lifespan of adults, and decreased the number of nonviable nymphs produced by female adults. The metabolites AA, (±)11-HETE, and prostaglandin B1 are potential biomarkers in neonicotinoid-resistant M. persicae. MpTHEM6a may become a potential target for combating neonicotinoid-resistant M. persicae.

Prostaglandin Metabolites Analysis in Urine by LC-MS/MS.

The analysis of prostaglandin urinary metabolites is valuable for assessing physiological processes and identifying disease biomarkers. These metabolites, derived from the breakdown of prostaglandins, offer a noninvasive means to gauge prostaglandin production and its potential impact on various biological functions. We report an efficient LC-MS method of four commonly analyzed prostaglandin urinary metabolites including tetranor-PGEM (derived from PGE2), tetranor-PGDM, 11β-PGF2α, and 2,3-dinor-11β-PGF2α (derived from PGD2). Each metabolite possesses distinct characteristics and clinical applications, collectively contributing to our understanding of prostaglandin-mediated pathways.

Genetic Foundation of Prostaglandin Metabolism Influences Patent Ductus Arteriosus Closure in Extremely Low Birth Weight Infants.

Prostaglandins (PGs) play a major role in maintaining patency of the ductal arteriosus (DA). Pulmonary 15-hydroxyprostaglandin dehydrogenase (PGDH), which is ecoded by the hydroxyprostaglandin dehydrogenase (HPGD) gene, is the primary enzyme responsible for PG breakdown. Animal studies have shown HPGD-knockout mice have significantly higher prostaglandin E2 levels and no ductal remodeling. Functional variants of the HPGD gene that alter PG breakdown have not been studied in preterm infants with patent ductus arteriosus (PDA). This was an observational cohort study including extreme low birth weight (ELBW) infants classified as having spontaneous, medical, or procedural (transcatheter or surgical ligation) closure of their DA. Urine prostaglandin E metabolite (PGEM) levels were measured in ELBW infants following ibuprofen treatment using competitive ELISA. HPGD genetic variants rs8752, rs2612656, and rs9312555 were analyzed. Kruskal-Wallis, Fisher's exact, chi square, logistic regression, and Wilcoxon signed-rank tests were used; p < 0.05 was considered significant. Infants in the procedural closure group had a younger gestational age (GA). The incidence of spontaneous closure or medical closure was higher compared to procedural closure in the presence of any minor allele of rs8752 (67 and 27%, respectively; p = 0.01), when adjusted for GA and gender. Haplotype analysis of three variants of HPGD revealed differences when comparing the spontaneous and medical closure group to the procedural group (p < 0.05). Urinary PGEM levels dropped significantly in those ELBW infants who responded to ibuprofen (p = 0.003) in contrast to those who did not respond (p = 0.5). There was a different genotype distribution for the rs8752 genetic variant of the HPGD gene-as it relates to the mode of treatment for ELBW infants with PDA. We speculate that medical management in the presence of this variant facilitated additional PG breakdown, significantly abrogating the need for procedural closure. Additionally, differences in genotype and haplotype distributions implicate a specific HPGD genetic foundation for DA closure in ELBW infants. · PGs and their metabolism play a major role in PDA patency or closure.. · Genetic variants of the HPGD gene influence mode of treatment of PDA in ELBW infants.. · ELBW infants with PDA that responded to medical closure had significantly decreased urine PGEM levels..

Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2

Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.

Multicentric investigations of the role in the disease severity of accelerated phospholipid changes in COVID-19 patient airway

ContextThe changes in host membrane phospholipids are crucial in airway infection pathogenesis. Phospholipase A2 hydrolyzes host cell membranes, producing lyso-phospholipids and free fatty acids, including arachidonic acid (AA), which contributes significantly to lung inflammation. AimFollow these changes and their evolution from day 1, day 3 to day 7 in airway aspirates of 89 patients with COVID-19-associated acute respiratory distress syndrome and examine whether they correlate with the severity of the disease. The patients were recruited in three French intensive care units. The analysis was conducted from admission to the intensive care unit until the end of the first week of mechanical ventilation. ResultsIn the airway aspirates, we found significant increases in the levels of host cell phospholipids, including phosphatidyl-serine and phosphatidyl-ethanolamine, and their corresponding lyso-phospholipids. This was accompanied by increased levels of AA and its inflammatory metabolite prostaglandin E2 (PGE2). Additionally, enhanced levels of ceramides, sphingomyelin, and free cholesterol were observed in these aspirates. These lipids are known to be involved in cell death and/or apoptosis, whereas free cholesterol plays a role in virus entry and replication in host cells. However, there were no significant changes in the levels of dipalmitoyl-phosphatidylcholine, the major surfactant phospholipid. A correlation analysis revealed an association between mortality risk and levels of AA and PGE2, as well as host cell phospholipids. ConclusionOur findings indicate a correlation between heightened cellular phospholipid modifications and variations in AA and PGE2 with the severity of the disease in patients. Nevertheless, there is no indication of surfactant alteration in the initial phases of the illness.

Elevated Prostaglandin E2 Synthesis Is Associated with Clinical and Radiological Disease Severity in Cystic Fibrosis.

Background: Previous studies found high but very variable levels of tetranor-PGEM and PGDM (urine metabolites of prostaglandin (PG) E2 and PGD2, respectively) in persons with cystic fibrosis (pwCF). This study aims to assess the role of cyclooxygenase COX-1 and COX-2 genetic polymorphisms in PG production and of PG metabolites as potential markers of symptoms' severity and imaging findings. Methods: A total of 30 healthy subjects and 103 pwCF were included in this study. Clinical and radiological CF severity was evaluated using clinical scoring methods and chest computed tomography (CT), respectively. Urine metabolites were measured using liquid chromatography/tandem mass spectrometry. Variants in the COX-1 gene (PTGS1 639 C>A, PTGS1 762+14delA and COX-2 gene: PTGS2-899G>C (-765G>C) and PTGS2 (8473T>C) were also analyzed. Results: PGE-M and PGD-M urine concentrations were significantly higher in pwCF than in controls. There were also statistically significant differences between clinically mild and moderate disease and severe disease. Patients with bronchiectasis and/or air trapping had higher PGE-M levels than patients without these complications. The four polymorphisms did not associate with clinical severity, air trapping, bronchiectasis, or urinary PG levels. Conclusions: These results suggest that urinary PG level testing can be used as a biomarker of CF severity. COX genetic polymorphisms are not involved in the variability of PG production.

Abstract 1416: Resolvins enhance immunotherapy to induce Fanconi anemia tumor regression via inflammation resolution

Abstract Fanconi anemia (FA) is a disorder characterized by early-onset solid tumors unresponsive to chemotherapy and radiation. Unresolved inflammation is a hallmark of FA, the mechanisms underlying the initiation and resolution of inflammation in FA are poorly characterized. We hypothesized that FA tumor progression is controlled by dysregulated resolution metabolomes and a systemic pro-inflammatory eicosanoid storm of inflammation-initiating mediators. Using a novel transplantable murine FA tumor model, we show that Fancc-/- HNSCC (head and neck squamous cell carcinoma) progression disrupts the resolution of inflammation via an imbalance between specialized pro-resolving lipid mediators (SPMs) and eicosanoids. Fancc-/- tumor-bearing mice exhibited an increase in eicosanoids, including leukotriene B4 (LTB4) and thromboxane B2 (TXB2) in the spleen and a 113% increase in prostaglandin E metabolite (PGEM), a marker of PGE2 production, in the plasma compared to non-tumor-bearing (NT) mice. Fancc-/- tumor-bearing mice exhibited a loss in the SPM/LTB4 ratio including RvD1/LTB4, RvD2/LTB4, and MaR1/LTB4, compared to NT mice. Given the activity of immune checkpoint blockade in mismatch repair deficient tumors including head and neck cancers, immunotherapy may be relevant to FA-induced cancers. Importantly, the number of absolute T cells and CD4+ T cell function is preserved in individuals with FA. We combined stimulation of the resolution of inflammation (i.e., treatment with RvDs) with immunotherapy in a new transplantable murine FA tumor model. While treatment with RvD4, RvD5, or anti-PD1 immunotherapy alone delayed tumor growth compared to control at treatment day 20, the tumors did escape monotherapy by treatment day 30. Remarkably, RvD4 or RvD5 combined with anti-PD1 immunotherapy induced sustained Fancc-/- tumor regression. Moreover, RvD4 and/or anti-PD1 immunotherapy inhibited orthotopic Fancc-/- tumor growth compared to control. Resolvins and immune checkpoint blockade synergistically induced Fancc-/- tumor regression via macrophage phagocytosis of apoptotic debris, counter-regulation of pro-angiogenic cytokines, and inhibition of angiogenesis. Triggering Receptor Expressed on Myeloid cells-2 (TREM2)-antagonism combined with resolvins and immunotherapy restored SPM/eicosanoid ratios in Fancc−/- tumor-bearing mice to pre-cancer levels. SPMs and eicosanoids provide potential early biomarkers and biological targets in FA-induced cancer progression. Stimulating the resolution of inflammation via pro-resolution lipid mediators to enhance immunotherapy is a novel host-centric therapeutic approach to prevent FA-induced cancer progression via debris clearance and cytokine suppression. These results provide evidence for targeting the resolution of inflammation via resolvins to enhance immunotherapy to prevent and/or reverse FA-induced cancer progression. Citation Format: Katherine Quinlivan, Haixia Yang, Diane R. Bielenberg, Susanne I. Wells, Charles N. Serhan, Dipak Panigrahy. Resolvins enhance immunotherapy to induce Fanconi anemia tumor regression via inflammation resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1416.

Inhibition of 15-prostaglandin dehydrogenase attenuates acetaminophen-induced liver injury via suppression of apoptosis in liver endothelial cells

Hepatic microvascular disruption caused by injury to liver sinusoidal endothelial cells (LSECs) is an aggravating factor for drug-induced liver injury (DILI). It is suggested that prostaglandin E2 (PGE2) may be able to attenuate LSEC injury. However, it is also known that 15-keto PGE2, a metabolite of PGE2 produced by 15-prostaglandin dehydrogenase (15-PGDH) that is not a ligand of PGE2 receptors, suppresses inflammatory acute liver injury as a ligand of peroxisome proliferator-activated receptor γ. In this study, we aimed to understand whether 15-PGDH activity is essential for preventing DILI by suppressing hepatic microvascular disruption in a mouse model of acetaminophen (APAP)-induced liver injury. To inhibit 15-PGDH activity prior to APAP-induced LSEC injury, we administered the 15-PGDH inhibitor, SW033291, 1 h before and 3 h after APAP treatment. We observed that LSEC injury preceded hepatocellular injury in APAP administered mice. Hepatic endogenous PGE2 levels did not increase up till the initiation of LSEC injury but rather increased after hepatocellular injury. Moreover, hepatic 15-PGDH activity was downregulated in APAP-induced liver injury. The inhibition of 15-PGDH attenuated LSEC injury and subsequently hepatic injury by inhibiting apoptosis in APAP administered mice. Our in vitro studies also suggested that PGE2 inhibited APAP-induced apoptosis via the EP4/PI3K pathway in endothelial cells. Therefore, a decrease in 15-PGDH activity would be beneficial for preventing APAP-induced liver injury by attenuating LSEC injury.

Urinary Prostaglandin E2 Excretion and the Risk of Cardiovascular and Kidney Disease.

Inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs is associated with cardiovascular mortality and kidney disease. This study hypothesizes that urinary prostaglandin E2 (PGE2) and PGE2 metabolite (PGEM) excretions are markers of cardiovascular and kidney health, because they reflect both systemic and kidney-derived PGE2 production. PGE2 and PGEM were measured in spot urine samples from 2291 participants (≥55 years old)of the population-based Rotterdam Study. Urinary PGE2 and PGEM excretions were analyzed using linear regression analyses to identify cross-sectional associations with cardiovascular risk factors and baseline estimated glomerular filtration rate (eGFR). Longitudinal associations with cardiovascular mortality and kidney outcomes (eGFR <60 or <45 mL/min per 1.73 m2 and the composite outcome 40% eGFR loss or kidney failure) were assessed with Cox regression. Urinary PGE2 and PGEM excretions were higher with increasing age, lower eGFR, smoking, diabetes, and albuminuria. A 2-fold higher urinary PGE2 and PGEM excretion was associated with a higher risk of cardiovascular mortality (28 825 patient-years; 160 events; PGE2 hazard ratio [HR], 1.27, [95% CI, 1.06-1.54]; PGEM HR, 1.36 [95% CI, 1.10-1.67]). Higher PGE2 excretions were also associated with a higher risk of incident eGFR <60 mL/min per 1.73 m2 (31 530 person-years; 691 events; HR, 1.13 [95% CI, 1.02-1.25]) with similar HRs for the other kidney outcomes. Urinary PGE2 and PGEM excretions are novel markers for the presence and progression of cardiovascular and kidney disease. Future studies should address whether these associations are causal and can be targeted to improve cardiovascular and kidney outcomes.

Prostaglandin E-major urinary metabolites as a new biomarker for acute mesenteric ischemia.

Acute mesenteric ischemia (AMI) is an emergent vascular disease caused by cessation of the blood supply to the small intestine. Despite advances in the diagnosis, intervention, and surgical procedures, AMI remains a life-threatening condition. Prostaglandin E2 major urinary metabolite (PGE-MUM), the urinary metabolite of prostaglandin E2, is known to be stable in urine and has been suggested to be a valuable biomarker for intestinal mucosal inflammation, such as ulcerative colitis. We therefore investigated whether or not PGE-MUM levels reflect the degree of ischemia in an intestinal ischemia-reperfusion model. Male rats were used to establish a superior mesenteric artery occlusion (SMAO) group, in which the superior mesenteric artery was clamped, and a sham group. The clamping times in the SMAO group were either 30 minutes or 60 minutes, and reperfusion times were either 3 hours or 6 hours, after which PGE-MUM values were measured. The histological injury score of the SMAO (30-minute ischemia and 6-hour reperfusion group, 1.8 ± 0.4; 60-minute ischemia and 6-hour reperfusion group, 4.7 ± 0.5) and were significantly greater than that of the sham group (0.4 ± 0.7, p < 0.05). The PGE-MUM levels in the SMAO group (30-minutes ischemia and 6-hour reperfusion group, 483 ± 256; 60-minutes ischemia and 6-hour reperfusion group, 889 ± 402 ng/mL) were significantly higher than in the sham group (30-minute and 6-hour observation group, 51 ± 20; 60-minute and 6-hour observation group, 73 ± 32 ng/mL; p < 0.05). Furthermore, the PGE-MUM value was corrected by the concentration of urinary creatinine (Cr). The PGE-MUM/urinary Cr levels in the SMAO group were also significantly higher than in the sham group ( p < 0.05). We found that intestinal ischemia-reperfusion increased urinary PGE-MUM levels depending on the ischemic time. This suggests the potential utility of PGE-MUM as a noninvasive marker of intestinal ischemia.

Predictors of upstream inflammation and oxidative stress pathways during early pregnancy

BackgroundInflammation and oxidative stress are critical to pregnancy, but most human study has focused on downstream, non-causal indicators. Oxylipins are lipid mediators of inflammation and oxidative stress that act through many biological pathways. Our aim was to characterize predictors of circulating oxylipin concentrations based on maternal characteristics. MethodsOur study was conducted among 901 singleton pregnancies in the LIFECODES Fetal Growth Study, a nested case-cohort with recruitment from 2007 to 2018. We measured a targeted panel of oxylipins in early pregnancy plasma and urine samples from several biosynthetic pathways, defined by the polyunsaturated fatty acid (PUFA) precursor and enzyme group. We evaluated levels across predictors, including characteristics of participants’ pregnancy, socioeconomic determinants, and obstetric and medical history. ResultsCurrent pregnancy and sociodemographic characteristics were the most important predictors of circulating oxylipins concentrations. Plasma oxylipins were lower and urinary oxylipins higher for participants with a later gestational age at sampling (13–23 weeks), higher prepregnancy BMI (obesity class I, II, or III), Black or Hispanic race and ethnicity, and lower socioeconomic status (younger age, lower education, and uninsured). For example, compared to those with normal or underweight prepregnancy BMI, participants with class III prepregnancy obesity had 45–46% lower plasma epoxy-eicosatrienoic acids, the anti-inflammatory oxylipins produced from arachidonic acid (AA) by cytochrome P450, and had 81% higher urinary 15-series F2-isoprostanes, an indicator of oxidative stress produced from non-enzymatic AA oxidation. Similarly, in urine, Black participants had 92% higher prostaglandin E2 metabolite, a pro-inflammatory oxylipin, and 41% higher 5-series F2-isoprostane, an oxidative stress indicator. ConclusionsIn this large pregnancy study, we found that circulating levels of oxylipins were different for participants of lower socioeconomic status or of a systematically marginalized racial and ethnic groups. Given associations differed along biosynthetic pathways, results provide insight into etiologic links between maternal predictors and inflammation and oxidative stress.

Mast cells, mediators, and symptomatic activation

&lt;abstract&gt; &lt;p&gt;Mast cells (MC) are central effectors of allergic disease and distinct subsets with varying amounts of tryptase, chymase, and carboxypeptidase A3, and cathepsin G is distributed throughout the body. Their involvement in a diverse range of non-allergic illnesses mediated by a complex range of preformed and newly synthesized mediators is now increasingly recognized. The latter especially include conditions under the umbrella term of mast cell activation syndrome. In allergic disease, much has been written about the mechanisms by which the early and rapidly acting mediators produce both localized and systemic allergic symptoms. The role of chymase is presently underappreciated but there is increased awareness that MCs contain significant amounts of preformed TNF alpha and synthesize and releases a wide range of inflammatory cytokines such as interleukins (IL) 1β, IL6, IL31, and IL33. These can aggravate itching and perpetuate inflammation and likely contribute to the late constitutional symptoms seen in allergic reactions. Importantly, their involvement helps to clarify the role of MCs in stress and non-parasitic infections. Presently, unexplained is the increasing incidence of significant acute allergic reactions within a relatively short time frame. In this context, there is increasing interest in the environmental, menstrual, endocrine, circadian, and psychological factors that influence MC activation as well as the endocrine pathways involving the renin angiotensin system that oppose hypotension. In non-allergic diseases with normal numbers of MCs, reduced thresholds for activation may be produced by various combinations of life and dietary factors. Diagnosing these conditions is difficult but may be helped by urinary analysis of prostaglandin metabolites. The investigation and management of mastocytosis with and without mutations of c-kit is also relevant to allergic disease and the new medications used may also be helpful in idiopathic anaphylaxis. This knowledge may open a new chapter in human diseases and mast cell regulation.&lt;/p&gt; &lt;/abstract&gt;

Protective Effect of Berberine on Acute Gastric Ulcer by Promotion of Tricarboxylic Acid Cycle-Mediated Arachidonic Acid Metabolism.

Peptic ulcer is a high incidence gastrointestinal disease in China. Berberine (BBR) is a natural product isolated from the Chinese herb Coptis chinensis Franch that has protective effects in digestive diseases. We aimed to evaluate the ability of BBR to attenuate acute gastric ulcer induced by one-time administration of ethanol in the rat. Tissue pathological morphology, macroscopic score, ulcer healing rate, and serum levels of the inflammatory cytokines nitric oxide (NO), interleukin-6 (IL-6), and prostaglandin E2 (PGE2), and anti-inflammatory interleukin-10 (IL-10) were used to determine the efficacy of BBR and evaluated to identify the optimal dosage. Subsequently, transcriptome and metabolome sequencing were conducted in Control, Model, and optimal dosage groups to explore the pathogenesis of the disease and the mechanism of action of the drug. The levels of malondialdehyde (MDA), myeloperoxidase (MPO), as well as those of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined by enzyme-linked immunosorbent assay to verify the results of transcriptomics and metabolomics analyses. BBR significantly improved the pathological morphology of gastric ulcers, increased the macroscopic score and healing rate, decreased serum levels of NO, IL-6, and PGE2, and increased serum levels of IL-10, thus effectively alleviating gastric ulcer severity. Transcriptome results showed that the therapeutic effect of BBR was mainly mediated by the arachidonic acid metabolism pathway at the gene level, which is closely associated with inflammation and increased levels of reactive oxygen species (ROS). The differentially accumulated metabolite prostaglandin E1, which is a negative regulator of ROS, was significantly up-regulated after BBR administration. The validation results indicated that BBR pretreatment increased SOD and GSH-Px enzyme activities, while reducing levels of the oxidative products MDA and MPO. This study demonstrated that BBR exerts a protective effect on acute gastric ulcer by promoting tricarboxylic acid cycle-mediated arachidonic acid metabolism.

The COX-2/PGE2 Response Pathway Upregulates Radioresistance in A549 Human Lung Cancer Cells through Radiation-Induced Bystander Signaling.

This study aimed to determine the mechanism underlying the modulation of radiosensitivity in cancer cells by the radiation-induced bystander effect (RIBE). We hypothesized that the RIBE mediates cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) in elevating radioresistance in unirradiated cells. In this study, we used the SPICE-QST microbeam irradiation system to target 0.07-0.7% cells by 3.4-MeV proton microbeam in the cell culture sample, such that most cells in the dish became bystander cells. Twenty-four hours after irradiation, we observed COX-2 protein upregulation in microbeam-irradiated cells compared to that of controls. Additionally, 0.29% of the microbeam-irradiated cells exhibited increased cell survival and a reduced micronucleus rate against X-ray irradiation compared to that of non-microbeam irradiated cells. The radioresistance response was diminished in both cell groups with the hemichannel inhibitor and in COX-2-knockout cells under cell-to-cell contact and sparsely distributed conditions. The results indicate that the RIBE upregulates the cell radioresistance through COX-2/PGE2 intercellular responses, thereby contributing to issues, such as the risk of cancer recurrence.

The effect of aspirin and eicosapentaenoic acid on urinary biomarkers of prostaglandin E2 synthesis and platelet activation in participants of the seAFOod polyp prevention trial.

Urinary prostaglandin (PG) E metabolite (PGE-M) and 11-dehydro (d)-thromboxane (TX) B2 are biomarkers of cyclooxygenase-dependent prostanoid synthesis. We investigated (1) the effect of aspirin 300 mg daily and eicosapentaenoic acid (EPA) 2000 mg daily, alone and in combination, on urinary biomarker levels and, (2) whether urinary biomarker levels predicted colorectal polyp risk, during participation in the seAFOod polyp prevention trial. Urinary PGE-M and 11-d-TXB2 were measured by liquid chromatography-tandem mass spectrometry. The relationship between urinary biomarker levels and colorectal polyp outcomes was investigated using negative binomial (polyp number) and logistic (% with one or more polyps) regression models. Despite wide temporal variability in PGE-M and 11-d-TXB2 levels within individuals, both aspirin and, to a lesser extent, EPA decreased levels of both biomarkers (74% [P ≤ .001] and 8% [P ≤ .05] reduction in median 11-d-TXB2 values, respectively). In the placebo group, a high (quartile [Q] 2-4) baseline 11-d-TXB2 level predicted increased polyp number (incidence rate ratio [IRR] [95% CI] 2.26 [1.11,4.58]) and risk (odds ratio [95% CI] 3.56 [1.09,11.63]). A low (Q1) on-treatment 11-d-TXB2 level predicted reduced colorectal polyp number compared to placebo (IRR 0.34 [0.12,0.93] for combination aspirin and EPA treatment) compared to high on-treatment 11-d-TXB2 values (0.61 [0.34,1.11]). Aspirin and EPA both inhibit PGE-M and 11-d-TXB2 synthesis in keeping with shared in vivo cyclooxygenase inhibition. Colorectal polyp risk and treatment response prediction by 11-d-TXB2 is consistent with a role for platelet activation during early colorectal carcinogenesis. The use of urinary 11-d-TXB2 measurement for a precision approach to colorectal cancer risk prediction and chemoprevention requires prospective evaluation.

Dietary Inflammatory Potential and the Risk of Serrated and Adenomatous Colorectal Polyps

Studies of dietary inflammation potential and risks of colorectal cancer precursors are limited, particularly for sessile serrated lesions (SSLs). This study examines the association using the energy-adjusted dietary inflammatory index (E-DIITM), a measure of anti- and/or pro-inflammatory diet, in a large US colonoscopy-based case-control study of 3246 controls, 1530 adenoma cases, 472 hyperplastic polyp cases, and 180 SSL cases. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression models. Analyses were stratified by participant characteristics, and urinary prostaglandin E2 metabolite (PGE-M) and high-sensitivity plasma C-reactive protein (hs-CRP) levels, inflammation biomarkers. Highest E-DII™ intake was associated with significantly increased risks of colorectal adenomas (OR 1.36, 95% CI 1.11, 1.67), and hyperplastic polyps (OR 1.43, 95% CI 1.06, 1.98), compared with participants consuming the lowest E-DII™ quartile. A similar, but non-significant, increased risk was also observed for SSLs (OR 1.41, 95% CI 0.82, 2.41). The positive association was stronger in females (pinteraction <0.001), normal weight individuals (ptrend 0.01), and in individuals with lower inflammatory biomarkers (ptrend 0.02 and 0.01 for PGE-M and hs-CRP, respectively). A high E-DII™ is associated with colorectal polyp risk, therefore promoting an anti-inflammatory diet may aid in preventing colorectal polyps.

The impact of cyclooxygenase inhibitor use on urinary prostaglandin metabolites in preterm infants

There is limited evidence on the association between the clinical course of patent ductus arteriosus (PDA) and prostaglandin (PG) metabolites. This study aimed to determine the influence of PDA treatment on urinary PG metabolite excretion in very-low-birth-weight (VLBW) infants. Urine samples were collected from 25 VLBW infants at 1, 3, and 7 days of age. Infants were separated into two groups: a PDA-treated group that received a cyclooxygenase-2 (COX) inhibitor (n=12) and a control group that did not receive a COX inhibitor during the first 7 days after birth (n=13). Urinary PG metabolite tetranor prostaglandin E2 metabolite (t-PGEM) and tetranor prostaglandin D2 metabolite (t-PGDM) levels were analyzed using liquid chromatography-tandem mass spectrometry. Urinary t-PGEM excretion levels were not significantly different between the groups at 1, 3, and 7 days of age. Urinary t-PGDM excretion levels at 1 day of age were higher in PDA-treated infants than in control infants (median [interquartile range]: 5.5 [2.6, 12.2] versus 2.1 [1.0, 3.9] ng/mg creatinine; p=0.017); however, among PDA-treated infants, the levels were significantly lower at 3 and 7 days than at 1 day of age (5.5 [2.6, 12.2] versus 3.4 [1.7, 4.5] and 4.0 [1.7, 5.3] ng/mg creatinine, respectively; p<0.05). The urinary t-PGDM excretion level in the control group did not significantly differ among the time points. PDA and COX inhibitor administration affected PG metabolism in VLBW infants. Our results indicated that urinary t-PGDM excretion was significantly associated with PDA-treatment in preterm infants.

The serum lipidomics reveal the action mechanism of Danggui-Yimucao herbal pair in abortion mice.

Medical abortion is a common medical procedure that women choose to terminate an unwanted pregnancy, but it often brings post-abortion complications. Danggui (Angelica sinensis Radix)-Yimucao (Leonuri Herba), as a herbal pair (DY) in clinical prescriptions of traditional Chinese medicine, is often used in the treatment of gynecological diseases and has the traditional functions of tonifying the blood, promoting blood circulation, removing blood stasis and regulating menstruation. In this study, serum lipidomics were adopted to dissect the mechanism of DY in promoting recovery after medical abortion. A total of 152 differential metabolites were screened by lipidomics. All metabolites were imported into MetaboAnalyst for analysis, and finally key metabolic pathways such as glycerophospholipid metabolism, linoleic acid metabolism and pentose and glucuronate interconversions were enriched. Our results indicated that metabolic disorders in abortion mice were alleviated by DY through glycerophospholipid metabolism, while prostaglandin and leukotriene metabolites might be the key targets of DY to promote post-abortion recovery.

Determination of milk concentrations and pharmacokinetics of salicylic acid following acetylsalicylic acid (aspirin) administration in postpartum dairy cows

The objectives of this descriptive study were to 1) describe the pharmacokinetics of salicylic acid (SA) in the milk and plasma of postpartum dairy cattle following oral administration of ace­tylsalicylic acid (ASA) (aspirin); 2) to estimate a recommended milk withdrawal period for dairy cattle treated with ASA; and 3) to determine the impact of ASA administration on plasma prostaglandin E2 metabolite (PGEM) concentrations. Adminis­tration of non-steroidal anti-inflammatory drugs, such as the widely available drug aspirin, or acetylsalicylic acid (ASA), may improve health and milk production in postpartum dairy cows. However, plasma pharmacokinetic data for salicylic acid (SA), the active metabolite of ASA, are unrepresentative of lactating dairy cows and current treatment regimens, and there are cur­rently no published milk residue and minimal pharmacody­namic data available for ASA or SA in dairy cows.

Effects of (20 R)-Panaxadiol on NAFLD using non‑targeted metabolomics in stool

Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by hepatocyte steatosis and adipose accumulation with the main lesion in the hepatic lobule, but without a history of excessive alcohol consumption. NAFLD ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), and may further accumulate fibrosis leading to cirrhosis. Many studies have found that ginseng can treat NAFLD. (20 R)-Panaxadiol (PD) is a panax ginseng diol type compound, has been proved that can treat the obesity. This study wants to investigate the effect of PD on non-alcoholic liver disease. We used 20 ob/ob mice and 10 C57BL/6 J mice. C57BL/6 J mice as CONTROL group, ob/ob mice were divided into model group and PD group. In PD group, ob/ob mice were treated with PD for eight weeks(10 mg/kg, the CON and OB group was given the same amount of sodium carboxymethyl cellulose), detected the weight, food intake and serum index, observed the HE staining of liver and intestine, performed the 16 S rRNA and untargeted metabolomics analysis used mice feces, and verify the results by detect the expression of TNF-α, MDA and SOD. In vivo results, PD can improve abnormal glucose and lipid metabolism and liver function. In 16 S rRNA result, we found beneficial bacteria Muribaculaceae and Lactobacillus increased; in untargeted metabolomics analysis, inflammatory metabolites prostaglandin (PG) and lipopolysaccharide (LPS) decreased, antioxidant metabolites FAD and lipoic acid increased. Then, we proceeded the association analysis of gut microbiota and metabolites, the result showed gut microbiota have strongly associated with anti-inflammatory and antioxidant metabolites. In addition, PD improves intestinal wall integrity. Meanwhile, the expression of TNF-α、MDA and SOD were detected, it was verified that PD has the effect of antioxidant and anti-inflammation. Our study showed that PD, as an active ingredient of ginseng, can play an anti-inflammatory and antioxidant role by improving intestinal metabolites, thereby preventing and treating non-alcoholic fatty liver disease to a certain extent.