Urinary Prostaglandin E2 Metabolite Research Articles

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.

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.

Airway and Systemic Prostaglandin E2 Association with COPD Symptoms and Macrophage Phenotype.

Polymorphisms and products of the cyclooxygenase (COX) pathway have been associated with the development of chronic obstructive pulmonary disease (COPD) and adverse outcomes. COX-produced prostaglandin E2 (PGE-2) may play a role in the inflammation observed in COPD, potentially through deleterious airway macrophage polarization. A better understanding of the role of PGE-2 in COPD morbidity may inform trials for therapeutics targeting the COX pathway or PGE-2. Urine and induced sputum were collected from former smokers with moderate-severe COPD. The major urinary metabolite of PGE-2 (PGE-M) was measured, and ELISA was performed on sputum supernatant for PGE-2 airway measurement. Airway macrophages underwent flow cytometry phenotyping (surface CD64, CD80, CD163, CD206, and intracellular IL-1β, TGF-β1). Health information was obtained the same day as the biologic sample collection. Exacerbations were collected at baseline and then monthly telephone calls. Among 30 former smokers with COPD (mean±SD age 66.4±8.88 years and forced expiratory volume in 1 second [FEV1] 62.4±8.37 percent predicted), a 1 pg/mL increase in sputum PGE-2 was associated with higher odds of experiencing at least one exacerbation in the prior 12 months (odds ratio 3.3; 95% confidence interval: 1.3 to15.0), worse respiratory symptoms and health status. PGE-M was not associated with exacerbations or symptoms. Neither airway PGE-2 nor urinary PGE-M was uniformly associated with an M1 or M2 polarization. Elevated levels of sputum PGE-2, rather than systemic PGE-2, is associated with increased respiratory symptoms and history of exacerbation among individuals with COPD. Additional studies focused on mechanism of action are warranted.

Association of urinary prostaglandin E2 metabolite and mortality among adults

Prostaglandins play a critical role in inflammatory response. To investigate the association of urinary PGE-M, a stable end-product of prostaglandin E2 (PGE2) with overall and cause-specific mortality and examine potential effect modifiers, we obtained urinary PGE-M levels of 2927 non-cancerous adults from our previous case-control studies nested in the Shanghai Women’s Health Study and Shanghai Men’s Health Study, two cohort studies conducted in Shanghai, China. Mortality data and modifiable factors associated with urinary PGE-M were obtained from the parent cohort studies. Using linear regression models, we found that high urinary PGE-M levels were significantly associated with low education, heaving smoking, old age at urine collection, and abdominal obesity. Using Cox proportional hazards models, we found that increase (per standard deviation) of urinary PGE-M levels were significantly associated with overall mortality (adjusted hazard ratio = 1.19, 95% confidence interval: 1.07, 1.33) and particularly deaths from cardiometabolic diseases (adjusted hazard ratio = 1.27, 95% confidence interval: 1.11, 1.44). The increased death risks persisted across different time intervals during the follow-up and were stronger among participants who were younger than 60 (P = 0.0014 for all- cause mortality and P = 0.007 for deaths from cardiometabolic diseases) at urine collection or perhaps among those who had higher education.

Effect of Dysglycemia on Urinary Lipid Mediator Profiles in Persons With Pulmonary Tuberculosis

BackgroundOxidized lipid mediators such as eicosanoids play a central role in the inflammatory response associated with tuberculosis (TB) pathogenesis. Diabetes mellitus (DM) leads to marked changes in lipid mediators in persons with TB. However, the associations between diabetes-related changes in lipid mediators and clearance of M. tuberculosis (Mtb) among persons on anti-TB treatment (ATT) are unknown. Quantification of urinary eicosanoid metabolites can provide insights into the circulating lipid mediators involved in Mtb immune responses.MethodsWe conducted a multi-site prospective observational study among adults with drug-sensitive pulmonary TB and controls without active TB; both groups had sub-groups with or without dysglycemia at baseline. Participants were enrolled from RePORT-Brazil (Salvador site) and RePORT-South Africa (Durban site) and stratified according to TB status and baseline glycated hemoglobin levels: a) TB-dysglycemia (n=69); b) TB-normoglycemia (n=64); c) non-TB/dysglycemia (n=31); d) non-TB/non-dysglycemia (n=29). We evaluated the following urinary eicosanoid metabolites: 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (major urinary metabolite of prostaglandin E2, PGE-M), tetranor-PGE1 (metabolite of PGE2, TN-E), 9α-hydroxy-11,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (metabolite of PGD2, PGD-M), 11-dehydro-thromboxane B2 (11dTxB2), 2,3-dinor-6-keto-PGF1α (prostaglandin I metabolite, PGI-M), and leukotriene E4 (LTE4). Comparisons between the study groups were performed at three time points: before ATT and 2 and 6 months after initiating therapy.ResultsPGE-M and LTE4 values were consistently higher at all three time-points in the TB-dysglycemia group compared to the other groups (p<0.001). In addition, there was a significant decrease in PGI-M and LTE4 levels from baseline to month 6 in the TB-dysglycemia and TB-normoglycemia groups. Finally, TB-dysglycemia was independently associated with increased concentrations of PGD-M, PGI-M, and LTE4 at baseline in a multivariable model adjusting for age, sex, BMI, and study site. These associations were not affected by HIV status.ConclusionThe urinary eicosanoid metabolite profile was associated with TB-dysglycemia before and during ATT. These observations can help identify the mechanisms involved in the pathogenesis of TB-dysglycemia, and potential biomarkers of TB treatment outcomes, including among persons with dysglycemia.

Urinary PGE-M in Men with Prostate Cancer.

Simple SummaryElevated levels of urinary prostaglandin E metabolite (PGE-M), a marker of inflammation, have previously been associated with cancer incidence and metastasis. Studies investigating PGE-M in prostate cancer are lacking even though chronic inflammation is a candidate risk factor for the disease. We investigated the association of PGE-M with lethal prostate cancer. We measured PGE-M in the urine of men with prostate cancer and in men without prostate cancer (population controls). Our participants included African American and European American men. Because African American men die more frequently from prostate cancer than European American men, we investigated whether high PGE-M may contribute to the increased mortality among African American prostate cancer patients. We did not observe a relationship between PGE-M and prostate cancer aggressiveness or prostate cancer-specific mortality in our study population, neither in the combined cohort nor in the race/ethnicity stratified analysis. Interestingly, however, we observed a significant relationship between high PGE-M and all-cause mortality in African American men with prostate cancer. Yet, there was no association between high PGE-M and all-cause mortality when these men were regular aspirin users.Urinary PGE-M is a stable metabolite of prostaglandin E2 (PGE2). PGE2 is a product of the inflammatory COX signaling pathway and has been associated with cancer incidence and metastasis. Its synthesis can be inhibited by aspirin. We investigated the association of PGE-M with lethal prostate cancer in a case–control study of African American (AA) and European American men. We measured urinary PGE-M using mass-spectrometry. Samples were obtained from 977 cases and 1022 controls at the time of recruitment. We applied multivariable logistic and Cox regression modeling to examine associations of PGE-M with prostate cancer and participant survival. Median survival follow-up was 8.4 years, with 246 deaths among cases. Self-reported aspirin use over the past 5 years was assessed with a questionnaire. Race/ethnicity was self-reported. Urinary PGE-M levels did not differ between men with prostate cancer and population-based controls. We observed no association between PGE-M and aggressive disease nor prostate-cancer-specific survival. However, we observed a statistically significant association between higher (>median) PGE-M and all-cause mortality in AA cases who did not regularly use aspirin (HR = 2.04, 95% CI 1.23–3.37). Among cases who reported using aspirin, there was no association. Our study does not support a meaningful association between urinary PGE-M and prostate cancer. Moreover, PGE-M levels were not associated with aggressive prostate cancer. However, the observed association between elevated PGE-M and all-cause mortality in AA non-aspirin users reinforces the potential benefit of aspirin to reduce mortality among AA men with prostate cancer.

Urinary 8-iso PGF2α and 2,3-dinor-8-iso PGF2α can be indexes of colitis-associated colorectal cancer in mice

Early diagnosis of colorectal cancer is needed to reduce the mortal consequence by cancer. Lipid mediators play critical role in progression of colitis and colitis-associated colon cancer (CAC) and some of their metabolites are excreted in urine. Here, we attempted to find novel biomarkers in urinary lipid metabolite of a murine model of CAC. Mice were received single administration of azoxymethane (AOM) and repeated administration of dextran sulfate sodium (DSS). Lipid metabolites in their urine was measured by liquid chromatography mass spectrometry and their colon was collected to perform morphological study. AOM and DSS caused inflammation and tumor formation in mouse colon. Liquid chromatography mass spectrometry-based comprehensive analysis of lipid metabolites showed that cyclooxygenase-mediated arachidonic acid (AA) metabolites, prostaglandins, and reactive oxygen species (ROS)-mediated AA metabolites, isoprostanes, were predominantly increased in the urine of tumor-bearing mice. Among that, urinary prostaglandin (PG)E2 metabolite tetranor-PGEM and PGD2 metabolite tetranor-PGDM were significantly increased in both of urine collected at the acute phase of colitis and the carcinogenesis phase. On the other hand, two F2 isoprostanes (F2-IsoPs), 8-iso PGF2α and 2,3-dinor-8-iso PGF2α, were significantly increased only in the carcinogenesis phase. Morphological study showed that infiltrated monocytes into tumor mass strongly expressed ROS generator NADPH (p22phox). These observations suggest that urinary 8-iso PGF2α and 2,3-dinor-8-iso PGF2α can be indexes of CAC.

Abstract A26: Pilot trial to examine the effect of ginger on the gut microbiome: The Minnesota Cancer Clinical Trials Network

Abstract Experimental and epidemiologic evidence shows that the use of ginger root may reduce the incidence of colorectal cancer (CRC), but the mechanism through which ginger exerts its effect is unclear. Recently, an imbalanced gut microbiome was linked to inflammation, immune response, and CRC risk. Thus, we hypothesize that ginger intake may decrease CRC risk via changing the gut microbiome. The goals of this study are (1) assess whether ginger intake shifts the distribution of the gut microbiome from proinflammatory, CRC-predisposing bacteria and towards anti-inflammatory, CRC-protective bacteria and (2) evaluate the feasibility of conducting a large randomized clinical trial (RCT) leveraging the recently established Minnesota Cancer Clinical Trials Network (MNCCTN). We will conduct a pilot double-blind RCT, called “GINGER,” of 95-100 subjects aged 50-75 years old who were diagnosed with colorectal adenoma within the last 5 years (ClinicalTrials.gov NCT03268655). The subjects will be randomized to receive either 2,000 mg of ginger extract per day or matching placebo (1:1) for 6 weeks; the treatment phase will be followed by a 6-week washout. Fecal samples to characterize the gut microbiome will be collected at baseline, midpoint (week 6), and study end. Microbiome composition will be characterized by sequencing microbial 16S ribosomal RNA genes. In addition, pre- and postexposure urine samples will be collected to examine the correlation between bacteria and urinary metabolite of prostaglandin E2, which is an inflammatory biomarker and a putative biomarker for CRC. The methodology for “GINGER” was informed by an RCT recently completed by our group that involved aspirin as the intervention. In that RCT, which included 50 subjects and 5 stool collections within 12 weeks, 49 subjects completed the entire study and all stool collections. Adherence rates for the aspirin measured by pill count was at least 90%. Thus, these pilot data support the feasibility of the GINGER study. To implement the “GINGER,” we are using the resources of the MNCCTN, established in 2017. The MNCCTN, funded by Minnesota legislature and led by Masonic Cancer Center, University of Minnesota, will bring the “GINGER” and subsequent cancer clinical trials to communities throughout Minnesota, thus reducing the patients’ burden of travel and related costs. The network partners with Minnesota’s five largest health care providers (Essentia Health, Sanford Health, Mayo Clinic Cancer Center, Metro-Minnesota Community Oncology Research Consortium, and Fairview Health System) to provide infrastructure for conducting cancer trials at 18 sites outside the Twin-Cities metro area and Rochester, Minnesota. The “GINGER”—the first study conducted within the network—will begin recruitment in 3 sites by the end of November and in 6 sites by the end of 2018. Based on our previous experience, we expect to recruit 24-25 (25%) subjects in 3 months, 50%, in 6 months and all subjects by the end of 2019. Citation Format: Anna Prizment, Timothy R. Church, Dorothy Hatsukami, Robert Madoff, Christopher Staley, Robert J. Straka, Allison Iwan, Jenn Stromberg, Ya-Feng Wen, Cheryl Stibbe, Marie Rahne. Pilot trial to examine the effect of ginger on the gut microbiome: The Minnesota Cancer Clinical Trials Network [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr A26.

Performance of candidate urinary biomarkers for pancreatic cancer - Correlation with pancreatic cyst malignant progression?

BackgroundIntraductal papillary mucinous neoplasms (IPMN) are precursors of pancreatic cancer. Potential biomarkers of IPMN progression have not been identified in urine. A few urinary biomarkers were reported to be predictive of pancreatic ductal adenocarcinoma (PDAC). Here, we seek to assess their ability to detect high-risk IPMN. MethodsUrine was collected from patients undergoing pancreatic resection and healthy controls. TIMP-1(Tissue Inhibitor of Metalloproteinase-1), LYVE-1(Lymphatic Vessel Endothelial Receptor 1), and PGEM(Prostaglandin E Metabolite) levels were determined by ELISA and analyzed by Kruskal-Wallis. ResultsMedian urinary TIMP-1 levels were significantly lower in healthy controls (n = 9; 0.32 ng/mg creatinine) compared to PDAC (n = 13; 1.95) but not significantly different between low/moderate-grade (n = 20; 0.71) and high-grade/invasive IPMN (n = 20; 1.12). No significant difference in urinary LYVE-1 was detected between IPMN low/moderate (n = 16; 0.37 ng/mg creatinine) and high/invasive grades (n = 21; 0.09). Urinary PGEM levels were not significantly different between groups. ConclusionsUrinary TIMP-1, LYVE-1, and PGEM do not correlate with malignant potential of pancreatic cysts.

Urinary prostaglandin D2 and E2 metabolites associate with abdominal obesity, glucose metabolism, and triglycerides in obese subjects

Obesity is associated with low-grade chronic inflammation, which contributes to the development of the metabolic syndrome and its associated complications, such as insulin resistance and type-2 diabetes. Limited data from animal and human studies support local generation of pro-inflammatory prostanoid lipid mediators in white adipose tissue. However, the link between systemic prostanoid levels and parameters characterizing the metabolic syndrome is missing in human obesity. Therefore, we performed a targeted lipidomic analysis using urine samples from obese human subjects (n = 45) and show for the first time in humans that urinary prostanoid levels correlate with metabolic parameters that indicate a dysregulated glucose and triglyceride metabolism. We identified tetranor-PGDM and tetranor-PGEM as the two major urinary prostanoid metabolites in obese subjects with levels of 247 ± 31 and 23.3 ± 4.0 pmol/mg creatinine, respectively. Tetranor-PGDM was significantly associated with serum triglycerides, while tetranor-PGEM was associated with abdominal obesity as defined by an increased waist-to-hip ratio (WHR), with glycated hemoglobin (HbA1c), and with impaired oral glucose tolerance. These results confirm the previously established notion of low-grade chronic inflammation in obesity and further identify an association of the prostanoid pathway with obesity-associated dyslipidemia, abdominal obesity, and insulin resistance.

Effects of cessation of cigarette smoking on eicosanoid biomarkers of inflammation and oxidative damage.

The urinary metabolites “prostaglandin E2 metabolite” (PGE-M) and (Z)-7-[1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopentyl]hept-5-enoic acid (8-iso-PGF2α) are biomarkers of inflammation and oxidative damage, respectively, and are elevated in cigarette smokers. Relatively little is known about the effects of smoking cessation on these biomarkers. To investigate this, current cigarette smokers interested in quitting were recruited and invited to participate in a smoking cessation study where varenicline (Chantix) and brief supportive behavioral counseling were offered at each visit after baseline. Subjects returned to the clinic during the 12 week treatment phase for 9 visits post cessation on days 3, 7, 14, 21, 28, 42, 56, 70 and 84. Urine samples were collected at each visit and analyzed by liquid chromatography-tandem mass spectrometry for PGE-M, 8-iso-PGF2α, and cotinine. Cotinine values demonstrated that 15 of 38 subjects quit smoking for the entire 84 day period. Significant decreases in mean levels of PGE-M and 8-iso-PGF2α per milligram creatinine were observed in these subjects, by 44% (p = 0.0014) and 27% (p<0.001), respectively. The results of this study demonstrate that cessation of smoking for 84 days results in modest but significant declines in urinary PGE-M and 8-iso-PGF2α indicating reductions in systemic inflammation and oxidative damage. Given that levels were only modestly decreased, these markers are not specific to tobacco-smoke exposure. The modest declines in these biomarkers should be considered when planning studies with ex-smokers. There is a “hangover” from smoking that lasts at least 3 months.

Effects of fish oil supplementation on eicosanoid production in patients at higher risk for colorectal cancer.

Fish oil supplementation may represent a potential chemopreventive agent for reducing colorectal cancer risk. The mechanism of action of fish oil is unknown but presumed to be related to eicosanoid modification. The purpose of this study was to evaluate the effects of fish oil supplementation on the levels of urinary and rectal eicosanoids. We conducted a randomized, double-blind, controlled trial of 2.5 g of fish oil per day compared with olive oil supplementation over a 6-month period. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1), which affects tissue levels of arachidonic acid. A total of 141 participants were randomized. Urinary prostaglandin E2 metabolite (PGE-M) was measured at baseline, 3, and 6 months and rectal prostaglandin E2 (PGE2) at baseline and 6 months. Repeated-measures linear regression was used to determine the effect of the intervention on each outcome measure. Overall, fish oil supplementation was found to reduce urinary PGE-M production compared with olive oil (P=0.03). Fish oil did not reduce rectal PGE2 overall; however, it did significantly reduce PGE2 in the subgroup of participants not using aspirin or NSAIDs (P=0.04). FADS1 genotype did not seem to modify effects of fish oil on PGE2 production. We conclude that fish oil supplementation has a modest but beneficial effect on eicosanoids associated with colorectal carcinogenesis, particularly in those not taking aspirin or NSAIDs.

Urinary PGE2 metabolite levels in hospitalised infants with infections compared to age-matched controls.

To determine the urinary tetranor-prostaglandin E2 metabolite in healthy infants and in hospitalised infants with upper and lower respiratory tract as well as gastrointestinal infections. A prospective cross-sectional study to determine baseline concentrations of urinary tetranor-prostaglandin E2 metabolite was conducted in 81 healthy infants aged one week to one year and in 142 hospitalised infants with infections. Prostaglandin metabolite levels were measured by liquid chromatography tandem mass spectrometry. In healthy infants, urinary prostaglandin E2 metabolite levels decreased with age and did not differ between girls and boys. Infections of the lower respiratory (n=78) and gastrointestinal tract (n=12) correlated with increased levels of the prostaglandin E2 metabolite. In contrast, infants hospitalised with upper respiratory tract infections (n=23) exhibited similar levels as healthy, age-matched controls. Lower prostaglandin E2 levels were found after treatment with acetaminophen in hospitalised children. Prostaglandin E2 metabolite levels did not correlate with length of hospitalisation or need for respiratory support. This study first provides normal levels of urinary prostaglandin E2 metabolite in infants and secondly demonstrates elevated levels in hospitalised children with lower respiratory tract and gastrointestinal infections.

The impact of cyclooxygenase‐2 selective and non‐isoform selective NSAIDs on the gut microbiota

Nonsteroidal anti‐inflammatory drugs (NSAIDs) exert their analgesic and anti‐inflammatory effects by inhibiting the cyclooxygenase (COX)‐1 and/or COX‐2, enzymes involved in biotransformation of arachidonic acid into prostanoids. It was previously reported that some NSAIDs alter populations of bacteria in the gut and modify the way that NSAIDs work in the body. Here we directly compared the impact of NSAIDs, selective (celecoxib) and non‐selective (naproxen) for COX‐2 inhibition, on the composition of the gut microbiota in mice. We conducted a longitudinal study in adult male C57BL/6 mice that were fed ad libitum with a regular chow or with a diet containing celecoxib or naproxen for three weeks. Naproxen caused significant COX‐1 inhibition as reflected by a ~70% inhibition of urinary thromboxane metabolite (TxM), an in vivo index of COX‐1 activity, and a 60% inhibition of a COX‐1/COX‐2 urinary prostaglandin (PG)E2 metabolite (PGEM), as measured by LC‐MS/MS. The treatment with celecoxib caused a significant 40% reduction of PGEM, but had no significant effect on TxM. Fecal samples were collected on day zero and day 21, DNA purified, 16S rRNA gene segments amplified using V1V2 primers, and amplicons sequenced. Community structure was compared using UniFrac, which generates distances between all pairs of samples as shared distances on a common phylogenetic tree, allowing assessment of clustering and gradients in community composition. For the unweighted analysis, the control group did not show a significant change over time (p=0.34; Permutational Multivariate Analysis of Variance Using Distance Matrices (‘Adonis’ function in R)), while a strong change was seen for naproxen (p=0.007; Adonis), and a lesser change was seen for celecoxib (p=0.023; Adonis). For the weighted analysis, the control group again did not change (p=0.31; Adonis), naproxen showed a trend (p= 0.089; Adonis), and no change was seen with celecoxib (p= 0.23; Adonis). Analysis of specific lineages showed strong longitudinal changes in some sequence clusters (operational taxonomic units), including Bacteroidetes S24‐7 and Clostridiales both p values &lt; 10−4). Moreover, we observed that naproxen caused gastroenteropathy in mice. The stomach of naproxen‐treated mice showed pyloric mucosal erosion and ulcers while the small intestine showed ulceration, inflammation in the lamina propria and epithelium, and thickening and blunting of the villi. Significantly fewer and less severe lesions were observed in mice treated with celecoxib both in the stomach and in the intestine. Thus, both NSAIDs have an impact on the composition of the gut microbiota, with the stronger effects seen for naproxen versus celecoxib. Effects were most evident in the unweighted analysis, indicating a greater effect on community membership than on their relative proportions. These data are consistent with the hypothesis that microbial dysbiosis is involved in the NSAID‐induced enteropathy that is more common with non‐isoform selective than COX‐2 selective NSAIDs.Support or Funding InformationThis work was supported by NIH grant U54 HL117798 to Garret A. FitzGerald.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial

The overexpression of cyclooxygenase 2 (COX-2) gene, also known as prostaglandin-endoperoxide synthase 2 ( PTGS2), occurs in breast cancer, but whether it affects response to anticox drugs remains unclear. We investigated the relationships between PTGS2 expression, celecoxib use during neoadjuvant chemotherapy (NAC), and both event-free survival (EFS) and overall survival (OS). We analyzed a cohort of 156 patients with human epidermal growth factor receptor 2 -negative breast cancer from the REMAGUS02 (ISRCTN Registry No. 10059974) trial with pretreatment PTGS2 expression data. Patients were treated by sequential NAC (epirubicin plus cyclophosphamide followed by docetaxel with or without celecoxib). Experimental validation was performed on breast cancer cell lines. The Cancer and Leukemia Group B (CALGB) 30801 ( ClinicalTrials.gov identifier: NCT01041781) trial that tested chemotherapy with or without celecoxib in patients with lung cancer served as an independent validation cohort. After 94.5 months of follow-up, EFS was significantly lower in the celecoxib group (hazard ratio [HR], 1.7; 95% CI, 1 to 2.88; P = .046). A significant interaction between PTGS2 expression and celecoxib use was detected ( Pinteraction = .01). In the PTGS2-low group (n = 100), EFS was lower in the celecoxib arm (HR, 3.01; 95% CI, 1.45 to 6.24; P = .002) than in the standard treatment arm. Celecoxib use was an independent predictor of poor EFS, distant relapse-free survival, and OS. Celecoxib in addition to docetaxel enhanced cell viability in PTGS2-low cell lines but not in PTGS2-high cell lines. In CALGB 30801, a trend toward poorer progression-free survival was observed in the patients with low urinary metabolite of prostaglandin E2 who received celecoxib (HR = 1.57; 95% CI, 0.87 to 2.84; P = .13). Celecoxib use during chemotherapy adversely affected survival in patients with breast cancer, and the effect was more marked in PTGS2-low and/or estrogen receptor-negative tumors. COX-2 inhibitors should preferably be avoided during docetaxel use in patients with breast cancer who are undergoing NAC.

Investigating the Impact of Selective Cox-2 and 5-Lox Blockers on Inflammatory Markers within Urinary Samples of Smoker Volunteers

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) consumed arachidonate for the production of eicosanoids which play a role in the inflammation (like COPD), carcinogenesis (like lung cancer), and cardiovascular diseases. This study was designed to introduce noninvasive biomarkers and therapies that aim to reduce the risk for individuals with greater risk of developing smoking-related lung diseases. During this prospective randomized clinical trial, urinary concentration of prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), as markers of COX and 5-LOX inflammatory process, was measured in former (arm A); current (arm B); and never smoker subjects at zero time. The effect of the three treatment groups: etoricoxib and zileuton as a selective COX-2 and 5-LOX inhibitors, respectively, and their combination on the concentrations of these inflammatory markers were evaluated in the current and former smoking population, after 4 weeks. Analysis of variance (ANOVA), chi-square, and paired t-test were applied to analyze our data. At zero time, concentrations of both inflammatory markers were high and significantly associated with status of smoking, which confirmed by measurement of cotinine levels (p<0.05). Treatment with etoricoxib alone and etoricoxib – zileuton combination significantly reduced urinary PGE-M levels, while zileuton alone significantly elevated this marker, in both former and current smokers, compared with their pretreatment values (p<0.05). In addition, treatment with zileuton alone and etoricoxib – zileuton combination significantly reduced urinary LTE4 levels, while etoricoxib alone significantly elevated this marker, in both former and current smokers, compared with their pretreatment values (p<0.05). Former and current smokers were well tolerated with these therapeutic regimens, with no reports of any serious adverse effects. One can conclude that a subclinical respiratory inflammation may associate with smoking people, reflected by elevated levels of PGE-M and LTE4 within urinary samples. Combining etoricoxib and zileuton was associated with inhibition of both COX-2 and 5-LOX pathways manifested by reduced levels of urinary PGE-M and LTE4, for both former and current smokers.

Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study

Primary hypertrophic osteoarthropathy (PHO) is an inherited disease characterized by digital clubbing, periostosis, and pachydermia. Based on two causative genes, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1), PHO is categorized into two subtypes: hypertrophic osteoarthropathy, primary, autosomal recessive 1 (PHOAR1) and hypertrophic osteoarthropathy, primary, autosomal recessive 2 (PHOAR2). In this study, we summarized the clinical manifestations and analyzed SLCO2A1 gene in 23 PHOAR2 patients in our center. As a result, 18 patients displayed complete phenotypes of PHO with digital clubbing, periostosis, and pachydermia. 29 mutations were found in total, and 22 of them were novel mutations including 13 missense, three nonsense, four deletion, one frame-shift and one splicing site mutations. Compared with nine PHOAR1 patients we previously reported, PHO patients with SLCO2A1 mutations were all male and presented with a later onset age. Peptic ulcers and myelofibrosis occurred only in PHOAR2 patients. The urinary level of prostaglandin E2 metabolite (PGEM) is significantly higher in PHOAR2 patients than that in PHOAR1 group. In conclusion, this study was the largest cohort to date to summarize PHOAR2 patients and to assess the phenotypic difference between two subtypes of PHO. The difference of urinary PGEM concentration between two subtypes is helpful for the differential diagnosis of PHO.

Prospective study of urinary prostaglandin E2 metabolite and pancreatic cancer risk.

The cyclooxygenase 2 (COX-2) pathway is upregulated in many pancreatic cancer cells, and it is believed that carcinogenetic effects of COX-2 upregulation are largely through prostaglandin E2 (PGE2) overproduction. We tested this hypothesis by evaluating the association between urinary PGE2 metabolites (PGE-M), a biomarker of in vivo PGE2 overproduction, and pancreatic cancer risk. We conducted a case-control study with 722 subjects (239 cases and 483 controls) nested within two prospective cohort studies, the Shanghai Women's Health Study (SWHS) and Shanghai Men's Health Study (SMHS). Pre-diagnosis urine samples were measured for PGE-M using a liquid chromatography/tandem mass spectrometric method. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (95%CI), with adjustment for potential confounders. Compared to those with the lowest urine level of PGE-M (the first quartile), individuals with higher urine levels of PGE-M had an increased risk of developing pancreatic cancer, with adjusted ORs (95%CI) of 1.63 (0.98-2.73), 1.55 (0.90-2.69) and 1.94 (1.07-3.51), for the second to the fourth quartile groups, respectively (p for trend = 0.054). This dose-response positive association was more evident among those who had BMI <25 kg/m2 than overweight individuals (p for interaction = 0.058). After excluding cases diagnosed in the first year of follow-up and their matched controls, this positive association persisted (p for trend = 0.037) and the interaction became statistically significant (p for interaction = 0.017). Our study adds additional evidence that the COX-2 pathway is involved in pancreatic carcinogenesis and suggests that urinary PGE-M may serve as a biomarker for predicting pancreatic cancer risk.