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Fowler, Christopher JORCID iD iconorcid.org/0000-0002-6658-7874
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Publications (10 of 81) Show all publications
Deplano, A., Cipriano, M., Moraca, F., Novellino, E., Catalanotti, B., Fowler, C. J. & Onnis, V. (2019). Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors. Journal of enzyme inhibition and medicinal chemistry (Print), 34(1), 562-576
Open this publication in new window or tab >>Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors
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2019 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 34, no 1, p. 562-576Article in journal (Refereed) Published
Abstract [en]

Fatty Acid Amide Hydrolase (FAAH) is a serine hydrolase that plays a key role in controlling endogenous levels of endocannabinoids. FAAH inhibition is considered a powerful approach to enhance the endocannabinoid signalling, and therefore it has been largely studied as a potential target for the treatment of neurological disorders such as anxiety or depression, or of inflammatory processes. We present two novel series of amide derivatives of ibuprofen designed as analogues of our reference FAAH inhibitor Ibu-AM5 to further explore its structure-activity relationships. In the new amides, the 2-methylpyridine moiety of Ibu-AM5 was substituted by benzylamino and piperazinoaryl moieties. The obtained benzylamides and piperazinoarylamides showed FAAH inhibition ranging from the low to high micromolar potency. The binding of the new amides in the active site of FAAH, estimated using the induced fit protocol, indicated arylpiperazinoamides binding the ACB channel and the cytosolic port, and benzylamides binding the ACB channel.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Ibuprofen amides, FAAH inhibition, fatty acid amide hydrolase, endocannabinoids, induced fit docking
National Category
Pharmacology and Toxicology Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-156327 (URN)10.1080/14756366.2018.1532418 (DOI)000456778800001 ()30688118 (PubMedID)
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-02-13Bibliographically approved
Chen, Z., Mori, W., Deng, X., Cheng, R., Ogasawara, D., Zhang, G., . . . Liang, S. H. (2019). Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a "Tail Switching" Strategy on a Piperazinyl Azetidine Skeleton. Journal of Medicinal Chemistry, 62(7), 3336-3353
Open this publication in new window or tab >>Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a "Tail Switching" Strategy on a Piperazinyl Azetidine Skeleton
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2019 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 7, p. 3336-3353Article in journal (Refereed) Published
Abstract [en]

Monoacylglycerol lipase (MAGL) is a senile hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with C-11 or F-18. [C-11]8 ([C-11]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [C-11]17 ([C-11]PAD) and [F-18]37 ([F-18]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-158574 (URN)10.1021/acs.jmedchem.8b01778 (DOI)000464768300012 ()30829483 (PubMedID)
Available from: 2019-05-27 Created: 2019-05-27 Last updated: 2019-05-27Bibliographically approved
Alhouayek, M., Rankin, L., Gouveia-Figueira, S. C. & Fowler, C. J. (2019). Interferon γ treatment increases endocannabinoid and related N-acylethanolamine levels in T84 human colon carcinoma cells. Paper presented at 8th European Workshop on Cannabinoid Research, Roehampton, England, United Kingdom, 31 August - 2 September, 2017. British Journal of Pharmacology, 176(10), 1470-1480
Open this publication in new window or tab >>Interferon γ treatment increases endocannabinoid and related N-acylethanolamine levels in T84 human colon carcinoma cells
2019 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 176, no 10, p. 1470-1480Article in journal (Refereed) Published
Abstract [en]

Background and purpose: Endocannabinoids and related N-acylethanolamines (NAEs) are involved in regulation of gut function, but relatively little is known as to whether inflammatory cytokines such as IFN affect their levels. We have investigated this in vitro using cultures of T84 colon cancer cells.

Experimental approach: T84 cells, when cultured in monolayers, differentiate to form adult colonic crypt-like cells with excellent permeability barrier properties. The integrity of the permeability barrier in these monolayers was measured using transepithelial electrical resistance (TEER). NAE levels were determined by ultra-performance liquid chromatography-tandem mass spectrometric analysis. Expression of the enzymes involved in NAE and 2-arachidonoylglycerol (2-AG) turnover were assessed with qPCR.

Key results: IFN treatment for 8 or 24h increased levels of both endocannabinoids (anandamide and 2-AG) and the related NAEs. The treatment did not affect the rate of hydrolysis of either anandamide or palmitoylethanolamide by intact cells, and in both cases, fatty acid amide hydrolase (FAAH) rather than NAE-hydrolysing acid amidase (NAAA) was mainly responsible for the hydrolysis of these NAEs. IFN treatment reduced the TEER of the cells in a manner that was not prevented by inhibition of either FAAH or NAAA but was partially reversed by apical administration of the NAE palmitoylethanolamide.

Conclusion and implications: IFN treatment mobilized endocannabinoid and related NAE levels in T84 cells. However, blockade of anandamide or NAE hydrolysis was insufficient to negate the deleterious effects of this cytokine upon the permeability barrier of the cell monolayers.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-159393 (URN)10.1111/bph.14135 (DOI)000466968400010 ()29313885 (PubMedID)
Conference
8th European Workshop on Cannabinoid Research, Roehampton, England, United Kingdom, 31 August - 2 September, 2017
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Szeremeta, J., Karlsson, J., Alhouayek, M. & Fowler, C. J. (2019). Low mRNA expression and activity of monoacylglycerol lipase in human SH-SY5Y neuroblastoma cells. Prostaglandins & other lipid mediators, 142, 59-67
Open this publication in new window or tab >>Low mRNA expression and activity of monoacylglycerol lipase in human SH-SY5Y neuroblastoma cells
2019 (English)In: Prostaglandins & other lipid mediators, ISSN 1098-8823, E-ISSN 2212-196X, Vol. 142, p. 59-67Article in journal (Refereed) Published
Abstract [en]

Relatively little is known about the endocannabinoid system in human neuroblastoma cell lines. In the present study, we have investigated the expression of the genes coding for the enzymes involved in the synthesis and catabolism of endocannabinoids in the SH-SY5Y cell line. The expression of MGLL, the gene coding for the 2-arachidonoylglycerol hydrolytic enzyme monoacylglycerol lipase (MAGL), was found to be 85 and 340 fold lower than the expression levels for the genes coding for alpha/beta-hydrolase domain containing 6 and 12 (ABHD6, ABHD12), which are alternative hydrolytic enzymes for this endocannabinoid. In comparison, mRNA levels of MGLL were 1.5 fold higher than ABHD6 and 2 fold lower than the levels of ABHD12 in DU-145 human prostate cells. In functional assays, the hydrolysis of the 2-arachidonoylglycerol homologue 2-oleoylglycerol by intact SH-SY5Y cells was partially inhibited by the ABHD6 inhibitor WWL70, but not by the MAGL inhibitor JZL184, whereas the reverse was true in DU-145 cells. The combination of JZL184 + WWL70 did, however produce a significantly greater inhibition of 2-OG hydrolysis than seen with WWL70 alone in the SH-SY5Y cells. The low MGLL expression in the SH-SY5Y cells was not due to epigenetic silencing, since levels were not affected by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine and/or the histone acetylase inhibitor trichostatin A. The low MGLL expression in SH-SY5Y cells should be taken into account when using these cells in experiments investigating the involvement of the endocannabinoid system in models of physiological and pathological processes.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Monoacylglycerol Llipase, SH-SY5Y cells, Neuroblastoma, Endocannabinoid, DU-145 cells
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-160287 (URN)10.1016/j.prostaglandins.2019.04.003 (DOI)000469159100007 ()30978461 (PubMedID)
Available from: 2019-06-17 Created: 2019-06-17 Last updated: 2019-06-17Bibliographically approved
Alhouayek, M., Sorti, R., Gilthorpe, J. D. & Fowler, C. J. (2019). Role of pannexin-1 in the cellular uptake, release and hydrolysis of anandamide by T84 colon cancer cells. Scientific Reports, 9, Article ID 7622.
Open this publication in new window or tab >>Role of pannexin-1 in the cellular uptake, release and hydrolysis of anandamide by T84 colon cancer cells
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 7622Article in journal (Refereed) Published
Abstract [en]

The large pore ion channel pannexin-1 (Panx1) has been reported to play a role in the cellular uptake and release of anandamide (AEA) in the hippocampus. It is not known whether this is a general mechanism or limited to the hippocampus. We have investigated this pharmacologically using T84 colon cancer cells. The cells expressed Panx1 at the mRNA level, and released ATP in a manner that could be reduced by treatment with the Panx1 inhibitors carbenoxolone and mefloquine and the Panxl substrate SR101. However, no significant effects of these compounds upon the uptake or hydrolysis of exogenously applied AEA was seen. Uptake by T84 cells of the other main endocannabinoid 2-arachidonoylglycerol and the AEA homologue palmitoylethanolamide was similarly not affected by carbenoxolone or mefloquine. Total release of tritium from [H-3]AEA-prelabelled T84 cells over 10 min was increased, rather than inhibited by carbenoxolone and mefloquine. Finally, AEA uptake by PC3 prostate cancer and SH-SY5Y neuroblastoma cells, which express functional Panx1 channels, was not inhibited by carbenoxolone. Thus, in contrast to the hippocampus, Panx1 does not appear to play a role in AEA uptake and release from the cells studied under the conditions used.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-159858 (URN)10.1038/s41598-019-44057-x (DOI)000468281500052 ()31110238 (PubMedID)
Funder
Swedish Research Council, 12158
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Rankin, L., Stålnacke, B.-M., Fowler, C. J. & Gallego, G. (2018). Differences in Swedish and Australian medical student attitudes and beliefs about chronic pain, its management, and the way it is taught. Scandinavian Journal of Pain, 18(3), 533-544
Open this publication in new window or tab >>Differences in Swedish and Australian medical student attitudes and beliefs about chronic pain, its management, and the way it is taught
2018 (English)In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 18, no 3, p. 533-544Article in journal (Refereed) Published
Abstract [en]

Background and aims: Medical students receive training in the management of chronic pain, but the training is often suboptimal. Considering that the basis for physician’s knowledge is their medical education, it is important to explore the attitudes and beliefs of medical students with respect both to chronic pain management and to their views on current pain education. Therefore, the aim of this study was to compare Swedish and Australian medical student’s attitudes and beliefs about patients with chronic pain, and their perceptions regarding their chronic pain management education.

Methods: An online survey was conducted with final year Australian and Swedish medical students from two different universities between December 2016 and February 2017. Attitudes and beliefs towards chronic pain patients were measured using the Health Care Providers’ Pain and Impairment Scale (HC-PAIRS). A thematic analysis was conducted on open end questions regarding their views on their education and important skills for chronic pain management.

Results: A total of 57 Swedish and 26 Australian medical students completed the HC-PAIRS scale. The Swedish medical students showed statistically significantly lower total mean HC-PAIRS scores compared to Australian medical students (46 and 51, respectively). Australian students had statistically significantly higher scores than the Swedish students for two of four factors: functional expectations and need for cure, whereas no significant differences were seen for the factors social expectations or for projected cognition. From the open end questions it was evident that final year medical students are knowledgeable about key chronic pain items described in clinical guidelines. However, both cohorts described their chronic pain training as poor and in need of improvement in several areas such as more focus on the biopsychosocial model, working in multidisciplinary teams, seeing chronic pain patients and pharmacological training.

Conclusions: Attitudes and beliefs are formed during medical education, and our study exploring attitudes of medical students towards chronic pain and how it is taught have provided valuable information. Our survey provided detailed and cohesive suggestions for education improvement that also are in line with current clinical guidelines. This study indicates that the Swedish final year students have a more positive attitude towards chronic pain patients compared to their Australian counterparts. The majority of students in both cohorts perceived chronic pain management education in need of improvement.

Implications: This study highlights several areas of interest that warrant further investigation, for example, the impact of a changed medical curriculum in alignment with these clinical guidelines requested by students in this survey, and correspondingly if their attitudes towards chronic pain patients can be improved through education. Further, we conclude that it would be valuable to align the implementation of the HC-PAIRS instrument in order to achieve comparable results between future studies.

Place, publisher, year, edition, pages
Walter de Gruyter, 2018
Keywords
HC-PAIRS; attitudes; chronic pain; medical education; medical students
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-148376 (URN)10.1515/sjpain-2018-0039 (DOI)000439314200023 ()
Funder
Swedish Research Council, 12158
Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2018-10-29Bibliographically approved
Cheng, R., Mori, W., Ma, L., Alhouayek, M., Hatori, A., Zhang, Y., . . . Liang, S. H. (2018). In Vitro and in Vivo Evaluation of C-11-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies. Journal of Medicinal Chemistry, 61(6), 2278-2291
Open this publication in new window or tab >>In Vitro and in Vivo Evaluation of C-11-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 6, p. 2278-2291Article in journal (Refereed) Published
Abstract [en]

Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including C-11-carbonylation and spirocyclic iodonium ylide (SCIDY) radio fluorination. The lead compound [C-11]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-146565 (URN)10.1021/acs.jmedchem.7b01400 (DOI)000428356600007 ()29481079 (PubMedID)
Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-06-09Bibliographically approved
Alhouayek, M., Gouveia-Figueira, S., Hammarström, M.-L. & Fowler, C. J. (2018). Involvement of CYP1B1 in interferon gamma-induced alterations of epithelial barrier integrity. British Journal of Pharmacology, 175(6), 877-890
Open this publication in new window or tab >>Involvement of CYP1B1 in interferon gamma-induced alterations of epithelial barrier integrity
2018 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 175, no 6, p. 877-890Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE CYP1B1 and CYP1A1 are important extra-hepatic cytochromes, expressed in the colon and involved in the metabolism of dietary constituents and exogenous compounds. CYP1B1 expression is increased by pro-inflammatory cytokines, and it has been recently implicated in regulation of blood brain barrier function. We investigated its involvement in the increased permeability of the intestinal epithelial barrier observed in inflammatory conditions. EXPERIMENTAL APPROACH Epithelial monolayers formed by human T84 colon carcinoma cells cultured on transwells, were disrupted by incubation with IFN gamma (10 ng.mL(-1)). Monolayer integrity was measured using transepithelial electrical resistance. CYP1A1 and CYP1B1 inhibitors or inducers were applied apically. Potential mechanisms of action were investigated using RT-qPCR. KEY RESULTS IFN gamma disrupts the barrier integrity of the T84 monolayers and increases CYP1B1 and HIF1 alpha mRNA expression. CYP1B1 induction is inhibited by the NF-kappa B inhibitor ammonium pyrrolidinedithiocarbamate (100 mu M) but not by the HIF1 alpha inhibitor 3-(5-hydroxymethyl-2-furyl)-1-benzyl indazole (50 mu M). Inhibition of CYP1B1 with the selective inhibitor 2,4,3,5-tetramethoxystilbene (100 nM) partly reverses the effects of IFN gamma on epithelial permeability. CONCLUSIONS AND IMPLICATIONS These data suggest that increased expression of CYP1B1 is involved in the effects of IFN gamma on epithelial permeability. Inhibition of CYP1B1 counteracts the alterations of epithelial barrier integrity induced by IFN gamma and could thus have a therapeutic potential in disorders of intestinal permeability associated with inflammation.

Place, publisher, year, edition, pages
WILEY, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-145774 (URN)10.1111/bph.14122 (DOI)000426126500002 ()29232759 (PubMedID)
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-06-09Bibliographically approved
Bruun, S., Gouveia-Figueira, S., Domellöf, M., Husby, S., Jacobsen, L. N., Michaelsen, K. F., . . . Zachariassen, G. (2018). Satiety Factors Oleoylethanolamide, Stearoylethanolamide, and Palmitoylethanolamide in Mother's Milk Are Strongly Associated with Infant Weight at Four Months of Age: data from the Odense Child Cohort. Nutrients, 10(11), Article ID 1747.
Open this publication in new window or tab >>Satiety Factors Oleoylethanolamide, Stearoylethanolamide, and Palmitoylethanolamide in Mother's Milk Are Strongly Associated with Infant Weight at Four Months of Age: data from the Odense Child Cohort
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2018 (English)In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 10, no 11, article id 1747Article in journal (Refereed) Published
Abstract [en]

Regulation of appetite and food intake is partly regulated by N-acylethanolamine lipids oleoylethanolamide (OEA), stearoylethanolamide (SEA), and palmitoylethanolamide (PEA), which induce satiety through endogenous formation in the small intestine upon feeding, but also when orally or systemic administered. OEA, SEA, and PEA are present in human milk, and we hypothesized that the content of OEA, SEA, and PEA in mother's milk differed for infants being heavy (high weight-for-age Z-score (WAZ)) or light (low WAZ) at time of milk sample collection. Ultra-high performance liquid chromatography-mass spectrometry was used to determine the concentration of OEA, SEA, and PEA in milk samples collected four months postpartum from mothers to high (n = 50) or low (n = 50) WAZ infants. Associations between OEA, SEA, and PEA concentration and infant anthropometry at four months of age as well as growth from birth were investigated using linear and logistic regression analyses, adjusted for birth weight, early infant formula supplementation, and maternal pre-pregnancy body mass index. Mean OEA, SEA, and PEA concentrations were lower in the high compared to the low WAZ group (all p < 0.02), and a higher concentration of SEA was associated with lower anthropometric measures, e.g., triceps skinfold thickness (mm) (β = -2.235, 95% CI = -4.04, -0.43, p = 0.016), and weight gain per day since birth (g) (β = -8.169, 95% CI = -15.26, -1.08, p = 0.024). This raises the possibility, that the content of satiety factors OEA, SEA, and PEA in human milk may affect infant growth.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
infant growth, appetite regulation, N-acylethanolamines, OEA, SEA, PEA, breastfeeding, human milk composition, obesity
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-154357 (URN)10.3390/nu10111747 (DOI)000451547700185 ()30428553 (PubMedID)2-s2.0-85056620089 (Scopus ID)
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2018-12-18Bibliographically approved
Karlsson, J., Gouveia-Figueira, S., Alhouayek, M. & Fowler, C. J. (2017). Effects of tumour necrosis factor alpha upon the metabolism of the endocannabinoid anandamide in prostate cancer cells. PLoS ONE, 12(9), Article ID e0185011.
Open this publication in new window or tab >>Effects of tumour necrosis factor alpha upon the metabolism of the endocannabinoid anandamide in prostate cancer cells
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0185011Article in journal (Refereed) Published
Abstract [en]

Tumour necrosis factor a (TNF alpha) is involved in the pathogenesis of prostate cancer, a disease where disturbances in the endocannabinoid system are seen. In the present study we have investigated whether treatment of DU145 human prostate cancer cells affects anandamide (AEA) catabolic pathways. Additionally, we have investigated whether cyclooxygenase- 2 (COX-2) can regulate the uptake of AEA into cells. Levels of AEA synthetic and catabolic enzymes were determined by qPCR. AEA uptake and hydrolysis in DU145 and RAW264.7 macrophage cells were assayed using AEA labeled in the arachidonic and ethanolamine portions of the molecule, respectively. Levels of AEA, related N-acylethanolamines (NAEs), prostaglandins (PG) and PG-ethanolamines (PG-EA) in DU145 cells and medium were quantitated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. TNF alpha treatment of DU145 cells increased mRNA levels of PTSG2 (gene of COX-2) and decreased the mRNA of the AEA synthetic enzyme N-acylphosphatidylethanolamine selective phospholipase D. mRNA levels of the AEA hydrolytic enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase were not changed. AEA uptake in both DU145 and RAW264.7 cells was inhibited by FAAH inhibition, but not by COX-2 inhibition, even in RAW264.7 cells where the expression of this enzyme had greatly been induced by lipopolysaccharide + interferon. treatment. AEA and related NAEs were detected in DU145 cells, but PGs and PGE(2)-EA were only detected when the cells had been preincubated with 100 nM AEA. The data demonstrate that in DU145 cells, TNFa treatment changes the relative expression of the enzymes involved in the hydrolytic and oxygenation catabolic pathways for AEA. In RAW264.7 cells, COX-2, in contrast to FAAH, does not regulate the cellular accumulation of AEA. Further studies are necessary to determine the extent to which inflammatory mediators are involved in the abnormal endocannabinoid signalling system in prostate cancer.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-140467 (URN)10.1371/journal.pone.0185011 (DOI)000410859200126 ()28910408 (PubMedID)
Available from: 2017-10-25 Created: 2017-10-25 Last updated: 2018-06-09Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-6658-7874

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