umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Fowler, Christopher JORCID iD iconorcid.org/0000-0002-6658-7874
Alternative names
Publications (10 of 84) Show all publications
Alhouayek, M., Boldrup, L. & Fowler, C. J. (2019). Altered mRNA Expression of Genes Involved in Endocannabinoid Signalling in Squamous Cell Carcinoma of the Oral Tongue. Cancer Investigation, 37(8), 327-338
Open this publication in new window or tab >>Altered mRNA Expression of Genes Involved in Endocannabinoid Signalling in Squamous Cell Carcinoma of the Oral Tongue
2019 (English)In: Cancer Investigation, ISSN 0735-7907, E-ISSN 1532-4192, Vol. 37, no 8, p. 327-338Article in journal (Refereed) Published
Abstract [en]

Little is known about the endocannabinoid (eCB) system in squamous cell carcinoma of the oral tongue (SCCOT). Here we have investigated, at the mRNA level, expression of genes coding for the components of the eCB system in tumour and non-malignant samples from SCCOT patients. Expression of NAPEPLD and PLA2G4E, coding for eCB anabolic enzymes, was higher in the tumour tissue than in non-malignant tissue. Among genes coding for eCB catabolic enzymes, expression of MGLL was lower in tumour tissue while PTGS2 was increased. It is concluded that the eCB system may be dysfunctional in SCCOT.

Keywords
Squamous cell carcinoma of the oral tongue, endocannabinoids, cyclooxygenase-2, N-acyl- osphatidylethanolamine phospholipase D, monoacylglycerol lipase
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-163070 (URN)10.1080/07357907.2019.1638394 (DOI)000482287600001 ()31423851 (PubMedID)
Available from: 2019-11-27 Created: 2019-11-27 Last updated: 2019-11-27Bibliographically approved
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
Show others...
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: 2019-11-19Bibliographically approved
Gouveia-Figueira, S. C., Danielsson, K. & Fowler, C. J. (2019). Changes in Proportions of Linoleic Acid-derived Oxylipins in Oral Lichen Planus. Acta Dermato-Venereologica, 99(11), 1051-1052
Open this publication in new window or tab >>Changes in Proportions of Linoleic Acid-derived Oxylipins in Oral Lichen Planus
2019 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 99, no 11, p. 1051-1052Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Acta Dermato-Venereologica, 2019
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:umu:diva-164038 (URN)10.2340/00015555-3281 (DOI)000487762500025 ()31396636 (PubMedID)
Available from: 2019-10-16 Created: 2019-10-16 Last updated: 2019-11-19Bibliographically 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
Show others...
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: 2019-11-19Bibliographically 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: 2019-11-22Bibliographically 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: 2019-11-25Bibliographically approved
Rankin, L., Fowler, C. J., Stålnacke, B.-M. & Gallego, G. (2019). What influences chronic pain management?: A best-worst scaling experiment with final year medical students and general practitioners. British Journal of Pain, 13(4), 214-225
Open this publication in new window or tab >>What influences chronic pain management?: A best-worst scaling experiment with final year medical students and general practitioners
2019 (English)In: British Journal of Pain, ISSN 2049-4637, Vol. 13, no 4, p. 214-225Article in journal (Refereed) Published
Abstract [en]

Background: Chronic pain education is an essential determinant for optimal chronic pain management. Given that attitudes and preferences are involved in making treatment decisions, identifying which factors are most influential to final year medical students’ and general practitioners’ (GPs) chronic pain management choices is of importance. This study investigates Swedish and Australian students’ preferences with respect to a chronic pain condition, using a best–worst scaling (BWS) experiment, which is designed to rank alternatives.

Methods: BWS, a stated-preference method grounded in random utility theory, was used to explore the importance of factors influencing chronic pain management.

Results: All three cohorts considered the patients’ pain description and previous treatment experience as the most important factors in making treatment decisions, whereas their demographics and voices or facial expressions while describing their pain were considered least important. Factors such as social support, patient preferences and treatment adherence were, however, disregarded by all cohorts in favour of pain assessment factors such as pain ratings, description and history. Swedish medical students and GPs show very high correlation in their choices, although the GPs consider their professional experience as more important compared to the students.

Conclusion: This study suggests that the relative importance of treatment factors is cemented early and thus underline the critical importance of improving pain curricula during undergraduate medical education.

Keywords
Pain management, pain education, best-worst scaling, medical students, general practitioners
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-165668 (URN)10.1177/2049463719832331 (DOI)000489776800003 ()31656627 (PubMedID)
Funder
Swedish Research Council, 12158
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically 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
Show others...
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: 2019-11-19Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6658-7874

Search in DiVA

Show all publications