| 1. |
- Alhouayek, Mireille, et al.
(författare)
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Effects of orthotopic implantation of rat prostate tumour cells upon components of the N-acylethanolamine and monoacylglycerol signalling systems : an mRNA study
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- There is good evidence that the N-acylethanolamine (NAE)/monoacylglycerol (MAG) signalling systems are involved in the pathogenesis of cancer. However, it is not known how prostate tumours affect these systems in the surrounding non-malignant tissue and vice versa. In the present study we have investigated at the mRNA level 11 components of these systems (three coding for anabolic enzymes, two for NAE/MAG targets and six coding for catabolic enzymes) in rat prostate tissue following orthotopic injection of low metastatic AT1 cells and high metastatic MLL cells. The MLL tumours expressed higher levels of Napepld, coding for a key enzyme in NAE synthesis, and lower levels of Naaa, coding for the NAE hydrolytic enzyme N-acylethanolamine acid amide hydrolase than the AT1 tumours. mRNA levels of the components of the NAE/MAG signalling systems studied in the tissue surrounding the tumours were not overtly affected by the tumours. AT1 cells in culture expressed Faah, coding for the NAE hydrolytic enzyme fatty acid amide hydrolase, at much lower levels than Naaa. However, the ability of the intact cells to hydrolyse the NAE arachidonoylethanolamide (anandamide) was inhibited by an inhibitor of FAAH, but not of NAAA. Treatment of the AT1 cells with interleukin-6, a cytokine known to be involved in the pathogenesis of prostate cancer, did not affect the expression of the components of the NAE/MAG system studied. It is thus concluded that in the model system studied, the tumours show different expressions of mRNA coding for key the components of the NAE/MAG system compared to the host tissue, but that these changes are not accompanied by alterations in the non-malignant tissue.
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| 2. |
- Deplano, Alessandro, et al.
(författare)
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Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents
- 2021
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Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Taylor & Francis. - 1475-6366 .- 1475-6374. ; 36:1, s. 940-953
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Tidskriftsartikel (refereegranskat)abstract
- Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.
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| 3. |
- Deplano, Alessandro, et al.
(författare)
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Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen
- 2020
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Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Taylor & Francis. - 1475-6366 .- 1475-6374. ; 35:1, s. 815-823
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)−2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.
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| 4. |
- Deplano, Alessandro, et al.
(författare)
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The fatty acid amide hydrolase and cyclooxygenase-inhibitory properties of novel amide derivatives of carprofen
- 2020
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Ingår i: Bioorganic chemistry (Print). - : Elsevier. - 0045-2068. ; 101
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Tidskriftsartikel (refereegranskat)abstract
- In experimental animals, inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents that act by inhibition of cyclooxygenase (COX). This suggests that compounds able to inhibit both enzymes may be potentially useful therapeutic agents. In the present study, we have investigated eight novel amide analogues of carprofen, ketoprofen and fenoprofen as potential FAAH/COX dual action inhibitors. Carpro-AM1 (2-(6-Chloro-9H-carbazol-2-yl)-N-(3-methylpyridin-2-yl)propenamide) and Carpro-AM6 (2-(6-Chloro-9H-carbazol-2-yl)-N-(3-chloropyridin-2-yl)propenamide) were found to be fully re-versible inhibitors of the hydrolysis of 0.5 mu M [H-3]anandamide in rat brain homogenates with IC50 values of 94 and 23 nM, respectively, i.e. 2-3 orders of magnitude more potent than carprofen in this respect. Both compounds inhibited the cyclooxygenation of arachidonic acid by ovine COX-1, and were more potent inhibitors of human recombinant COX-2 when 2-arachidonoylglycerol was used as substrate than when arachidonic acid was used. It is concluded that Carpro-AM1 and Carpro-AM6 are dual-acting FAAH/substrate-selective COX inhibitors.
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| 5. |
- Karlsson, Jessica, 1987-
(författare)
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Endocannabinoid metabolism : the impact of inflammatory factors and pharmacological inhibitors
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The endocannabinoid (eCB) system is an endogenous signaling system consisting of ligands (referred to as endocannabinoids, eCBs), receptors and metabolic enzymes. The eCB system is involved in homeostatic control of a variety of biological functions such as neuronal signaling, mood, appetite and pathological conditions such as pain, inflammation and tumour progression. The main eCBs N- arachidonoylethanolamine (AEA, anandamide) and 2-arachidonoylglycerol (2-AG) are synthesised upon stimuli when and where their action is demanded. The signaling is brief and the eCBs are quickly degraded. The enzyme primarily responsible for eCB degradation is fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MAGL) for 2-AG. In addition, both substances are substrates for cyclooxygenase-2 (COX-2). COX-2 is upregulated in inflammation, pain and in several tumours including prostate cancers, but it is not known whether COX-2 contribute significantly to eCB metabolism under these conditions.Increasing endogenous levels of eCBs by inhibiting their degradation is exploited as a future therapy for pain conditions. One suggested therapeutic strategy is dual inhibition of enzymes FAAH and COX-2 to raise AEA levels. Paper I and II of this thesis investigates FAAH and COX inhibitory effects of: the major metabolites and enantiomers of derivatives (flu-AM1 and ibu-AM5) of the current clinically used NSAIDs ibuprofen and flurbiprofen. The metabolites 3 ́hydroxyibuprofen and 4 ́hydroxyflurbiprofen retained the FAAH and COX- inhibitory effects seen by the parent compounds although at lower potencies. Both enantiomers of flu-AM1 were equally potent as FAAH inhibitors and displayed a useful substrate selective COX-2 inhibition profile, favoring eCBs as substrates rather than arachidonic acid.Paper III explores the impact of COX-2 and the effect of (R)-flu-AM1 upon AEA levels and degradation in mouse leukemic macrophage RAW264.7 cells. Despite the high inhibitory potency in enzyme assays, neither (R)-flu-AM1 nor the combination of a FAAH inhibitor with flurbiprofen increased AEA levels in the intact cells to any great extent. This suggests that the eCB turnover in these cells is rather slow. Further, in paper IV, induction of COX-2 did not unmask an ability of this enzyme to “gate” the uptake of AEA analogous to that seen with FAAH.Paper IV and V focus upon the role of the eCB system in prostate cancer. The eCB system is altered in cancer and is linked to the progression and prognosis of prostate cancer. How and whereby this change occurs is unknown. This thesis explores the impact of the inflammatory factors TNFα, IL-6 and lactic acid induced low pH upon the mRNA levels of eCB related enzymes and the functional impact upon AEA degradation in human DU145 and rat AT-1 prostate cancer cells. TNFα treatment of DU145 and IL-6 and lactic acid induced low pH exposure of AT-1 changed the mRNA levels of 2-AG related enzymes leaving AEA rather unaffected other than for a substantial induction of COX-2 mRNA in DU145 cells. Thus, AEA homeostasis was not shifted in prostate cancer cell lines exposed to inflammatory factors. The results suggest that COX-2 does not gate the uptake of AEA and is a minor contributor to AEA degradation in intact cells.
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| 6. |
- karlsson, jessica, 1987-, et al.
(författare)
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Metabolism of N-acylethanolamines: To Phase II and Back Again
- 2017
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Ingår i: eLS. - Chichester : John Wiley & Sons. - 1618-2863.
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Forskningsöversikt (refereegranskat)abstract
- N-acylethanolamines (NAEs) are a family of endogenous signalling molecules involved in various effects of the body including pain, inflam- mation, appetite and sleep. NAEs are mainly degraded by fatty acid amide hydrolase (FAAH) andN-acylethanolamine acid amidase (NAAA). FAAH inhibitors have shown promising results in pre- clinical studies of pain, inflammation and anxiety, mediating effects mainly via increased cannabi- noid receptor activity. However, FAAH inhibitors have failed in clinical pain trials, and in a recent phase I trial, an irreversible compound caused one death and sustained impairments in healthy vol- unteers. The latter is most likely due to off-target effects of that compound, rather than an FAAH-mediated effect, and design of dual-action FAAH-NAAA, -TRPV1 or -cyclooxygenase-2 inhibitory compounds may solve the pain efficacy issue. NAAA inhibitors are still in preclinical testing and show a promising anti-inflammatory profile mainly due to increased palmitoylethanolamide and oleoylethanolamide levels.
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| 7. |
- Qvick, Alvida, 1990-, et al.
(författare)
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Liquid biopsy as an option for predictive testing and prognosis in patients with lung cancer
- 2021
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Ingår i: Molecular Medicine. - : Springer. - 1076-1551 .- 1528-3658. ; 27:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate the clinical value of liquid biopsy as a primary source for variant analysis in lung cancer. In addition, we sought to characterize liquid biopsy variants and to correlate mutational load to clinical data.Methods: Circulating cell-free DNA was extracted from plasma from patients with lung cancer (n = 60) and controls with benign lung disease (n = 16). Variant analysis was performed using the AVENIO ctDNA Surveillance kit and the results were correlated to clinical and variant analysis data from tumor tissue or cytology retrieved from clinical routine diagnostics.Results: There were significantly more variants detected in lung cancer cases compared to controls (p = 0.011), but no difference between the histological subgroups of lung cancer was found (p = 0.465). Furthermore, significantly more variants were detected in patients with stage IIIb-IV disease compared to patients with stage I-IIIa (median 7 vs 4, p = 0.017). Plasma cfDNA mutational load was significantly associated with overall survival (p = 0.010). The association persisted when adjusted for stage and ECOG performance status (HR: 3.64, 95% CI 1.37-9.67, p = 0.009). Agreement between tumor and plasma samples significantly differed with stage; patients with stage IIIb-IV disease showed agreement in 88.2% of the cases with clinically relevant variants, compared to zero cases in stage I-IIIa (p = 0.004). Furthermore, one variant in EGFR, two in KRAS, and one in BRAF were detected in plasma but not in tumor samples.Conclusion: This study concludes that in the vast majority of advanced NSCLC patients a reliable variant analysis can be performed using liquid biopsy from plasma. Furthermore, we found that the number of variants in plasma is associated with prognosis, possibly indicating a strategy for closer follow up on this crucial patient group.
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| 8. |
- Szeremeta, Janis, et al.
(författare)
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Low mRNA expression and activity of monoacylglycerol lipase in human SH-SY5Y neuroblastoma cells
- 2019
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Ingår i: Prostaglandins & other lipid mediators. - : Elsevier. - 1098-8823 .- 2212-196X. ; 142, s. 59-67
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Wehner, Jessica, 1987-, et al.
(författare)
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Coronapandemins effekter på det svenska godstransportsystemet : analys av åren 2020 och 2021
- 2023
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Coronapandemin som i Sverige tog fart i mars 2020 hade en genomgripande påverkan på det svenska samhället. Restriktioner och nedstängningar i Sverige och utomlands förändrade konsumenters inköps[1]och resmönster och därmed även företagens agerande. Den fråga som rapporten fokuserar på är hur det svenska godstransportsystemet påverkades av pandemin under åren 2020 och 2021. Mer specifikt analyseras hur fordonsrörelser och godsflöden förändrats under pandemin, undersöks vilka effekter av coronapandemin som haft störst inverkan på det svenska godstransportsystemet och hur de påverkat systemet, och studeras vilken betydelse som pandemin haft för godstransportsystemet i jämförelse med tidigare kriser. Studien genomfördes med både kvantitativ och kvalitativ dataanalys. Den kvantitativa dataanalysen bygger på fem olika datakällor, av vilka två baseras på GPS-data från enskilda fordon respektive fartyg och som endast fångar upp deras lägen och rörelser. Två källor utgörs av mikrodata från Trafikanalys undersökningar om sjötrafik och lastbilstransporter, vilka även innehåller data om godset som fraktas, och ytterligare en källa är årsmedeldygnstrafik från Trafikverket. Den kvalitativa dataanalysen inkluderar en intervjustudie med tio aktörer från transportbranschen samt en litteraturstudie. Resultaten av aggregerade data visar att skillnaderna mellan 2020 och 2021 och de tre föregående åren generellt är jämförelsevis små. I så mening kan man säga att det svenska godstransportsystemet på makronivå visat sig vara robust för den typen av störningar som coronapandemin inneburit. Högupplösta data av enskilda fordon har möjliggjort studier av snabba eller kortvariga reaktioner på pandemin för lastbilstransporterna. Exempelvis har i många fall en snabb initial minskning av lastbilstransporter skett under pandemins inledande skede (slutet av mars och början av april 2020). Intervjuerna indikerar att på mikronivå har det svenska godstransportsystemet visat sig vara resilient och haft en god förmåga att anpassa sig till förändringarna, bland annat genom automatisering av processer, digitalisering och smarta överlämningssätt. Att dra lärdomar för framtida kriser är dock svårare eftersom varje extern, störande händelse är unik, men godstransportsystemet har visat sig ha goda förutsättningar att hantera sådana händelser.
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