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| 2. |
- Birkholtz, Lyn-Marie, et al.
(författare)
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Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities
- 2011
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Ingår i: Biochemical Journal. - London : The Biochemical Society. - 0264-6021 .- 1470-8728. ; 438, s. 229-244
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Forskningsöversikt (refereegranskat)abstract
- New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness. Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies.
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| 3. |
- Castro-Oropeza, R., et al.
(författare)
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Aminooxy analog of histamine is an efficient inhibitor of mammalian l-histidine decarboxylase: combined in silico and experimental evidence
- 2014
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Ingår i: Amino Acids. - : Springer Science and Business Media LLC. - 0939-4451 .- 1438-2199. ; 46:3, s. 621-631
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Tidskriftsartikel (refereegranskat)abstract
- Histamine plays highlighted roles in the development of many common, emergent and rare diseases. In mammals, histamine is formed by decarboxylation of l-histidine, which is catalyzed by pyridoxal-5'-phosphate (PLP) dependent histidine decarboxylase (HDC, EC 4.1.1.22). The limited availability and stability of the protein have delayed the characterization of its structure-function relationships. Our previous knowledge on mammalian HDC, derived from both in silico and experimental approaches, indicates that an effective competitive inhibitor should be capable to form an "external aldimine-like structure" and have an imidazole group, or its proper mimetic, which provides additional affinity of PLP-inhibitor adduct to the HDC active center. This is confirmed using HEK-293 cells transfected to express human HDC and the aminooxy analog of histidine, 4(5)-aminooxymethylimidazole (O-IMHA, IC50 a parts per thousand 2 x 10(-7) M) capable to form a PLP-inhibitor complex (oxime) in the enzyme active center. Taking advantage of the availability of the human HDC X-ray structure, we have also determined the potential interactions that could stabilize this oxime in the active site of mammalian HDC.
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| 4. |
- Grossi, Mario, et al.
(författare)
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Inhibition of Polyamine Formation Antagonizes Vascular Smooth Muscle Cell Proliferation and Preserves the Contractile Phenotype.
- 2014
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 115:5, s. 379-388
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Tidskriftsartikel (refereegranskat)abstract
- The polyamines putrescine, spermidine and spermine play essential roles in cell proliferation and migration, two processes involved in the development of vascular disease. Thus, intervention with polyamine formation may represent a way to inhibit unwanted vascular smooth muscle cell (VSMC) proliferation. The aim of the present study was to assess the importance of polyamines for VSMC proliferation and vascular contractility. The rate-limiting step in polyamine biosynthesis is catalyzed by ornithine decarboxylase. Treatment with α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, reduced DNA synthesis in primary rat VSMCs in a concentration-dependent manner with an IC50 value of 100 μM. Moreover, DFMO reduced VSMC migration assessed in a scratch assay. The DFMO-induced attenuation of VSMC proliferation was associated with lowered cellular amount of polyamines. The anti-proliferative effect of DFMO was specific since supplementation with polyamines reversed the effect of DFMO on proliferation and normalized cellular polyamine levels. Isometric force recordings in cultured rat tail artery rings showed that DFMO counteracts the decrease in contractility caused by culture with foetal bovine serum as growth stimulant. We conclude that inhibition of polyamine synthesis by DFMO may limit the first wave of cell proliferation and migration, which occurs in the acute phase after vascular injury. Besides its anti-proliferative effect, DFMO may prevent loss of the smooth muscle contractile phenotype in vascular injury. This article is protected by copyright. All rights reserved.
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| 5. |
- Grossi, Mario, et al.
(författare)
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Vascular smooth muscle cell proliferation depends on caveolin-1-regulated polyamine uptake
- 2014
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Ingår i: Bioscience Reports. - 0144-8463. ; 34, s. 729-741
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Tidskriftsartikel (refereegranskat)abstract
- Much evidence highlights the importance of polyamines for VSMC (vascular smooth muscle cell) proliferation and migration. Cav-1 (caveolin-1) was recently reported to regulate polyamine uptake in intestinal epithelial cells. The aim of the present study was to assess the importance of Cav-1 for VSMC polyamine uptake and its impact on cell proliferation and migration. Cav-1 KO (knockout) mouse aortic cells showed increased polyamine uptake and elevated proliferation and migration compared with WT (wild-type) cells. Both Cav-1 KO and WT cells expressed the smooth muscle differentiation markers SM22 and calponin. Cell-cycle phase distribution analysis revealed a higher proportion of Cav-1 KO than WT cells in the S phase. Cav-1 KO cells were hyper-proliferative in the presence but not in the absence of extracellular polyamines, and, moreover, supplementation with exogenous polyamines promoted proliferation in Cav-1 KO but not in WT cells. Expression of the solute carrier transporters Slc7a1 and Slc43a1 was higher in Cav-1 KO than in WT cells. ODC (ornithine decarboxylase) protein and mRNA expression as well as ODC activity were similar in Cav-1 KO and WT cells showing unaltered synthesis of polyamines in Cav-1 KO cells. Cav-1 was reduced in migrating cells in vitro and in carotid lesions in vivo. Our data show that Cav-1 negatively regulates VSMC polyamine uptake and that the proliferative advantage of Cav-1 KO cells is critically dependent on polyamine uptake. We provide proof-of-principle for targeting Cav-1-regulated polyamine uptake as a strategy to fight unwanted VSMC proliferation as observed in restenosis.
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| 6. |
- Huang, Xiaoli, et al.
(författare)
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Semisynthesis of SY-1 for Investigation of Breast Cancer Stem Cell Selectivity of C-Ring-Modified Salinomycin Analogues.
- 2014
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8937 .- 1554-8929. ; 9:7, s. 1587-1594
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Tidskriftsartikel (refereegranskat)abstract
- Salinomycin, a naturally occurring polyether ionophore was recently found to selectively reduce the proportion of CD44(+)/CD24(-) cells, a phenotype associated with breast cancer stem cells. Subsequent studies from our group showed that chemical modification of the allylic C20 hydroxyl of salinomycin, located at the C-ring, can enhance the activity of derivatives against breast cancer cells over 5-fold compared to the native structure. Access to C-ring-modified salinomycin analogues is thus of interest from both a mechanistic and a synthetic perspective. Here, we report efficient strategies for gram scale synthesis of the natural product SY-1 (20-deoxy salinomycin), and a saturated analogue, 18,19-dihydro SY-1, for a comparative in vitro investigation of the biological profiles of these compounds with that of salinomycin. Across several assays, the deoxygenated structures required higher concentrations to elicit similar cellular responses to that of salinomycin. Similarly to salinomycin, SY-1 or 18,19-dihydro SY-1 treatment was found to reduce the proportion of CD44(+)/CD24(-) cells with essentially complete selectivity up to ∼IC25. Importantly, the proportion of CD44(+)/CD24(-) cells showed a pronounced U-shaped dose response curve for salinomycin and its derivatives, but not for paclitaxel. The concentration for maximum response in this assay followed differences in IC50 for salinomycin and its analogues, which emphasizes the importance of taking concentration dependence into account when comparing effects on the CD44(+)/CD24(-) phenotype. Small differences in the global conformation within the triad of compounds investigated together with differences in activity across assays emphasize the importance of substitution at C20 for the activity of salinomycin and its derivatives.
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| 7. |
- Näslund, Joacim, 1985, et al.
(författare)
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Hatchery tank enrichment affects cortisol levels and shelter-seeking in Atlantic salmon (Salmo salar)
- 2013
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Ingår i: Canadian Journal of Fisheries and Aquatic Sciences. - : Canadian Science Publishing. - 0706-652X .- 1205-7533. ; 70:4, s. 585-590
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Tidskriftsartikel (refereegranskat)abstract
- Stocking programs using hatchery-reared salmon are often implemented for augmenting natural populations. However, survival of these fish is often low compared with wild conspecifics, possibly because of genetic, physiological, and behavioural deficiencies. Here, we compared presmolt Atlantic salmon (Salmo salar) from three different environmental treatments (barren environment, plastic tube enrichment, and plastic shredding enrichment) with regard to plasma cortisol levels, shelter-seeking behaviour, and fin deterioration. Basal plasma cortisol levels were higher in barren-reared fish, indicating higher stress levels, while no differences were found in acute cortisol response after a 30 min confinement test. Shelter-seeking was higher in salmon reared in enriched tanks when tested alone, but not when tested in small groups. Barren-reared fish had higher levels of fin deterioration over winter, potentially owing to higher aggression levels. These results suggest that enrichment can reduce the impact of stressors experienced in the hatchery and thus increase fish welfare. Tank enrichment may also be used to produce salmon better adapted for the more complex environment encountered after release.
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| 8. |
- Persson, Lo, et al.
(författare)
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The effect of shelter on welfare of juvenile Atlantic salmon Salmo salar reared under a feed restriction regimen
- 2014
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Ingår i: Journal of Fish Biology. - : Wiley. - 0022-1112 .- 1095-8649. ; 85, s. 645-656
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated whether shelter (presence or absence) affected the frequency of fin damage in Atlantic salmon Salmo salar exposed to feed restrictions (0.73 or 0.33% of body mass day(-1)). The presence of shelter had a positive effect on the pectoral fins at both feed ration levels and on the dorsal fin at the higher ration level but it had a negative effect on survival. The reduced feed rations resulted in fish of the same size and nutritional status as wild fish. The provision of shelter has potential to mitigate the negative effects of feed restrictions on fin quality, but the optimal shelter design requires some additional investigation. (C) 2014 The Fisheries Society of the British Isles
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| 9. |
- Silva, Tania M., et al.
(författare)
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Increased breast cancer cell toxicity by palladination of the polyamine analogue N-1,N-11-bis(ethyl)norspermine
- 2014
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Ingår i: Amino Acids. - : Springer Science and Business Media LLC. - 0939-4451 .- 1438-2199. ; 46:2, s. 339-352
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is one of the most common malignant tumor forms among women and many women succumb to their disease. Thus, new anticancer agents that can efficiently improve patient survival are of the utmost importance. In this study, the effects of the polyamine analogues N (1),N (11)-bis(ethyl)norspermine (BENSpm) and N (1)-cyclo-propylmethyl-N (11)-ethylnorspermine (CPENSpm) and the synthesized dinuclear complexes Pd(2)BENSpm (Pd-BENSpm), Pt(2)CPENSpm (Pt-CPENSpm) and Pd(2)Spm (Pd-Spm) were investigated in normal-like breast epithelial MCF-10A cells and the breast cancer cell lines JIMT-1 and L56BR-C1. The overall data show that palladination of BENSpm resulted in enhanced cytotoxicity, in contrast to platination of CPENSpm that reduced cytotoxicity, which might be explained by differences in the cellular uptake of Pd-BENSpm and Pt-CPENSpm. BENSpm and Pd-BENSpm treatment reduced the CD44(+)CD24(-) putative cancer stem cell population, evaluated by flow cytometry. Furthermore, Pd-BENSpm was the most efficient compound regarding induction of DNA damage and decrease in colony formation in soft agar. Pt-CPENSpm and Pd-Spm, on the other hand, were shown to be the least toxic compounds of all tested. Pd-Spm efficiently reduced the cellular glutathione levels, which probably was a consequence of its metabolic inactivation by conjugation to this endogenous thiol. The normal-like cells were found to be less sensitive to the agents than the breast cancer cells. Our findings show that Pd-BENSpm exhibits promising anticancer effects which render it suitable for further optimization to develop a new metal-based chemotherapeutic drug for breast cancer treatment.
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