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- Banfi, C, et al.
(författare)
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Prenylcysteine oxidase 1, an emerging player in atherosclerosis
- 2021
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4:1, s. 1109-
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Tidskriftsartikel (refereegranskat)abstract
- The research into the pathophysiology of atherosclerosis has considerably increased our understanding of the disease complexity, but still many questions remain unanswered, both mechanistically and pharmacologically. Here, we provided evidence that the pro-oxidant enzyme Prenylcysteine Oxidase 1 (PCYOX1), in the human atherosclerotic lesions, is both synthesized locally and transported within the subintimal space by proatherogenic lipoproteins accumulating in the arterial wall during atherogenesis. Further, Pcyox1 deficiency in Apoe-/- mice retards atheroprogression, is associated with decreased features of lesion vulnerability and lower levels of lipid peroxidation, reduces plasma lipid levels and inflammation. PCYOX1 silencing in vitro affects the cellular proteome by influencing multiple functions related to inflammation, oxidative stress, and platelet adhesion. Collectively, these findings identify the pro-oxidant enzyme PCYOX1 as an emerging player in atherogenesis and, therefore, understanding the biology and mechanisms of all functions of this unique enzyme is likely to provide additional therapeutic opportunities in addressing atherosclerosis.
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- Boguszewski, M. C., et al.
(författare)
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Insulin-like growth factor-1, leptin, body composition, and clinical status interactions in children with cystic fibrosis
- 2007
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Ingår i: Horm Res. - : S. Karger AG. - 0301-0163. ; 67:5, s. 250-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Children with cystic fibrosis (CF) are of increased risk of reduced fat body mass (FBM) and lean body mass (LBM). Serum concentrations of insulin-like growth factor-1 (IGF-1)and leptin could be markers of LBM and/or FBM depletion. To evaluate the relationships between disease activity, body composition, IGF-1 and leptin concentrations in CF children. METHODS: A cross-sectional study with 26 CF children aged 5.0-15.5 years and 33 healthy controls, mean age 9.4 years. Body composition was evaluated by dual-energy X-ray absorptiometry. Fasting blood samples were analyzed for leptin, IGF-1 and IGFBP-3. RESULTS: FBM standard deviation score (SDS; CF boys -0.02 +/- 0.88 vs. 0.78 +/- 0.65, p < 0.01; CF girls -0.37 +/- 1.15 vs. 0.70 +/- 0.97, p < 0.05), leptin concentration (CF boys 2.07 +/- 0.79 vs. 3.07 +/- 1.28 ng/ml, p < 0.05; CF girls 2.71 +/- 0.86 vs. 5.00 +/- 2.95 ng/ml, p < 0.05) and IGF-1SDS (CF boys -1.43 +/- 1.50 vs. -0.32 +/- 0.88, p < 0.05; CF girls -0.66 +/- 1.66 vs. 0.64 +/- 0.57, p < 0.01) were lower in CF children compared to controls. Shwachman score was the strongest predictor of lean body mass (R = 0.63). Leptin levels explain 60% of the variability in FBM. CONCLUSION: Serum concentrations of IGF-1 and leptin are decreased in children with CF and are associated with clinical conditions and body composition.
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- Knecht, W., et al.
(författare)
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Drosophila deoxyribonucleoside kinase mutants with enhanced ability to phosphorylate purine analogs
- 2007
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Ingår i: Gene Therapy. - : Springer Science and Business Media LLC. - 0969-7128 .- 1476-5462. ; 14:17, s. 1278-1286
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Tidskriftsartikel (refereegranskat)abstract
- Transduced deoxyribonucleoside kinases (dNK) can be used to kill recipient cells in combination with nucleoside prodrugs. The Drosophila melanogaster multisubstrate dNK (Dm-dNK) displays a superior turnover rate and has a great plasticity regarding its substrates. We used directed evolution to create Dm-dNK mutants with increased specificity for several nucleoside analogs (NAs) used as anticancer or antiviral drugs. Four mutants were characterized for the ability to sensitize Escherichia coli toward analogs and for their substrate specificity and kinetic parameters. The mutants had a reduced ability to phosphorylate pyrimidines, while the ability to phosphorylate purine analogs was relatively similar to the wild-type enzyme. We selected two mutants, for expression in the osteosarcoma 143B, the glioblastoma U-87M-G and the breast cancer MCF7 cell lines. The sensitivities of the transduced cell lines in the presence of the NAs fludarabine (F-AraA), cladribine (CdA), vidarabine and cytarabine were compared to the parental cell lines. The sensitivity of 143B cells was increased by 470-fold in the presence of CdA and of U-87M-G cells by 435fold in the presence of F-AraA. We also show that a choice of the selection and screening system plays a crucial role when optimizing suicide genes by directed evolution.
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- Sandrini, Michael P. B., et al.
(författare)
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Nucleoside analogues are activated by bacterial deoxyribonucleoside kinases in a species-specific manner
- 2007
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 1460-2091 .- 0305-7453. ; 60:3, s. 510-520
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate the bactericidal activity of antiviral and anticancer nucleoside analogues against a variety of pathogenic bacteria and characterize the activating enzymes, deoxyribonucleoside kinases (dNKs). Methods: Several FDA-approved nucleoside analogue drugs were screened for their potential bactericidal activity against several clinical bacterial isolates and type strains. We identified and subcloned the genes coding for putative deoxyribonucleoside kinases in Escherichia coli, Pasteurella multocida, Salmonella enterica, Yersinia enterocolitica, Bacillus cereus, Clostridium perfringens and Listeria monocytogenes. These genes were tested for their ability to increase the susceptibility of a dNK-deficient E. coli strain to various analogues. We overexpressed, purified and characterized the substrate specificity and kinetic properties of the recombinant enzymes from S. enterica and B. cereus. Results: The tested Gram-negative bacteria were susceptible to 3 '-azido-3 '-deoxythymidine (AZT) in the concentration range 0.032-31.6 mu M except for a single E. coli isolate and two Pseudomonas aeruginosa isolates which were resistant to the tested AZT concentrations. Purified recombinant S. enterica thymidine kinase phosphorylated AZT efficiently with a K-m of 73.3 mM and k(cat)/K-m of 6.6 x 10(4) s(-1)M(-1) and is the activator of this drug in vivo. 2 ',2 '-Difluoro-2 '-deoxycytidine ( gemcitabine) was a potent antibiotic against Gram-positive bacteria in the concentration range between 0.001 and 1.0 mu M. The B. cereus deoxyadenosine kinase had a Km for gemcitabine of 33.5 mM and kcat/Km of 5.1 x 10(3) s(-1) M-1 and activates gemcitabine in vivo. S. enterica and B. cereus are now amongst the first bacteria with a completely characterized set of dNK enzymes. Conclusions: Bacterial dNKs efficiently activate nucleoside analogues in a species-specific manner. Therefore, nucleoside analogues have a potential to be employed as antibiotics in the fight against emerging multiresistant bacteria.
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