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- Ahlstedt, Jonas, et al.
(författare)
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Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys.
- 2015
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Ingår i: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 5:4, s. 333-347
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Tidskriftsartikel (refereegranskat)abstract
- Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected (125)I- and non-labelled recombinant human A1M and the (111)In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT.
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| 2. |
- Romantsik, Olga, et al.
(författare)
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The heme and radical scavenger α1-microglobulin (A1M) confers early protection of the immature brain following preterm intraventricular hemorrhage
- 2019
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Germinal matrix intraventricular hemorrhage (GM-IVH) is associated with cerebro-cerebellar damage in very preterm infants, leading to neurodevelopmental impairment. Penetration, from the intraventricular space, of extravasated red blood cells and extracellular hemoglobin (Hb), to the periventricular parenchyma and the cerebellum has been shown to be causal in the development of brain injury following GM-IVH. Furthermore, the damage has been described to be associated with the cytotoxic nature of extracellular Hb-metabolites. To date, there is no therapy available to prevent infants from developing either hydrocephalus or serious neurological disability. Mechanisms previously described to cause brain damage following GM-IVH, i.e., oxidative stress and Hb-metabolite toxicity, suggest that the free radical and heme scavenger α1-microglobulin (A1M) may constitute a potential neuroprotective intervention. Methods: Using a preterm rabbit pup model of IVH, where IVH was induced shortly after birth in pups delivered by cesarean section at E29 (3 days prior to term), we investigated the brain distribution of recombinant A1M (rA1M) following intracerebroventricular (i.c.v.) administration at 24 h post-IVH induction. Further, short-term functional protection of i.c.v.-administered human A1M (hA1M) following IVH in the preterm rabbit pup model was evaluated. Results: Following i.c.v. administration, rA1M was distributed in periventricular white matter regions, throughout the fore- and midbrain and extending to the cerebellum. The regional distribution of rA1M was accompanied by a high co-existence of positive staining for extracellular Hb. Administration of i.c.v.-injected hA1M was associated with decreased structural tissue and mitochondrial damage and with reduced mRNA expression for proinflammatory and inflammatory signaling-related genes induced by IVH in periventricular brain tissue. Conclusions: The results of this study indicate that rA1M/hA1M is a potential candidate for neuroprotective treatment following preterm IVH.
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| 3. |
- Ahlstedt, Jonas, et al.
(författare)
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Human Anti-Oxidation Protein A1M-A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy.
- 2015
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 16:12, s. 30309-30320
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Forskningsöversikt (refereegranskat)abstract
- Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.
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| 4. |
- Almerud, Pernilla, 1978, et al.
(författare)
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Low personal exposure to benzene and 1,3-butadiene in the Swedish petroleum refinery industry
- 2017
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 0340-0131 .- 1432-1246. ; 90:7, s. 713-724
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Tidskriftsartikel (refereegranskat)abstract
- Petroleum refinery workers are exposed to the carcinogens benzene and 1,3-butadiene. Declining exposures have been reported internationally but information on current exposure in the Swedish refinery industry is limited. The aim was to examine refinery workers' personal exposure to benzene and 1,3-butadiene and increase awareness of exposure conditions by collaboration with involved refineries. Altogether 505 repeated personal exposure measurements were performed among workers at two refineries. Full-shift measurements were conducted in different exposure groups using Perkin Elmer diffusive samplers filled with Carbopack X. Mean levels were calculated using mixed-effects models. A large fraction of measurements below the limit of detection (LOD) required imputation of computer-generated data. Mean benzene exposure among process technicians was 15.3 A mu g/m(3) (95% CI 10.4-22.5 A mu g/m(3)) and 13.7 A mu g/m(3) (95% CI 8.3-22.7 A mu g/m(3)) for Refinery 1 and 2, respectively. Process technicians working outdoors had higher exposure than maintenance workers (20.7 versus 5.9 A mu g/m(3), p < 0.01). Working in the harbour and tank park (Refinery 1), compared with the process area, was associated with higher exposure. The 1,3-butadiene exposure was low, 5.4 and 1.8 A mu g/m(3), respectively. The total variation was generally attributed to within-worker variability. Low benzene and 1,3-butadiene levels were found among refinery workers. Mean benzene exposure was about 1% of the Swedish occupational limit (1500 A mu g/m(3)) and for 1,3-butadiene, exposure was even lower. A large fraction of values below the LOD can be managed by carefully modelled, computer-generated data.
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| 5. |
- Alvarado, Gerardo, et al.
(författare)
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Heme-induced contractile dysfunction in Human cardiomyocytes caused by oxidant damage to thick filament proteins.
- 2015
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849. ; 89:sep 23, s. 248-262
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Tidskriftsartikel (refereegranskat)abstract
- Intracellular free heme predisposes to oxidant-mediated tissue damage. We hypothesized that free heme causes alterations in myocardial contractility via disturbed structure and/or regulation of the contractile proteins. Isometric force production and its Ca(2+)-sensitivity (pCa50) were monitored in permeabilized human ventricular cardiomyocytes. Heme exposure altered cardiomyocyte morphology and evoked robust decreases in Ca(2+)-activated maximal active force (Fo) while increasing Ca(2+)-independent passive force (Fpassive). Heme treatments, either alone or in combination with H2O2, did not affect pCa50. The increase in Fpassive started at 3µM heme exposure and could be partially reversed by the antioxidant dithiothreitol. Protein sulfhydryl (SH) groups of thick myofilament content decreased and sulfenic acid formation increased after treatment with heme. Partial restoration in the SH group content was observed in a protein running at 140kDa after treatment with dithiothreitol, but not in other proteins, such as filamin C, myosin heavy chain, cardiac myosin binding protein C, and α-actinin. Importantly, binding of heme to hemopexin or alpha-1-microglobulin prevented its effects on cardiomyocyte contractility, suggesting an allosteric effect. In line with this, free heme directly bound to myosin light chain 1 in human cardiomyocytes. Our observations suggest that free heme modifies cardiac contractile proteins via posttranslational protein modifications and via binding to myosin light chain 1, leading to severe contractile dysfunction. This may contribute to systolic and diastolic cardiac dysfunctions in hemolytic diseases, heart failure, and myocardial ischemia-reperfusion injury.
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| 10. |
- Andersson, Charlotte, et al.
(författare)
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rA1M, a kidney protector during PRRT?
- 2019
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Ingår i: European Radiation Protection Week, Stockholm, Sweden, 2019, 14-18 October.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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