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Articles, pre-eclampsia


Current research articles – preeclampsia

Recombinant alpha-1-microglobulin: a potential treatment for preeclampsia
Rolf Gunnarsson, Bo Åkerström, Stefan R. Hanssonand Magnus Gram (2016)
A review article describing preeclampsia, A1M and A1M Pharma’s treatment principle.
Drug Discovery Today


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Fetal hemoglobin, α1-microglobulin and hemopexin are potential predictive first trimester biomarkers for preeclampsia.
Anderson UD, Gram M, Ranstam J, Thilaganathan B, Åkerström B, Hansson SR. (2016)
The work in this article shows that HbF and A1M are involved in the development of preeclampsia. The results also suggest that preeclampsia may be predicted as early as the first trimester of the pregnancy by measurement of HbF, A1M and the protein hemopexin in combination with Doppler ultrasound.
Pregn Hypertens. DOI: 10.1016/j.preghy.2016.02.003


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The human endogenous protection system against cell-free hemoglobin and heme is overwhelmed in preeclampsia and provides potential biomarkers and clinical indicators. 
Gram M, Anderson UD, Johansson ME, Edström-Hägerwall A, Larsson I, Jälmby M, Hansson SR, Åkerström B. (2015)
The results in this article shows that HbF and A1M are involved in the development of preeclampsia. Here, the molecules HbF, haptoglobin, hemopexin and A1M were measured in maternal blood samples at delivery of the babies.
PloS One 10(9):e0138111.


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A1M ameliorates preeclampsia-like symptoms in placenta and kidney induced by cell-free fetal hemoglobin in rabbit. 
Nääv Å, Erlandsson L, Axelsson J, Larsson I, Johansson M, Wester Rosenlöf L, Mörgelin M, Casslén V, Gram M, Åkerström B, Hansson SR. (2015)
An in vivo Proof-of-Concept study of successful treatment of preeclampsia with A1M-infusion in pregnant rabbits.
PloS One, 10(5):e0125499.


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Syncytiotrophoblast vesicles show altered micro-RNA and haemoglobin content after ex-vivo perfusion of placentas with haemoglobin to mimic preeclampsia.
Cronqvist T, Saljé K, Familari M, Guller S, Schneider H, Gardiner C, Sargent IL, Redman CW, Mörgelin M, Åkerström B, Gram M, Hansson SR. (2014)
A study of the mechanisms of how HbF may induce preeclampsia: by leaking from the placental tissue in small membrande-bound vesicles to the maternal blood system.
PLoS One 9(2), e90020.


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Extracellular fetal hemoglobin (HbF) induces increases in glomerular permeability. Inhibition with α1-microglobulin (A1M) and Tempol. 
Sverrisson K, Axelsson J, Rippe A, Gram M, Åkerström B, Hansson SR. Rippe B. (2014)
In this in-vivo experiment we show that HbF damage the kidneys and the unique therapeutic effects of A1M, preventing the Hb damaging effects in a rat kidney perfusion model. 
Am J Physiol Renal Physiol 306(4), F442-448. DOI: 10.1152/ajprenal.00502.2013


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A1M/α1-microglobulin protects from heme-induced placental and renal damage in a pregnant sheep model of preeclampsia.
Wester-Rosenlöf L, Casslén V, Axelsson J, Edström-Hägerwall A, Gram M, Holmquist M, Johansson ME, Larsson I, Ley D, Marsal K, Mörgelin M, Rippe B, Rutardottir S, Shohani B, Åkerström B, Hansson SR. (2014)
The first in vivo Proof-of-Concept study of successful treatment of preeclampsia with A1M in animals: pregnant sheep.
PLoS One 9 (1), e86353.


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Perfusion of human placenta with haemoglobin introduces preeclampsia-like injuries that are prevented by α 1-microglobulin. 
May K, Rosenlöf L, Olsson MG, Centlow M, Mörgelin M, Larsson I, Cederlund M, Rutardottir S, Schneider H, Siegmund W, Åkerström B, Hansson SR. (2011)
In this experimental proof-of-concept paper, we show that free HbF causes placental injuries that are similar to those seen in preeclampsia. Furthermore, we show the unique therapeutic effects of A1M, preventing the Hb damaging effects ex-vivo. 
Placenta 32(4), 323-332. DOI: 10.1016/j.placenta.2011.01.017


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Fetal hemoglobin and α 1-microglobulin as first and early second trimester predictive biomarkers of preeclampsia. 
Anderson UD, Rutardottir S, Centlow M, Olsson MG, Kristensen, K, Isberg PE, Thilaganatan B, Åkerström B, Hansson SR. (2011)
In this clinical paper, we show the unique findings that free HbF and A1M, can be measured in maternal blood as early as the first trimester, with a high predictive value, identify women who later in their pregnancies will develop preeclampsia. 
Am J Obst Gynecol 204, DOI: 10.1016/j.ajog.2011.01.058


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Increased levels of free hemoglobin, oxidation markers, and the antioxidative heme scavenger α 1-microglobulin in preeclampsia.
Olsson MG, Centlow M, Rutardottir S, Stenfors I, Larsson J, Hosseini-Maaf B, Olsson ML, Hansson SR, Åkerström B. (2010) 
This is the first article that shows that HbF and A1M are increased in blood plasma during preeclampsia, and it suggests that they may be used as biomarkers for diagnosis of the disease. 
Free Rad. Biol. Med. 48, 284-291. DOI: 10.1016/j.freeradbiomed.2009.10.052


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Current research articles – A1M protein

The Role of Mitochondria, Oxidative Stress, and the Radical-binding Protein A1M in Cultured Porcine Retina. 
Åkerström B, Cederlund M, Bergwik J, Manouchehrian O, Arnér K, Holmgren Taylor I, Ghosh F, Taylor L. (2017)
The protein A1M is produced by the retina in the eye and is involved in local antioxidation defense of the retinal cells.
Current Eye Research


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High Presence of Extracellular Hemoglobin in the Periventricular White Matter Following Preterm Intraventricular Hemorrhage. 
Ley D, Romantsik O, Vallius S, Sveinsdóttir K, Sveinsdóttir S, Agyemang A, Baumgarten M, Mörgelin M, Lutay N, Bruschettini M, Holmqvist B, Gram M. (2016)
This study shows that intraventricular bleeding (IVH) of prematurely born rabbit pups can induce brain damage in a process that involves free Hb toxicity. The study suggests that IVH in human babies may be treated by combatting Hb-induced oxidative stress.
Frontiers in Physiology 7, 24-91. DOI: 10.3389/fphys.2016.00330


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Structural and biochemical characterization of two heme binding sites on α1-microglobulin using site directed mutagenesis and molecular simulation. 
Rutardottir S, Karnaukhova E, Nantasenamat C, Songtawee N, Prachayasittikul V, Rajabi M, Wester Rosenlöf L, Alayash AI, Åkerström B. (2016)
This paper describes in biochemical detail how each A1M-molecule binds two heme-molecules.
Biochim Biophys Acta 1864(1), 29-41. DOI: 10.1016/j.bbapap.2015.10.002


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Heme-induced contractile dysfunction in human cardiomyocytes caused by oxidant damage to thick filament proteins. 
Alvarado G, Jenney V, Toth A, Csösz E, Kallo G, Huynh TA, Hajnal C, Kalasz J, Pasztor ET, Edes Im Gram M, Åkerström B, Smith A, Eaton JW, Balla G, Papp Z, Balla J. (2015)
Heme, a degradation product of Hb and other molecules involved in inflammation and atherosclerosis, can damage heart contraction. This paper describes the mechanisms of this damage and that A1M can be used as a protection agent.
Free Radic Biol Med 89, 248-262. DOI: 10.1016/j.freeradbiomed.2015.07.158


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Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys. 
Ahlstedt J, Tran TA, Strand F, Holmqvist B, Strand S-E, Gram M, Åkerström B. (2015)
Am J Nucl Med Mol Imaging 5(4):333-47. PMCID: PMC4529588


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A1M/α1-microglobulin is proteolytically activated by myeloperoxidase, binds its heme-group and inhibits low density lipoprotein oxidation. 
Cederlund M, Deronic A, Sørensen OE, Åkerström B. (2015)
A1M protects against atherosclerosis by interfering with the inflammation protein myeloperoxidase, which is involved in the atherosclerosis process.
Front Physiol 6, 11. doi: 10.3389/fphys.2015.00011.


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Extracellular haemoglobin – mediator of inflammation and cell death in the choroid plexus following preterm intraventricular haemorrhage. 
Gram M, Sveinsdottir S, Cinthio M, Sveinsdottir K, Hansson SR, Mörgelin M, Åkerström B, Ley D. (2014)
This study shows that intraventricular bleeding (IVH) of prematurely born babies is an inflammatory process involving free Hb.
J Neuroinflam 11(1), 200. DOI: 10.1186/s12974-014-0200-9


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Characterization of heme binding to recombinant α1-microglobulin. 
Karnaukhova E, Rutardottir S, Majabi M, Wester Rosenlöf L, Alayash AI, Åkerström B. (2014)
This paper describes in biochemical detail how each A1M-molecule binds two heme-molecules.
Front Physiol 5, 465. doi: 10.3389/fphys.2014.00465.


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Hemoglobin induces inflammation after preterm intraventricular hemorrhage by methemoglobin formation.
Gram M, Sveinsdottir S, Ruscher K, Hansson SR, Cinthio M, Åkerström B, Ley D. (2013)
This study shows that intraventricular bleeding (IVH) of prematurely born babies is an inflammatory process involving oxidation of free Hb and suggests that the disease may be treated with A1M.
J Neuroinflam. doi 10.1186/10.1186/1742-2094-10-100.


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The cysteine 34 residue of A1M/α1-microglobulin is essential for protection of irradiated cell cultures and reduction of carbonyl groups. 
Rutardottir S, Nilsson EJC, Pallon J, Gram M, Åkerström B. (2013)
A1M protects cells and extracellular matrix against radiation-induced damage. One specific amino acid, cysteine-34, is especially important for the protection properties.
Free Radic Res 47 (6-7), 541-550. DOI: 10.3109/10715762.2013.801555


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Vitreous levels of oxidative stress biomarkers and the radical scavenger α1-microglobulin/A1M in human rhegmatogenous retinal detachment. 
Cederlund M, Ghosh F, Arnér K, Andréasson S, Åkerström B. (2013)
A1M is found in the eyes and the concentration of A1M is correlated to the severity of retinal detachment. This suggests that the eyes respond to the disease by producing more A1M. 
Graefes Arch Clin Exp Ophtalmol 251 (3), 725-732. DOI: 10.1007/s00417-012-2113-6


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The radical-binding lipocalin A1M binds to a Complex I subunit and protects mitochondrial structure and function.
Olsson MG, Rosenlöf LW, Kotarsky H, Olofsson T, Leanderson T, Mörgelin M, Fellman V, Åkerström B. (2013)
During stress conditions, all cells import A1M to protect the function of mitochondria, the energy plants of the cells. 
Antiox Redox Signal. 18 (16), 2017-2028. DOI: 10.1089/ars.2012.4658


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Insertion of heme b into the structure of the Cys34-carbamidomethylated human lipocalin α1-microglobulin. Formation of a [(heme)21-microglobulin)]3 complex. 
Siebel JF, Kosinsky RL, Åkerström B, Knipp M. (2012)
The binding of heme to A1M is investigated in detail. 
ChemBioChem 13(6), 879-887. DOI: 10.1002/cbic.201100808


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Increased levels of hemoglobin and the radical scavenger and antioxidant α 1-microglobulin in Huntington’s disease. 
Olsson MG, Davidsson S, Muhammad ZD, Lahiri N, Tabrizi SJ, Åkerström B, Björkqvist M. (2012)
Hb and A1M are involved in the hereditary Huntington’s Disease. 
Front Biosci 4, 950-957.


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Up-regulation of A1M/α1-microglobulin in skin by heme and reactive oxygen species gives protection from oxidative damage. 
Olsson MG, Allhorn M, Larsson J, Cederlund M, Lundqvist, K, Schmidtchen A, Sørensen OE, Mörgelin M, Åkerström B. (2011)
A1M is used by the skin to protect cells and molecules during bleeding and UV-irradiation. In this paper, we also show that A1M is especially efficient in protecting collagen fibers. This may be important for future applications in skin therapy. 
PLoS One 6(11):e27505.


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Bystander cell death and stress response is inhibited by the radical scavenger α 1-microglobulin in irradiated cell cultures. 
Olsson MG, Nilsson EJC, Rutardottir S, Paczesny J, Pallon J, Åkerström B. (2010)
Here, we show that A1M very efficiently protects cells from ionizing irradiation, which is known to induce oxidative stress. 
Rad Res 174, 590-600. DOI: 10.1667/RR2213.1


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Review articles

Human anti-oxidation protein A1M – a potential kidney protection agent in peptide receptor radionuclide therapy. 
Ahlstedt J, Tran TA, Gram M, Strand SE, Åkerström B. (2016)
Int J Mol Sci. 16(12), 30309-30320. DOI: 10.3390/ijms161226234


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Inventory of animal models addressing etiology of preeclampsia in the development of new therapeutic/intervention opportunities. 
Erlandsson L, Nääv Å, Hennessey A, Vaiman D, Gram M, Åkerström B, Hansson SR. (2016)
Am J Repr Immunol. 75(3), 402-410. DOI: 10.1111/aji.12460


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First trimester prediction of preeclampsia. 
Anderson UD, Gram M, Åkerström B, Hansson SR. (2015)
Curr Hypertens Rep 17(9), 584. doi: 10.1007/s11906-015-0584-7.


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A1M, an extravascular tissue cleaning and housekeeping protein. 
Åkerström B, Gram M. (2014)
Free Radic Biol Med 74, 274-282. DOI: 10.1016/j.freeradbiomed.2014.06.025

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Pathological conditions involving extracellular hemoglobin: Molecular mechanisms, clinical significance and novel therapeutic opportunities for α1–microglobulin. 
Olsson MG, Allhorn M, Bülow L, Hansson SR, Ley D, Olsson ML, Schmidtchen A, Åkerström B. (2012)
Antiox Redox Signal. 17(5), 813-846. DOI: 10.1089/ars.2011.4282

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Older research articles

The lipocalin alpha-1-microglobulin has radical scavenger activity 
Åkerström B, Maghzal G, Winterbourn CC, Kettle T.
J Biol Chem 2007; 282:31493-31503


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Up-regulation of alpha-1-microglobulin by hemoglobin and reactive oxygen species in hepatoma and blood cell lines 
Olsson MG, Allhorn M, Olofsson T, Åkerström B.
Free Rad Biol Med 2007; 42:842-851


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Placental expression profiling in preeclampsia: local overproduction of hemoglobin may drive pathological changes.
Centlow M, Carninci P, Nemeth K, Mezey E, Brownstein M, Hansson SR. (2008) 
Fertil Steril 90(5), 1834-1843. DOI: 10.1016/j.fertnstert.2007.09.030


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Processing of the lipocalin alpha-1-microglobulin by hemoglobin induces heme-binding and heme-degradation properties 
Allhorn M, Berggård T, Nordberg J, Olsson ML, Åkerström B.
Blood 2002; 99:1894-1901

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