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Articles, pre-eclampsia


Current research articles – preeclampsia

Rolf Gunnarsson, Bo Åkerström, Stefan R. Hanssonand Magnus Gram (2016)
Recombinant alpha-1-microglobulin: a potential treatment for preeclampsia
Drug Discovery Today


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Anderson UD, Gram M, Ranstam J, Thilaganathan B, Åkerström B, Hansson SR. (2016)
Fetal hemoglobin, α1-microglobulin and hemopexin are potential predictive first trimester biomarkers for preeclampsia.
Pregn Hypertens. DOI: 10.1016/j.preghy.2016.02.003


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Gram M, Anderson UD, Johansson ME, Edström-Hägerwall A, Larsson I, Jälmby M, Hansson SR, Åkerström B. (2015)
The human endogenous protection system against cell-free hemoglobin and heme is overwhelmed in preeclampsia and provides potential biomarkers and clinical indicators. 
PloS One 10(9):e0138111.


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


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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)
Syncytiotrophoblast vesicles show altered micro-RNA and haemoglobin content after ex-vivo perfusion of placentas with haemoglobin to mimic preeclampsia.
PLoS One 9(2), e90020.


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Sverrisson K, Axelsson J, Rippe A, Gram M, Åkerström B, Hansson SR. Rippe B. (2014)
Extracellular fetal hemoglobin (HbF) induces increases in glomerular permeability. Inhibition with α1-microglobulin (A1M) and Tempol. 
Am J Physiol Renal Physiol 306(4), F442-448. DOI: 10.1152/ajprenal.00502.2013

In this in-vivo experiment we show that fetal haemoglobin damage the kidneys and the unique therapeutic effects of alpha-1-microglobulin, preventing the haemoglobin damaging effects in a rat kidney perfusion model. (Comment by S.R. Hansson)


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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)
A1M/α1-microglobulin protects from heme-induced placental and renal damage in a pregnant sheep model of preeclampsia.
PLoS One 9 (1), e86353.


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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)
Perfusion of human placenta with haemoglobin introduces preeclampsia-like injuries that are prevented by α 1-microglobulin. 
Placenta 32(4), 323-332. DOI: 10.1016/j.placenta.2011.01.017

In this experimental proof-of-concept paper, we show that free fetal haemoglobin causes placental injuries that are similar to those seen in preeclampsia. Furthermore, we show the unique therapeutic effects of alpha-1-microglobulin, preventing the haemoglobin damaging effects ex-vivo. One patent and one company (A1M Pharma) are founded based on the findings in this paper. (Comment by S.R. Hansson)


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Anderson UD, Rutardottir S, Centlow M, Olsson MG, Kristensen, K, Isberg PE, Thilaganatan B, Åkerström B, Hansson SR. (2011)
Fetal hemoglobin and α 1-microglobulin as first and early second trimester predictive biomarkers of preeclampsia. 
Am J Obst Gynecol 204, DOI: 10.1016/j.ajog.2011.01.058

In this clinical paper, we show the unique findings that free fetal haemoglobin and alpha- 1-microglobulin, can be measured in maternal blood as early as the first trimester, a with a high predictive value, identify women who later in their pregnancies will develop preeclampsia. Two patents and one company (Preelumina Diagnostics) are founded based on findings in this and papers 2 and 5. (Comment by S.R. Hansson)


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Olsson MG, Centlow M, Rutardottir S, Stenfors I, Larsson J, Hosseini-Maaf B, Olsson ML, Hansson SR, Åkerström B. (2010)
Increased levels of free hemoglobin, oxidation markers, and the antioxidative heme scavenger α 1-microglobulin in preeclampsia. 
Free Rad. Biol. Med. 48, 284-291. DOI: 10.1016/j.freeradbiomed.2009.10.052

This is the first article that shows that fetal hemoglobin and A1M are increased in blood plasma during preeclampsia, and it suggests that they may be used as biomarkers for diagnosis of the disease. (Comment by B. Åkerström)

Current research articles – general

Åkerström B, Cederlund M, Bergwik J, Manouchehrian O, Arnér K, Holmgren Taylor I, Ghosh F, Taylor L. (2017)
The Role of Mitochondria, Oxidative Stress, and the Radical-binding Protein A1M in Cultured Porcine Retina. 
Current Eye Research


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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)
High Presence of Extracellular Hemoglobin in the Periventricular White Matter Following Preterm Intraventricular Hemorrhage. 
Frontiers in Physiology 7, 24-91. DOI: 10.3389/fphys.2016.00330


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


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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-induced contractile dysfunction in human cardiomyocytes caused by oxidant damage to thick filament proteins. 
Free Radic Biol Med 89, 248-262. DOI: 10.1016/j.freeradbiomed.2015.07.158


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


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Cederlund M, Deronic A, Sørensen OE, Åkerström B. (2015)
A1M/α1-microglobulin is proteolytically activated by myeloperoxidase, binds its heme-group and inhibits low densisty lipoprotein oxidation. 
Front Physiol 6, 11. doi: 10.3389/fphys.2015.00011.


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Gram M, Sveinsdottir S, Cinthio M, Sveinsdottir K, Hansson SR, Mörgelin M, Åkerström B, Ley D. (2014)
Extracellular haemoglobin – mediator of inflammation and cell death in the choroid plexus following preterm intraventricular haemorrhage. 
J Neuroinflam 11(1), 200. DOI: 10.1186/s12974-014-0200-9


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Karnaukhova E, Rutardottir S, Majabi M, Wester Rosenlöf L, Alayash AI, Åkerström B. (2014)
Characterization of heme binding to recombinant α1-microglobulin. 
Front Physiol 5, 465. doi: 10.3389/fphys.2014.00465.


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Gram M, Sveinsdottir S, Ruscher K, Hansson SR, Cinthio M, Åkerström B, Ley D. (2013)
Hemoglobin induces inflammation after preterm intraventricular hemorrhage by methemoglobin formation.
J Neuroinflam. doi 10.1186/10.1186/1742-2094-10-100.


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Rutardottir S, Nilsson EJC, Pallon J, Gram M, Åkerström B. (2013)
The cysteine 34 residue of A1M/α1-microglobulin is essential for protection of irradiated cell cultures and reduction of carbonyl groups. 
Free Radic Res 47 (6-7), 541-550. DOI: 10.3109/10715762.2013.801555


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Cederlund M, Ghosh F, Arnér K, Andréasson S, Åkerström B. (2013)
Vitreous levels of oxidative stress biomarkers and the radical scavenger α1-microglobulin/A1M in human rhegmatogenous retinal detachment. 
Graefes Arch Clin Exp Ophtalmol 251 (3), 725-732. DOI: 10.1007/s00417-012-2113-6

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. (Comment by B. Åkerström)


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

This is a new, surprising and very important finding. During stress conditions, all cells import A1M to protect the function of mitochondria, the energy plants of the cells. (Comment by B. Åkerström)


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

The binding of heme to A1M is investigated in detail. (Comment by B. Åkerström)


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

Hemoglobin and A1M are involved in the hereditary Huntington’s Disease. (Comment by B. Åkerström)


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Olsson MG, Allhorn M, Larsson J, Cederlund M, Lundqvist, K, Schmidtchen A, Sørensen OE, Mörgelin M, Åkerström B. (2011)
Up-regulation of A1M/α1-microglobulin in skin by heme and reactive oxygen species gives protection from oxidative damage. 
PLoS One 6(11):e27505.

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. (Comment by B. Åkerström)


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Olsson MG, Nilsson EJC, Rutardottir S, Paczesny J, Pallon J, Åkerström B. (2010)
Bystander cell death and stress response is inhibited by the radical scavenger α 1-microglobulin in irradiated cell cultures. 
Rad Res 174, 590-600. DOI: 10.1667/RR2213.1

Here, we show that A1M very efficiently protects cells from ionizing irradiation, which is known to induce oxidative stress. (Comment by B. Åkerström)

Review articles

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


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


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


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

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


Older research articles

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


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


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


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

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