Human α2-macroglobulin: genotype–phenotype relation

Birkenmeier, Gerd; Müller, R; Huse, Klaus; Forberg, Jochen; Gläser, Christiane; Hedrich, Hans-Jürgen; Nicklisch, Silke; Reichenbach, Andreas

doi:10.1016/s0014-4886(03)00110-9

Cited by 24 publications

(30 citation statements)

References 34 publications

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“…Furthermore, the decline in alpha-2-macroglobulin with increasing age could be explained by the genetic association between alpha-2-macroglobulin polymorphisms in Alzheimer's disease. Specifically, the underlying assumption is that the (5 base pair intronic) deletion in the Alpha-2-macroglobulin gene may affect the functionality and quantity of the resultant Alpha-2-macroglobulin protein in circulation, therefore contributing to Alzheimer's disease pathology [22]. Alternatively, it is possible that neither genetic predisposition nor Alpha-2-macroglobulin quantity contribute towards the pathology of Alzheimer's disease, but rather differences in post-translational modification of this protein.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Differences in Plasma Proteins: How Plasma Proteins Change from Neonates to Adults

et al. 2011

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The incidence of major diseases such as cardiovascular disease, thrombosis and cancer increases with age and is the major cause of mortality world-wide, with neonates and children somehow protected from such diseases of ageing. We hypothesized that there are major developmental differences in plasma proteins and that these contribute to age-related changes in the incidence of major diseases. We evaluated the human plasma proteome in healthy neonates, children and adults using the 2D-DIGE approach. We demonstrate significant changes in number and abundance of up to 100 protein spots that have marked differences in during the transition of the plasma proteome from neonate and child through to adult. These proteins are known to be involved in numerous physiological processes such as iron transport and homeostasis, immune response, haemostasis and apoptosis, amongst others. Importantly, we determined that the proteins that are differentially expressed with age are not the same proteins that are differentially expressed with gender and that the degree of phosphorylation of plasma proteins also changes with age. Given the multi-functionality of these proteins in human physiology, understanding the differences in the plasma proteome in neonates and children compared to adults will make a major contribution to our understanding of developmental biology in humans.

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Section: Discussionmentioning

confidence: 99%

Age-Related Differences in Plasma Proteins: How Plasma Proteins Change from Neonates to Adults

et al. 2011

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“…A, separation of purified native A2M and methylamine-transformed A2M by rate electrophoresis. An amount of 10 g of purified A2M (lane 1, slow-migrating form) and methylamine-treated A2M-MA (lane 2, fast-migrating form), respectively, was separated by rate electrophoresis and stained by Coomassie Brilliant Blue R-250 as described previously (Birkenmeier et al, 2003). B, Western blot of different A2M-PMB conjugates separated by nonreduced and reduced SDS-polyacrylamide gel electrophoresis.…”

Section: Preparation Of A2m-pmb Conjugatesmentioning

confidence: 99%

“…We have recently shown that TNF-␣ binds preferably to transformed A2M rather than to the native inhibitor (Birkenmeier et al, 2003). Whether the covalent modification of A2M by PMB interferes with TNF-␣ binding was a question of interest.…”

Section: A2m-pmb Retained Binding Of Tnf-␣mentioning

confidence: 99%

Polymyxin B-Conjugated α2-Macroglobulin as an Adjunctive Therapy to Sepsis: Modes of Action and Impact on Lethality

Birkenmeier

Nicklisch²,

Pockelt³

et al. 2006

J Pharmacol Exp Ther

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A drug targeting both the inflammatory initiators (lipopolysaccharide; LPS) and mediators [tumor necrosis factor-␣ (TNF-␣)]should have advantage over a "single-factor targeting strategy" in sepsis prevention trials. We have prepared conjugates of polymyxin B (PMB) and the cytokine binding protein ␣2-macroglobulin (A2M). The conjugate binds TNF-␣ as well as LPS as studied by electrophoresis and phase partitioning. Compared with free PMB, the conjugate is nontoxic to cells and does not affect the viability of human monocytes. The A2M-PMB conjugate binds to the A2M receptor (CD91/low-density lipoprotein receptor-related protein 1) with affinity similar to that of the nonmodified protein. Fluorescein isothiocyanate-labeled LPS in the presence of A2M-PMB is rapidly transported into fibroblasts for degradation via receptor-mediated endocytosis. In vitro, A2M-PMB demonstrated inhibition of LPS-induced secretion of TNF-␣ from isolated monocytes as well as in the whole blood assay. The efficacy of the drug was tested in mice after induction of acute inflammation (LPS model) and after induction of a polymicrobial sepsis by cecal ligation and puncture (CLP) model. Treatment of mice with A2M-PMB up to 250 g/g body weight was not toxic to the animal. When the drug was administered 30 min before or 30 min after the LPS challenge, a survival rate of 90 and 70%, respectively, was obtained compared with the placebo control group (5%). A2M-PMB also protected mice after induction of polymicrobial sepsis when administered 30 min before CLP. These results support our hypothesis that A2M-PMB acts as a polyvalent drug to target different host mediators as well as sepsis inducer at the same time.In the past several years, mortality in patients with sepsis syndrome has decreased somewhat, but in those patients with septic shock and multiple organ failure, mortality still exceeds 50% (Danai and Martin, 2005). This high mortality is observed despite ventilatory, hemodynamic, metabolic, and renal support. Some patients-in particular, patients with genetic polymorphisms associated with low or moderate TNF response-survive the ordeal more often, but it remains frustrating not being able to stop the downhill course leading to multiple organ failure and death in other patients that results from overwhelming inflammation. New therapies have been sought and tested, including those preventing the biological activity of pathogen-associated molecular patterns, such as endotoxin or the downhill host response, most notably TNF-␣. Based on a wealth of animal studies, anti-inflammatory strategies, such as neutralizing TNF-␣, have been advocated to provide adjunctive therapy to the patient who continues to deteriorate in the face of considerable support in the intensive care unit. Unfortunately, these anticytokine therapies have not dramatically reduced mortality in doubleblind, placebo-controlled trials involving thousands of patients, although there is a consistent but statistically non-

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“…In the light of these findings, we assume that the decline in the A2M blood level found at higher age may therefore facilitate tumor development (50).…”

Section: Discussionmentioning

confidence: 81%

α2-Macroglobulin Inhibits the Malignant Properties of Astrocytoma Cells by Impeding β-Catenin Signaling

et al. 2010

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Targets that could improve the treatment of brain tumors remain important to define. This study of a transformation-associated isoform of α2-macroglobulin (A2M*) and its interaction with the low-density lipoprotein receptor-related protein-1 (LRP1) suggests a new mechanism for abrogating the malignant potential of astrocytoma cells. LRP1 bound A2M* found to be associated with an inhibition of tumor cell proliferation, migration, invasion, spheroid formation, and anchorage-independent growth. Transcriptional studies implicated effects on the Wnt/β-catenin signaling pathway. Notably, LRP1 antibodies could phenocopy the effects of A2M*. Our findings suggest a pathway of tumor suppression in astrocytoma that might be tractable to therapeutic exploitation. Cancer Res; 70(1); 277-87. ©2010 AACR.

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Human α2-macroglobulin: genotype–phenotype relation

Cited by 24 publications

References 34 publications

Age-Related Differences in Plasma Proteins: How Plasma Proteins Change from Neonates to Adults

Age-Related Differences in Plasma Proteins: How Plasma Proteins Change from Neonates to Adults

Polymyxin B-Conjugated α2-Macroglobulin as an Adjunctive Therapy to Sepsis: Modes of Action and Impact on Lethality

α2-Macroglobulin Inhibits the Malignant Properties of Astrocytoma Cells by Impeding β-Catenin Signaling

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