13 research outputs found
Triisopropyltriazacyclononane Copper(II):Â An Efficient Phosphodiester Hydrolysis Catalyst and DNA Cleavage Agent
Host Determinants of Expression of the Helicobacter pylori BabA Adhesin
Expression of the Helicobacter pylori blood group antigen binding adhesin A (BabA) is more common in strains isolated from patients with peptic ulcer disease or gastric cancer, rather than asymptomatic colonization. Here we used mouse models to examine host determinants that affect H. pylori BabA expression. BabA expression was lost by phase variation as frequently in WT mice as in RAG2-/- mice that do not have functional B or T cells, and in MyD88-/-, TLR2-/- and TLR4-/- mice that are defective in toll like receptor signaling. The presence of other bacteria had no effect on BabA expression as shown by infection of germ free mice. Moreover, loss of BabA expression was not dependent on Le(b) expression or the capacity of BabA to bind Leb. Surprisingly, gender was the host determinant most associated with loss of BabA expression, which was maintained to a greater extent in male mice and was associated with greater bacterial load. These results suggest the possibility that loss of BabA expression is not driven by adaptive immunity or toll-like receptor signaling, and that BabA may have other, unrecognized functions in addition to serving as an adhesin that binds Le(b)
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Host Determinants of Expression of the Helicobacter pylori BabA Adhesin.
Expression of the Helicobacter pylori blood group antigen binding adhesin A (BabA) is more common in strains isolated from patients with peptic ulcer disease or gastric cancer, rather than asymptomatic colonization. Here we used mouse models to examine host determinants that affect H. pylori BabA expression. BabA expression was lost by phase variation as frequently in WT mice as in RAG2-/- mice that do not have functional B or T cells, and in MyD88-/-, TLR2-/- and TLR4-/- mice that are defective in toll like receptor signaling. The presence of other bacteria had no effect on BabA expression as shown by infection of germ free mice. Moreover, loss of BabA expression was not dependent on Leb expression or the capacity of BabA to bind Leb. Surprisingly, gender was the host determinant most associated with loss of BabA expression, which was maintained to a greater extent in male mice and was associated with greater bacterial load. These results suggest the possibility that loss of BabA expression is not driven by adaptive immunity or toll-like receptor signaling, and that BabA may have other, unrecognized functions in addition to serving as an adhesin that binds Leb
Selective Inhibition of Collagen Prolyl 4‑Hydroxylase in Human Cells
Collagen is the most abundant protein
in animals. Its overproduction
is associated with fibrosis and cancer metastasis. The stability of
collagen relies on post-translational modifications, the most prevalent
being the hydroxylation of collagen strands by collagen prolyl 4-hydroxylases
(CP4Hs). Catalysis by CP4Hs enlists an iron cofactor to convert proline
residues to 4-hydroxyproline residues, which are essential for the
conformational stability of mature collagen. Ethyl 3,4-dihydroxybenzoate
(EDHB) is commonly used as a “P4H” inhibitor in cells,
but suffers from low potency, poor selectivity, and off-target effects
that cause iron deficiency. Dicarboxylates of 2,2′-bipyridine
are among the most potent known CP4H inhibitors but suffer from a
high affinity for free iron. A screen of biheteroaryl compounds revealed
that replacing one pyridyl group with a thiazole moiety retains potency
and enhances selectivity. A diester of 2-(5-carboxythiazol-2-yl)Âpyridine-5-carboxylic
acid is bioavailable to human cells and inhibits collagen biosynthesis
at concentrations that neither cause general toxicity nor disrupt
iron homeostasis. These data anoint a potent and selective probe for
CP4H and a potential lead for the development of a new class of antifibrotic
and antimetastatic agents
The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron–sulfur cluster biogenesis
Iron Regulatory Protein-1 Protects against Mitoferrin-1-deficient Porphyria.
Mitochondrial iron is essential for the biosynthesis of heme and iron-sulfur ([Fe-S]) clusters in mammalian cells. In developing erythrocytes, iron is imported into the mitochondria by MFRN1 (mitoferrin-1, SLC25A37). Although loss of MFRN1 in zebrafish and mice leads to profound anemia, mutant animals showed no overt signs of porphyria, suggesting that mitochondrial iron deficiency does not result in an accumulation of protoporphyrins. Here, we developed a gene trap model to provide in vitro and in vivo evidence that iron regulatory protein-1 (IRP1) inhibits protoporphyrin accumulation. Mfrn1(+/)(gt);Irp1(-/-) erythroid cells exhibit a significant increase in protoporphyrin levels. IRP1 attenuates protoporphyrin biosynthesis by binding to the 5\u27-iron response element (IRE) of alas2 mRNA, inhibiting its translation. Ectopic expression of alas2 harboring a mutant IRE, preventing IRP1 binding, in Mfrn1(gt/gt) cells mimics Irp1 deficiency. Together, our data support a model whereby impaired mitochondrial [Fe-S] cluster biogenesis in Mfrn1(gt/gt) cells results in elevated IRP1 RNA-binding that attenuates ALAS2 mRNA translation and protoporphyrin accumulation. J Biol Chem 2014 Mar 14; 289(11):7835-43