Biomedical subjects

Alex Strongin

Publications and source records attributed to Alex Strongin.

4 recordsLinked to original sources

PubMed2005

Convergent evolution as a mechanism for pathogenic adaptation.

The survival of human pathogens depends on their ability to modulate defence pathways in human host cells. This was thought to be attained mainly by pathogen specific "virulence factors". However, pathogens are increasingly being discovered that use distant homologs of the human regulatory proteins as virulence factors. We analyzed several cases of this approach, with a particular focus on virulence proteases. The analysis reveals clear cases of bacterial proteases mimicking the specificity of their human counterparts, such as strong similarities in their active and/or binding sites. With more sensitive tools for distant homology recognition, we could expect to discover many more such cases.

Adaptation, Physiological↗

PubMed2005

Nicotinic acetylcholine receptor-mediated stimulation of endothelial cells results in the arrest of haematopoietic progenitor cells on endothelium.

The function of endothelial cells that contribute to the regulation of haematopoietic stem/progenitor cells (HSPC) migration from peripheral blood into bone marrow can be influenced by extrinsic factors including nicotine. Therefore, the effect of nicotine on HSPC extravasation was studied. Using a parallel laminar flow chamber, we demonstrated an increase in the number of HSPC adhering to the nicotine-exposed endothelium under conditions of physiological shear stress in vitro. Nicotine-induced adhesion of HSPC was inhibited by mecamylamine, a non-selective nicotinic acetylcholine receptor (nAchR) antagonist. The enhanced adhesive interactions of HSPC with nicotine-exposed endothelial monolayers coincided with the nicotine-induced activation of endothelial cells. Nicotine induced fast cytoskeletal reorganization and formation of filopodia in endothelial cells through interaction with the non-neuronal nAchR expressed by these cells. In addition, nicotine treatment stimulated rapid phosphorylation of Erk1/2 and p-38 in endothelial cells. Finally, nicotine inhibited the stroma derived factor-1-mediated transendothelial migration of HSPC. Decreased migration of HSPC correlated with diminished matrix metalloproteinase-9 activity secreted by bone marrow cells and decreased expression of CD44 on the surface of endothelial cells. Overall, our data suggest that exposure to nicotine causes endothelial cell dysfunction and leads to the pathological arrest of HSPC on endothelium, interfering with their proper migration process.

Animals↗

PubMed2004

Prostaglandin FP agonists alter metalloproteinase gene expression in sclera.

PURPOSE: The present study was undertaken to determine whether exposure of the sclera to prostaglandin (PG)F(2alpha) or to the PGF(2alpha) analogue latanoprost acid alters mRNA for matrix metalloproteinases. METHOD: Fifteen human eye bank eyes were studied. Circular pieces of sclera were either immediately preserved in a stabilization reagent or cultured in low-serum DMEM/F-12 medium. The cultures were treated for 24 hours with medium supplemented with PGF(2a), latanoprost acid, or vehicle. Total RNA was then isolated, and the expression of mRNA for matrix metalloproteinase (MMP)-1, -2, -3, -8, -9, -10, and -12 were determined by real-time PCR. All results were normalized according to the GAPDH mRNA in each sample. Altered mRNA expression after PG treatments also was evaluated with microarrays containing 19 MMP genes and 4 tissue inhibitor of matrix metalloproteinase (TIMP) genes. RESULTS: Real-time PCR results showed that 24 hours of exposure to 100 nM PGF(2alpha) significantly increased mRNA for MMP-1 and -9 (P < 0.06 Wilcoxon test) and that exposure to 100 nM latanoprost acid significantly increased mRNA for MMP-9 (P < 0.06 Wilcoxon test). Array analysis demonstrated increases of MMP-3 and -10 mRNA after exposure to 100 nM latanoprost and further increases after exposure to 200 nM latanoprost. The array results also showed that latanoprost induced dose-dependent increases in the expression of TIMP-1, -2, and -3 mRNA in the scleral cultures. CONCLUSIONS: PGF(2alpha) and latanoprost acid induce coordinated alterations of MMP gene transcription in scleral organ cultures. These results indicate that PGs can directly trigger MMP gene transcription changes within the sclera. These changes support a role for increased MMPs in the enhancement of uveoscleral outflow that occurs after topical treatment with latanoprost.

Aged↗

PubMed2002

S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death.

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of neurodegenerative diseases and stroke. However, the mechanism of MMP activation remains unclear. We report that MMP activation involves S-nitrosylation. During cerebral ischemia in vivo, MMP-9 colocalized with neuronal nitric oxide synthase. S-Nitrosylation activated MMP-9 in vitro and induced neuronal apoptosis. Mass spectrometry identified the active derivative of MMP-9, both in vitro and in vivo, as a stable sulfinic or sulfonic acid, whose formation was triggered by S-nitrosylation. These findings suggest a potential extracellular proteolysis pathway to neuronal cell death in which S-nitrosylation activates MMPs, and further oxidation results in a stable posttranslational modification with pathological activity.

Animals↗