Biochemical and biophysical research communications
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Biochem. Biophys. Res. Commun. · Jul 2011
Liberation of desmosine and isodesmosine as amino acids from insoluble elastin by elastolytic proteases.
The development of atherosclerotic lesions and abdominal aortic aneurysms involves degradation and loss of extracellular matrix components, such as collagen and elastin. Releases of the elastin cross-links desmosine (DES) and isodesmosine (IDE) may reflect elastin degradation in cardiovascular diseases. This study investigated the production of soluble elastin cross-linking structures by proteinases implicated in arterial diseases. ⋯ DES and IDE were also released from insoluble elastin exposed to monocyte/macrophage cell lines or human primary macrophages derived from peripheral blood monocytes. Elastin oxidized by reactive oxygen species (ROS) liberated more unconjugated DES and IDE than did non-oxidized elastin when incubated with MMP-12 or neutrophil elastase. These results support the exploration of free DES and IDE as biomarkers of elastin degradation.
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Biochem. Biophys. Res. Commun. · Jul 2011
Attenuation of neurodegenerative phenotypes in Alzheimer-like presenilin 1/presenilin 2 conditional double knockout mice by EUK1001, a promising derivative of xanomeline.
The M1/M4-preferring muscarinic agonist xanomeline was found to have some benefit in the treatment of the memory impairment of Alzheimer's disease (AD), but side effects precluded further development. EUK1001, a fluorinated derivative of xanomeline, because of greater affinity for M1 muscarinic receptors, is likely to have a significantly better side effect profile than xanomeline. We have now studied the effects of 3-month chronic administration of EUK1001 and xanomeline (0.5mg/kg/day) in AD-like presenilin 1/presenilin 2 conditional double knockout (PS cDKO) mice. ⋯ Both compounds effectively suppressed the elevation of brain tau phosphorylation in the PS cDKO mice, but neither inhibited the increased inflammatory responses. These results indicate that EUK1001 showed superiority to xanomeline with regard to attenuation of several AD-like neurodegenerative phenotypes in PS cDKO mice. These results suggest further investigation of the development of EUK1001 for the treatment of AD is indicated.