Preventing the formation of insoluble polyglutamine containing protein aggregates in neurons may represent an attractive therapeutic strategy to ameliorate Huntington's disease (HD). Therefore, the ability to screen for small molecules that suppress the self-assembly of huntingtin would have potential clinical and significant research applications. We have developed an automated filter retardation assay for the rapid identification of chemical compounds that prevent HD exon 1 protein aggregation in vitro. Using this method, a total of 25 benzothiazole derivatives that inhibit huntingtin fibrillogenesis in a dose-dependent manner were discovered from a library of Ϸ184,000 small molecules. The results obtained by the filter assay were confirmed by immunoblotting, electron microscopy, and mass spectrometry. Furthermore, cell culture studies revealed that 2-amino-4,7-dimethylbenzothiazol-6-ol, a chemical compound similar to riluzole, significantly inhibits HD exon 1 aggregation in vivo. These findings may provide the basis for a new therapeutic approach to prevent the accumulation of insoluble protein aggregates in Huntington's disease and related glutamine repeat disorders.
Cathodoluminescence and fluorescence microscopy have been used to study vasogenic edema in experimentally induced brain tumors in rats. Both methods are suited for the demonstration of FITC- or TRITC-coupled antiserum, and thus allow the evaluation of serum protein extravasation. Cathodoluminescence is more time consuming and laborious than fluorescence microscopy, but it has distinct advantages: Contrast enhancement improves the differentiation between certain cell types, and the higher resolution of the scanning electron microscope allows the identification of subcellular regions which cannot be recognized by conventional fluorescence microscopy.
Marfan's syndrome and marble bone disease are used as examples of systemic bone lesions. Scanning electron microscopy shows cancellous bone structures with multiple defects for Marfan's syndrome and for marble bone disease, very compact bone structures. These bone diseases seem to be caused by different enzymatic defects. Zusammenfassung. Als Beispiel yon Knochensystemerkrankungen werden das Marfan-Syndrom und die Marmorknochenkrankheit vorgestellt. Die Rasterelektronenmikroskopie zeigt ffir das Marfan-Syndrom spongiosaartige Knochenstrukturen mit multiplen AbbrUchen. Die Marmorknochenkrankheit enth~tlt sehr kompakte Faserstrukturen. Beide Erkrankungen deuten auf unterschiedliche enzymatische Defekte. Schliisselw6rter: Rasterelektronenmikroskopie -R6ntgenmikrobereichsanalyse -Marfan-Syndrom -Marmorknochenkrankheit.Summary. Neutral proteases (elastase, cathepsin G and cathepsin B1) from human leukocytes were isolated and the dose-dependent influence of glycosaminoglycanpotysulfate (GAGPS, Luitpoldwerke MUnchen) on the activity of these enzymes was tested using chromogenic substrates. The inhibition of elastase up to 70 % (as reported in the literature) could be confirmed, whereas cathepsin G and cathepsin Bx were resistant to inhibition under the applied conditions. Because the inhibition ofelastase has already been achieved at concentrations of 1 gg/ml, these results may account for the therapeutic efficiency of Arteparon.
Zusammenfassung. Es wurden die neutralen Proteasen (Elastase, Kathepsin G und Kathepsin Bx) aus denGranula menschlicher Leukocyten isoliert und der dosisabh~ingige EinfluB yon Glykosaminoglykanpolysulfat (GAGPS, Luitpoldwerke Mfinchen) aufdie Aktivit/it dieser Enzyme mit chromogenen Substraten getestet. Eine 70 ~oige Hemmung yon Elastase, wie in der Literatur beschrieben, konnten wir best~itigen. Dagegen wird die enzymatische Aktivit/it von Kathepsin G und Kathepsin B1 von GAGPS nicht beeinfluBt. Da eine Hemmung yon Elastase bereits mit Inhibitorkonzentrationen yon llag/ml erreicht wird, erklfiren diese Befunde die therapeutische Wirksamkeit yon Arteparon.Sehliisselw~Jrter: PMN-Proteasen -Antirheumatische Substanzen.
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