Inhibition lysosomal

As discussed in detail by Dillard et al. and by Mittman et al. the possible relationship of lysosomal proteases to chronic lung disease has been inferred from the finding of an increased incidence of emphysema in subjects deficient in serum ai>antitrypsin factor, an -globulin that can inhibit lysosomal proteases. (No effect of ozone on serum aj-antitrypsin inhibitor was noted in rabbits chronically exposed to ozone. ) Thus, an ozone-induced increase in concentrations of such enzymes in the lung might produce excess proteolysis and result in eventual chronic lung disease. However, the available evidence is inadequate to support the belief that such a process occurs in humans intermittently exposed to ozone. Further studies of this potential hazard would be of value. 

Investigation of the inhibitory effects on glycosidases has been carried out for the hydroxylated pyrrolidines [65] and piperidines [73]. Among the pyrrolidines prepared only the l,4-dideoxy-l,4-imino-L-allitol (23) (Scheme 7) and its C-5 isomer showed any remarkable effects. They inhibited lysosomal a-manno-sidase rather than the processing a-mannosidases I and II [65], and their specificity is in accord with the structural requirements of azafuranose analogues of mannose for inhibiting mammalian a-o-mannosidases [80]. 

E4. Eldred, G. E., Lipofuscin fluorophore inhibits lysosomal protein degradation and may cause early stages of macular degeneration. Gerontology 41 Suppl. 2, 15—28 (1995). 

Addition of proteinase inhibitors to cells or their injection in vivo not only inhibits lysosomal proteinase activities but also causes formation of autophagic vacuoles 115) and induces synthesis of hemoglobinhydrolyzing thiol proteinase 16, 63). Increase of autophagic vacuoles in cells by treatment with leupeptin is responsible for inhibition of lysosomal thiol proteinase activities with consequent decrease of protein degradation. 

Licochalcones A and B from G. inflata strongly inhibited lysosomal enzyme release and degranulation from human polymorphonuclear ueutrophils. ... 

Pompe disease (which causes lysosomal accumulation of glycogen and, in consequence, cardiac and skeletal muscle degeneration), castanospermine (654) was found to inhibit lysosomal human recombinant acid a-glucosidase significantly K < 1 pM) and to confer thermal stability on the enzyme. ... 

Furthermore, when castanospermine is fed to mice over 4 5 days, it inhibits lysosomal a-glucosidase and causes the accumulation of partially degraded glycogen within the lysosomal structures [55]. This accumulation resembles the accumulation of glycogen particles in the lysosomal storage disease, Pompe s disease, where individuals lack the lysosomal a-glucosidase [56]. 

A number of mannosidase inhibitors have been isolated from various plants and fungi, and the specificity and activity of many of these inhibitors has been outlined in Table 1. The first glycoprotein processing inhibitor to be identified was the in-dolizidine alkaloid, swainsonine whose structure is presented in Figure 1B. Swain-sonine was shown to specifically inhibit plant and animal mannosidase II [78]. This alkaloid also inhibits lysosomal a-mannosidase and jack bean a-mannosidase, but... 

However, agents that inhibit lysosomal trafficking markedly increased nuclear delivery, suggesting that the majority of the lactosylated polyplexes trafficked to the endolysosomal pathway (210). 

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