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Small-Molecule Modulators of Autophagy

The identification of novel, potent and selective autophagy inducers or inhibitors is required to further characterize this process and to be able to modulate it, either positively or negatively, both in basic research and with a final therapeutic aim. Some efforts have already been made to identify chemical modulators of autophagy. However, most of the detected compounds act simultaneously on different cellular pathways, which results in toxic or pleiotropic effects. Hence, there is still a clear need for more selective compounds that can block or induce autophagy without causing additional effects. [Pg.67]

Lysosomotropic agents are small molecules that get trapped in the lysosome as a result of protonation caused by the lysosomal acidic environment. As a consequence of this behavior, lysosomotropic agents accumulate preferentially in the lysosomes and ultimately cause the neutralization of the acid lysosomal pH. [Pg.67]

In summary, there is still a clear need for novel chemical modulators that act selectively on this process, particularly if a final therapeutic aim is considered. Moreover, there is also a need for the identification of novel targets that enable a selective modulation of autophagy without affecting other cellular processes. Important attempts have aheady been done in this field and will be discussed subsequently. However, major advances are currently under way, which suggests that in the near future more selective inhibitors and novel targets will be identified. [Pg.68]

An important fact that needs to be taken into account is that, as mentioned earher, autophagosome or LC3-II accumulation may be produced as a result of an induction of autophagy but can also be produced for an inefficient fusion with lysosome or an inabihty of the lysosomes to degrade autophagosome content once fusion has taken place, caused, for example, by inhibition of lysosomal function after acidification of lysosomal pH. For these reasons, determination of LC3 levels should be always accompanied by measurements of autophagic flux (Box 5.1) in order to ensure a correct interpretation of the results. [Pg.70]

DAPI is a dye employed for selective staining of DNA. DAPI acts by binding to the minor groove of double-stranded DNA, which results in a 20-fold increase in its fluorescence. It is one of the most commonly used methods for selective nuclear staining owing to its selectivity and high cell permeability. [Pg.72]


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