4-PBA is fatty acid with low-molecular weight and
has been found to have chaperone-like activities. 4-PBA is approved for clinical
use as an ammonia scavenger in children with urea cycle upsets (Engin and
Hotamisligil, 2010).

 

     4-PBA
has also been counted as a hopeful candidate in the treatment of thalassemias, since
it has been reported that it induces the transcription of ?- and ? -globin
proteins (Collins et al., 1995). It was also suggested as a
chemotherapeutic agent because of its capacity to suppress histone deacetylases
(HDACs) at high concentrations (Takai and Narahara, 2010).

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     PBA’s
chaperone-like activity was first reported when examining its influence on the
trafficking of cystic fibrosis transmembrane conductance regulator protein
(CFTR) (Kerem, 2005). Mutations in this protein have been associated
with a failure of CFTR to be properly processed in the ER and its subsequent
failure to transport to the cell surface. PBA could act to stabilize and
prevent mutant protein to be directed to degradation pathway in the ER and
facilitate its translocation to the cell surface (Inden et al., 2007).

 

     4-PBA administration also results in
approximately 45% reduction in apoptosis, as evident in significant decrease in
activated caspase-12 and proapoptotic CHOP protein levels (Jian et al.,
2016).

 

    It has
been suggested that it stabilizes the misfolded proteins (Figure 1.8), decrease
their aggregation, assist the mutant proteins to escape the cell’s quality
control systems and alter the activity of endogenous molecular chaperones to
assist the transportation of mutant proteins to the right subcellular localization.
Furthermore, it is proposed that 4-PBA may potentially alleviate the ER stress
by affecting protein trafficking through its HDAC inhibitor activity. The HDAC inhibitory activity of PBA enables it
to regulate the transcription of several genes involved in the UPR system