When as ‘chemical chaperones’ by increasing the

When the cell encounters ER stress, the pro-apoptotic
proteins from the B-cell lymphoma 2 family (Bcl2), Bcl-2 homologous antagonist killer
(Bak) and Bcl-2-associated X protein (Bax), undergo conformational changes in
the ER membrane, allowing Ca2+ efflux from the ER. The elevated
concentration of Ca2+ in the cytoplasm stimulates the calcium
dependent protease m-calpain which cleaves and activates procaspase-12, located in the ER membrane. Activated caspase-12 cleaves and
activates procaspase-9 which resulting in activation of the caspase cascade (Boyce and Yuan, 2006).

Figure (1.6) ER stress induced apoptosis. (van der Kallen et al., 2009).

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     Under diabetic
conditions, it seems that a potential ER stress is present because of
glucotoxicity and lipotoxicity which can overload the cell and disrupt ER and
mitochondrial functions (Figure 1.7). The chronic hyperglycemia in T2DM increases
proinsulin biosynthesis that may overwhelm the ER protein folding capacity, resulting
in chronic activation of the UPR. In addition, there are many unfolded and
premature proteins in the ER of pancreatic ?-cells. These unfolded and
premature proteins can easily become targets of ROS.  The chronically stressed ER produces several
proapoptotic signals (JNK- and CHOP mediated cell death pathways), induces
oxidative stress, and initiates mitochondrial apoptosis. Consequently, ?-cell
function deteriorates and cells eventually die (Demirtas et al.,
2016).

Figure (3.7) Amplified endoplasmic reticulum (ER) stress and ?-cell death
in T2DM (Back and Kaufman, 2012).

 

 

 

 

 

 

·    
 ER
stress and Chemical chaperones:

     Chemical chaperones are small molecules
that are non-selective in their ability to stabilize mutant proteins and
facilitate their proper folding. Several studies indicated that in animal
models of obesity, IR and T2DM, reducing ER stress via administration of
chemical chaperones can alleviate the disease symptoms (Erbay et al.,
2009).

 

     Most
chemical chaperones are usually osmotically active such that they equilibrate
cellular osmotic pressure. These osmolytes are compatible with protein function
and can act as ‘chemical chaperones’ by increasing the stability of native
proteins and assisting refolding of unfolded polypeptides. Chemical chaperones belong to mainly three
classes of osmolytes including carbohydrates (sorbitol, glycerol, inositol),
amino acids and derivatives (taurine, glycine, alanine, proline) and
methylamines (betaine, trimethylamine N-oxide) (Engin and
Hotamisligil, 2010).

 

     Currently,
two chemical chaperones, namely, 4-phenylbutyric acid (4-PBA) and
tauroursodeoxycholic acid (TUDCA) are approved by US Food and Drug
Administration (FDA) for use in humans.

 

 

 

 

 

 

 

 

·    
 4-Phenylbutyric
acid (4-PBA):

     4-PBA
is fatty acid with low-molecular weight and has been found to possess
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 due to its capacity to suppress histone deacetylases
(HDACs) at high concentrations (Takai and Narahara, 2010).

 

     PBA’s
chaperone-like activity was first discovered 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 about 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 (Engin and Hotamisligil, 2010).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure
(1.8): The mechanisms of action of 4-PBA.
(Kolb et al., 2015) (A): 4-PBA acts as a chemical chaperone. (B): 4-PBA acts as an
HDAC inhibitor.

 

Experimentally Induced
Rodent Model of T2DM:

     Experimentally
induced or non-genetic models are so-named as they use non-genetic animal
strains those that are not diabetic under normal circumstances. Experimentally
induced models can be induced either by dietary manipulation or by chemical
means or by their combination. No single model displays the full
pathophysiology of T2DM. However, rodent models, that are available, exhibit one
or both of the two major pathogenic characterizations of T2DM, these being the progression
of pancreatic ?-cell dysfunction and insulin resistance (Islam and Wilson,
2012).

 

·    
 Fat-Fed
Streptozotocin Models:

     The most
common experimental model for induction of T2DM is using a combination of high
fat diet (HFD) and low dose of streptozotocin (STZ). STZ is a
natural antibiotic produced by the bacterial species Streptomyces
achromogenes and is used to
induce both T1DM and T2DM depending on its dose. It is a structural
analogue of N-acetyl glucosamine which acts as a potent alkylating agent which results
in disrupted glucokinase activity, glucose transport as well as the breakdown
of multiple DNA strands. Since STZ is a nitric oxide (NO) donor and NO was
found to bring about the destruction of pancreatic ?-cells, it was proposed
that this molecule contributes to STZ-induced DNA damage (Eleazu et al.,
2013).

 

     In
fat-fed STZ-injected model, animals are usually fed with HFD to induce insulin
resistance followed by injection with low dose of STZ to induce partial
pancreatic ?-cell dysfunction. This model has a major advantage over genetic
models since it replicates the natural pathogenesis with producing multiple
characteristics which are in parallel to the human pathogenesis of T2DM (Chen
and Wang, 2005). Therefore, this model appears to be a best choice for use
as a rodent model for T2DM either for rapid and routine pharmacological
screening of anti-diabetic drugs and natural products (Islam and Wilson,
2012).

 

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