Abstract
BackgroundImbalance between protein synthesis and endoplasmic reticulum (ER) capacity to modify and fold proteins lead to the accumulation of unfolded proteins resulting in ER stress and apoptosis. Chaperones are major defense molecules assisting in protein folding, transport, and cellular signaling. ER stress plays a major role in the pathogenesis of diabetes mellitus (DM) and its complications, e.g., diabetic cataract. In the present investigation, the chemical chaperones 4-phenylbutyric acid (4-PBA), tauroursodeoxycholic acid (TUDCA), and trimethylamine N-oxide (TMAO) are used as potential therapeutic agents for alleviation of DM-induced ER stress and diabetic cataract in rats. Animals are subjected to biochemical analysis of blood and lenses for ER stress and apoptosis markers. Moreover, ophthalmologic examination and histopathologic examination of the lenses were done to confirm the results.ResultsBoth ophthalmic and lens histopathologic examination revealed that treatment with 4-PBA and TUDCA retarded the occurrence of cataract markedly. Whereas, treatment with TMAO caused a partial improvement of cataract. Moreover, biochemical tests showed that both 4-PBA and TUDCA produced a remarkable improvement in the ER marker levels (VEGF and caspase-12), GSH, MDA, TAC levels in lens tissues. On the other hand, TMAO had no significant effect on these parameters. However, Western blot analysis of lens homogenates showed a suppressed expression of GRP78 and CHOP after treatment with 4-PBA, TUDCA, and TMAO. Moreover, all treated groups showed a significant improvement of lens soluble proteins and their UV spectra absorption. A significant improvement in fasting blood sugar, GSH, serum MDA, and TAC were noted in all treated groups. 4-PBA produced a significant decrease in insulin resistance, whereas TUDCA and TMAO showed insignificant change.ConclusionThe present research found that the tested chaperones could be used as a therapeutic approach for clinically relevant disorders featuring ER dysfunction such as DM and for reducing its complications in the eye mainly cataract. However, TUDCA and 4-PBA were found to have a more potential efficacy in reducing most of the tested parameters as compared to TMAO.
Highlights
The endoplasmic reticulum (ER) is a central multifunctional organelle entrusted with post-translational modification, folding and maturation of proteins, lipid synthesis, and calcium storage (Walter and Johnson 1994)
In group 5, treatment with trimethylamine N-oxide (TMAO) caused improvement of cataract as 26.7% were of stage 0 and 40% of stage 1 but still 20% of animals were of stage 3 and 13.3% of stage 4
This study aims to spot a light on the role of endoplasmic reticulum (ER) stress in the pathogenesis of diabetic cataract
Summary
The endoplasmic reticulum (ER) is a central multifunctional organelle entrusted with post-translational modification, folding and maturation of proteins, lipid synthesis, and calcium storage (Walter and Johnson 1994). Salt concentration, water, lipid bilayer, and chaperones play an important role in proper protein folding (Browm and Naidoo 2012). Imbalance between protein synthesis and ER capacity to modify and fold proteins can lead to the accumulation of unfolded proteins in the ER lumen. This condition is called ER stress (Balasubramanyam et al 2010). Imbalance between protein synthesis and endoplasmic reticulum (ER) capacity to modify and fold proteins lead to the accumulation of unfolded proteins resulting in ER stress and apoptosis. Ophthalmologic examination and histopathologic examination of the lenses were done to confirm the results
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