Potential prophylactic effect of chemical chaperones for alleviation of endoplasmic reticulum stress in experimental diabetic cataract

Abstract

Background: 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. 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. Results: Both 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. Conclusion: The 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.

Cigarette smoke induces endoplasmic reticulum stress and suppresses efferocytosis through the activation of RhoA

“…We also showed that CSE-induced RhoA activation was normalized by GSK2606414, a PERK inhibitor, and TUDCA. TUDCA has been known to function as not only a chemical chaperone but also an antioxidative agent in animal models of neurodegenerative disorders and ocular disorders 33 – 37 . Furthermore, TUDCA can be safely administered to humans and has been shown to have a pharmacological effect 38 – 41 .…”

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

“…Beneficial effects of TUDCA have also been suggested in studies of diabetic cataract [23] and diabetic retinopathy [100]. TUDCA was demonstrated to markedly retard the occurrence of cataract due to reduced ER stress and diminished oxidative stress [23].…”

“…Type 2 diabetes is typically associated with normal insulin production, but lower insulin sensitivity of cells, which in consequence leads to elevated glucose levels in the blood [12,84]. An increasing number of reports from experimental and clinical studies also indicate a higher prevalence of cardiac damage [98], obesity [99], vision impairment [23,100], and nephropathy [101,102] in diabetic patients. According to a growing number of data, ER stress is a key contributor to the pathology of diabetes and is associated with pancreatic beta cell loss and insulin resistance [103,104].…”

“…A set of recent research have shown that TUDCA may also be beneficial in controlling the outcome of certain obesity/diabetes-related disorders. It has been found to present a favorable effect in morbidities such as cardiac failure [98,104,121] and vision impairment [23,100]. In a mice model of obesity-induced myocardial dysfunction, treatment with TUDCA resulted in increased expression and activity of sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) and alleviation of augmented levels of p-IRS Ser307 , cJun, p-cJun, p-JNK, and ER stress markers [98,104,121].…”

“…TUDCA is one such compound that is known for its chaperoning activity [12][13][14][15]. Until now, various studies have demonstrated good efficiency of TUDCA in alleviating or resolving ER stress, playing a role as a chemical chaperone; however, the exact chemical interactions involved in such activity are still debatable [18][19][20][21][22][23].…”