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Curcumin ameliorates streptozotocin-induced liver damage through modulation of endoplasmic reticulum stress-mediated apoptosis in diabetic rats.

Afrin R, Arumugam S, Soetikno V, Thandavarayan RA, Pitchaimani V, Karuppagounder V, Sreedhar R, Harima M, Suzuki H, Miyashita S, Nomoto M, Suzuki K, Watanabe K - Free Radic. Res. (2015)

Bottom Line: Moreover, treatment with curcumin markedly decreased the sub-arm of the UPR signaling protein such as phospho-double-stranded RNA-dependent protein kinase-like ER kinase, CCAAT/enhancer-binding protein homologous protein, tumor necrosis factor receptor-associated factor 2, and inositol-requiring enzyme1α; and inhibited tumor necrosis factor α, interleukin 1β, phospho-p38 mitogen-activated protein kinase, and apoptosis signal-regulating kinase 1 in liver tissues of diabetic rats.Apoptotic and anti-apoptotic signaling proteins, such as cleaved caspase-3 and B-cell lymphoma 2, were significantly increased and decreased, respectively in diabetic rats; curcumin treatment prevented all of these alterations.In summary, our results indicate that curcumin has the potential to protect the diabetic liver by modulating hepatic ERS-mediated apoptosis, and provides a novel therapeutic strategy for the diabetic liver damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences , Niigata , Japan.

ABSTRACT
We investigated the effect of curcumin on liver injury in diabetic rats induced by streptozotocin (STZ) through modulation of endoplasmic reticulum stress (ERS) and unfolded protein response (UPR). Experimental diabetes was induced by a single intraperitoneal injection of STZ (55 mg/kg), and curcumin was given at 100 mg/kg by gavage for 56 days. We observed that curcumin improved the morphological and histopathological changes, significantly decreased hepatic ERS marker protein: glucose-regulated protein 78, and improved liver function in diabetic rats. Moreover, treatment with curcumin markedly decreased the sub-arm of the UPR signaling protein such as phospho-double-stranded RNA-dependent protein kinase-like ER kinase, CCAAT/enhancer-binding protein homologous protein, tumor necrosis factor receptor-associated factor 2, and inositol-requiring enzyme1α; and inhibited tumor necrosis factor α, interleukin 1β, phospho-p38 mitogen-activated protein kinase, and apoptosis signal-regulating kinase 1 in liver tissues of diabetic rats. Apoptotic and anti-apoptotic signaling proteins, such as cleaved caspase-3 and B-cell lymphoma 2, were significantly increased and decreased, respectively in diabetic rats; curcumin treatment prevented all of these alterations. In summary, our results indicate that curcumin has the potential to protect the diabetic liver by modulating hepatic ERS-mediated apoptosis, and provides a novel therapeutic strategy for the diabetic liver damage.

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Expression of hepatic proteins involved in UPR signaling pathway. Representative Western blots (lower panel) show specific bands for p-PERK (A), p-IRE1α (B), and ATF6α (C); representative histograms (upper panel) show the band densities with relative β-tubulin, PERK (for p-PERK), and IRE1α (p-IRE1a). The blots are representatives of five independent experiments. Each bar represents mean ± SE. Normal, age-matched normal rats; Control, untreated diabetic rats; Curcumin, diabetic rats treated with curcumin 100 mg/kg/day. ∗p < 0.05, ∗∗∗p < 0.001 versus Normal, #p < 0.05 versus Control based on one-way ANOVA followed by Tukey's test.
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Figure 3: Expression of hepatic proteins involved in UPR signaling pathway. Representative Western blots (lower panel) show specific bands for p-PERK (A), p-IRE1α (B), and ATF6α (C); representative histograms (upper panel) show the band densities with relative β-tubulin, PERK (for p-PERK), and IRE1α (p-IRE1a). The blots are representatives of five independent experiments. Each bar represents mean ± SE. Normal, age-matched normal rats; Control, untreated diabetic rats; Curcumin, diabetic rats treated with curcumin 100 mg/kg/day. ∗p < 0.05, ∗∗∗p < 0.001 versus Normal, #p < 0.05 versus Control based on one-way ANOVA followed by Tukey's test.

Mentions: The signals from activated UPR molecules to the relevant effector proteins are conveyed by three different proteins: PERK, IRE1α, and ATF6α. As expected, here we have found that the phosphorylation of PERK protein was significantly increased in the diabetic rats compared with that in the normal Sprague-Dawley (SD) rats (Figure 3A). Diabetic rats have displayed a significant upregulation in the hepatocyte expression levels of p-IRE1α protein compared with the normal SD rats (Figure 3B). Curcumin treatment significantly attenuated the increased liver p-PERK and p-IRE1α levels. But interestingly, we did not find any significant difference in the level of ATF6α protein expression in the diabetic rats compared with that in the normal SD rats (Figure 3C).


Curcumin ameliorates streptozotocin-induced liver damage through modulation of endoplasmic reticulum stress-mediated apoptosis in diabetic rats.

Afrin R, Arumugam S, Soetikno V, Thandavarayan RA, Pitchaimani V, Karuppagounder V, Sreedhar R, Harima M, Suzuki H, Miyashita S, Nomoto M, Suzuki K, Watanabe K - Free Radic. Res. (2015)

Expression of hepatic proteins involved in UPR signaling pathway. Representative Western blots (lower panel) show specific bands for p-PERK (A), p-IRE1α (B), and ATF6α (C); representative histograms (upper panel) show the band densities with relative β-tubulin, PERK (for p-PERK), and IRE1α (p-IRE1a). The blots are representatives of five independent experiments. Each bar represents mean ± SE. Normal, age-matched normal rats; Control, untreated diabetic rats; Curcumin, diabetic rats treated with curcumin 100 mg/kg/day. ∗p < 0.05, ∗∗∗p < 0.001 versus Normal, #p < 0.05 versus Control based on one-way ANOVA followed by Tukey's test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389763&req=5

Figure 3: Expression of hepatic proteins involved in UPR signaling pathway. Representative Western blots (lower panel) show specific bands for p-PERK (A), p-IRE1α (B), and ATF6α (C); representative histograms (upper panel) show the band densities with relative β-tubulin, PERK (for p-PERK), and IRE1α (p-IRE1a). The blots are representatives of five independent experiments. Each bar represents mean ± SE. Normal, age-matched normal rats; Control, untreated diabetic rats; Curcumin, diabetic rats treated with curcumin 100 mg/kg/day. ∗p < 0.05, ∗∗∗p < 0.001 versus Normal, #p < 0.05 versus Control based on one-way ANOVA followed by Tukey's test.
Mentions: The signals from activated UPR molecules to the relevant effector proteins are conveyed by three different proteins: PERK, IRE1α, and ATF6α. As expected, here we have found that the phosphorylation of PERK protein was significantly increased in the diabetic rats compared with that in the normal Sprague-Dawley (SD) rats (Figure 3A). Diabetic rats have displayed a significant upregulation in the hepatocyte expression levels of p-IRE1α protein compared with the normal SD rats (Figure 3B). Curcumin treatment significantly attenuated the increased liver p-PERK and p-IRE1α levels. But interestingly, we did not find any significant difference in the level of ATF6α protein expression in the diabetic rats compared with that in the normal SD rats (Figure 3C).

Bottom Line: Moreover, treatment with curcumin markedly decreased the sub-arm of the UPR signaling protein such as phospho-double-stranded RNA-dependent protein kinase-like ER kinase, CCAAT/enhancer-binding protein homologous protein, tumor necrosis factor receptor-associated factor 2, and inositol-requiring enzyme1α; and inhibited tumor necrosis factor α, interleukin 1β, phospho-p38 mitogen-activated protein kinase, and apoptosis signal-regulating kinase 1 in liver tissues of diabetic rats.Apoptotic and anti-apoptotic signaling proteins, such as cleaved caspase-3 and B-cell lymphoma 2, were significantly increased and decreased, respectively in diabetic rats; curcumin treatment prevented all of these alterations.In summary, our results indicate that curcumin has the potential to protect the diabetic liver by modulating hepatic ERS-mediated apoptosis, and provides a novel therapeutic strategy for the diabetic liver damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences , Niigata , Japan.

ABSTRACT
We investigated the effect of curcumin on liver injury in diabetic rats induced by streptozotocin (STZ) through modulation of endoplasmic reticulum stress (ERS) and unfolded protein response (UPR). Experimental diabetes was induced by a single intraperitoneal injection of STZ (55 mg/kg), and curcumin was given at 100 mg/kg by gavage for 56 days. We observed that curcumin improved the morphological and histopathological changes, significantly decreased hepatic ERS marker protein: glucose-regulated protein 78, and improved liver function in diabetic rats. Moreover, treatment with curcumin markedly decreased the sub-arm of the UPR signaling protein such as phospho-double-stranded RNA-dependent protein kinase-like ER kinase, CCAAT/enhancer-binding protein homologous protein, tumor necrosis factor receptor-associated factor 2, and inositol-requiring enzyme1α; and inhibited tumor necrosis factor α, interleukin 1β, phospho-p38 mitogen-activated protein kinase, and apoptosis signal-regulating kinase 1 in liver tissues of diabetic rats. Apoptotic and anti-apoptotic signaling proteins, such as cleaved caspase-3 and B-cell lymphoma 2, were significantly increased and decreased, respectively in diabetic rats; curcumin treatment prevented all of these alterations. In summary, our results indicate that curcumin has the potential to protect the diabetic liver by modulating hepatic ERS-mediated apoptosis, and provides a novel therapeutic strategy for the diabetic liver damage.

Show MeSH
Related in: MedlinePlus