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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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Effect of curcumin on histopathological changes. Histological staining with PAS in liver (A) shows that glycogen contents of rat liver decreased in diabetic animals when compared with those of normal control animals, but these levels increased to near normal after treatment with curcumin. In H&E, (B) light microscopic photographs of livers of experimental animal showed the liver of normal control group, lipid accumulation indicated by the unstained area in liver tissues, microvascular fattening and focal necrosis, and portal inflammation in the untreated diabetic group; in curcumin-treated diabetic group, the severity of these changes was less than those in the untreated diabetic group. (C and C1) Immunohistochemical staining for macrophage (ED1-positive cells) and its quantification graph in each group. (D) Immunohistochemical staining for fibronectin in liver section. 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 < 0.01 versus Normal, ##p < 0.01 versus Control.
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Figure 7: Effect of curcumin on histopathological changes. Histological staining with PAS in liver (A) shows that glycogen contents of rat liver decreased in diabetic animals when compared with those of normal control animals, but these levels increased to near normal after treatment with curcumin. In H&E, (B) light microscopic photographs of livers of experimental animal showed the liver of normal control group, lipid accumulation indicated by the unstained area in liver tissues, microvascular fattening and focal necrosis, and portal inflammation in the untreated diabetic group; in curcumin-treated diabetic group, the severity of these changes was less than those in the untreated diabetic group. (C and C1) Immunohistochemical staining for macrophage (ED1-positive cells) and its quantification graph in each group. (D) Immunohistochemical staining for fibronectin in liver section. 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 < 0.01 versus Normal, ##p < 0.01 versus Control.

Mentions: Normal histology was seen in the normal control rats (Figure 7). The normal liver contains a large amount of glycogen. This, therefore, leads to the intense pink staining of hepatocytes with a PAS stain. In the PAS staining, examined liver sections of normal control rats showed the normal pattern distribution of glycogen granules and a liver section of diabetic rats showed marked depletion in the glycogen granules; meanwhile this glycogen level became increased in curcumin-treated animals (Figure 7A). Fatty liver was shown by H&E staining as an unstained area in liver parenchymal cells (Figure 7B). In the untreated diabetic rats, microvascular vacuolization, focal necrosis, and inflammation in the portal area were significantly apparent compared with the normal rats and curcumin-treated diabetic rats (Figure 7B).


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)

Effect of curcumin on histopathological changes. Histological staining with PAS in liver (A) shows that glycogen contents of rat liver decreased in diabetic animals when compared with those of normal control animals, but these levels increased to near normal after treatment with curcumin. In H&E, (B) light microscopic photographs of livers of experimental animal showed the liver of normal control group, lipid accumulation indicated by the unstained area in liver tissues, microvascular fattening and focal necrosis, and portal inflammation in the untreated diabetic group; in curcumin-treated diabetic group, the severity of these changes was less than those in the untreated diabetic group. (C and C1) Immunohistochemical staining for macrophage (ED1-positive cells) and its quantification graph in each group. (D) Immunohistochemical staining for fibronectin in liver section. 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 < 0.01 versus Normal, ##p < 0.01 versus Control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Effect of curcumin on histopathological changes. Histological staining with PAS in liver (A) shows that glycogen contents of rat liver decreased in diabetic animals when compared with those of normal control animals, but these levels increased to near normal after treatment with curcumin. In H&E, (B) light microscopic photographs of livers of experimental animal showed the liver of normal control group, lipid accumulation indicated by the unstained area in liver tissues, microvascular fattening and focal necrosis, and portal inflammation in the untreated diabetic group; in curcumin-treated diabetic group, the severity of these changes was less than those in the untreated diabetic group. (C and C1) Immunohistochemical staining for macrophage (ED1-positive cells) and its quantification graph in each group. (D) Immunohistochemical staining for fibronectin in liver section. 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 < 0.01 versus Normal, ##p < 0.01 versus Control.
Mentions: Normal histology was seen in the normal control rats (Figure 7). The normal liver contains a large amount of glycogen. This, therefore, leads to the intense pink staining of hepatocytes with a PAS stain. In the PAS staining, examined liver sections of normal control rats showed the normal pattern distribution of glycogen granules and a liver section of diabetic rats showed marked depletion in the glycogen granules; meanwhile this glycogen level became increased in curcumin-treated animals (Figure 7A). Fatty liver was shown by H&E staining as an unstained area in liver parenchymal cells (Figure 7B). In the untreated diabetic rats, microvascular vacuolization, focal necrosis, and inflammation in the portal area were significantly apparent compared with the normal rats and curcumin-treated diabetic rats (Figure 7B).

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