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Grape seed proanthocyanidin extract-mediated regulation of STAT3 proteins contributes to Treg differentiation and attenuates inflammation in a murine model of obesity-associated arthritis.

Jhun JY, Moon SJ, Yoon BY, Byun JK, Kim EK, Yang EJ, Ju JH, Hong YS, Min JK, Park SH, Kim HY, Cho ML - PLoS ONE (2013)

Bottom Line: The antiobesity effect of GSPE was associated with increased populations of regulatory T (Treg) cells and those of decreased Th17 cells.Decrease of Th17 cells was associated with significant inhibition of their key transcriptional factors, pSTAT3(Tyr705) and pSTAT3(Ser727).To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization.

View Article: PubMed Central - PubMed

Affiliation: Conversant Research Consortium in Immunologic disease, College of Medicine, The Catholic University of Korea, Seoul, South Korea ; Rheumatism Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

ABSTRACT
Grape seed proanthocyanidin extract (GSPE) is a natural flavonoid that exerts anti-inflammatory properties. Obesity is an inflammatory condition and inflammatory cells and their secretion of pro-inflammatory molecules contribute to the pathogenesis of obesity. Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by inflammation of joints lined by synovium. Previously, we demonstrated that obesity augmented arthritis severity in collagen induced arthritis (CIA), a murine model of human RA. Here, we investigated whether oral administration of GSPE showed antiobesity and anti-arthritic effects in high-fat diet-induced obese (DIO) mice and in obese CIA mice, respectively. The pathophysiologic mechanisms by which GSPE attenuates weight gain and arthritis severity in vivo were also investigated. In DIO mice, GSPE administration significantly inhibited weight gain, reduced fat infiltration in liver and improved serum lipid profiles. The antiobesity effect of GSPE was associated with increased populations of regulatory T (Treg) cells and those of decreased Th17 cells. Decrease of Th17 cells was associated with significant inhibition of their key transcriptional factors, pSTAT3(Tyr705) and pSTAT3(Ser727). On the contrary, GSPE-induced Treg induction was associated with enhanced pSTAT5 expression. To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization. GSPE treatment significantly attenuated the development of autoimmune arthritis in obese CIA model. In line with DIO mice, GSPE administration decreased Th17 cells and reciprocally increased Treg cells by regulating STAT proteins in autoimmune arthritis model. The expressions of pro-inflammatory cytokines and nitrotyrosine in synovium were significantly inhibited by GSPE treatment. Taken together, GSPE functions as a reciprocal regulator of T cell differentiation - suppression of Th17 cells and induction of Tregs in both DIO and obese CIA mice. GSPE may act as a therapeutic agent to treat immunologic diseases related with enhanced STAT3 activity such as metabolic disorders and autoimmune diseases.

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In vivo treatment with GSPE in mice significantly prevented obesity induced by a high-fat diet (HFD).The mice received continuous feeding of a HFD after 4 weeks of age and euthanized at 50 days (11 weeks of age) after feeding (n = 6 for each group). (A) Weight gain was significantly attenuated in mice administered with GSPE (300 mg/kg) during the experimental period when compared to control mice. (B) Representative photomicrographs (100×) of liver sections from control or GSPE-treated mice stained with Oil Red O. Red staining indicates lipid deposition (left panel). The graphs show the number of positive cells (middle panel). Representative immunohistochemical staining for nitrotyrosine in liver and spleen isolated from each group (original magnification, 200×) (right panel). (C) Glucose level and lipoprotein profiles were determined in sera that were isolated at 50 days after feeding. Values are the means ± SD. (D) Splenocytes of each group of mice were cultured with or without 0.5 µg/ml, or 2 µg/ml of anti-CD3 mAb for 72 hrs. The proliferative responses were determined by [3H] thymidine incorporation assay. The data presents the mean counts per min (cpm) ± SD. *P<0.05, ** P<0.01, *** P<0.001 indicated significant differences from the control.
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pone-0078843-g001: In vivo treatment with GSPE in mice significantly prevented obesity induced by a high-fat diet (HFD).The mice received continuous feeding of a HFD after 4 weeks of age and euthanized at 50 days (11 weeks of age) after feeding (n = 6 for each group). (A) Weight gain was significantly attenuated in mice administered with GSPE (300 mg/kg) during the experimental period when compared to control mice. (B) Representative photomicrographs (100×) of liver sections from control or GSPE-treated mice stained with Oil Red O. Red staining indicates lipid deposition (left panel). The graphs show the number of positive cells (middle panel). Representative immunohistochemical staining for nitrotyrosine in liver and spleen isolated from each group (original magnification, 200×) (right panel). (C) Glucose level and lipoprotein profiles were determined in sera that were isolated at 50 days after feeding. Values are the means ± SD. (D) Splenocytes of each group of mice were cultured with or without 0.5 µg/ml, or 2 µg/ml of anti-CD3 mAb for 72 hrs. The proliferative responses were determined by [3H] thymidine incorporation assay. The data presents the mean counts per min (cpm) ± SD. *P<0.05, ** P<0.01, *** P<0.001 indicated significant differences from the control.

Mentions: To induced DIO model, C57BL/6 mice were fed a high fat diet (60 Kcal). When the mice weighed 25 g, they were given orally GSPE or control (saline). Since 13 days after feeding with high-fat diet, GSPE-treated DIO mice group had shown a significantly attenuated weight gain (Figure 1A). GSPE treatment significantly suppressed liver lipid content, demonstrated by Oil red O staining, when compared with control DIO mice (Figure 1B, left panels). We also investigated the expressions of nitrotyrosine, a oxidative stress marker, in liver and spleen tissues of each group of mice with DIO. Oral administration of GSPE in obese mice profoundly reduced the numbers of nitrotyrosine-expressing cells in liver as well as spleens, suggesting its antioxidative effects (Figure 1B, right panels). To assess the effects of GSPE on metabolic profiles, glucose, cholesterol and low-density lipoprotein (LDL) cholesterol levels were measured in mice. Of interest, plasma glucose, total cholesterol, and LDL-cholesterol levels were significantly decreased in GSPE-treated obese mice (Figure 1C).


Grape seed proanthocyanidin extract-mediated regulation of STAT3 proteins contributes to Treg differentiation and attenuates inflammation in a murine model of obesity-associated arthritis.

Jhun JY, Moon SJ, Yoon BY, Byun JK, Kim EK, Yang EJ, Ju JH, Hong YS, Min JK, Park SH, Kim HY, Cho ML - PLoS ONE (2013)

In vivo treatment with GSPE in mice significantly prevented obesity induced by a high-fat diet (HFD).The mice received continuous feeding of a HFD after 4 weeks of age and euthanized at 50 days (11 weeks of age) after feeding (n = 6 for each group). (A) Weight gain was significantly attenuated in mice administered with GSPE (300 mg/kg) during the experimental period when compared to control mice. (B) Representative photomicrographs (100×) of liver sections from control or GSPE-treated mice stained with Oil Red O. Red staining indicates lipid deposition (left panel). The graphs show the number of positive cells (middle panel). Representative immunohistochemical staining for nitrotyrosine in liver and spleen isolated from each group (original magnification, 200×) (right panel). (C) Glucose level and lipoprotein profiles were determined in sera that were isolated at 50 days after feeding. Values are the means ± SD. (D) Splenocytes of each group of mice were cultured with or without 0.5 µg/ml, or 2 µg/ml of anti-CD3 mAb for 72 hrs. The proliferative responses were determined by [3H] thymidine incorporation assay. The data presents the mean counts per min (cpm) ± SD. *P<0.05, ** P<0.01, *** P<0.001 indicated significant differences from the control.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3818494&req=5

pone-0078843-g001: In vivo treatment with GSPE in mice significantly prevented obesity induced by a high-fat diet (HFD).The mice received continuous feeding of a HFD after 4 weeks of age and euthanized at 50 days (11 weeks of age) after feeding (n = 6 for each group). (A) Weight gain was significantly attenuated in mice administered with GSPE (300 mg/kg) during the experimental period when compared to control mice. (B) Representative photomicrographs (100×) of liver sections from control or GSPE-treated mice stained with Oil Red O. Red staining indicates lipid deposition (left panel). The graphs show the number of positive cells (middle panel). Representative immunohistochemical staining for nitrotyrosine in liver and spleen isolated from each group (original magnification, 200×) (right panel). (C) Glucose level and lipoprotein profiles were determined in sera that were isolated at 50 days after feeding. Values are the means ± SD. (D) Splenocytes of each group of mice were cultured with or without 0.5 µg/ml, or 2 µg/ml of anti-CD3 mAb for 72 hrs. The proliferative responses were determined by [3H] thymidine incorporation assay. The data presents the mean counts per min (cpm) ± SD. *P<0.05, ** P<0.01, *** P<0.001 indicated significant differences from the control.
Mentions: To induced DIO model, C57BL/6 mice were fed a high fat diet (60 Kcal). When the mice weighed 25 g, they were given orally GSPE or control (saline). Since 13 days after feeding with high-fat diet, GSPE-treated DIO mice group had shown a significantly attenuated weight gain (Figure 1A). GSPE treatment significantly suppressed liver lipid content, demonstrated by Oil red O staining, when compared with control DIO mice (Figure 1B, left panels). We also investigated the expressions of nitrotyrosine, a oxidative stress marker, in liver and spleen tissues of each group of mice with DIO. Oral administration of GSPE in obese mice profoundly reduced the numbers of nitrotyrosine-expressing cells in liver as well as spleens, suggesting its antioxidative effects (Figure 1B, right panels). To assess the effects of GSPE on metabolic profiles, glucose, cholesterol and low-density lipoprotein (LDL) cholesterol levels were measured in mice. Of interest, plasma glucose, total cholesterol, and LDL-cholesterol levels were significantly decreased in GSPE-treated obese mice (Figure 1C).

Bottom Line: The antiobesity effect of GSPE was associated with increased populations of regulatory T (Treg) cells and those of decreased Th17 cells.Decrease of Th17 cells was associated with significant inhibition of their key transcriptional factors, pSTAT3(Tyr705) and pSTAT3(Ser727).To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization.

View Article: PubMed Central - PubMed

Affiliation: Conversant Research Consortium in Immunologic disease, College of Medicine, The Catholic University of Korea, Seoul, South Korea ; Rheumatism Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

ABSTRACT
Grape seed proanthocyanidin extract (GSPE) is a natural flavonoid that exerts anti-inflammatory properties. Obesity is an inflammatory condition and inflammatory cells and their secretion of pro-inflammatory molecules contribute to the pathogenesis of obesity. Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by inflammation of joints lined by synovium. Previously, we demonstrated that obesity augmented arthritis severity in collagen induced arthritis (CIA), a murine model of human RA. Here, we investigated whether oral administration of GSPE showed antiobesity and anti-arthritic effects in high-fat diet-induced obese (DIO) mice and in obese CIA mice, respectively. The pathophysiologic mechanisms by which GSPE attenuates weight gain and arthritis severity in vivo were also investigated. In DIO mice, GSPE administration significantly inhibited weight gain, reduced fat infiltration in liver and improved serum lipid profiles. The antiobesity effect of GSPE was associated with increased populations of regulatory T (Treg) cells and those of decreased Th17 cells. Decrease of Th17 cells was associated with significant inhibition of their key transcriptional factors, pSTAT3(Tyr705) and pSTAT3(Ser727). On the contrary, GSPE-induced Treg induction was associated with enhanced pSTAT5 expression. To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization. GSPE treatment significantly attenuated the development of autoimmune arthritis in obese CIA model. In line with DIO mice, GSPE administration decreased Th17 cells and reciprocally increased Treg cells by regulating STAT proteins in autoimmune arthritis model. The expressions of pro-inflammatory cytokines and nitrotyrosine in synovium were significantly inhibited by GSPE treatment. Taken together, GSPE functions as a reciprocal regulator of T cell differentiation - suppression of Th17 cells and induction of Tregs in both DIO and obese CIA mice. GSPE may act as a therapeutic agent to treat immunologic diseases related with enhanced STAT3 activity such as metabolic disorders and autoimmune diseases.

Show MeSH
Related in: MedlinePlus