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Ghrelin reduces liver impairment in a model of concanavalin A-induced acute hepatitis in mice.

Mao Y, Wang J, Yu F, Cheng J, Li H, Guo C, Fan X - Drug Des Devel Ther (2015)

Bottom Line: Inflammatory cytokines were significantly reduced by ghrelin pretreatment.However, the Akt kinase inhibitor reversed the decrease of Bax and caspase 3, 8, 9, and reduced the protein level of p-Akt and Bcl-2.These effects could be interrupted by an Akt kinase inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China.

ABSTRACT

Background and aims: Ghrelin is a 28-amino-acid gut hormone that was first discovered as a potent growth hormone secretagogue. Recently, it has been shown to exert a strong anti-inflammatory effect. The purpose of the study reported here was to explore the effect and mechanism of ghrelin on concanavalin (Con) A-induced acute hepatitis.

Methods: Balb/C mice were divided into four groups: normal control (NC) (mice injected with vehicle [saline]); Con A (25 mg/kg); Con A + 10 μg/kg ghrelin; and Con A + 50 μg/kg ghrelin (1 hour before Con A injection). Pro-inflammatory cytokine levels were detected. Protein levels of phosphoinositide 3-kinase (PI3K); phosphorylated Akt (p-Akt); caspase 3, 8, and 9; and microtubule-associated protein 1 light chain 3 (LC3) were also detected. Perifosine (25 mM) (an Akt inhibitor) was used to investigate whether the protective effect of ghrelin was interrupted by an Akt inhibitor. Protein levels of p-AKT; Bcl-2; Bax; and caspase 3, 8, and 9 were also detected.

Results: Aspartate aminotransferase, alanine aminotransferase, and pathological damage were significantly ameliorated by ghrelin pretreatment in Con A-induced hepatitis. Inflammatory cytokines were significantly reduced by ghrelin pretreatment. Bcl-2; Bax; and caspase 3, 8, and 9 expression were also clearly affected by ghrelin pretreatment, compared with the Con A-treated group. However, the Akt kinase inhibitor reversed the decrease of Bax and caspase 3, 8, 9, and reduced the protein level of p-Akt and Bcl-2. Ghrelin activated the PI3K/Akt/Bcl-2 pathway and inhibited activation of autophagy.

Conclusion: Our results demonstrate that ghrelin attenuates Con A-induced acute immune hepatitis by activating the PI3K/Akt pathway and inhibiting the process of autophagy, which might be related to inhibition of inflammatory cytokine release, and prevention of hepatocyte apoptosis. These effects could be interrupted by an Akt kinase inhibitor.

No MeSH data available.


Related in: MedlinePlus

Ghrelin pretreatment ameliorates Con A-induced hepatitis.Notes: (A) Serum ALT and AST levels are expressed as the mean ± SD of six animals per group at 4, 8, and 24 h after Con A injection in mice and the effects of both low (10 μg/kg) and high (50 μg/kg) dose ghrelin pretreatment at the same time. (B) Hematoxylin and eosin staining of liver sections. The cellular necrotic or edematous areas were analyzed with Image-Pro® Plus (v 6.0); (n=6). *P<0.05 for NC vs Con A, #P<0.05 for Con A vs Con A + 10 μg/kg ghrelin, †P<0.05 for Con A + 50 μg/kg ghrelin vs Con A + 10 μg/kg ghrelin, and †,*P>0.05 for Con A + 50 μg/kg ghrelin vs Con A + 10 μg/kg ghrelin.Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Con, concanavalin; h, hours; NC, normal control.
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f2-dddt-9-5385: Ghrelin pretreatment ameliorates Con A-induced hepatitis.Notes: (A) Serum ALT and AST levels are expressed as the mean ± SD of six animals per group at 4, 8, and 24 h after Con A injection in mice and the effects of both low (10 μg/kg) and high (50 μg/kg) dose ghrelin pretreatment at the same time. (B) Hematoxylin and eosin staining of liver sections. The cellular necrotic or edematous areas were analyzed with Image-Pro® Plus (v 6.0); (n=6). *P<0.05 for NC vs Con A, #P<0.05 for Con A vs Con A + 10 μg/kg ghrelin, †P<0.05 for Con A + 50 μg/kg ghrelin vs Con A + 10 μg/kg ghrelin, and †,*P>0.05 for Con A + 50 μg/kg ghrelin vs Con A + 10 μg/kg ghrelin.Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Con, concanavalin; h, hours; NC, normal control.

Mentions: Con A significantly increased serum ALT and AST levels, with a peak at 8 hours after Con A injection, whereas both 10 and 50 μg/kg doses of ghrelin clearly reduced them, as shown in Figure 2A. Histopathological changes in the three groups were examined after H&E staining (Figure 2B). Massive areas of hepatic tissue inflammation and necrosis were observed in the mice treated with Con A alone, which was significantly ameliorated in the ghrelin and Con A co-treated group. Image-Pro Plus software showed that there were significant differences of hepatic injury between the Con A-treated and Con A and ghrelin co-treated groups.


Ghrelin reduces liver impairment in a model of concanavalin A-induced acute hepatitis in mice.

Mao Y, Wang J, Yu F, Cheng J, Li H, Guo C, Fan X - Drug Des Devel Ther (2015)

Ghrelin pretreatment ameliorates Con A-induced hepatitis.Notes: (A) Serum ALT and AST levels are expressed as the mean ± SD of six animals per group at 4, 8, and 24 h after Con A injection in mice and the effects of both low (10 μg/kg) and high (50 μg/kg) dose ghrelin pretreatment at the same time. (B) Hematoxylin and eosin staining of liver sections. The cellular necrotic or edematous areas were analyzed with Image-Pro® Plus (v 6.0); (n=6). *P<0.05 for NC vs Con A, #P<0.05 for Con A vs Con A + 10 μg/kg ghrelin, †P<0.05 for Con A + 50 μg/kg ghrelin vs Con A + 10 μg/kg ghrelin, and †,*P>0.05 for Con A + 50 μg/kg ghrelin vs Con A + 10 μg/kg ghrelin.Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Con, concanavalin; h, hours; NC, normal control.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4592035&req=5

f2-dddt-9-5385: Ghrelin pretreatment ameliorates Con A-induced hepatitis.Notes: (A) Serum ALT and AST levels are expressed as the mean ± SD of six animals per group at 4, 8, and 24 h after Con A injection in mice and the effects of both low (10 μg/kg) and high (50 μg/kg) dose ghrelin pretreatment at the same time. (B) Hematoxylin and eosin staining of liver sections. The cellular necrotic or edematous areas were analyzed with Image-Pro® Plus (v 6.0); (n=6). *P<0.05 for NC vs Con A, #P<0.05 for Con A vs Con A + 10 μg/kg ghrelin, †P<0.05 for Con A + 50 μg/kg ghrelin vs Con A + 10 μg/kg ghrelin, and †,*P>0.05 for Con A + 50 μg/kg ghrelin vs Con A + 10 μg/kg ghrelin.Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Con, concanavalin; h, hours; NC, normal control.
Mentions: Con A significantly increased serum ALT and AST levels, with a peak at 8 hours after Con A injection, whereas both 10 and 50 μg/kg doses of ghrelin clearly reduced them, as shown in Figure 2A. Histopathological changes in the three groups were examined after H&E staining (Figure 2B). Massive areas of hepatic tissue inflammation and necrosis were observed in the mice treated with Con A alone, which was significantly ameliorated in the ghrelin and Con A co-treated group. Image-Pro Plus software showed that there were significant differences of hepatic injury between the Con A-treated and Con A and ghrelin co-treated groups.

Bottom Line: Inflammatory cytokines were significantly reduced by ghrelin pretreatment.However, the Akt kinase inhibitor reversed the decrease of Bax and caspase 3, 8, 9, and reduced the protein level of p-Akt and Bcl-2.These effects could be interrupted by an Akt kinase inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China.

ABSTRACT

Background and aims: Ghrelin is a 28-amino-acid gut hormone that was first discovered as a potent growth hormone secretagogue. Recently, it has been shown to exert a strong anti-inflammatory effect. The purpose of the study reported here was to explore the effect and mechanism of ghrelin on concanavalin (Con) A-induced acute hepatitis.

Methods: Balb/C mice were divided into four groups: normal control (NC) (mice injected with vehicle [saline]); Con A (25 mg/kg); Con A + 10 μg/kg ghrelin; and Con A + 50 μg/kg ghrelin (1 hour before Con A injection). Pro-inflammatory cytokine levels were detected. Protein levels of phosphoinositide 3-kinase (PI3K); phosphorylated Akt (p-Akt); caspase 3, 8, and 9; and microtubule-associated protein 1 light chain 3 (LC3) were also detected. Perifosine (25 mM) (an Akt inhibitor) was used to investigate whether the protective effect of ghrelin was interrupted by an Akt inhibitor. Protein levels of p-AKT; Bcl-2; Bax; and caspase 3, 8, and 9 were also detected.

Results: Aspartate aminotransferase, alanine aminotransferase, and pathological damage were significantly ameliorated by ghrelin pretreatment in Con A-induced hepatitis. Inflammatory cytokines were significantly reduced by ghrelin pretreatment. Bcl-2; Bax; and caspase 3, 8, and 9 expression were also clearly affected by ghrelin pretreatment, compared with the Con A-treated group. However, the Akt kinase inhibitor reversed the decrease of Bax and caspase 3, 8, 9, and reduced the protein level of p-Akt and Bcl-2. Ghrelin activated the PI3K/Akt/Bcl-2 pathway and inhibited activation of autophagy.

Conclusion: Our results demonstrate that ghrelin attenuates Con A-induced acute immune hepatitis by activating the PI3K/Akt pathway and inhibiting the process of autophagy, which might be related to inhibition of inflammatory cytokine release, and prevention of hepatocyte apoptosis. These effects could be interrupted by an Akt kinase inhibitor.

No MeSH data available.


Related in: MedlinePlus