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GSK-3β inhibition attenuates CLP-induced liver injury by reducing inflammation and hepatic cell apoptosis.

Zhang H, Wang W, Fang H, Yang Y, Li X, He J, Jiang X, Wang W, Liu S, Hu J, Liu A, Dahmen U, Dirsch O - Mediators Inflamm. (2014)

Bottom Line: The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release.In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages.In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, Wuhan 430070, China.

ABSTRACT
Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

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GSK-3β inhibition prevents the CLP-induced hepatic apoptosis. (a) Mice were subjected to CLP and treated with either SB216763 (25 mg/kg, i.p.) or vehicle (DMSO). Liver samples were harvested at 20 h after CLP. The caspase-3 activity was measured. Data are shown as mean ± SD. n = 6 per group. #P < 0.01 compared with vehicle-treated group. (b) The expression levels of the cleaved caspase-3 and the cleaved caspase-7 were examined by western blotting analysis.
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fig6: GSK-3β inhibition prevents the CLP-induced hepatic apoptosis. (a) Mice were subjected to CLP and treated with either SB216763 (25 mg/kg, i.p.) or vehicle (DMSO). Liver samples were harvested at 20 h after CLP. The caspase-3 activity was measured. Data are shown as mean ± SD. n = 6 per group. #P < 0.01 compared with vehicle-treated group. (b) The expression levels of the cleaved caspase-3 and the cleaved caspase-7 were examined by western blotting analysis.

Mentions: To test whether GSK-3β inhibition could attenuate hepatic apoptosis, the caspase-3 activity in the liver was evaluated at 20 h following CLP insult. Compared to the activity in the sham operated animals, the caspase-3 activity was significantly increased in the vehicle-treated animals. The inhibition of GSK-3β significantly reduced the induction of caspase-3 activity by CLP (Figure 6(a)). Furthermore, the vehicle-treated animals expressed higher levels of cleaved caspase-3 and cleaved caspase-7 protein, which were significantly reduced by the GSK-3β inhibition (Figure 6(b)). This finding indicated that inhibition of GSK-3β could attenuate CLP-induced apoptosis.


GSK-3β inhibition attenuates CLP-induced liver injury by reducing inflammation and hepatic cell apoptosis.

Zhang H, Wang W, Fang H, Yang Y, Li X, He J, Jiang X, Wang W, Liu S, Hu J, Liu A, Dahmen U, Dirsch O - Mediators Inflamm. (2014)

GSK-3β inhibition prevents the CLP-induced hepatic apoptosis. (a) Mice were subjected to CLP and treated with either SB216763 (25 mg/kg, i.p.) or vehicle (DMSO). Liver samples were harvested at 20 h after CLP. The caspase-3 activity was measured. Data are shown as mean ± SD. n = 6 per group. #P < 0.01 compared with vehicle-treated group. (b) The expression levels of the cleaved caspase-3 and the cleaved caspase-7 were examined by western blotting analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4265684&req=5

fig6: GSK-3β inhibition prevents the CLP-induced hepatic apoptosis. (a) Mice were subjected to CLP and treated with either SB216763 (25 mg/kg, i.p.) or vehicle (DMSO). Liver samples were harvested at 20 h after CLP. The caspase-3 activity was measured. Data are shown as mean ± SD. n = 6 per group. #P < 0.01 compared with vehicle-treated group. (b) The expression levels of the cleaved caspase-3 and the cleaved caspase-7 were examined by western blotting analysis.
Mentions: To test whether GSK-3β inhibition could attenuate hepatic apoptosis, the caspase-3 activity in the liver was evaluated at 20 h following CLP insult. Compared to the activity in the sham operated animals, the caspase-3 activity was significantly increased in the vehicle-treated animals. The inhibition of GSK-3β significantly reduced the induction of caspase-3 activity by CLP (Figure 6(a)). Furthermore, the vehicle-treated animals expressed higher levels of cleaved caspase-3 and cleaved caspase-7 protein, which were significantly reduced by the GSK-3β inhibition (Figure 6(b)). This finding indicated that inhibition of GSK-3β could attenuate CLP-induced apoptosis.

Bottom Line: The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release.In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages.In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, Wuhan 430070, China.

ABSTRACT
Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

Show MeSH
Related in: MedlinePlus