Limits...
SPA0355 attenuates ischemia/reperfusion-induced liver injury in mice.

Bae UJ, Yang JD, Ka SO, Koo JH, Woo SJ, Lee YR, Yu HC, Cho BH, Zhao HY, Ryu JH, Lee SM, Jeon R, Park BH - Exp. Mol. Med. (2014)

Bottom Line: Concomitantly, the expression of NF-κB target genes such as IL-1β, IL-6, TNF-α and iNOS was significantly downregulated.Lastly, the liver antioxidant enzymes superoxide dismutase, catalase and glutathione were upregulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde.Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonbuk, Republic of Korea.

ABSTRACT
Hepatic ischemia/reperfusion (I/R) injury leads to oxidative stress and acute inflammatory responses that cause liver damage and have a considerable impact on the postoperative outcome. Much research has been performed to develop possible protective techniques. We aimed to investigate the efficacy of SPA0355, a synthetic thiourea analog, in an animal model of hepatic I/R injury. Male C57BL/6 mice underwent normothermic partial liver ischemia for 45 min followed by varying periods of reperfusion. The animals were divided into three groups: sham operated, I/R and SPA0355 pretreated. Pretreatment with SPA0355 protected against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and reduced parenchymal necrosis and apoptosis. Liver synthetic function was also restored by SPA0355 as reflected by the prolonged prothrombin time. To gain insight into the mechanism involved in this protection, we measured the activity of nuclear factor-κB (NF-κB), which revealed that SPA0355 suppressed the nuclear translocation and DNA binding of NF-κB subunits. Concomitantly, the expression of NF-κB target genes such as IL-1β, IL-6, TNF-α and iNOS was significantly downregulated. Lastly, the liver antioxidant enzymes superoxide dismutase, catalase and glutathione were upregulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde. Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.

Show MeSH

Related in: MedlinePlus

Effect of SPA0355 on I/R-induced hepatocellular injury in mice. Mice were pretreated with the indicated concentrations of SPA0355 intraperitoneally three times before undergoing 45 min of hepatic ischemia. After 6 h reperfusion, serum levels of ALT and AST (a) and prothrombin time (b) were analyzed. (c) After 24 h reperfusion, liver tissues were fixed by 10% formalin, and liver necrosis and apoptosis were assessed by H&E and TUNEL staining, respectively. The area of necrosis was analyzed as described in the Materials and methods and TUNEL-positive apoptotic cells were counted and expressed as a percentage of all hepatocytes. Values are the mean±s.e.m. of three independent experiments (n=9 mice per group). **P<0.01 vs sham-operated mice; #P<0.05, ##P<0.01 vs I/R mice. H&E, hematoxylin and eosin; SPA5, 5 μgkg−1 SPA0355; VEH, vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4150932&req=5

fig2: Effect of SPA0355 on I/R-induced hepatocellular injury in mice. Mice were pretreated with the indicated concentrations of SPA0355 intraperitoneally three times before undergoing 45 min of hepatic ischemia. After 6 h reperfusion, serum levels of ALT and AST (a) and prothrombin time (b) were analyzed. (c) After 24 h reperfusion, liver tissues were fixed by 10% formalin, and liver necrosis and apoptosis were assessed by H&E and TUNEL staining, respectively. The area of necrosis was analyzed as described in the Materials and methods and TUNEL-positive apoptotic cells were counted and expressed as a percentage of all hepatocytes. Values are the mean±s.e.m. of three independent experiments (n=9 mice per group). **P<0.01 vs sham-operated mice; #P<0.05, ##P<0.01 vs I/R mice. H&E, hematoxylin and eosin; SPA5, 5 μgkg−1 SPA0355; VEH, vehicle.

Mentions: Liver injury was assessed by measuring serum levels of AST and ALT, and by determining prothrombin time. I/R injury induced significant increases in serum ALT and AST levels compared with sham-operated mice (Figure 2a). However, pre-treatment with SPA0355 administered intraperitoneally three times before I/R injury augmented the elevation of serum ALT and AST levels in a dose-dependent manner. Specifically, 2.5 μgkg−1 SPA0355 reduced the AST level by 19.6% (P<0.05) and the ALT level by 21.3% (P<0.05), and the 5 μgkg−1 dose further reduced AST and ALT levels by 60.8% (P<0.01) and 59.2% (P<0.01), respectively. It is worth noting that no statistical difference was found between 5 and 10 μgkg−1 SPA0355, suggesting that 5 μgkg−1 of SPA0355 is sufficient to achieve full efficacy. In addition, prothrombin time was measured as a marker of liver synthetic function. I/R injury resulted in prolonged prothrombin time at 6 h after reperfusion, which was significantly decreased by pretreatment with 5 μgkg−1 SPA0355 (Figure 2b).


SPA0355 attenuates ischemia/reperfusion-induced liver injury in mice.

Bae UJ, Yang JD, Ka SO, Koo JH, Woo SJ, Lee YR, Yu HC, Cho BH, Zhao HY, Ryu JH, Lee SM, Jeon R, Park BH - Exp. Mol. Med. (2014)

Effect of SPA0355 on I/R-induced hepatocellular injury in mice. Mice were pretreated with the indicated concentrations of SPA0355 intraperitoneally three times before undergoing 45 min of hepatic ischemia. After 6 h reperfusion, serum levels of ALT and AST (a) and prothrombin time (b) were analyzed. (c) After 24 h reperfusion, liver tissues were fixed by 10% formalin, and liver necrosis and apoptosis were assessed by H&E and TUNEL staining, respectively. The area of necrosis was analyzed as described in the Materials and methods and TUNEL-positive apoptotic cells were counted and expressed as a percentage of all hepatocytes. Values are the mean±s.e.m. of three independent experiments (n=9 mice per group). **P<0.01 vs sham-operated mice; #P<0.05, ##P<0.01 vs I/R mice. H&E, hematoxylin and eosin; SPA5, 5 μgkg−1 SPA0355; VEH, vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150932&req=5

fig2: Effect of SPA0355 on I/R-induced hepatocellular injury in mice. Mice were pretreated with the indicated concentrations of SPA0355 intraperitoneally three times before undergoing 45 min of hepatic ischemia. After 6 h reperfusion, serum levels of ALT and AST (a) and prothrombin time (b) were analyzed. (c) After 24 h reperfusion, liver tissues were fixed by 10% formalin, and liver necrosis and apoptosis were assessed by H&E and TUNEL staining, respectively. The area of necrosis was analyzed as described in the Materials and methods and TUNEL-positive apoptotic cells were counted and expressed as a percentage of all hepatocytes. Values are the mean±s.e.m. of three independent experiments (n=9 mice per group). **P<0.01 vs sham-operated mice; #P<0.05, ##P<0.01 vs I/R mice. H&E, hematoxylin and eosin; SPA5, 5 μgkg−1 SPA0355; VEH, vehicle.
Mentions: Liver injury was assessed by measuring serum levels of AST and ALT, and by determining prothrombin time. I/R injury induced significant increases in serum ALT and AST levels compared with sham-operated mice (Figure 2a). However, pre-treatment with SPA0355 administered intraperitoneally three times before I/R injury augmented the elevation of serum ALT and AST levels in a dose-dependent manner. Specifically, 2.5 μgkg−1 SPA0355 reduced the AST level by 19.6% (P<0.05) and the ALT level by 21.3% (P<0.05), and the 5 μgkg−1 dose further reduced AST and ALT levels by 60.8% (P<0.01) and 59.2% (P<0.01), respectively. It is worth noting that no statistical difference was found between 5 and 10 μgkg−1 SPA0355, suggesting that 5 μgkg−1 of SPA0355 is sufficient to achieve full efficacy. In addition, prothrombin time was measured as a marker of liver synthetic function. I/R injury resulted in prolonged prothrombin time at 6 h after reperfusion, which was significantly decreased by pretreatment with 5 μgkg−1 SPA0355 (Figure 2b).

Bottom Line: Concomitantly, the expression of NF-κB target genes such as IL-1β, IL-6, TNF-α and iNOS was significantly downregulated.Lastly, the liver antioxidant enzymes superoxide dismutase, catalase and glutathione were upregulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde.Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonbuk, Republic of Korea.

ABSTRACT
Hepatic ischemia/reperfusion (I/R) injury leads to oxidative stress and acute inflammatory responses that cause liver damage and have a considerable impact on the postoperative outcome. Much research has been performed to develop possible protective techniques. We aimed to investigate the efficacy of SPA0355, a synthetic thiourea analog, in an animal model of hepatic I/R injury. Male C57BL/6 mice underwent normothermic partial liver ischemia for 45 min followed by varying periods of reperfusion. The animals were divided into three groups: sham operated, I/R and SPA0355 pretreated. Pretreatment with SPA0355 protected against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and reduced parenchymal necrosis and apoptosis. Liver synthetic function was also restored by SPA0355 as reflected by the prolonged prothrombin time. To gain insight into the mechanism involved in this protection, we measured the activity of nuclear factor-κB (NF-κB), which revealed that SPA0355 suppressed the nuclear translocation and DNA binding of NF-κB subunits. Concomitantly, the expression of NF-κB target genes such as IL-1β, IL-6, TNF-α and iNOS was significantly downregulated. Lastly, the liver antioxidant enzymes superoxide dismutase, catalase and glutathione were upregulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde. Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.

Show MeSH
Related in: MedlinePlus