SIRT3 Mediates The Study Of Sepsis-associated Encephalopathy By Regulating CypD Acetylation

Objective:To investigate the expression of CypD and acetylated CypD on the sepsis-associated encephalopathy in mice and their effects on the sepsis-associated encephalopathy.Methods:Male C57BL/6 mice,at the age of 3?4 months,were randomly assigned to two groups:sham group and cecal ligation puncture(CLP)group(n=21).Animals in CLP group underwent CLP surgery.The cognitive function was assessed using the learning version of the Morris water maze test in 4th?6th days after surgery.HE stained sections were used to observe the hippocampus in mice.Elisa method was used to detect the levels of interleukin 6(IL-6)and tumor necrosis factor-?(TNF-?).Then,the level of CypD and acetylated CypD in the hippocampus were determined.Results:1.Compared with the Sham group,the mice suffering CLP spent more time to find the platform(P<0.05).The mice in the sham group spent more time in the third quadrant where the platform was located compared with those undergoing CLP surgery(P<0.05).Swimming speeds were also analyzed,and no significant differences were observed in these two groups(P>0.05).2.Compared with the Sham Group,the damage to hippocampus tissue in the CLP group was more aggravated(P<0.05).However,the damage to hippocampus was most hard in the 4th day after CLP operation.3.Compared with the Sham Group,the expression of IL-6 and TNF-a were increased in the CLP group(P<0.05).However,the levels of IL-6 and TNF-a were increased most in the 4th day after surgery.4.Compared with the Sham Group,the expression of CypD and acetylated CypD were increased in the CLP group(P<0.05).However,the levels of CypD and acetylated CypD were increased most in the 4th day after surgery.Conclusion:The damage to hippocampus was more aggravates in SAE mice and the expression of IL-6?TNF-??CypD and acetylated CypD were increased after CLP,and these level were increased most in the 4th day.Objective:The present study aimed to investigate cognitive dysfunction in the hippocampus induced by sepsis-associated encephalopathy(SAE)via acetylation of cyclophilin D(CypD)and opening of mitochondrial permeability transition pore(mPTP).It also explored whether activating sirtuin 3(SIRT3)can mediate deacetylation of CypD and prevent the development of SAE.Methods:Male mice were randomly assigned to six groups:sham group,cecal ligation puncture(CLP)group,CypD siRNA transfection(CypD-si)group,CypD control siRNA transfection(CypD-c)group,SIRT3 overexpression vector pcDNA3.1(SIRT3-p)group,and SIRT3 empty vector pcDNA3.1(SIRT3-v)group(n = 18).The CypD-si and CypD-c groups were transfected with CypD siRNA and CypD control siRNA,respectively.The SIRT3-p and SIRT3-v groups were injected with SIRT3 pcDNA3.1 and vector pcDNA3.1,respectively.The cognitive function was assessed using the learning version of the Morris water maze test.Then,cell apoptosis and the levels of CypD,acetylated CypD,SIRT-3,interleukin 6(IL-6),tumor necrosis factor-?(TNF-?),and caspase-3 in the hippocampus were determined.Results:1.Compared to the Sham group,the latency of the mice underwent CLP surgery was longer and they spent less time to find the platform(P<0.05).Compared to the CLP group the latency of the CypD-si group and SIRT3-p group was shorter,and they spent more time to find the platform(P<0.05).There are no significant differences in swimming speeds among these groups(P>0.05).2.Compared to the Sham group,the cell apoptosis in the hippocampus of the mice underwent CLP increased(P<0.05).Compared to the CLP group,the cell apoptosis of CypD-si group and SIRT3-? group decreased significantly(P<0.05).3.Compared to the Sham group,the mPTP opening in the hippocampus of the mice underwent CLP operation increased significantly(P<0.05).Compared to the CLP group,the mPTP opening of CypD-si group and SIRT3-p group decreased(P<0.05).4.Compared to the Sham group,the expression of IL-6?TNF-??CypD and acetylated CypD increased,the level of SIRT3 decreased(P<0.05).Compared to the CLP group,the expression of IL-6?TNF-??caspase-3?CypD and acetylated CypD decreased,and the level of SIRT3 increased significantly(P<0.05).Conclusions:Activating SIRT3-mediated deacetylation of CypD attenuated learning and memory dysfunction induced by SAE.