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Objective To evaluate the effect of resuscitation with hypertonic sodium chloride hydroxyethyl starch 40 injection (HSH40) mixed with suberoylanilide hydroxamic acid (SAHA) on oxidative stress responses of lung tissues and histone acetylation in a rat model of lethal hemorrhagic shock after entering high altitude for the first time.Methods Forty-five healthy male Wistar rats,aged 3-4 months,weighing 250-300 g,were transported from the breeding area at altitude 1500 m to the experimental area at altitude 3 780 m.The rats were divided into 3 groups (n=15 each) using a random number table:sham operation group (group Sham),hemorrhagic shock group (group HS),and resuscitation with HSH40 mixed with SAHA group (group HSH/SAHA).Lethal hemorrhagic shock was induced by removing 40％ of blood volume from the left femoral artery at a constant speed within 10 min,followed by removing 15％ of blood volume from the right femoral vein at a constant speed within 50 min.Only cannulation was performed,and the rats received no blood letting or resuscitation in group Sham.The animals were resuscitated via the right femoral artery after successful establishment of the model,SAHA 7.5/Kg dissolved in HSH40 4 ml/kg was infused within 5 min in group HSH+SAHA.Immediately before blood letting,immediately after blood letting and at 3 h after resuscitation (at the time of death for the rats survived less than 3 h),arterial blood samples were obtained for blood gas analysis,and pH value,partial pressure of arterial carbon dioxide (PaCO2),partial pressure of arterial oxygen (PaO2) and arterial oxygen saturation (SaO2) were recorded.The rats were sacrificed after blood samples were collected from the abdominal aorta at 3 h after resuscitation (at the time of death for the rats died within 3 h after resuscitation),and lungs were removed for examination of the pathologic changes which were scored (with a light microscope) and for determination of wet to dry weight ratio (W/D ratio),activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA) and expression of histone H3 acetylation at lysine 9 (Ac-H3K9) in lung tissues (by Western blot).Results Compared with group Sham,the lung injury score,W/D ratio and content of MDA were significantly increased,and the activity of SOD was decreased in HS and HSH+SAHA groups,pH value and PaCO2 were significantly decreased and PaO2 and SaO2 were increased immediately after blood letting and at 3 h after resuscitation in group HS,and PaO2 and SaO2 were significantly increased immediately after blood letting and at 3 h after resuscitation,pH value and PaCO2 were decreased immediately after blood letting,and the expression of Ac-H3K9 was up-regulated in group HSH+SAHA (P＜0.05).Compared with group HS,pH value,PaCO2,PaO2 and SaO2 were significantly increased at 3 h after resuscitation,the lung injury score,W/D ratio and content of MDA were decreased,the activity of SOD was increased,and the expression of Ac-H3K9 was up-regulated in group HSH+SAHA (P＜0.05).Conclusion The mechanism by which resuscitation with HSH40 mixed with SAHA exerts lung protection may be related to inhibiting oxidative stress responses and histone acetylation in lung tissues in a rat model of lethal hemorrhagic shock after entering high altitude for the first time.
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Objective To investigate the effect of suberoylanilide hydroxamic acid (SAHA) on sufentanil postconditioning-induced cardioprotection in rats with type 2 diabetes mellitus (T2DM).Methods Male SPF Sprague-Dawley rats,weighing 250-300 g,aged 5-6 weeks,were used in the study.T2DM was induced by high-fat diet (4 weeks) and intraperitoneal 1％ streptozotocin 35 mg/kg,and confirmed by fasting blood glucose level≥ 16.7 mmol/L.Forty rats with T2DM were divided into 5 groups (n=8 each) using a random number table:sham operation group (grou T2DM-S);ischemia-reperfusion group (group T2DM-I/R);sufentanil postconditioning group (group T2DM-SP);SAHA group (group T2DM-SA);SAHA plus sufentanil postconditioning group (group T2DM-SASP).In T2DM-SA and T2DM-SASP groups,SAHA 25 mg/kg was injected intraperitoneally once a day for 5 consecutive days before operation.Their hearts were excised and retrogradely perfused in a Langendorff apparatus.The hearts were subjected to 30 min of global ischemia followed by 120 min of reperfusion to establish the model of ischemia/reperfusion injury.At 30 min of equilibration and 30,60 and 120 min of reperfusion,the left ventricular systolic pressure (LVSP),heart rate (HR),and the maximum rate of increase and decrease of ventricular pressure (±dp/dtmax) were recorded.At 120 min of reperfusion,the left ventricular mass (LVM) and infarct size (IS) were measured,and IS/LVM ratio was calculated.The expression of glycogen synthesis kinase 3β (GSK-3β) and phosphorylated GSK-3β (p-GSK-3β) in the myocardium was detected by Western blot.Results Compared with group T2DM-S,the LVSP,HR and ±dp/dtmax were significantly decreased,the IS and IS/LVM ratio were significantly increased,and the expression of myocardial p-GSK-3β was significantly down-regulated in group T2DM-I/R (P＜0.05).Compared with group T2DM-I/R,the ±dp/dtmax was significantly increased,the IS and IS/LVM ratio were significantly decreased,and the expression of myocardial p-GSK-3β was significantly up-regulated in group T2DM-SASP (P＜0.05),and no significant change was found in the parameters mentioned above in T2DM-SA and T2DM-SP groups (P＞0.05).Compared with group T2DM-SP,the ±dp/dt was significantly increased,the 1S and IS/LVM ratio were significantly decreased,and the expression of myocardial p-GSK-3β was significantly upregulated in group T2DM-SASP (P＜0.05).Conclusion SAHA can improve cardioprotection induced by sufentanil postconditioning to some extent in the rats with T2DM.
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Objective To observe the effects of histone deacetylases inhibitor (HDACi) on cognitive performance and cerebral tau phosphorylation in transgenic mice coexpressed five familial Alzheimer' s disease mutations (5XFAD).Method The total 12 5XFAD-CC and 12 wild type (WT) mice were administrated with suberoylanilide hydroxamic acid ( SAHA,n =7) and vehicle ( n =5 ),respectively.The cognitive performance was assessed by Y-maze and Morris water maze.The protein levels of acetylated α-tubulin,total tau and phosphorylated tau and phosphorylated glycogen synthase kinase-3β (GSK3β) were determined by Western blotting.Results SAHA ameliorated learning and memory deficits in 5XFAD-CC mice (39.10％ ±2.25％,t =2.688,P =0.0312 for total numbers of entrance in novel arm; 26.81％ ±0.78％,t =3.271,P =0.017 for time spending in novel arm; F =5.936,P =0.045 for hidden platform;31.70％ ±4.21％,t =2.317,P =0.049 for probe trial).Administration of SAHA significantly increased acetylated α-tubulin in hippocampus of WT and 5XFAD-CC mice (26.42％ and 29.64％,respectively).Additionally,SAHA attenuated tau-pSer396,tau-pSer404 and tau-pThrThr231 in hippocampus of 5XFAD-CC mice (24.22％,48.98％ and 26.95％,respectively). Moreover,hippocampal phosphorylated GSK3β was markedly reduced in SAHA-treated 5XFAD-CC mice (31.29％). Conclusion SAHA may improve cognitive performance in 5XFAD-CC mice, which is associated with its significant effects on the phosphorylation of tau and GSK3β.