Ischemia-reperfusion (I/R) cannot be avoided in liver transplantation procedures, and apoptosis is a central mechanism of cell death after liver reperfusion. Protective effect of recombinant erythropoietin (rhEPO) on liver apoptosis has not been clearly investigated. This work investigated intraportal (IP) rhEPO-protective effect in a rat model of hepatic I/R-induced apoptosis and its appropriated time and dose of administration. Eight groups were included (n = 10/group): sham-operated, I/R (45 min ischemia and 2 h reperfusion), preconditioned rhEPO I/R (24 h or 30 min before ischemia), and postconditioned rhEPO I/R (before reperfusion) using two different rhEPO doses (1,000 and 5,000 IU/kg). When compared with the sham-operated group, the I/R group showed significant increase of serum levels of aspartate and alanine aminotransferases (AST, ALT), hepatic caspase-9 activity(894.99 ± 176.90 relative fluorescence units (RFU)/mg/min versus 458.48 ± 82.96 RFU/mg/min), and Fas ligand (FasL) expression, histopathological damages, and significant decrease in the antiapoptotic Bcl-xL/apoptotic Bax ratio(0.38 ± 0.21 versus 3.35 ± 0.77) rhEPO-improved ALT and AST but failed to reduce FasL expression in all groups compared with the I/R group. Thirty minutes and 24 h preconditioning with rhEPO (1,000 IU/kg) increased Bcl-xL/Bax ratio and reduced caspase-9 activity, and the same effect was observed when higher dose was given 24 h before ischemia. Preconditioning was more effective than postconditioning in improving caspase-9 activity, and no dose-dependent effect was observed. In conclusion, single IP rhEPO injection 30 min before ischemia has an advantage over rhEPO postconditioning in improving post-hepatic I/R-induced apoptosis with no additional time- and dose-dependent effects which may provide potentially useful guide in liver transplantation procedures.
Obesity is an important risk factor for heart disease. This study investigated the effects of omega-3 (omega-3) on reversal of high fat (HF) diet-induced changes in the expression of the cardiac adiponectin and adiponectin receptors R1 and R2. Male rats were fed low-fat (LF; 10% energy from fat) or HF (45% energy from fat) for 16 weeks, LF-omega-3 or a HF-omega-3 (LF or HF for 16 weeks supplemented by omega-3 as 36 g/kg diet for the last 6 weeks, respectively) and a HF diet for 10 weeks to demonstrate HF effect before omega-3 administration. HF diet induced obesity, glucose intolerance, increased heart end systolic and diastolic volumes, decreased serum adiponectin, reduced expression of cardiac and adipose tissue adiponectin and adipo R1 & R2 with elevated serum tumour necrosis factor-alpha (TNF-alpha) compared to the LF diet. On the other hand, the HF-omega-3 group compared with the HF group had improved glucose tolerance (area under the glucose curve 837.14 +/- 45.7 versus 1158.5 +/- 69.8) and insulin resistance with a significant increase in serum adiponectin (4.22 +/- 0.39 versus 2.82 +/- 0.69 ng/ml) and a significant decrease in serum TNF-alpha (129.84 +/- 13.63 versus 209.8 +/- 16.42 pg/ml) and triglycerides independent of obesity. Also the data showed significant increases in the expression of cardiac and adipose tissue adiponectin and adiponectin R1 and adipose tissue adipo R2 as well as cardiac pAMP kinase with improvement in end-systolic and -diastolic volumes. These parameters were also improved compared to initial values in HF-10-week group. In conclusion, dietary omega-3 supplementation has a beneficial effect on fat-induced cardiac dysfunction and insulin resistance partly through increasing adiponectin and adiponectin receptors expression in heart and adipose tissue.
Type 2 diabetes mellitus is one of the common metabolic disorders that ultimately afflicts large number of individuals. Adrenomedullin (AM) is a potent vasodilator peptide; previous studies reported development of insulin resistance in aged AM deficient mice. In this study, we employed a gene delivery approach to explore its potential role in insulin resistance. Four groups were included: control, diabetic, non-diabetic injected with the AM gene and diabetic injected with the AM gene. One week following gene delivery, serum glucose, insulin, triglycerides, leptin, adiponectin and corticosterone were measured as well as the insulin resistance index (HOMA-IR). Soleus muscle glucose uptake and RT-PCR of both AM and glucose transporter-4 (GLUT 4) gene expressions were assessed. A single tail vein injection of adrenomedullin gene in type 2 diabetic rats improved skeletal muscle insulin responsiveness with significant improvement of soleus muscle glucose uptake, HOMA-IR, serum glucose, insulin and triglycerides and significant increase in muscle GLUT 4 gene expression (P < 0.05) compared with the non-injected diabetic rats. The beneficial effects of AM gene delivery were accompanied by a significant increase in the serum level of adiponectin (2.95 ± 0.09 versus 2.33 ± 0.17 lg/ml in the non-injected diabetic group) as well as a significant decrease in leptin and corticosterone levels (7.51 ± 0.51 and 262.88 ± 10.
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