The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis.

Sepsis is one of the most common causes of mortality in intensive care units. Although sepsis-associated encephalopathy (SAE) is reported to be a leading manifestation of sepsis, its pathogenesis remains to be elucidated. In this study, we investigated whether exogenous recombinant human erythropoietin (rhEPO) could protect brain from neuronal apoptosis in the model of SAE. We showed that application of rhEPO enhanced Bcl-2, decreased Bad in lipopolysaccharide treated neuronal cultures, and improved neuronal apoptosis in hippocampus of cecal ligation and peroration rats. We also found that rhEPO increased the expression of phosphorylated AKT, and the antiapoptotic role of rhEPO could be abolished by phosphoinositide 3-kinase (PI3K)/AKT inhibitor LY294002 or SH-5. In addition, systemic sepsis inhibited the hippocampal-phosphorylated mammalian target of rapamycin (mTOR) and p70S6K (downstream substrates of PKB/AKT signaling), which were restored by administration of exogenous rhEPO. Moreover, treatment with mTOR-signaling inhibitor rapamycin or transfection of mTOR siRNA reversed the neuronal protective effects of rhEPO. Finally, exogenous rhEPO rescued the emotional and spatial cognitive defects without any influence on locomotive activity. These results illustrated that exogenous rhEPO improves brain dysfunction by reducing neuronal apoptosis, and AKT/mTOR signaling is likely to be involved in this process. Application of rhEPO may serve as a potential therapy for the treatment of SAE.

Losartan reduced connexin43 expression in left ventricular myocardium of spontaneously hypertensive rats.

OBJECTIVE: To assess the effect of angiotensin II type 1 (AT(1)) receptor antagonist losartan on myocardium connexin43 (Cx43) gap junction (GJ) expression in spontaneously hypertensive rats (SHRs) and investigate possible mechanisms. METHODS: Sixteen 9-week-old male SHRs and 8 age-matched male Wistar-Kyoto (WKY) rats were included in this study. SHRs were randomly divided into two groups to receive losartan at 30 mg/(kg x d) by oral gavage once daily for 8 weeks (SHR-L) or vehicle (0.9% saline) to act as controls (SHR-V); WKY rats receiving vehicle for 8 weeks served as normotensive controls. At the end of the experiment, rats were sacrificed and the hearts were removed. Expressions of Cx43 and nuclear factor-kappaB p65 (NF-kappaB p65) proteins in all three groups were observed and further investigations on the effect of angiotensin II type 1 receptor antagonist losartan (30 mg/(kg x d), 8 weeks) on Cx43 expression were conducted with Western blot and immunohistochemistry. NF-kappaB p65 protein in nuclear extracts was determined by Western blot. RESULTS: Left ventricular (LV) hypertrophy was prominent in SHRs, Cx43 and NF-kappaB p65 protein expressions were obviously upregulated and Cx43 distribution was dispersed over the cell surface. Treatment with losarton reduced the over-expressions of Cx43 and NF-kappaB p65 in LV myocardium. The distribution of Cx43 gap junction also became much regular and confined to intercalated disk after losartan treatment. CONCLUSION: Cx43 level was upregulated in LV myocardium of SHR during early stage of hypertrophy. Angiotensin II type 1 receptor antagonist losartan prevented Cx43 gap junction remodeling in hypertrophied left ventricles, possibly through the NF-kappaB pathway.

Intra-abdominal pressure monitoring in predicting outcome of patients with severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) is a serious disease with many complications, high mortality and poor prognosis. It is characterized by rapid deterioration and poses one of the most difficult challenges in clinical practice. Previous investigations suggest that SAP is one of the main causes of intra-abdominal pressure (IAP) increase. The aim of this study was to evaluate the utility of IAP-monitoring in predicting the severity and prognosis of SAP. METHODS: Eighty-nine patients with SAP who had been treated from February 2001 to December 2005 were studied. Since bladder pressure accurately reflects IAP, we measured it instead of IAP. Bladder pressure was measured at the time of admission and every 12 hours in the course of the disease, 9 consecutive times in all. The APACHE II scores of all patients were obtained within 24 hours after admission. According to a maximum bladder pressure <10 cmH2O, all patients were divided into two groups, mildly-elevated and severely-elevated. Mortality and mean APACHE II scores in the two groups were calculated. In addition, the mean bladder pressure and APACHE II scores in survivors were compared with those in deaths. RESULTS: Sixty-eight of the 89 patients were in the severely-elevated group. Mortality and mean APACHE II scores in this group were much higher than those in the mildly-elevated group (mortality, 39.71% vs. 9.52%; mean APACHE II score, 23.15+/-7.42 vs. 15.95+/-5.35, P<0.01). The mean bladder pressures and APACHE II scores in deaths were significantly greater than those in survivors (mean bladder pressure, 14.1+/-3.8 vs. 9.2+/-2.3 cmH2O, P<0.01; mean APACHE II score, 27.83+/-4.87 vs. 18.37+/-6.74, P<0.01). CONCLUSION: It is suggested that IAP may be used as a marker of the severity and prognosis of SAP.