Isoflurane reduces pain and inhibits apoptosis of myocardial cells through the phosphoinositide 3-kinase/protein kinase B signaling pathway in mice during cardiac surgery.

Heart bypass surgery is the most common treatment for myocardial ischemia. Clinical investigations have revealed that isoflurane anesthesia is efficient to alleviate pain during cardiac surgery, including heart bypass surgery. Previous studies have revealed the protective effects of isoflurane on myocardial cells of patients with myocardial ischemia during the perioperative period. The present study aimed to investigate the mechanism underlying the protective effects of isoflurane on myocardial cells in mice with myocardial ischemia. ELISA, flow cytometry, immunofluorescence and western blotting were used to analyze the effects of isoflurane anesthesia on myocardial cells. Briefly, myocardial cell apoptosis and viability, pain, phosphoinositide 3­kinase/protein kinase B (PI3K/AKT) signaling pathway expression and the pharmacodynamics of isoflurane were studied in mice treated with isoflurane for heart bypass surgery. The results demonstrated that isoflurane anesthesia efficiently attenuated pain in mice during surgery. Viability and apoptosis of myocardial cells was also improved by isoflurane in vitro and in vivo. The PI3K/AKT pathway was upregulated in myocardial cells on day 3 post­operation. Mechanistically, isoflurane promoted PI3K/AKT activation, upregulated B­cell lymphoma 2 (Bcl­2)­associated X protein and Bcl­2 expression levels, and reduced the expression levels of caspase­3 and caspase­8 in myocardial cells. In conclusion, the findings indicated that isoflurane is beneficial for pain attenuation and inhibits apoptosis of myocardial cells via the PI3K/AKT signaling pathway in mice during cardiac surgery.

Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo.

Cisplatin-based therapy is one of the most important chemotherapy treatments for cancers. However, its efficacy is greatly limited by drug resistance and undesirable side effects. Therefore, it is of great importance to develop effective chemosensitization agents to cisplatin. In the present study, we demonstrated the strategy to use shikonin, a natural product from the root of Lithospermum erythrorhizon, as a synergistic agent of cisplatin and elucidated their action mechanisms. The combination of shikonin and cisplatin exhibited synergistic anticancer efficacy and achieved greater selectivity between cancer cells and normal cells. By inducing intracellular oxidative stress, shikonin potentiated cisplatin-induced DNA damage, followed by increased activation of mitochondrial pathway. In addition, inhibition of ROS reversed the apoptosis induced by shikonin and cisplatin, and recovered the depletion of mitochondrial membrane potential, which revealed the vital role of ROS in the synergism. Moreover, HCT116 xenograft tumor growth in nude mice was more effectively inhibited by combined treatment with shikonin and cisplatin. Our findings suggest that the strategy to apply shikonin as a synergistic agent to cisplatin could be a highly efficient way to achieve anticancer synergism by inducing intracellular oxidative stress. Shikonin may be a promising candidate as a chemosensitizer to cisplatin-based therapy for cancer treatments.

[Effect of hydroxyethyl starch 130/0.4 on S100B protein level and cerebral oxygen metabolism in open cardiac surgery under cardiopulmonary bypass].

OBJECTIVE: To observe the effect of hydroxyethyl starch (HES) 130/0.4 on S100B protein level and cerebral metabolism of oxygen in open cardiac surgery under cardiopulmonary bypass (CPB) and to explore whether it has the protective effect of 6%HES130/0.4 as priming solution on cerebral injury during CPB and explore the probable mechanism. METHODS: Forty patients with atrioseptal defect or ventricular septal defect scheduled for elective surgical repair under CPB with moderate hypothermia were randomly divided into two equal groups: HES 130/0.4 group (HES group) in which HES 130/0.4 (voluven) was used as priming solution and gelatin group (GRL group) in which gelofusine (succinylated gelatin) was used as priming solution. ECG, heart rate (HR), blood pressure (BP), mean arterial pressure (MAP), central venous pressure (CVP), arterial partial pressure of oxygen (P(a)O(2),), arterial partial pressure of carbon dioxide (P(et)CO(2)) and body temperature (naso-pharyngeal and rectal) were continuously monitored during the operation. Blood samples were obtained from the central vein for determination of blood concentrations of S100B protein at the following time points: before CPB (T(0)), 20 minutes after the beginning of CPB (T(1)), immediately after the termination of CPB (T(2)), 60 minutes after the termination of CPB (T(3)), and 24 hours after the termination of CPB (T(4)). The serum S100B protein levels were measured by ELISA. At the same time points blood samples were obtained from the jugular vein and radial artery to undergo blood gas analysis and measurement of blood glucose, based on which the cerebral oxygen metabolic rate/cerebral metabolic rate of glucose (CMRO(2)/CMR(GLU)) was calculated. RESULTS: Compared with the time point of immediately before CPB (T(0)), The S100B protein level of the 2 groups began to increase since the time point T(1), peaked at the time point T(2), began to decrease gradually since the time point T(3), and were still significantly higher than those before CPB at the time point T(4) (all P < 0.01), and the S100B protein levels at different time points of the HES group were all significantly lower than those of the GEL group (all P < 0.01). The S(jv)O(2) and CMRO(2)/CMR(GLU) levels of both groups increased at the time point T(1), decreased at the time points T(2) and T(3), and then restored to normal at the time points T(4). In the GEL group there were no significant differences in the levels between any 2 different time points, however, in the HES group S(jv)O(2) and CMRO(2)/CMR(GLU) levels at T(1) was significantly higher than those at the other time points (P < 0.05 or P < 0.01). CONCLUSION: S100B protein increases significantly in open cardiac surgery under CPB. HES130/0.4 lowers the S100B protein levels from the beginning of CPB to one hour after the termination of CPB with the probable mechanism of improving the cerebral metabolism of oxygen. 6%HES130/0.4 as priming solution may play a protective role in reduction of cerebral injury during CPB and open cardiac surgery.