Interplay between RAGE and TLR4 Regulates HMGB1-Induced Inflammation by Promoting Cell Surface Expression of RAGE and TLR4.

Receptor for advanced glycation end-products (RAGE) and TLR4 play an important role in the inflammatory response against High-mobility group box 1 protein (HMGB1), a late proinflammatory cytokine and a damage-associated molecular pattern. As cell surface receptors, both RAGE and TLR4 are constantly trafficking between the cytoplasm and plasma membrane. However, whether TLR4 is related to the intracellular transport of RAGE in HMGB1-induced inflammation remains unknown. In this study, we demonstrated that HMGB1 not only increased RAGE expression in both the cytoplasm and plasma membrane but also upregulated the expression of TLR4 in the plasma membrane. Knocking out of RAGE led to decreased MAPK activation, TLR4 cellular membrane expression, and corresponding inflammatory cytokine generation. Meanwhile, inhibiting MAPK activation also decreased TLR4 surface expression. These results indicated that HMGB1 may bind to cell surface RAGE receptors on the cell surface, leading to MAPK activation, thus promoting TLR4 translocation on the cell surface, but does not regulate its transcription and translation. In contrast, TLR4 can increase the transcription and translation of RAGE, which translocates to the cell surface and is able to bind to more HMGB1. The cell surface receptors TLR4 and RAGE bind to HMGB1, leading to the transcription and secretion of inflammatory cytokines. Finally, we also observed these results in the mice pseudofracture model, which is closely related to HMGB1-induced inflammatory response. All these results demonstrated that the interplay between RAGE and TLR4 are critical for HMGB1-induced inflammatory response.

Propofol enhances BCR-ABL TKIs' inhibitory effects in chronic myeloid leukemia through Akt/mTOR suppression.

BACKGROUND: The anti-cancer activities of intravenous anesthetic drug propofol have been demonstrated in various types of cancers but not in chronic myeloid leukemia (CML). METHODS: We systematically examined the effect of propofol and its combination with BCR-ABL tyrosine kinase inhibitors (TKIs) in CML cell lines, patient progenitor cells and mouse xenograft model. We analyzed propofol's underlying mechanism focusing on survival pathway in CML cells. RESULTS: We show that propofol alone is active in inhibiting proliferation and inducing apoptosis in KBM-7, KU812 and K562 cells, and acts synergistically with imatinib or dasatinib, in in vitro cell culture system and in vivo xenograft model. In addition, propofol is more effective in inducing apoptosis and inhibiting colony formation in CML CD34 progenitor cells than normal bone marrow (NBM) counterparts. Combination of propofol and dasatinib significantly eliminates CML CD34 without affecting NBM CD34 cells. We further demonstrate that propofol suppresses phosphorylation of Akt, mTOR, S6 and 4EBP1 in K562. Overexpression of constitutively active Akt significantly reverses the inhibitory effects of propofol in K562, confirm that propofol acts on CML cells via inhibition of Akt/mTOR. Interestingly, the levels of p-Akt, p-mTOR and p-S6 are lower in cells treated with combination of propofol and imatinib than cells treated with propofol or imatinib alone, suggesting that propofol augments BCR-ABL TKI's inhibitory effect via suppressing Akt/mTOR pathway. CONCLUSION: Our work shows that propofol can be repurposed to for CML treatment. Our findings highlight the therapeutic value of Akt/mTOR in overcoming resistance to BCR-ABL TKI treatment in CML.

Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1α.

Stroke is the leading cause of death in China and produces a heavy socio-economic burden in the past decades. Previous studies have shown that dexmedetomidine (DEX) is neuroprotective after cerebral ischemia. However, the role of autophagy during DEX-mediated neuroprotection after cerebral ischemia is still unknown. In this study, we found that post-conditioning with DEX and DEX+3-methyladenine (3-MA) (autophagy inhibitor) reduced brain infarct size and improved neurological deficits compared with DEX+RAPA (autophagy inducer) 24 h after transient middle cerebral artery artery occlusion (tMCAO) model in mice. DEX inhibited the neuronal autophagy in the peri-ischemic brain, and increased viability and decreased apoptosis of primary cultured neurons in oxygen-glucose deprivation (OGD) model. DEX induced expression of Bcl-1 and p62, while reduced the expression of microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1 in primary cultured neurons through inhibition of apoptosis and autophagy. Meanwhile, DEX promoted the expression of hypoxia-inducible factor-1α (HIF-1α) both in vivo and in vitro, and 2-Methoxyestradiol (2ME2), an inhibitor of HIF-1α, could reverse DEX-induced autophagic inhibition. In conclusion, our study suggests that post-conditioning with DEX at the beginning of reperfusion protects mouse brain from ischemia-reperfusion injury via inhibition of neuronal autophagy by upregulation of HIF-1α, which provides a potential therapeutic treatment for acute ischemic injury.

Ischemic preconditioning attenuates ischemia/reperfusion injury in rat steatotic liver: role of heme oxygenase-1-mediated autophagy.

Steatotic livers are more susceptible to ischemia/reperfusion (I/R) injury, which is ameliorated by ischemic preconditioning (IPC). Autophagy possesses protective action on liver I/R injury and declines in steatotic livers. The aim of this study was to test the hypothesis that the increased susceptibility of steatotic livers to I/R injury was associated with defective hepatic autophagy, which could be restored by IPC via heme oxygenase-1 (HO-1) signaling. Obesity and hepatic steatosis was induced using a high fat diet. Obesity impaired hepatic autophagy activity and decreased hepatic HO-1 expression. Induction of HO-1 restored autophagy activity and inhibited calpain 2 activity. Additionally, suppression of calpain 2 activity also restored autophagy activity. Mitochondrial dysfunction and hepatocellular injury were significantly increased in steatotic livers compared to lean livers in response to I/R injury. This increase in sensitivity to I/R injury was associated with defective hepatic autophagy activity in steatotic livers. IPC increased autophagy and reduced mitochondrial dysfunction and hepatocellular damage in steatotic livers following I/R injury. Furthermore, IPC increased HO-1 expression. Inhibition of HO-1 decreased the IPC-induced autophagy, increased calpain 2 activity and diminished the protective effect of IPC against I/R injury. Inhibition of calpain 2 restored autophagic defect and attenuated mitochondrial dysfunction in steatotic livers after I/R. Collectively, IPC might ameliorate steatotic liver damage and restore mitochondrial function via HO-1-mediated autophagy.

Differential role of intravenous anesthetics in colorectal cancer progression: implications for clinical application.

Anesthetics are unavoidable to colorectal cancer (CRC) patients who underwent surgical treatment. Thus, the molecular mechanisms underlying the role of the intravenous anesthetics in CRC metastasis are still unclear. In this study, the effects of intravenous anesthetics, such as propofol, etomidate and dexmedetomidine, on cell migration were determined. The migration of CRC cells was inhibited by propofol in vitro, but not in vivo. Etomidate, however, promoted the migration of CRC cells both in vitro and in vivo. Epithelial-mesenchymal transition (EMT) mediated the promotive effect of propofol and etomidate on the migration of CRC cells through PI3K/AKT signaling pathway. Dexmedetomidine alone or in combination with propofol or etomidate had minor effect on the migration of CRC cells. These findings indicate that propofol inhibites CRC cell migration in vitro. Etomidate playes a role for prompting CRC metastasis progression by activating (PI3K)/AKT signaling and inducing EMT. It provides an important hint for the clinical application of these anesthetics.

[Effects of dexmedetomidine on propofol dosage in target-controlled infusion and hemodynamics during laparoscopic surgery under general anesthesia].

OBJECTIVE: To assess the effects of dexmedetomidine (Dex) on propofol dosage in target-controlled infusion (TCI) and hemodynamics in patients undergoing laparoscopic surgery under general anesthesia. METHODS: Sixty patients undergoing laparoscopic surgery under general anesthesia were randomly divided into control group (n=30) and the Dex group (n=30). The patients in Dex group received a loading dose of Dex (1 µg/kg, infused within 10 min) before the surgery followed by continuous infusion at the rate of 0.3 µg·kg(-1)·h(-1) till the end of the surgery, and the control patients received saline infusion in the same manner. Heart rate, blood pressure, bispectral index (BIS), and propofol dose in TCI were recorded during induction and maintenance of anesthesia. The incidence of hypotension and bradycardia were observed during and after the surgery. RESULTS: No difference was found in the incidence of hypotension and bradycardia between the control group and Dex group (P>0.05), but heart rate and blood pressure were lower in Dex group during extubation (P<0.05). The dose of propofol in TCI was significantly less in Dex group than in the control group (P<0.05). CONCLUSION: Dex can reduce hemodynamic abnormalities caused by extubation and decrease the dosage of propofol in TCI, and may serve as an ideal adjuvant drug for general anesthesia.

Anesthesia for endovascular treatment of acute ischemic stroke.

The initial treatment of patients with acute ischemic stroke (AIS) focuses on rapid recanalization, which often includes the use of endovascular therapies. Endovascular treatment depends upon micronavigation of catheters and devices into the cerebral vasculature, which is easier and safer with a motionless patient. Unfortunately, many stroke patients are unable to communicate and sufficiently cooperate with the procedure. Thus, general anesthesia (GA) with endotracheal intubation provides an attractive means of keeping the patient comfortable and motionless during a procedure that could otherwise be lengthy and uncomfortable. However, several recent retrospective studies have shown an association between GA and poorer outcomes in comparison with conscious sedation for endovascular treatment of AIS, though prospective studies are lacking. The underlying reasons why GA might produce a worse outcome are unknown but may include hemodynamic instability and hypotension, delays in treatment, prolonged intubation with or without neuromuscular blockade, or even neurotoxicity of the anesthetic agent itself. Currently, the choice between GA and conscious sedation should be tailored to the individual patient, on the basis of neurologic deficits, airway and hemodynamic status, and treatment plan. The use of institutional treatment protocols may best support efficient and effective care for AIS patients undergoing endovascular therapy. Important components of such protocols would include parameters to choose anesthetic modality, timeliness of induction, blood pressure goals, minimization of neuromuscular blockade, and planned extubation at the end of the procedure.

[Prophylactic effect of acupuncture on nausea and vomiting after laparoscopic operation].

OBJECTIVE: To explore the prophylactic effect of acupuncture Neiguan (PC 6) on nausea and vomiting after laparoscopic operation. METHODS: One hundred patients with laparoscopic gastrointestinal operation were randomly divided into an acupuncture group and a control group, 50 patients in each group. The operation was carried out with the combined infusion and inhalation anesthesia. The patients in the acupuncture group were being punctured at bilateral Neiguan (PC 6) before anesthesia and during the operation. The needles were extracted after operation, and the acupoints were covered with opaque tape. In contrast, the patients in the control group only accepted tape covering without acupuncture. After operation, all patients were given the self-controlled intravenous analgesia, and followed up at 6 h, 12 h, 24 h, 48 h for recording the incidence rate of the nausea, retching and vomiting, then scoring with VAS. RESULTS: At 6 h, 12 h, 24 h, 48 h after operation, in the acupuncture group, the incidence rates of the nausea were 12.0%, 6.0%, 6.0% and 2.0%, and the incidence rates of the retching were 0, 0, 2.0% and 2.0%, respectively; in the control group, the incidence rates of the nausea were 28.0%, 20.0%, 12.0% and 2.0%, and the incidence rates of the retching were 2.0%, 6.0%, 2.0% and 0, respectively. At 6 h, 12 h after operation, the incidence rates of the nausea and retching in the acupuncture group were lower than those of the control group (P < 0.05, P < 0.001). The vomiting was not happened in both groups. There was no difference between the two groups according to the scoring with VAS. CONCLUSION: Acupuncturing at Neiguan (PC 6) can reduce the incidence rates of the patients' nausea and retching after laparoscopic operation, especially in 24 h.

[Changes of approximate entropy in rats during focal cerebral infarction].

OBJECTIVE: To investigate the changes of EEG approximate entropy (ApEn) in rats during focal cerebral infarction. METHODS: Twenty-four Sprague-Dawley (SD) rats were randomly divided into infarction group (n=12) with middle cerebral artery occlusion and sham-operated group (n=12). The EEG data (ApEn) was recorded in the bilateral areas (C3, C4) of the rats with focal cerebral infarction before the infarction and immediately and at 5, 15, 30, and 60 min after the infarction. The same measurement was carried out in the sham-operated group. RESULTS: In the sham-operated group, ApEn in C3 and C4 showed no obvious differences at the time points (P>0.05), but in the infarction group, ApEn in C3 and C4 increased significantly after the infarction. ApEn in the ischemic area (C4) was significantly lower than that in the non-ischemic area (C3) (P<0.05). The bilateral ApEn decreased with the passage of time. ApEn in the ischemic area (C4) was significantly lowered at 30 min after the infarction in comparison with that before infarction (P<0.05). In the sham-operated group, ApEn showed no significant difference between C3 and C4. ApEn was comparable between the two groups before the operation. CONCLUSION: ApEn can help monitor the occurrence of focal cerebral infarction of rats, and may be used to assess the extent of cerebral ischemia after infarction.

[Comparison of unconsciousness prediction probability with approximate entropy and bispectral index during sedation].

OBJECTIVE: To compare the unconsciousness prediction probability (Pk) estimated by approximate entropy (ApEn) and bispectral index (BIS) during the sedation produced by target-controlled infusion (TCI) of propofol. METHODS: Twenty patients (ASA class I-II) scheduled for elective lower limb operations under epidural anesthesia were studied. TCI of propofol was initiated at target plasma concentration of 0.5 microg/ml, and increased by 0.3 to 0.5 microg/ml until loss of consciousness, and then decreased until consciousness recovery. Each target plasma concentration of propofol lasted for 12 min. ApEn and BIS were recorded simultaneously during the periods of consciousness and unconsciousness every 3 min. The Pk of unconsciousness with ApEn and BIS were calculated and compared. RESULTS: ApEn was 0.84+/-0.05 in the state of consciousness and 0.71+/-0.06 upon loss of consciousness, and BIS in the corresponding stages were 80.2+/-6.2 and 67.3+/-7.9, respectively. The Pk of unconsciousness between ApEn (Pk=0.97+/-0.06) and BIS (Pk=0.91+/-0.11) did not significantly differ (P>0.05). CONCLUSION: ApEn as well as BIS is acceptable for predicting consciousness and unconsciousness produced by TCI propofol.

[Inhibiting effect of intrathecal fentanyl on intraoperative vomiting during cesarean delivery under epidural anesthesia].

OBJECTIVE: To observe the inhibiting effect of intrathecal (IT) fentanyl on nausea and vomiting during cesarean delivery under epidural anesthesia. METHODS: Thirty healthy parturients (ASA grade I to II) were randomly assigned in equal numbers into control and fentanyl groups (n=15 each, patients in the latter group treated with IT fentanyl at the dose of 20 microgram/3ml). The incidence of nausea and vomiting during the elective cesarean delivery under epidural anesthesia between the 2 groups were compared and the neonates' Apgar scores assessed after the delivery. RESULTS: Intraoperative nausea and vomiting/retching were reduced in the IT fentanyl group as compared with the control group (6.7 % vs 33.3 % and 0 vs 26.7 %, P>0.05 and P<0.05 respectively). The neonates' Apgar scores were not significantly different between the 2 groups (P>0.05). CONCLUSION: IT fentanyl can decrease intraoperative vomiting during cesarean delivery performed under epidural anesthesia.

[Brain uptake of propofol during target-controlled infusion when effect compartment concentration is targeted].

OBJECTIVE: To study the correlation between the effect compartment concentration (ECC) and the brain uptake of propofol during sedation by target-controlled infusion (TCI). METHOD: Twelve ASA physical status I to II patients with neither cardiac nor intracranial diseases were scheduled for elective abdominal operation. Computer-assisted target-controlled infusion of propofol was performed for general anesthesia in all patients with the target ECC set at 4.0 microgram/ml. The plasma propofol concentrations were measured simultaneously from the radial artery and the jugular bulb at different time points by high performance liquid chromatography (HPLC), and the area under time-concentration curve (AUC(a-jv)) was calculated. RESULT: Before reaching the target propofol concentration of 4.0 microgram/ml (4.7+/-0.16 min), EEC was positively correlated with AUC(a-jv) (r(ECC-AUC)=0.977, P<0.001), but neither the arterial (Ca) nor jugular bulb propofol concentrations (Cjbv) showed such relation to AUC(a-jv) (r(Ca-AUC)= 0.054, P=0.92; r(Cjbv-AUC)=0.335, P=0.516). When ECC was controlled at 4.00 microgram/ml by TCI, Ca was comparable with Cjbv (P=0.512). Positive correlation was noted between AUCa-jv and ECC (r(ECC-AUC)=0.942, P<0.005) after the termination of infusion till the consciousness recovery of the patients, and Ca and Cjbv showed similar correlation with AUC(a-jv) (r(Ca-AUC)=0.986, P<0.001; r(Cjbv-AUC)=0.974, P<0.001). CONCLUSION: During TCI of propofol with ECC as the target concentration, ECC is significantly correlated with AUC(a-jv) to reflect the dynamic changes in cerebral propofol uptake.