HIV-1 fusion inhibitors are a new class of anti-HIV compounds, which block the entry of HIV into target cells through preventing the fusion between viral and cell plasma membrane and thus interrupt the initial steps of viral replication. T-20 (enfuvirtide), which has been clinically approved as the first fusion inhibitor of HIV-1 by U.S. FDA in 2003, can suppress replication of HIV variants with multi-drug resistance to reverse transcriptase and protease inhibitors. Peptides and small molecules display potent anti-HIV fusion activities by targeting gp41 thus inhibit its fusogenic function. In recent years, with the development of studies on the molecular mechanism of HIV membrane fusion process and the function of gp41, many new fusion inhibitors are found and some have been in advanced clinical trials. This review discusses recent progress in the development of HIV-1 fusion inhibitors targeting the gp41.

In recent years, the importance of tyrosine phosphorylation in the nervous system of mammalian is gaining recognition. Tyros ine protein kinases exert important modulatory effect on the proliferation, diff erentiation, migration and metabolism-related singal transduction pathways in c ells. In this paper we reviewed the signal cascade process of three different ty rosine protein kinase families, including Trk, Src and Eph tyrosine protein kina se families. Furthermore, we discussed important role and possible mechanisms of these tyrosine protein kinases on the neuron synapse plasticity and learning an d memory process.

AIM: To evaluate the cytotoxicity of a novel anticholinergic drug penehyclidine hydrochloride (PHC) and its four optical isomers R-1, R-2, S-1, and S-2. METHODS: Two in vitro assays, MTT assay and neutral red uptake assay, were used to evaluate the cytotoxicity following PHC and its isomers exposure to HepG2 cells at different concentrations. RESULTS: PHC and its isomers induced decreases of viability of HepG2 cells in a concentration-dependent manner. Comparison of the cytotoxicity of the five anticholinergic agents with 50% inhibitory concentration (IC50) values indicated that the order of potency was PHC>R-2>R-1>S-2>S-1 for MTT assay, and R-2>PHC≈R-1>S-2>S-1 for neutral red uptake assay. CONCLUSION: With respect to the cytotoxicity of the four isomers on HepG2 cells, the R configuration was more potent than the S configuration, and R-2 was the most potent isomer whereas S-1 was the least potent isomer among the four optical isomers.

Objective To evaluate the effect of hydrogen on the expression of nuclear factor E2?related factor 2 ( Nrf2 ) during endotoxin?induced oxidative injury to macrophages. Methods Normally cultured Raw264.7 cells were divided into 4 groups ( n=36 each) using a random number table: control group (group C), hydrogen?rich saline group ( group H), endotoxin group ( group E) and endotoxin plus hydrogen?rich saline group (group EH). In E and EH groups, endotoxin was added with the final concentration of 1 μg∕ml. Hydrogen?rich saline ( hydrogen concentration 0. 06 mmol∕L) was added in H and EH groups. All the cells were incubated for 48 h. At 6, 24 and 48 h of incubation, cells were collect?ed to detect the activity of reactive oxygen species ( ROS) , and cells were collected and proteins extracted for determination of superoxide dismutase ( SOD) and catalase ( CAT) activities and Nrf2 expression by Western blot. Results Compared with group C, the ROS activity was significantly increased, the levels of SOD and CAT were significantly decreased, and the expression of Nrf2 was significantly up?regulated in E and EH groups (P<0.05), and no significant change was found in the parameters mentioned above in group H (P>0.05). Compared with group E, the ROS activity was significantly decreased, the levels of SOD and CAT were significantly increased, and the expression of Nrf2 was significantly up?regulated in group EH (P<0.05). Conclusion Hydrogen can attenuate endotoxin?induced oxidative injury to macro?phages, and the mechanism may be related to up?regulated expression of Nrf2.

ABSTRACT:Objective To study the effects of propofol on the metastasis of tumor cells related PI3K/Akt signaling pathway.Methods The breast cancer model was established by transplanting human derived breast cancer cell lines into immunodeficient mice with naked gene.The mice,inoculated successfully,were randomly divided into 4 groups:control group (C group,n =6),propofol group (P group,n =6),propofol+PI3K inhibitor (BYL71 9)group (P+B group,n =6),and PI3K inhibitor group (BYL71 9)(B group,n =6).The expressions of PI3K,p-Akt and Akt were examined by Western blot at week 4 after administration;the gene levels of PI3KR1, Akt1 and Akt2 were detected by RT-PCR at week 4 after administration;the number of metastatic lung nodules from both lungs was also observed at week 4 after administration.Results Compared with those in C group,the expressions of PI3K and p-Akt were significantly higher in P group (P <0.05),the level of PI3KR1 mRNA but not Akt1 and Akt2 mRNA was significantly increased(P < 0.05 ),and metastatic lung nodules significantly decreased (P <0.05).In B group,the expressions of PI3K and p-Akt were significantly decreased (P <0.05 ),the levels of PI3KR1,Akt1 and Akt2 mRNA were not significantly increased (P >0.05),but metastatic lung nodules significantly increased (P < 0.05 ).Compared with those in B group,in P+ B group the expressions of PI3K and p-Akt were markedly higher (P <0.05),the level of PI3KR1 mRNA but not Akt1 and Akt2 mRNA was significantly increased (P <0.05),and metastatic lung nodules significantly decreased (P <0.05).Conclusion Propofol can inhibit the metastasis of tumor cells through the upregulated and activated PI3K/Akt signaling pathway.

Objective To evaluate the value of central venous pressure (CVP),central venous oxygen saturation (ScvO2) and venous-arterial carbon dioxide partial pressure gradient (Pv-aCO2) in the diagnosis of septic shock-induced left ventricular dysfunction.Methods Consecutive patients with septic shock were enrolled from September 2013 to September 2014 in ICU at Peking Union Medical College Hospital.The data of CVP,Pv-aCO2 and ScvO2 were recorded and analyzed.According to the left ventricular ejection fraction (LVEF) tested by bedside echocardiography,the patients were divided into two groups:new onset of left ventricular dysfunction (LVEF ＜ 50％) group and non-left ventricular dysfunction (LVEF ≥ 50％) group.A diagnostic model was created by logistic regression.The diagnostic performance and cut-off values of CVP,Pv-aCO2,ScvO2 were determined using receiver operating characteristic (ROC) curve analysis.Results Among 93 patients enrolled,39 were diagnosed with left ventricular dysfunction.In the new onset group,CVP [(12.5±3.9) mmHg(1 mmHg=0.133 kPa) vs (10.4±2.5)mmHg;P=0.005] and Pv-aCO2 [(7.5 ± 3.9) mmHg vs (4.5 ± 2.6) mmHg;P ＜ 0.001] were significantly higher than those in the non-left ventricular dysfunction group,while ScvO2 [(62.4 ± 10.5) ％ vs (72.6 ± 9.0) ％;P ＜ 0.001] was significantly lower.As far as the diagnostic value of these three parameters were concerned for left ventricular dysfunction,the sensitivity of CVP ≥ 12.5 mmHg was 46.2％,specificity 81.5％ with an area under ROC curve (AUCROC) 0.674;the sensitivity of Pv-aCO2 ≥ 5.0 mmHg 76.9％,specificity 37.0％,AUCROC 0.738;the sensitivity of ScvO2 ≤65.8％ 64.1％,specificity 78.6％,AUCROC 0.775.When the cut-off values were determined by ROC,the diagnostic performance of the model was ≥0.377 with the sensitivity,specificity and AUCROC 82.1％,79.6％ and 0.835,respectively.Conclusion In patients with septic shock,the logistic regression model established by CVP,Pv-aCO2 and ScvO2 contributes to the diagnosis of septic shock-induced left ventricular dysfunction.

Objective:To evaluate the effects of vitamin K 2 on sevoflurane-induced cognitive decline in aged mice. Methods:A total of 72 SPF healthy female C57BL/6J mice, aged 12 months, weighing 20-25 g, were divided into 4 groups ( n=18 each) using a random number table method: control+ corn oil group (group Con+ Oil), sevoflurane+ corn oil group (group Sevo+ Oil), control+ vitamin K 2 group (group Con+ K 2) and sevoflurane+ vitamin K 2 group (group Sevo+ K 2). The mice in Sevo+ Oil and Sevo+ K 2 groups were anesthetized with 2.5% sevoflurane+ 33% oxygen for 2 h. The mice in Con+ Oil and Con+ K 2 groups were treated with 33% oxygen only.The animals in Con+ Oil and Sevo+ Oil groups were intraperitoneally injected with corn oil 100 μl at 30 min before oxygen or sevoflurane inhalation.Vitamin K 2 (dissolved in corn oil, concentration 1 mg/ml) 100 mg/kg was injected intraperitoneally in Con+ K 2 and Sevo+ K 2 groups.At 24 h after sevoflurane inhalation, 8 mice from each group were randomly selected and sacrificed, and the hippocampal tissues were removed for determination of activity of ATPase, contents of interleukin-1beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNF-α) (by enzyme-linked immunosorbent assay) and the expression of AT8 and PHF1 (by Western blot). The remaining 10 mice in each group received standardized feeding, and the cognitive function was assessed using Y-maze at 1, 3, 5, 7 and 14 days after sevoflurane inhalation. Results:Compared with group Con+ Oil, the contents of IL-1β, IL-6 and TNF-α were significantly increased, expression of AT8 and PHF1 were up-regulated, activity of ATPase was decreased, and spontaneous alternation percentage was decreased at 1, 3, 5, 7 and 14 days after sevoflurane inhalation in group Sevo+ Oil ( P<0.05). Compared with group Sevo+ Oil, the contents of IL-1β, IL-6 and TNF-α were significantly decreased, expression of AT8 and PHF1 were down-regulated, activity of ATPase was increased, and spontaneous alternation percentage was increased at 1, 3, 5, 7 and 14 days in group Sevo+ K 2 ( P<0.05). There was no significant difference in the above indicators between group Con+ K 2 and group Sevo+ K 2 ( P>0.05). Conclusion:Vitamin K 2 can improve sevoflurane-induced cognitive decline in aged mice, the mechanism is related to increasing activity of ATPase and inhibiting the up-regulation of AT8 and PHF1 expression in hippocampus.

The fifth muscarinic receptor (M5), the last one of the mus ca rinic receptor family to be cloned, has the same basic formation characterizatio n as G-protein coupled receptor family. M5 transduces signals by coupling with G-proteins, which then modulate the activities of a number of effector enzymes and ion channels. As M5 also plays a variety of prominent physiological roles by regulating central transmitters NO and DA, it has been considered as a novel dr ug therapy target for drug addiction, dysfunction of dopamine-ergic nervous sys tem, Alzheimers disease and cerebral ischemia.

Objective To find the efficient modification groups of anti-proteinase hydrolyzation in polypeptide by investigat-ing and comparing the relation between the functional groups and their ability to inhibit proteinase hydrolyzation. Methods Reverse phase-high performance liquid chromatography(RP-HPLC)method was developed to investigate in vitro metabolisms of new drug LXT101 and its structural modified analogs LZN series and LMP series in pancreatin system. All the separations of peptide drugs and their digested fragments were monitored at 225 nm. Results The good linear range was 4.0-400 μg/ml(r>0.9990)for new drug LXT101 and its structural modified analogs,i.e.,LZN series and LMP series. The recoveries of all peptide drugs ranged from 95.0%to 98.7%in pancreatin systems. The relative standard derivations(RSD)of intra-day and inter-day were less than 1.5%and 2.5%,re-spectively. The revealed order of digested half-life of the peptide drugs was LZN series>LMP series>LXT101. Conclusion The study of different sites and different functional groups on the lifetime indicates that the half-lives of peptides are prolonged by introducing the functional groups in the suitable sites of peptide,which feature as proteinase inhibitors,such as carbamoyl(Cbm),acetyl(Ac),para-amino-phenylalanine(Aph)or para-uramido-phenylalanine(Uph),which work as either proton donor or acceptor. Our results can pro-vide some useful and valuable information on structural design of peptide drug with long lifetime and high activity.

AIM To evaluate the antagonizing activity of iQWcF, a modified tripeptide, to endothelin receptors. METHORDS ①Vasoconstriction experiments with aorta strips of rats. ② In vivo experiments:male normotensive Wistar rats were anesthetized with pentobarbital Na (50 mg?kg -1 ),and catheterized into the carotic artery for measurement of blood pressure, and into the femoral vein for administration of iQWcF (30 mg?kg -1 ) and ET 1(0 9 nmol?kg -1 ). The test compound was given intravenously 5 min before the bolus injection of ET 1. Control animals received saline on the same time schedule.The blood pressure was recorded at different time interval after injecting ET 1. RESULTS ①iQWcF prohibited the vascontriction of aorta induced by ET 1 in a concentration dependent fashion.②The compound(30 mg?kg -1 .iv) markedly antagonized ET 1 induced the long lasting pressor phase mediated by ET A without affecting early transient depressor phase by ET B. CONCLUSION iQWcF is one of ET A selective antagonists.