Cs2CO3 catalyzed direct aza-Michael addition of azoles to α,ß-unsaturated malonates.

A highly efficient method for the synthesis of azole derivatives via a direct aza-Michael addition of azoles to α,ß-unsaturated malonates using Cs2CO3 as a catalyst, has been successfully developed. A series of azole derivatives have been obtained in up to 94% yield and the reaction could be amplified to gram scale in excellent yield in the presence of 10 mol% of Cs2CO3.

[Effect of lupeol on invasion and metastasis of human hepatoma HepG2 and SK-HEP-1 cells and its mechanism].

Epithelial-mesenchymal transformation(EMT) exists in embryonic development and is closely related to cell migration and invasion. The increased EMT level in tumors showed that E-cadherin was replaced by N-cadherin, and the expression of interstitial markers such as α-SMA and vimentin was up-regulated. It has been reported that lupeol can reduce the expression of matrix metalloproteinase-2(MMP-2), matrix metalloproteinase-9(MMP-9) and N-cadherin to inhibit the metastasis of osteoma cells. However lupeol has been less studied in liver cancer. Therefore, this paper investigated the effect of lupanol on invasion and metastasis of human hepatoma cell line HepG2 and SK-HEP-1 and its possible mechanism. MTT assay and Annexin V/PI double staining were used to investigate the effect of lupeol on activity and apoptosis of HepG2 cells and SK-HEP-1 cells. Moreover, the effect of lupeol on the invasion of HepG2 cells and SK-HEP-1 cells were evaluated by Transwell assay. The expressions of E-cadherin, N-cadherin, α-SMA, vimentin and MMP-9 were measured by Western blot. The model of subcutaneous transplantation of nude mice and the lung metastasis model of H22 hepatocellular carcinoma cells were established to evaluate the efficacy of lupeol in vivo on tumor growth and lung metastasis by HE staining combined with immunohistochemical assay. The results showed that lupeol inhibited the activity and invasion of HepG2 cells and SK-HEP-1 cells in a dose-dependent manner and induced apoptosis. Western blot showed that the expression of E-cadherin, a landmark protein for EMT, was induced by lupeol, and the expressions of N-cadherin, α-SMA, vimentin and MMP-9 were decreased. In vivo experiments showed that lupeol inhibited tumor growth in mice bearing xenograft. In addition, immunohistochemical experiments confirmed that lupeol could up-regulate the expression of E-cadherin in tumor tissues of nude mice, reduce the expression of N-cadherin, and inhibit the metastasis of liver cancer H22 cells in the lungs of mice. The above results indicated that the mechanism of lupeol inhibiting the invasion and metastasis of HCC cells may be related to the regulation of EMT process.

[Wrist-ankle needle combined with opioid drugs on refractory cancer pain: a randomized controlled trial].

OBJECTIVE: To compare the clinical effect of wrist-ankle needle combined with opioid drugs and opioid drugs alone in treating refractory cancer pain. METHODS: Sixty patients were randomly divided into an observation group and a control group, 30 cases in each one. The opioid drugs in accordance with the three-step analgesic principle and other auxiliary drugs were treated in the control group. On the basis of the treatment in the control group, wrist-ankle needle was added in the observation group, and acupoints were selected according to the pain site and the primary focus, the treatment was given once a day for 10 days. The visual analogue scale (VAS) score, the times of pain outbreaks and the incidence of adverse reactions were compared at the 2nd, 4th, 6th, 8th and 10th days of treatment and the 3rd and 7th days after treatment. The therapeutic effect in the two groups were compared after treatment. RESULTS: Compared with the control group, the VAS scores in the observation group were significantly reduced from the 2nd day of wrist-ankle needle treatment, and continued to the 3rd day after the end of the treatment (P<0.05), but there was no statistically significant difference between the two groups on the 7th day after the end of the treatment (P>0.05); compared with the control group, the times of pain outbreaks in the observation group decreased from the 2nd day to the 10th day of treatment (all P<0.05); the incidence of nausea, vomiting and constipation in the observation group was significantly reduced compared with the control group (P<0.05); the total effective rate in the observation group was 86.7% (26/30), which was higher than 76.7% (23/30) in the control group (P<0.05). CONCLUSION: Wrist-ankle needle combined with opioid drugs can increase the efficacy of the refractory cancer pain and reduce the adverse reactions of opioid drugs.

ß-elemene regulates endoplasmic reticulum stress to induce the apoptosis of NSCLC cells through PERK/IRE1α/ATF6 pathway.

Endoplasmic reticulum stress (ERs) has been regarded as an important cause for the pathogenesis of non-small-cell lung cancer (NSCLC). ß-elemene is an active component in the essential oil extracted from a medicinal herb, Curcuma wenyujin, and has been reported to be effective against non-small-cell lung cancer (NSCLC). However, the potential effect and underlying mechanisms of ß-elemene on regulating ERs to inhibit NSCLC are still unclear. In the present study, A549 cells and Lewis tumor-bearing C57BL/6J mice were established to evaluate this effect. Visualsonics Vevo 2100 Small Animal Dedicated High-frequency Color Ultrasound was performed to observe tumor volume in vivo. 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) was used to evaluate cell vitality of A549 cells. Furthermore, western blotting (WB), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (q-PCR) were applied to detect the ERs-related proteins. Flow cytometry was also applied to detect cell apoptosis and assay kit for reactive oxygen species (ROS) generation. Our results showed that ß-elemene inhibited lung cancer tumor growth and cell vitality in a dose- and time-dependent manner. Not only that, ß-elemene could up-regulate ERs-related proteins like PERK, IRE1α, ATF6, ATF4, CHOP and down-regulate the Bcl-2 expression. More importantly, ERs inhibitor 4-PBA, IRE1α inhibitor STF-083010, ATF6 inhibitor Anti-ATF6 and PERK inhibitor GSK2656157 can all reduce the amplitude of protein expression changes and apoptosis rates, then weaken the anti-tumor effect of ß-elemene. Therefore, the present in vivo and in vitro study revealed that the anti-NSCLC effect of ß-elemene is closely related to the activation of ERs through PERK/IRE1α/ATF6 pathway, and this might be beneficial for clinical therapy of NSCLC.

Synergistic effects of Endostar combined with ß-elemene on malignant ascites in a mouse model.

To explore an effective combination therapy for malignant ascites, the therapeutic value of the combination of Endostar, a modified recombinant human endostatin, and ß-elemene, an active component of a traditional Chinese herb, in an H22 mouse malignant ascites model was investigated. The optimal dose combination of Endostar and ß-elemene was determined by evaluating the inhibition of ascites volume and increase in the survival rate of the mice. Other therapeutic effects and the underlying mechanisms were investigated under the optimal dose combination (8 mg/kg Endostar plus 100 mg/kg ß-elemene). The mice were randomly divided into four treatment groups and received intraperitoneal injection once a day for eight days: control (0.9% normal saline), Endostar (8 mg/kg), ß-elemene (100 mg/kg) or optimal dose combination (8 mg/kg Endostar plus 100 mg/kg ß-elemene), respectively. The results of this study revealed that the combination therapy had significant synergistic effects on the inhibition of ascites formation and a deceased number of tumor cells and protein levels in ascites compared with the results of treatment with a single agent. A decreased peritoneal microvascular permeability and reduction in VEGF, MMP-2 and hypoxia inducible factor 1α (HIF1α) was noted in the combination group, when compared with single agent treatment. These studies found that in the ascitic tumor cells, the protein levels of VEGF and MMP-2, as well as levels of VEGF mRNA, were significantly inhibited by the combination therapy. The potentiating effects of the combination of Endostar with ß-elemene suggest that this novel therapy may yield an effective therapy for the treatment of malignant ascites.