Journal of Chinese Pharmaceutical Sciences

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2014, 23(9): 591-594.

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A mechanism study on the tamoxifen-mediated cellular internalization of liposomes

Xiaoyou Wang, Xianhui Chen, Xiucong Yang, Bing He, Wenbing Dai, Xueqing Wang, Jiancheng Wang, Xuan Zhang, Qiang Zhang

2014, 23(9): 595-600. DOI: 10.5246/jcps.2014.09.076

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It was reported previously that tamoxifen (TAM) could increase the intracellular accumulation of drug-loaded liposomes, but the exact mechanism is unknown although it was supposed that TAM might enhance the cell uptake by inhibiting the drug efflux caused by P-glycoprotein (P-gp). To identify the mechanism of increased cellular uptake of liposomesinduced by tamoxifen, PEGgylated liposomes (SSL) ofP-gp-substrate doxorubicin (DOX) or non-P-gp-substrate coumarin (Cou) were prepared with or without TAM. The cell uptake of these liposome systems was investigated in cell lines with different P-gp-expressing levels and the interaction of TAM with lipid membrane was also studied. As the results, the co-encapsulation of TAM with DOX-SSL increased the intracellular uptake in all three tumor cell lines. In P-gp-highly-expressing MCF-7/Adr cells, the effect of TAM was the strongest and in negative control Hela cells, the impact weakened but still significant. The improvement was also observed in the cellular uptake of Cou-SSL. Surface plasmon resonance (SPR) studies demonstrated that TAM-SSL exhibited a much stronger affinity with model biomembrane compared with empty SSL, and further test with isothermal titration calorimetry (ITC) showed that free TAM had an obvious interaction with lipid membrane. In conclusion, TAM could increase the affinity of liposomes with biomembrane and enhance the intracellular accumulation of liposomes via both TAM-mediated P-gp inhibition and the increased interaction between hydrophobic TAM molecules and lipid membrane.

Effects of compound YSY-01A, a novel proteasome inhibitor, on MGC-803 cells and its related mechanism

Yixin Chen, Xia Yuan, Zemei Ge, Fuxiang Ran, Jun Wu, Runtao Li, Jingrong Cui

2014, 23(9): 601-609. DOI: 10.5246/jcps.2014.09.077

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As a novel proteasome inhibitor, remarkable proliferation inhibitory effect of compound YSY-01A was shownon tumor cells in previous studies. However, few studies has reported its effect on gastric cancer and related mechanism. We evaluated the anti-proliferative effect of compound YSY-01A using MGC-803 cells and its anti-tumor effect using xenograft nu-BALB/c mouse model. Cell proliferation inhibition was assessed by SRB assay. Related protein expression levels were determined by Western blot assay. We observed that the compound YSY-01A had a significant proliferation inhibitory effect on MGC-803 cells in vitro. Experiment in vivo showed that the compound YSY-01A had a remarkable growth inhibitory effect on MGC-803 cells xenograft tumor when it was used either alone or in combination with the conventional chemotherapeutic agent5-fluorouracil (5-FU). Furthermore, YSY-01A and 5-FU had a synergistic effect on xenograft tumor. Results of molecular experiment showed that the compound YSY-01A had a remarkable inhibitory effect on TNF-α and IFN induced NF-κB nuclear translocation. At the same time, the compound YSY-01A could reduce the expression of IKK-β, IL-1β and iNOS, while it significantly enhanced the expression of COX-2 in MGC-803 cells. Taken together, compound YSY-01A had an impressive tumor inhibitory effect, and it worked in NF-κB-related pathway, suggesting that the compound YSY-01A was an effective therapeutic drug for patients with gastric cancer. Higher tumor cell growth inhibition after the treatment in a combination with 5-FU indicated that combining YSY-01A with 5-FU might be more effective for displaying tumor cell growth inhibitory effects on gastric cancer cells.

IC5, a dithiocarbamate derivative, inhibits colon cancer cell proliferation in vitro and colitis-associated colorectal carcinogenesis in vivo

Wanwan Ma, Shunan Tang, Mingnan Cao, Zemei Ge, Runtao Li, Siwang Yu

2014, 23(9): 610-616. DOI: 10.5246/jcps.2014.09.078

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Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths, and inflammatory bowel diseases and dysregulated cell proliferation play important roles in colorectal carcinogenesis. Therefore, inhibition of inflammatory signalingand cell proliferation is used as a major strategy for chemoprevention of CRC. In the present study, it was found that IC5, a dithiocarbamate derivative, could inhibit the proliferation of LoVo human colon cancer cells in a concentration-dependent manner, with an IC₅₀ of 22μM. The anti-proliferation effect of IC5 was accompanied by a significant cell cycle arrest in G2/M phase. Further study revealed that IC5 significantly inhibited NF-κB signaling in LoVo cells, suggesting that IC5 could inhibitinflammatory responses. We then evaluated the in vivo efficacy of IC5 to inhibit colitis-associated colorectal carcinogenesis using an azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model. AOM/DSS treatment resulted in a CRC incidence of 58.3%, while the incidences were decreased to 37.5% and 25% in mice orally administered with 50 and 100 mg/kg IC5, respectively. In addition, IC5 also reduced the plasma levels of alanine aminotransferase and asparatate aminotransferase. Taken together, these results suggested that IC5 could prevent colitis-associated colorectal carcinogenesis, and more attention should be paid to it as a cancer chemopreventive agent in further investigation.

Comparison of berberine and its five analogues on cell viability and COX-2 expression during glucose-oxygen deprivation and reperfusion in PC12 cells

Yunong Pang, Jun Hu, Yushuang Chai, Hao Wu, Yugang Wang, Fan Lei, Dongming Xing, Lijun Du

2014, 23(9): 617-625. DOI: 10.5246/jcps.2014.09.079

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Berberine, an isoquinoline alkaloid component of Rhizoma Coptidishas been demonstrated to be the key active ingredient involved in its protective effect against cerebral ischemia-reperfusion. However, the comparison among the analogues to the protective effect against oxygen and glucose deprivation/reoxygenation (OGD-R) was mediated by inhibition of cyclooxygenase-2 (COX-2) has never been reported. The aim of this study is to investigate the protective effect of berberine and its five analogues against OGD-R in PC12 cells, as well as to determine whether the protective effect was regulated through COX-2. An established in vitro OGD-R model of PC12 cells by oxygen glucose deprivation of 4 h and reperfusion of 24 h was used in our study. After cells were treated with berberine or its five analogues, we examined the cell viability assay by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cells were also collected to determine the levels of mRNA and protein of COX-2 by real time PCR and Western blot. We found that berberine and its analogues improved the viability of PC12 cells against OGD-R. Whereas berberine and berberrubine presented stronger activity with the most effective dose of 0.31 μg/mL and the minimum effective doses of 0.02 and 0.04 μg/mL. Palmatine possessed potentially weaker protective effect. The mRNA level of COX-2 in cells treated with berberine, coptisine and epiberberine was decreased significantly. The protein level of COX-2 was significantly down-regulated in cells treated with berberine. Studies suggested the important role of methylenedioxy groups (R₂ and R₃) of berberine analogues in COX-2 inhibitory effect, and methylenedioxy groups (R₂, R₃, R₉ and R₁₀) in berberine analogues in binding affinity with COX-2. Substituted hydroxyl group at R₉ did not affect the activity of berberine. In summary, our study illustrated the protective effects of berberine and its analogues in PC12 cells against OGD-R and to elucidate the structure-activity relationships. Docking analysis indicates that methylenedioxys at R₂ and R₃is involved in the effect. More studies in other cells are needed to confirm our results.

Design, synthesis and biological evaluation of sulfonamide flavone derivatives as potential 20S proteasome inhibitors

Guanyu Yang, Qi Sun, Chao Wang, Lei Liang, Fengrong Xu, Yan Niu, Ping Xu

2014, 23(9): 626-630. DOI: 10.5246/jcps.2014.09.080

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A new series of sulfonamide flavone derivatives are designed as non-covalent inhibitors of proteasome assisted with computer-aided drug design (CADD). The desired compounds were synthesized successfully and the biological evaluation was subsequently accomplished. The results showed negligible improvement from our lead compound (IC₅₀ for β5 subunit was 14.0 μM). Thus, these flavone derivatives might be improved as potential 20S proteasome inhibitors.

Investigations of the fragmentation behavior of 11 isoflavones with ESI-IT-TOF-MSn

Yazhou Zhang, Feng Xu, Jianye Zhang, Tao Yi, Yina Tang, Jun Xu, Wanling Peng, Hubiao Chen

2014, 23(9): 631-641. DOI: 10.5246/jcps.2014.09.081

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The fragmentation behavior of isoflavones was studied using electrospray ionization-ion trap-time of flight mass spectrometry (ESI-IT-TOF-MSⁿ). It was found that the isoflavone glycoside bond was easily broken. The fragmentation occurred mostly on the C-ring, and the fragment ions of A^1,3+ produced bythe RDA cracking will predict the hydroxylation replacement on A-ring or B-ring. In addition, four carbonyl groups on the C-ring were fragmented through neutral loss of 28 (-CO). A and B-rings primarily lose substituents which including a neutral losses of 32 (-CH₃OH), 16 (-CH₄), or 16 (-O), and 18 (-H₂O). A-ring in the presence of adjacent hydroxylation, also easily made to be a neutral losses of 28 (-CO) or 18 (-H₂O). It is likewise common to see methoxy replaced with a neutral losses of 16 (-CH₄) or 32 (-CH₃OH) in B-ring, also the hydroxylation on benzene ring can occasionally results with the neutral loss of 28 (-CO).

Simultaneous determination of seven caffeoylquinic acids and three flavonoids in Pyrrosia petiolosa (Christ) Ching by RP-UFLC-DAD

Biao Ren, Hongyang Sun, Hong Wang

2014, 23(9): 642-648. DOI: 10.5246/jcps.2014.09.082

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An efficient, sensitive, accurate and rapid analytical ultra-fast liquid chromatography (UFLC) method for quality evaluations of Pyrrosia petiolosa (Christ) Ching from 20 regions of China was developed in this study. Ten marker compounds were simultaneously quantified, including 5-caffeoylquinic acid (5-CQA), 3-caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA), 1-caffeoylquinic acid (1-CQA), 3,5-dicaffeoylquinic acid (3,5-diCQA), 4,5-dicaffeoylquinic acid (4,5-diCQA), 3,4-dicaffeoylquinic acid (3,4-diCQA), astragalin, kaempferol-3,7-di-O-glucoside and (±)eriodictyol-7-O-β-D-glucuronide. Chromatographywas performed on a Kromasil 100-2.5C₁₈ (100 mm×2.1 mm, 2.5 μm) C₁₈ column with gradient elution. The mobile phases consisted of 0.1% formic acid/water (A) and 0.1% formic acid/methanol (B). The detection wavelength was set at 326 nm and the flow rate was 0.4 mL/min. Ten components were separated well with good linearity (r²>0.9998), precision, repeatability, stability. The recovery was in the range of 99.08%-102.77%. The results showed that the content determination using RP-UFLC-DAD fingerprint technique provides an efficient, sensitive, accurate and rapid analytical method for quality assessment of P. petiolosa (Christ)Ching. Cluster analysis and principal components analysis were successfully applied to analyze 20 samples, the results revealed that the method was efficient and authentic to distinguish producing areas and the source of P. petiolosa (Christ) Ching.

A validated HPLC method for the determination of cefazolin sodium level in rabbit synovial fluid

Jing Li, Weiwei Lin, Dai Li, Yingfang Ao, Haisong Yang, Xiaomei Ling

2014, 23(9): 649-653. DOI: 10.5246/jcps.2014.09.083

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A sensitive and specific high performance liquid chromatography method was established for measuring cefazolin sodium level in rabbit synovial fluid.Acetonitrile was used to precipitate proteins and antipyrine was used as internal standard. Samples were analyzed on a Dionex Ultimate U3000 HPLC system equipped with Phenomenex Luna C₁₈ column (150 mm×4.60 mm, 5 μm, 100 A). The mobile phase consisted of acetonitrile and 0.1% formic acid in water. The flow rate was 1 mL/min. The detectionwavelength was set at 272 nm. The column temperature was maintained at 25 ºC.The calibration curve was linear in the range of 1.0-100.0 μg/mL(r² = 0.9999). The limit of detection (LOD, S/N = 3) was 0.07 μg/mL. The limit of quantitation (LOD, S/N = 10) was 0.22 μg/mL. The recovery of cefazolin sodium (low, medium and high) was 124.6%, 117.8%, and 100.6% (RSD% = 1.9%, 4.0%, 1.1%, n = 5), respectively. The intra-day and inter-day precision values were in the range of 0.5%-2.7%.The method was simple, sensitive and reliable. It can be used for the quantitative determination of cefazolin sodium in rabbit synovial fluid.

Parecoxib pretreatment effectively relieved pain after ambulatory gynecological surgery: a randomized controlled trial

Chunjing Li, Xiaolan Yu, Dongxin Wang, Yuan Qu, Jia Liu, Dongliang Mu

2014, 23(9): 654-659. DOI: 10.5246/jcps.2014.09.084

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Although parecoxib plays an important role in pain management after ambulatory gynecological surgery, its exact effect remains to be fully elucidated. In the present study, we aimed to investigate the effect of parecoxib pretreatment in reducing pain intensity after ambulatory gynecological surgery. A total of 200 female patients who were scheduled to selective ambulatory gynecological surgery were randomly divided into two groups. Patients in the control group received normal saline as placebo, whereas 40 mg parecoxib was given to the patients in the parecoxib group 30 min prior to anesthesia induction. Visual analoguescore (0 mm = no pain, and 100 mm = most severe pain) was used to evaluate postoperative pain severity. Pain scores were significantly lower in the parecoxib group than those in the control group after surgery. Compared with the control group, the incidence of intraoperative hypoxemia was significantly lower, and the recovery time from end of anesthesia to eye opening and birth date recollection were significantly shorter in the parecoxib group. Patients in the parecoxib group also had significantly improved overall satisfaction than those in the control group.

Introduction of Professor Binghe Wang

Journal of Chinese Pharmaceutical Sciences

2014, 23(9): 660-661.

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