Table of Content

01 September 2016, Volume 25 Issue 8

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Cancer prevention by traditional Chinese medicine and plant phytochemicals column

Nrf2-mediated antioxidant and detoxifying enzyme induction by a combination of curcumin and sulforaphane

Francisco Fuentes, Yury Gomez, Ximena Paredes-Gonzalez, Avantika Barve, Sujit Nair, Siwang Yu, Constance Lay Lay Saw, Ah-Ng Tony Kong

2016, 25(8):  559-569.  DOI: 10.5246/jcps.2016.08.062

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The dietary phytochemicals curcumin (CUR) and sulforaphane (SFN) have shown remarkable cancer chemopreventive effects in many model systems. This study was designed to investigate the induction of Nrf2-mediated antioxidant enzymes by combining doses of CUR and SFN and the effect of their combination on the Nrf2-ARE (antioxidant response element) response in HepG2-C8 cells. We hypothesized that the combination of the polyphenol CUR and the isothiocyanate SFN could enhance the induction of AREs and Nrf2-target enzymes. HepG2-C8 cells were treated with a combination of low doses of CUR, SFN or both. The induction of Nrf2-mediated antioxidant and phase II detoxifying enzymes–heme oxygenase-1 (HO-1) and UDP-glucuronosyltransferase-1A (UGT1A)–was measured by real-time RT-PCR and western blotting. ARE-luciferase activity was also quantified. Low doses of CUR (10 µM) and SFN (12.5 µM) significantly induced the expression of HO-1 and UGT1A1 proteins. Through the use of chemical inhibitors of mRNA and protein synthesis, the combination of CUR and SFN was shown to affect the transcriptional regulation of both HO-1 and UGT1A1. Additionally, the combination of CUR and SFN synergisticallyinduced the expression of Nrf2- and ARE-luciferase activity in HepG2-C8 cells. Thus, CUR and SFN at low concentrations augment therapeutic effects in HepG2-C8 cells. The enhanced ARE-luciferase activity of combined CUR and SFN treatment could partly explain the significant induction of the Nrf2-target enzymes HO-1 and UGT1A1. Taken together, our results suggest that combining low doses of CUR and SNF could be a promising strategy for cancer chemoprevention in humans.



Original articles

The preparation and characteristics of sterically stabilized liposomes containing paclitaxel and super-paramagnetic iron oxide nanoparticles

Wei Ren, Shuang Zhang, Ting Zhong, Dan Huang, Xin Yao, Yang Guo, Xiaochuan Duan, Yifan Yin, Shushi Zhang, Xuan Zhang

2016, 25(8):  570-575.  DOI: 10.5246/jcps.2016.08.063

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Theranostics, combining therapy and diagnosis, is an appealing approach for chemotherapy. In the present study, we selected paclitaxel (PTX) as a therapeutic agent, super-paramagnetic iron oxide nanoparticles (SPIO) as a diagnostic agent and sterically stabilized liposomes as a carrier to prepare theranostic liposomes. The SPIO were prepared and characterized. Moreover, the sterically stabilized liposomes containing PTX and SPIO (PTX/SPIO-SSL) were prepared. The characteristics of PTX/SPIO-SSL were investigated. The results indicated that prepared SPIO exhibited super-paramagnetic and could be used for MRI. The average particle size of PTX/SPIO-SSL was about 170 nm, with a polydispersity index (PDI) less than 0.3. The zeta potential of PTX/SPIO-SSL was negative. The PTX entrapment efficiency of PTX/SPIO-SSL was more than 98%. The TEM results indicated the spherical structure and dense SPIO content in PTX/SPIO-SSL. The in vitro release of PTX from PTX/SPIO-SSL and PTX-SSL was almost identical at both pH 6.8 and 7.4. In conclusion, the PTX/SPIO-SSL were prepared and characterized in vitro. The anti-tumor and diagnostic activity of PTX/SPIO-SSL should be investigated deeply in future study. 



A simple and sensitive gradient elution liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the quantification of doxorubicin in rabbit plasma

Jialin Li, Liying Guo, Xiaoya Qin, Tianyuan Fan

2016, 25(8):  576-581.  DOI: 10.5246/jcps.2016.08.064

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In the present study, we developed and validated a simple and sensitive gradient elution liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of doxorubicin in rabbit plasma. Daunorubicin was used as an internal standard (IS). The doxorubicin and IS were extracted with ethyl acetate from plasma samples. The chromatographic separations were achieved on a C₁₈ column (2.1 mm×50 mm, 2.5 μm) configured with a C₁₈ guard column (2.1 mm×10 mm, 2.5 μm). The mobile phase of 0.1% formic acid-water solution and acetonitrile was delivered using a gradient elution program at a flow rate of 0.4 mL/min. The temperature for column was maintained at 40 ºC. The electrospray ionization (ESI) source was operated in the positive ion mode, and the quantification was conducted using multiple reaction monitoring (MRM) of the transitions m/z 544.07→396.96 and m/z 528.06→321.05 for doxorubicin and IS, respectively. The calibration curve of doxorubicin was linear (r > 0.999) within the range of 2-600 ng/mL. The lower limit of quantification was 2 ng/mL. The relative errors of intra­day and inter-day accuracies ranged from -2.48% to 0.18% and from -3.78% to 1.94%, respectively. The relative standard deviations of intra­day and inter-day precisions were less than 8.65% and 6.41%, respectively. The method exhibited satisfactory results in terms of specificity, sensitivity, matrix effect, recovery and stability. The newly developed LC-MS/MS method was reliable to monitor doxorubicin concentrations in rabbit plasma.



Protective effects of β-dihydroagarofuran-type sesquiterpene against Aβ25-35-induced neuronal apoptosis and oxidative damage

Shasha Ji, Yun Lei, Xiaotian Huang, Zhiqin Gao

2016, 25(8):  582-589.  DOI: 10.5246/jcps.2016.08.065

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Excessive beta-amyloid (Aβ) plays a detrimental role in the pathogenesis of Alzheimer’s disease (AD), which is closely associated with apoptosis and oxidative stress in neurons. Therefore, identification of active small molecules with potent effects on neutralizing Aβ-induced neurotoxicity would be a promising strategy for delaying or preventing AD progression. In the present study, we discovered that pretreatment with CF-1 ((1R,2S,4R,5S,7R,9S,10S)-1,15-diacetoxy-2-benzoyloxy-9-cinnamoyloxy-β-di-hydroagarofuran), a sesquiterpene isolated from the seeds of Celastrus flagellaris, attenuated Aβ_25-35-induced reduction in cell viability in a concentration-dependent manner, as evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Above neuroprotective effect of CF-1 was associated with a significant decrease of apoptotic cells as measured by 4,6-diamidino-2-phenylindole (DAPI) staining, which concurrently happened with marked inhibition in the level of cleaved Caspase-3, an apoptotic executive protein. CF-1 pretreatment also markedly reduced the intracellular accumulation of reactive oxygen species (ROS) following Aβ exposure in SH-SY5Y neuroblastoma cells, but such pretreatment had no notable influence on 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging. In conclusion, we demonstrated that a novel natural product, CF-1, possessed promising effects against Aβ-induced neuronal apoptosis and oxidative stress, which could be a potential drug lead or candidate for the treatment of Aβ-associated neurotoxicity.



TRHH-herb pair prevents IL-1β-induced degeneration of endplate chondrocytes in vitro

Kai Niu, Chenguang Li, Song Yuan, Lei Zhang, Qi Shi, Yongjun Wang, Weichao Zheng

2016, 25(8):  590-597.  DOI: 10.5246/jcps.2016.08.066

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The inflammatory cytokine interleukin-1 beta (IL-1β) plays a key role in the process of intervertebral disc degeneration (IVDD). In the present study, we aimed to evaluate the effect of pharmaco-serum of "Taoren-Honghua-herb pair" on IL-1β-induced chondrocyte degeneration in vitro. Taoren (Semen persicae) and Honghua (Safflower carthamus) were administered to the rats, and the pharmaco-serum was collected and prepared. Chondrocytes of the third passage, isolated from the rat’s vertebral endplates, were treated by standard medium only (Group NC), IL-1β (Group IL) or combination of IL-1β and pharmaco-serum (Group TRHH). Cell proliferation and apoptosis were determined, and the expression of aggrecan, Col2α1, Col10α1, IL-6 and SOX9 at the mRNA level in chondrocytes was quantified by real-time PCR. Immunohistochemistry staining of type II and X collagen and Safranine O staining were also used to evaluate the chondrocytes. Compared with the Group NC, IL-1β treatment inhibited the cell proliferation and induced the cell apoptosis (P<0.05), and the expression of aggrecan, Col2α1 and SOX9 at the mRNA level was down-regulated. In contrast, the expression of Col10α1 and IL-6 was up-regulated after IL-1β treatment (P<0.05). Meanwhile, the immune-staining of type II collagen and Safranine O staining were decreased, while the staining of type X collagen was increased. Compared with the Group IL, cell proliferation was increased, and apoptosis of chondrocytes was decreased when cells were treated with the pharmaco-serum of TRHH-herb pair (P<0.05). The expression of aggrecan, Col2α1 and SOX9 at the mRNA level was up-regulated, while that of Col10α1 and IL-6 was down-regulated (P<0.05). Safranine O staining also showed increased positive staining (P<0.05). Taken together, the treatment of pharmaco-serum of TRHH-herb pair could prevent endplate chondrocyte degeneration induced by IL-1β.



002C-3 protects the brain against ischemia-reperfusion injury by inhibiting autophagy and stimulating CaMKK/CaMKIV/HDAC4 pathways in mice

Jingliang Zhang, Tao Hu, Xiaoyan Liu, Yuanjun Zhu, Xiaoling Chen, Ye Liu, Yinye Wang

2016, 25(8):  598-604.  DOI: 10.5246/jcps.2016.08.067

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This study was designed to investigate the effect of 002C-3, a derivative of magnolol, on transient cerebral middle occlusion (tMCAO) in a mice model and to identify the underlying mechanisms. 002C-3 (100 and 150 μg/kg, i.v. after ending occlusion) significantly reduced neurological deficit scores, infarct volumes, and brain water contents after 1.5 h MCAO and 24 h reperfusion. 002C-3 (75-150 µg/kg) decreased the exudation of Evans blue from brain capillaries. 002C-3 (100 μg/kg) significantly inhibited the activity of MMP-9 and MMP-2 in the injured hemisphere. 002C-3 decreased the expression of autophagy-associated proteins, Beclin-1 and LC3B-II, and increased the level of p62 in injured hemisphere. 002C-3 (100 μg/kg) significantly increased the expression of p-CaMKIV and p-HDAC4 in injured hemisphere. In conclusion, 002C-3 shows a neuroprotective effect on tMCAO injury in mice, and its mechanisms may be associated with alleviation of blood-brain barrier damage caused by the activation of MMPs, inhibition of autophagy, and stimulation of calcium signals related to cell survival. These findings suggest that 002C-3 is a neuroprotective agent that acts on multiple pathways.



Cinnamaldehyde promotes mitochondrial function and reduces Aβ toxicity in neural cells

Lidan Bai, Xue Li, Qing Chang, Rui Wu, Jing Zhang, Xiaoda Yang

2016, 25(8):  605-613.  DOI: 10.5246/jcps.2016.08.068

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Cinnamon and its major active component, cinnamaldehyde, have been shown to be neuroprotective in models of Alzheimer’s disease (AD). To further investigate the mechanism of cinnamaldehyde, we investigated the effects of cinnamaldehyde focusing on mitochondrial function in SH-SY5Y neural cells. The results demonstrated that cinnamaldehyde could enhance neural cell viability with or without increased Aβ levels. Cinnamaldehyde facilitated the maintenance of normal mitochondrial morphology, preserved the mitochondrial membrane potential (ΔΨ_m), and reduced production of reactive oxygen species (ROS). Cinnamaldehyde also decreased the expression of dynamin-related protein 1 (Drp1), a protein critically involved in mitochondrial dynamics. In addition, cinnamaldehyde inhibited Aβ oligomerization, but it had no effects on Tau phosphorylation. In overall, cinnamaldehyde promoted mitochondrial function and inhibited Aβ toxicity, and these two properties may both contribute to the neuroprotective effect. These results suggest that cinnamaldehyde could be a potential nutriceutical in the prevention and even therapeutic treatment of AD as well as other aging-related metabolic syndromes.



Sesquiterpenes from Alisma plantago-aquatica

Jingyi Yu, Jun Wang, Hong Liang, Qingying Zhang, Shizhong Chen, Pengfei Tu

2016, 25(8):  614-620.  DOI: 10.5246/jcps.2016.08.069

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Six sesquiterpenes, including three guaiane type sesquiterpenes (1–3), one oplopanone type sesquiterpene (4), one xanthane type sesquiterpene (5) and one salvialane type sesquiterpene (6), were isolated from Alisma plantago-aquatica for the first time. The structures of these six compounds were elucidated as alismoxide (1), alismol (2), orientalol B (3), oplopanone (4), gibberodione (5), and 7α,10α-epoxy-salvialan-10β-ol (6), respectively, among which 6 was a new natural product. Xanthane type and salvialane type sesquiterpenes were obtained from the genus Alisma for the first time. In addition, a plausible biosynthetic pathway for all isolates was discussed.



Clinical pharmacy column

A systematic review of magnesium sulfate for acute asthma in adults

Zhuo Ma, Xiangli Cui, Lihong Liu

2016, 25(8):  621-631.  DOI: 10.5246/jcps.2016.08.070

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In order to provide evidence for making clinical decision, the role of intravenous and nebulized MgSO₄ in treatment of adult’s acute asthma was systematically estimated in the present study. Pubmed, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, WanFang) were systematically searched up to January 2016. Randomized controlled trails (RCTs) that compared the clinical outcomes of MgSO₄ groups and placebo groups were included. The primary outcome was hospital admission. Secondary outcomes included pulmonary function, symptom scores, vital signs and adverse events. The methodological quality of the included studies was evaluated, and the forest plots with meta-analysis were drawn by RevMan 5.2. A total of 24 RCTs derived from 2931 patients were included. Both intravenous MgSO₄ and nebulized MgSO₄ treatments had no effect upon hospital admission (RR 0.91, 95% CI 0.80 to 1.03, P = 0.14; RR 0.78, 95% CI 0.56 to 1.08, P = 0.14). Both intravenous MgSO₄ and nebulized MgSO₄ treatments were associated with significant evidence upon respiratory function (SMD 0.23, 95% CI 0.03 to 0.43, P = 0.02; SMD 0.37, 95% CI 0.11 to 0.64, P = 0.006), but sensitivity analyses showed that outcomes were changed by omitting studies of less than 100 individuals (SMD 0.05, 95% CI -0.05 to 0.15, P = 0.35; SMD 0.05, 95% CI -0.16 to 0.25, P = 0.64). There were no statistically significant differences in clinical symptom scores and vital signs (heart or pulse rate; systolic blood pressure; respiratory rate) in either form of MgSO₄ compared with placebo groups (P>0.05). There were no serious adverse events reported in any literature. Overall, there was no role for intravenous and nebulized MgSO₄ in the management of acute asthma in adults. Considering the low risk of serious adverse effects and easy availability, it seemed reasonable to use intravenous or nebulized MgSO₄ treatment in adults with life threatening asthma in whom any potential benefit would justify the risks of treatment.



Other

FDA: A Great Place for Science…and for Scientists on the New Frontier of Regulatory Science

Robert M. Califf, M.D.

2016, 25(8):  632-632. 

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    As FDA Commissioner, I’m proud of our agency’s extraordinary commitment to using the best available science to support our mission to protect and promote the health of the American public. This is especially critical today, as rapid scientific and technological advances are helping to expand our understanding of human biology and underlying disease mechanisms and to identify the molecular profile of a food contaminant.
    These breakthroughs offer unprecedented opportunities for us to develop new treatments and cures and to protect our food supply with a robust system that meets the challenges of globalization.
    But there’s another benefit that derives from our application of cutting-edge science to the challenges we face, which has become increasingly evident to me through my conversations with some of FDA’s more than 10,000 scientists. And that’s the deep personal and professional satisfaction gained from working in FDA’s state-of-the-art laboratories on front-line issues that make a real difference in the lives of all Americans. As one FDA scientist commented, “At FDA, your work is really at the crossroads of cutting-edge technology, patient care, tough scientific questions, and regulatory science.”