Table of Content

    20 November 2015, Volume 24 Issue 11
    Advances of N-terminal modifications of GLP-1 and their applications for the treatment of type 2 diabetes
    Xiaohui Bai, Youhong Niu, Decai Xiong, Yanfen Wu, Yunsen Li
    2015, 24(11):  701-711.  DOI: 10.5246/jcps.2015.11.090
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    Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV (DPP-IV). To overcome this problem, various N-terminal modifications of GLP-1 have been performed to prolong the in vivo biological activity,by improving the DPP-IV resistance while retaining receptor affinity and receptor activation. These studies have included modifications of His7, Ala8 or Glu9 at the N-terminus of GLP-1 and some other modifications. Among them, Ala8 substitutions with glycine (Gly8) and α-aminoisobutyric acid (Aib8) have been clinically applied in the development of diabetic therapy, such as Exenatide, Semaglutide, Albiglutide and Taspoglutide. In this review, we introduce N-terminal modifications of GLP-1 that have been reported, and discuss their potential and challenges for the treatment of type 2 diabetes.

    Original articles
    Preparation and characterization of mesoporous silica nanoparticles with enlarged pores capped with crosslinked PEI
    Lu Sun, Yujie Liu, Zhenzhen Yang, Xianrong Qi
    2015, 24(11):  712-720.  DOI: 10.5246/jcps.2015.11.091
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    The epidemiological statistics reveals the striking patterns of cancer in women and highlights the need for novel therapeutic strategies. In this work, mesoporous silica nanoparticles (MSNs) as representative of inorganic nanoparticles were prepared for loading siRNA that plays a role of gene silencing to treat breast carcinoma (MCF-7) cells. The critical processes of synthesis were optimized for the nanoparticles with desired quality attributes that have the enlarged pores for elevated loading capacity.After siRNA loading into mesoporous, crosslinked-polyethylenimine was employed as the cap to coat the enlarged MSN pores and protect the cargo from leakage. The elevated quantity of siRNA (35 μg siRNA/mg MSNs) were loaded in the MSNs. The as-synthesized MSNs were further evaluated on MCF-7 cells in vitro and shown negligible cytotoxicity.As expected, the siRNA loaded in the as-synthesized MSNs was readily internalized into MCF-7 cells and displayed 420 times higher intake than that of naked siRNA. The MSNs may be exploited to become an effective siRNA cell delivery strategy and further studied for the anti-tumor efficacy.

    Development and validation of a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the determination of sunitinib in rabbit plasma
    Yongjie Yang, Jialin Li, Huan Wang, Xiaoya Qin, Xiaojing Lu, Lanxin Zhang, Yue Zhang, Mengjie Gu, Tianyuan Fan
    2015, 24(11):  721-725.  DOI: 10.5246/jcps.2015.11.092
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    A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the measurement of sunitinib in rabbit plasma. After protein precipitation with acetonitrile, samples were analyzed on a Zorbax Extend-C18 column (150 mm×4.6 mm, 5μm). The mobile phase consisted of a mixture of acetonitrile and deionized water (containing 0.05% formic acid)at a ratio of 27:73 (v/v), and the flow rate was set at 0.8 mL/min.The column temperature was maintained at 30 oC. The LC eluate was detected by an electrospray ionization (ESI) source operated in the positive ion mode, and quantification was conducted using MRM of the transitions m/z 399.24→283.01 and m/z 415.19→178.00 for sunitinib and internal standard (IS, diltiazem hydrochloride), respectively. The calibration curve was linear in the range of 2–600 ng/mL. The lower limit of quantification was 2 ng/mL. The method also exhibited satisfactory results in terms of sensitivity, specificity, accuracy (with relative error ranging from –4.0% to 1.1%), precision (with intra- and inter-day relative standard deviations ranging from 2.8% to 9.5%),matrix effect, recovery as well as stability. Taken together, our newly developed method was reliable to monitor sunitinib concentrations in rabbit plasma.

    Role of vanadyl acetylacetonate-induced elevation of reactive oxygen species in the regulation of lipolysis and glucose metabolism in 3T3L1 adipocytes
    Yi Li, Jingcheng Liu, You Yu, Weixia Bian, Xia Hu, Xiaogai Yang
    2015, 24(11):  726-733.  DOI: 10.5246/jcps.2015.11.093
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    In the present study, we investigated the role of reactive oxygen species (ROS) elevation induced by an anti-diabetic vanadium compound, vanadyl acetylacetonate (VO(acac)2), in the regulation of lipolysis and glucose metabolism using differentiated 3T3L1 adipocytes as a model system. By confocal laser scanning microscopy, we found that VO(acac)2 induced ROS generation under high glucose stimulation, and the pretreatment of NADPH oxidase inhibitors could significantly reduce the elevated ROS level. Meanwhile, the decreased phosphorylated levels of AKT and the two key modulators of lipolysis (HSL and perilipin) were observed by western blot analysis. We also found that the contents of glycerol release were further reduced as well. In addition, the levels of key regulatory proteins, AS160 and GSK3β, in glucose metabolism pathway were correspondingly reduced. These findings demonstrated that ROS induced by vanadium compounds could act as a metabolic signal to activate AKT pathway to inhibit lipolysis and promote glucose transport and glycogen synthesis rather than by direct action by themselves. Our study contributed to elucidate the anti-diabetic effects of vanadium compounds and provided a theoretical basis for the further development of new vanadium complexes in the prevention and therapeutics of diabetes.

    The long-term toxicity and hypoglycemic effect of vanadyl complexes on non-diabetic and type II diabetic mice
    Ziwei Wang, Na Wang, Meiling Huang, Xiaoda Yang
    2015, 24(11):  734-743.  DOI: 10.5246/jcps.2015.11.094
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    Vanadium compounds are promising anti-diabetic agents. However, the concern in the toxicity, especially the long-term renal side effect along with diabetic status, is restricting the further development of this metal drug. Recently, we have prepared a bis((5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2-hydroxy-benzoatato) oxovanadium (BSOV), which exhibited excellent hypoglycemic effect with low acute toxicity. In order to facilitate the development of anti-diabetic vanadium complexes, especially BSOV, we studied the long-term toxicity and hypoglycemic effect of BSOV in comparison with bis(maltolato)oxovanadium (BMOV) on both non-diabetic and type II diabetic mice. The experiments confirmed a stable hypoglycemic effect for both the vanadium complexes over the testing period (6–7 months). However, the chronic administration of vanadium compounds slightly increased oxidative stress in ICR mice and the induced renal interstitial edema (RIE) in a part of the diabetic animals associated with low levels of serum albumin. The use of an antioxidant dietary supplement (a combination of vitamin C and Zinc gluconate) could prevent vanadium-induced oxidative stress but have marginal effect on RIE. However, BSOV caused much lower incidence of RIE than BMOV did, suggesting that BSOV is an important step towards the successful development of anti-diabetic vanadium drugs.

    Effects of cilnidipine and L-type calcium channel blockers on renal functions in hypertensive patients: a meta-analysis of the randomized trials
    Xiaochun Ye, Zhi Dong, Chunjing Zhao, Di Li, Yan Qian
    2015, 24(11):  744-753.  DOI: 10.5246/jcps.2015.11.095
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    In the present study, we aimed to evaluate the effects of cilnidipine and L-type calcium channel blockers (L-type CCBs) on renal function in hypertensive patients. The randomized controlled trials (RCTs) of cilnidipine and L-type CCBs on hypertension treatment were selected from Pubmed, Embase, Google Scholar, CNKI, Science Direct, Ebsco, Springer, Ovid, Cochrane Library, Medline, VIP and Wanfang databases (from the date of databases’ establishment to September 2014). Data were independently evaluated following the Jadad standard. The percentage changes of serum creatinine (SCr) value, urinary protein excretion (UPE), urinary protein/creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) pre- and post-treatment were extracted for the subsequent meta-analysis. The mean difference (MD) and the 95% confidence interval (95% CI) were determined using RevMan 5.3 software.A total of 10 RCTs of high quality were included and analyzed by fixed- or random-effect models. The results indicated that UPE (MD = –36.59, 95% CI: –70.85, –2.33) or UPCR (MD = –46.56, 95% CI: –88.50, –4.62) was significantly reduced by cilnidipine compared with L-type CCBs. However, such significant difference was not detected in reduction of SCr (MD = 0.01, 95% CI: –2.97, 2.98) or eGFR (MD = 1.56, 95% CI: –0.19, 3.31). Compared with L-type CCBs, cilnidipine was more effective in reducing proteinuria or preventing the proteinuria progression. In addition, we did not find significant differences in SCr and eGFR between the two groups.

    Impacts of National Basic Medical Insurance Drug List adjustment on drug utilization in China: an interrupted time series study
    Geng Weng, Lili Ma, Yi Liu, Xiaodong Guan, Luwen Shi
    2015, 24(11):  754-763.  DOI: 10.5246/jcps.2015.11.096
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    Under Chinese medicine and health care system, Medicine Catalogue for National Basic Medical Insurance (2009) was issued in 2009 in China to fulfill the basic drug demands of the insured Chinese and to control the medical expenses. In this study, the influence of the list adjustment on drug utilization was investigated. With the comparison between inpatients’ use of drugs before and after adjustment of Basic Medical Insurance Drug List, we classified the drugs adjusted in national list into six categories: class A to class B, class B to class A, class A to class C, class B to class C, class C to class A, and class C to class B (class A referring to overall insured drugs, class B referring to partial reimbursement drugs, class C referring to self-funded drugs in China), and drug utilization and expenditure were analyzed with time series model. We analyzed the overall expenditure and average expenditure per 10 000 people based on the comparison before and after the adjustment of 2009 Basic Medical Insurance Drug List. The drug expenditure from class A to class B was decreased by 13.87% of overall expenditure and 16.37% of average expenditure per 10 000 people, and it was decreased by 38.74% and 48.03% from class A to class C; respectively, the drug expenditure from class B to class A was increased by 74.12% and 94.52%, while it was reduced by 19.79% and 14.52% from class B to class C; expenditure declined by 31.77% and 36.22% from class C to class A, and expenditure was increased by 12.42% and 22.05% from class C to class B, respectively, both were lower than before. The adjustment of National Basic Medical Insurance Drug List reduced the overall drug expenditure.

    Determination of the heavy metal content of Entoban herbal medicinal product
    Sadia Shakeel, Zeeshan Ahmed Sheikh, Khan Usmanghani, Somia Gul, Safila Naveed
    2015, 24(11):  764-769.  DOI: 10.5246/jcps.2015.11.097
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    The levels of As, Cd, Pb and Hg were investigated in the medicinal herbal syrup Entoban, which is widely used in the management of non-specific diarrhea and acute intestinal infections of various etiologies. The ingredients in Entoban syrup include 6 potent herbal drugs: Aegle marmelose, Berberis aristata, Butea frondosa, Holarrhena antidysenterica, Myrtus communis, and Quercus infectoria. Entoban medicinal plant syrup was analyzed for As, Cd, Pb and Hg by flame atomic absorption spectroscopy (FAAS). Contents of heavy metals in the examined samples were in the range: As (0.074–10.0 ppm); Cd (0.020–0.3 ppm); Pb (0.00–10.0 ppm) and Hg (0.00–1.0 ppm). Results were compared with permissible limit acceptability intake (AHPA). According to determined amounts of heavy metals, the investigated Entoban syrup samples were validated and considered safe for human consumption.

    Short communication
    Microbial specific carboxylation of (–)-huperzine A by Streptomyces griseus
    Ridao Chen, Dan Xie, Jungui Dai
    2015, 24(11):  770-772.  DOI: 10.5246/jcps.2015.11.098
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    In a scale-up microbial transformation of (-)-huperzine A (1) by Streptomyces griseus CACC 200300, a specific carboxylated derivative (2)was yielded together with two known hydroxylated metabolites. The structure of 2 was characterized as 16-carboxyl huperzine A on the basis of IR, HRMS and NMR spectroscopic data analysis.