Lan Shen

Shanghai University of Traditional Chinese Medicine, Shanghai, Shanghai Shi, China

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Publications (85)249.18 Total impact

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    ABSTRACT: The two herbs Ligusticum chuanxiong (LC) Hort. (Umbelliferae) and Gastrodia elata (GE) Blume (Orchidaceae), are widely used in the clinic for the treatment of migraine. This article aims to understand the effects of LC and GE on blood-brain barrier (BBB) permeability in migraine rats. Serotonin, excitatory amino acids (EAAs) and matrix metalloproteinase-9 (MMP-9) were determined at different sampling times to assess BBB disruption during a migraine attack. BBB permeability was examined by fluorescence imaging and Evans blue dye (EBD) extravasation. The results showed that the expression of serotonin in migraine rat brain was enhanced from 30 min to 120 min and glutamate (Glu) was suppressed from 30 min to 60 min in LC-GE group compared with the model group (p < 0.05 or 0.01), while the MMP-9 levels in migraine rat blood was increased at 30 min as well as decreased at 120 min in LC-GE group compared with the model group (p < 0.05 or 0.01). EBD levels in rat brain were significantly lower at 30-60 min and 120-150 min in LC-GE group than that of the model group (p < 0.05 or 0.01). Our findings demonstrated that LC and GE might decrease BBB permeability and maintain its integrity through regulating serotonin, EAAs and MMP-9 in migraine rats.
    Pharmazie 06/2015; 70(6). DOI:10.1691/ph.2015.4852 · 1.00 Impact Factor
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    ABSTRACT: Transcriptional co-activator with PDZ-binding motif (TAZ) has been reported to be associated with carcinogenesis. However, the cellular function of TAZ in human hepatocellular carcinoma (HCC) remains elusive. In this study, an immunohistochemistry analysis revealed that the expression of TAZ in cancer tissue samples from 180 HCC patients was significantly higher than that in adjacent normal tissues. In addition, TAZ overexpression was significantly correlated with aggressive tumor characteristics such as tumor size, TNM stage, lymph node or distant metastasis, histological differentiation and recurrent HCC (P<0.05). The Kaplan—Meier test showed that TAZ-positive expression was related to a poor prognosis compared to TAZ-negative expression (P<0.05). Furthermore, the expression level of TAZ was generally correlated with the invasiveness of cancer cells. The overexpression of TAZ in the Huh7 cell line, which endogenously expresses TAZ at low levels, significantly promoted cell proliferation, migration and invasion and inhibited apoptosis, whereas RNA interference—mediated knockdown of TAZ in the highly invasive cell line MHCC-97H significantly suppressed cell proliferation, migration and invasion in vitro and tumor formation in vivo.Taken together, these results suggest that TAZ plays an important role in the proliferation, apoptosis, migration and invasion of HCC cells and that the expression of TAZ in HCC patients is closely related to their prognosis. Thus, TAZ is a potential novel biomarker for predicting prognosis and guiding personalized therapeutic strategies. This article is protected by copyright. All rights reserved
    Journal of Cellular Biochemistry 02/2015; DOI:10.1002/jcb.25117 · 3.37 Impact Factor
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    ABSTRACT: Although PEGylation plays an important role in drug delivery, knowledge about the distribution behavior of PEGylated drugs in ischemic myocardia is rather limited compared to nanoparticles. This work therefore aims to characterize the targeting behavior of the anti-myocardial ischemic mono-PEGylated conjugates of Radix Ophiopogonis polysaccharide (ROP) in two clinically relevant animal models, ie, the myocardial infarction (MI) model and the ischemia/reperfusion (IR) model. To determine the effect of the molecular size of conjugates, two representative conjugates (20- and 40-kDa polyethylene glycol mono-modified ROPs), with hydrodynamic size being approximately and somewhat beyond 10 nm, respectively, were studied in parallel at three time points postdose after a method for determining them quantitatively in biosamples was established. The results showed that the cardiac distribution of the two conjugates was significantly enhanced in both MI and IR rats due to the enhanced permeability and retention effect induced by ischemia. In general, the cardiac targeting efficacy of the conjugates in MI and IR rats was approximately 2; however, different changing in targeting efficacy with time was observed between MI and IR rats and also between the conjugates. Although the enhanced permeability and retention effect-based targeting efficacy for mono-PEGylated ROPs was not high, they, as dissolved macromolecules, are prone to diffusion in the cardiac interstitium space, and thus, facilitate the drug to reach perfusion-deficient and nonperfused areas. These findings are helpful in choosing the cardiac targeting strategy.
    International Journal of Nanomedicine 01/2015; 10:409-18. DOI:10.2147/IJN.S73462 · 4.20 Impact Factor
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    ABSTRACT: Cancers are characterized by aberrant cell signaling that results in accelerated proliferation, suppressed cell death, and reprogrammed metabolism to provide sufficient energy and intermediate metabolites for macromolecular biosynthesis. Here, we summarize the emerging "unconventional" roles of these regulators based on their newly identified interaction partners, different subcellular localizations, and/or structural variants. For example, the epidermal growth factor receptor (EGFR) regulates DNA synthesis, microRNA maturation and drug resistance by interacting with previously undescribed partners; cyclins and cyclin-dependent kinases (CDKs) crosstalk with multiple canonical pathways by phosphorylating novel substrates or by functioning as transcriptional factors; apoptosis executioners play extensive roles in necroptosis, autophagy, and in the self-renewal of stem cells; and various metabolic enzymes and their mutants control carcinogenesis independently of their enzymatic activity. These recent findings will supplement the systemic functional annotation of cancer regulators and provide new rationales for potential molecular targeted cancer treatments. Copyright © 2014. Published by Elsevier Ireland Ltd.
    Cancer Letters 11/2014; 357(1). DOI:10.1016/j.canlet.2014.11.048 · 5.62 Impact Factor
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    ABSTRACT: Radix Ophiopogonis polysaccharide (ROP), a highly hydrophilic macromolecule, has a unique anti-ischemic action in the myocardium. One of the main problems with its use is its relatively short half-life in vivo. To solve this problem, injectable long-acting drug delivery systems, which combine mono-PEGylation (PEG, polyethylene glycol) with the in situ formation of poly(d,l-lactide-co-glycolide) copolymer (PLGA) depots, were tested in this study. Through a moderate coupling reaction between 20 kDa amino-terminated methoxy-PEG and excessive ROP with activated hydroxyls, a long-circulating and bioactive mono-PEGylated ROP was prepared and characterized. A reasonable and applicable range of PLGA formulations loaded with the mono-PEGylated ROP were prepared, characterized, and evaluated in vivo. Relative to ROP, the half-life of which was only 0.5 hours, the conjugate alone, following subcutaneous administration, showed markedly prolonged retention in the systemic circulation, with a mean residence time in vivo of approximately 2.76 days. In combination with in situ-forming PLGA depots, the residence time of the conjugate in vivo was prolonged further. In particular, a long-lasting and steady plasma exposure for nearly a month was achieved by the formulation comprising 40% 30 kDa PLGA in N-methyl-2-pyrrolidone. Long-lasting and steady drug exposure could be achieved using mono-PEGylation in combination with in situ formation of PLGA depots. Such a combination with ROP would be promising for long-term prophylaxis and/or treatment of myocardial ischemia. For high-dose and highly hydrophilic macromolecular drugs like ROP, more than one preparation technology might be needed to achieve week-long or month-long delivery per dosing.
    International Journal of Nanomedicine 11/2014; 9:5555-63. DOI:10.2147/IJN.S71819 · 4.20 Impact Factor
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    ABSTRACT: Co-processed excipients withgelatinized or non-gelatinized starch were prepared by spray drying. Powder and tablet properties of corocessed excipients prepared were compared with those of physical mixtures and spray-dried lactose. Their applicability in traditional Chinese medicine (TCM) powder tableting was tested on two TCM extracts, i.e., the gardenia extract and the Herba Sedi extract. It was shown that gelatinizing starch before co-spray drying with lactose could improve the performance and efficiency of starch as a binder, resulting in remarkable improvement in physicomechanical properties of co-processed excipients prepared. Conpared to self-made and commercially available spray-dried lactose, co-processed excipients achieved better compactability and higher drug loading for TCM extracts. In conclusion, the lactose-gelatinized starch co-processed excipient, with excellent physicomechanical properties, is promising to be explored as a new excipient for direct tableting.
    Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 11/2014; 39(22):4329-34.
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    ABSTRACT: In the area of injectable long-acting formulations, the in situ forming system (ISFS) is an attractive alternative for its various superiorities. In this study, both hydrophilic and hydrophobic in situ forming systems, using Poloxamer and sucrose acetate isobutyrate (SAIB) or poly(D,L-lactide-co-glycolide) copolymer (PLGA) as carrier, respectively, were investigated for Radix Ophiopogonis polysaccharide (ROP), a natural anti-myocardial ischemic fructan. A reasonable and applicable range of formulations were selected from each carrier for in vivo study by investigating their rheological property. The results from in vivo evaluation show that relatively promising sustained behaviors were achieved by formulations 24% P407/10% P188, 40% PLGA30k/NMP, and 30% PLGA50k/NMP. Significant differences of drug release kinetics were observed between in situ thermally-induced Poloxamer-based hydrogels and in situ solvent exchange-induced hydrophobic PLGA depots. This suggests that different ISFS could be chosen to provide different application purpose for polysaccharide drugs. In the case of ROP, Poloxamer-based ISFS is promising for short-term acute therapies; however, PLGA-based ISFS might be promising for long-term precaution or/and cure of myocardial ischemia.
    International Journal of Biological Macromolecules 09/2014; 72. DOI:10.1016/j.ijbiomac.2014.09.009 · 3.10 Impact Factor
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    ABSTRACT: Traditional processes are mostly adopted in traditional Chinese medicine (TCM) preparation production and the quality of products is mostly controlled by terminal. Potential problems of the production in the process are unpredictable and is relied on experience in most cases. Therefore, it is hard to find the key points affecting the preparation process and quality control. A pattern of research and development of traditional Chinese medicine preparation process based on the idea of Quality by Design (QbD) was proposed after introducing the latest research achievement. Basic theories of micromeritics and rheology were used to characterize the physical property of TCM raw material. TCM preparation process was designed in a more scientific and rational way by studying the correlation among enhancing physical property of raw material, preparation process and product quality of preparation. So factors affecting the quality of TCM production would be found out and problems that might occur in the pilot process could be predicted. It would be a foundation for the R&D and production of TCM preparation as well as support for the "process control" of TCMIs gradually realized in the future.
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    ABSTRACT: To evaluate in vivo pharmacokinetics of Ophiopogonis Radix polysaccharide MDG-1 oily suspension injection prepared with different prescriptions in rats, and explore the feasibility of the long-acting drug delivery of MDG-1 Injection by using the oily suspension drug release system.
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    ABSTRACT: Abstract This study is aimed to investigate the applicability of poloxamer 407 (P407) and 188 (P188)-based temperature-sensitive in situ hydrogel (TSHG) in sustained delivery of hydrophilic macromolecules following intramuscular administration. Polyethylene glycols (PEGs) with molecular weight of 5-, 20-, and 40-kDa were used as model drugs, which can represent the common size range of hydrophilic macromolecular drugs using TSHG. The correlation between the level of poloxamers and thermogelling transition temperatures (Tsol-gel) was established and two formulations "20% P407/10% P188" and "24% P407/10% P188" were chosen for further study. The results showed that the release kinetics of PEGs was close to zero order. Sustained in vivo behaviors were achieved by both of the two formulations for all the PEGs though variations were seen. Lower molecular weight PEG showed more remarkable pharmacokinetic improvements. No significant differences in pharmacokinetics were observed between the two formulations for the same PEG. This suggested that 20-24% P407/10% P188 formulations, with accordingly Tsol-gel in the range of 24.6 °C-31.7 °C, might be freely chosen to achieve comparable pharmacokinetics for hydrophilic macromolecular drugs after intramuscular injection.
    Drug Delivery 03/2014; 22(3). DOI:10.3109/10717544.2014.891272 · 2.20 Impact Factor
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    ABSTRACT: Our previous study on proteomic analysis has shown that clusterin (CLU) is significantly decreased in the cerebrospinal fluid (CSF) of patients with epilepsy. Therefore, the present study aimed to confirm CLU concentration reduction in the CSF of patients with drug-resistant epilepsy and drug-responsive epilepsy. Fifty-two patients with epilepsy (23 drug resistance and 29 drug effectivity) and 20 control individuals were recruited. The concentrations of CSF and serum CLU were detected. Moreover, alteration of CLU was detected in the rat hippocampus over time after pilocarpine-induced status epilepticus (SE). Our results showed that human CSF-CLU levels were decreased in patients with both drug-resistant epilepsy and drug-responsive epilepsy compared to controls, and concentration of CSF-CLU was obviously lower in drug-resistant epilepsy than in drug-responsive epilepsy. In the pilocarpine-induced seizure rats, expression of neuronal CLU was gradually decreased in a time-dependent manner from acute phase to chronic phase after the onset of SE. In conclusion, CLU level is decreased in the CSF of human epilepsy and the similar alteration is confirmed in a rat model with epilepsy. Therefore, CLU might contribute to the development of epilepsy and be a potential CSF biomarker for resistant epilepsy.
    Journal of Molecular Neuroscience 02/2014; DOI:10.1007/s12031-014-0237-3 · 2.76 Impact Factor
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    ABSTRACT: The quantitative characterization and evaluation of the synchrony of multi-component release behavior are bottlenecks which urgently need to be solved in the study of multi-component release kinetics and the quality control of multi-component traditional Chinese medicine (MCTCM). MCTCM is made using original prescriptions and preparations. At present, MCTCM is generally evaluated using pharmacodynamics evaluation. However, this method lacks convenience and cannot clearly reveal the correlation between the whole dynamic process of drug release and in vivo absorption. It is also very limited by the preparation of MCTCM. In addition, there are various types of effective ingredients in MCTCM, which show distinctly different physicochemical properties. These differences may lead to the asynchrony of drug release between MCTCM and the original preparation, which thereby directly affects the efficacy. However, we can't find the core reason for this issue through the use of pharmacodynamics evaluation. The papers reported previously were confined to studying the release characteristics of one or a few components in MCTCM and the drug release evaluation method reported was too macroscopic to specifically identify the components which caused the integral asynchrony. In this paper, in order to reveal the MCTCM release synchronous characteristics, Fuzhenghuayu capsules were selected as the model, an original preparation used, and the integral release evaluation method based on a mathematics set was established in guiding the preparation of MCTCM. This method can not only be used in evaluating the release characteristics of MCTCM by the parameter of the asynchronous coefficient, but can also be used in adjusting the dose of the release unit by the relative error parameter. The results demonstrated that this evaluation method was feasible, stable and reproducible. Also the Fuzhenghuayu pellets guided by this method showed release synchrony and similar pharmacodynamics with the original capsules, and the drug release mechanism was mainly frame erosion. Through this study, we could then evaluate the quantifiable release characteristics of MCTCM and apply an integral synchronous evaluation method for MCTCM.
    Analytical methods 01/2014; 6(7):2260-2269. DOI:10.1039/c3ay41850b · 1.94 Impact Factor
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    ABSTRACT: Metabolic disorders such as hyperglycemia, dislipidemia, and insulin resistance often occur in obese populations long before the manifestation of type 2 diabetes mellitus (T2DM), cardiovascular disease, and cancer. The prevention of metabolic disorders in obese individuals might decrease the morbidity of diabetes and other metabolic diseases. Ophiopogon japonicus is a traditional Chinese medicine used for thousands of years to treat patients with diabetes. We showed in previous work that MDG-1, a polysaccharide extracted from Ophiopogon japonicus, could treat T2DM. To investigate whether MDG-1 can prevent metabolic disorders, metabonomic methods, together with multivariate analysis, were used to evaluate the role of MDG-1 in the prevention of metabolic disorders in a high-fat, diet-induced obesity (DIO) model. Thirty-six male C57BL/6 mice (8 weeks old) were randomly divided into a control group (normal chow), a model group (high-fat chow), and an MDG-1 group (high-fat chow dosed with 300 mg kg−1 MDG-1). After 16 weeks of treatment, urinary metabonomic studies were performed using ultra-performance liquid chromatography-time of flight mass spectrometry in combination with multivariate statistical analysis. Indices of body weight, food intake, fasting and fed blood glucose, oral glucose tolerance test (OGTT), and OGTT plasma insulin were collected. MDG-1 treatment was shown to exert mild ameliorative effects on bodyweight gain, fed blood glucose levels, OGTT, and the insulin resistance of DIO mice. In addition, 21 potential biomarkers of glucose, fatty acid, phospholipid and amino acid metabolism, the tricarboxylic acid cycle and purine metabolism were identified. Based on these compounds, it is suggested that MDG-1 could reduce glucose, the glucose-related products lactic acid and N-acetyl-D-glucosamine, and lipids, thus normalizing tricarboxylic acid cycle activity while decreasing purine, hence alleviating oxidative stress in DIO mice. Although there was no obvious alteration in visible biomedical indices, invisible metabolic disturbances did occur with MDG-1 supplementation, which may lead to the possible elucidation of the action of MDG-1 against metabolic disorders.
    Analytical methods 01/2014; 6(12):4171. DOI:10.1039/c4ay00796d · 1.94 Impact Factor
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    ABSTRACT: The configuration of (−)-brevianamides was assigned as (2S,13S) based on X-ray structure analysis and hydrolysis experiments. However, our theoretical investigation of its chiroptical properties strongly implied that the correct configuration should be (2R,13R). The reasons for the incorrect earlier assignment are analyzed by calculations of conversion energy barriers among different intermediates, starting materials and final products. This study demonstrates that conflicting theoretical and, experimental results suggest that it is premature to assign the configuration of a natural product.
    Tetrahedron 12/2013; 69(48):10351-10356. DOI:10.1016/j.tet.2013.10.004 · 2.82 Impact Factor
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    ABSTRACT: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder with systemic complications and has been a worldwide epidemic. Ophiopogon japonicus is a traditional Chinese medicine used to treat diabetes for thousands of years. From our previous work, we know that MDG-1, a water-soluble β-d-fructan polysaccharide from O. japonicas could treat T2DM experimentally. However, MDG-1 is poorly absorbed and its mechanism of action is still unknown. Therefore, a GC TOF/MS-based metabonomic approach in combination with multivariate statistical analysis was performed to investigate the mechanism of MDG-1 in a spontaneous diabetic model. Female diabetic KKay mice (21 weeks old) were randomly divided into a diabetic group (n = 6, gavaged with distilled water) and a MDG-1-Diabetic group (n = 7, gavaged with MDG-1, 300 mg kg(-1)) and female C57BL/6 mice (21 weeks old) were set as controls (n = 6, gavaged with distilled water). After 8-weeks of treatment, feces samples were collected for GC-TOF/MS analysis. Consequently, 12 potential biomarkers were identified, including monosugars (d-tagatose, d-lyxose, d-erythrose, xylo-hexos-5-ulose, 2-deoxy-galactose), butanedioic acid, amino acids (phenylalanine, l-lysine, l-methionine, l-aspartic acid) and purine derivatives (7H-purine, 2'-deoxyinosine). We assume the monosugars and butanedioic acid were the fermentation products of MDG-1 by intestinal microbes and MDG-1 actions against diabetes might be accomplished through the absorbable monosugars and butanedioic acid via suppressing intestinal glucose absorption, enhancing liver glycogenesis, inhibiting glycogenolysis and promoting GLP-1 secretion. Besides, MDG-1 might alleviate diabetes and diabetic nephropathy by reducing 7H-purine and 2'-deoxyinosine. Further omics-driven studies including genomics, proteomics and metabonomics were considered to be carried out to provide direct evidence of gut microbiome contribution to MDG-1 actions.
    Molecular BioSystems 11/2013; 10(2). DOI:10.1039/c3mb70392d · 3.18 Impact Factor
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    ABSTRACT: Because neuroprotective effects of estrogen remain controversial, we aimed to investigate the effect of different doses of estradiol (E2) on cerebral ischemia using both in vivo and in vitro experiments. PC12 cells were cultured at physiological (10 nM and 20 nM) or pharmacological (10 muM and 20 muM) dosages of E2 for 24 hours (h). The results of 5-bromodeoxyuridine (Brdu) incorporation and flow cytometric analysis showed that physiological doses of E2 enhanced cell proliferation and pharmacological doses of E2 inhibited cell proliferation. After the cells were exposed to oxygen and glucose deprivation (OGD) for 4 h and reperfusion for 20 h, the results of 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyl tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release assay, flow cytometric analysis and Western blot analysis showed that physiological doses of E2 enhanced cell viability, reduced cell apoptosis and decreased the expression of pro-apoptotic protein caspase-3. In contrast, pharmacological doses of E2 decreased cell viability and induced cell apoptosis. In vivo, adult ovariectomized (OVX) female rats received continuous subcutaneous injection of different doses of E2 for 4 weeks. Transient cerebral ischemia was induced for 2 h using the middle cerebral artery occlusion (MCAO) technique, followed by 22 h of reperfusion. The results of Garcia test, 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that 6 mug/kg and 20 mug/kg E2 replacement induced an increase in neurological deficit scores, a decrease in the infarct volume and a reduction in the expression of caspase-3 when compared to animals in the OVX group without E2 treatment. However, 50 mug/kg E2 replacement treatment decreased neurological deficit scores, increased the infarct volume and the expression of caspase-3 when compared to animals in the control group and 6 up/kg or 20 mug/kg E2 replacement group. We conclude that physiological levels of E2 exhibit neuroprotective effects on cerebral ischemia; whereas, pharmacological or supraphysiological doses of E2 have damaging effects on neurons after cerebral ischemia.
    BMC Neuroscience 10/2013; 14(1):118. DOI:10.1186/1471-2202-14-118 · 2.85 Impact Factor
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    ABSTRACT: Breviscapine, one of cardiovascular drugs extracted from a Chinese herb Erigeron breviscapinus, has been frequently used to treat cardiovascular diseases such as hypertension, angina pectoris, coronary heart disease and stroke. However, its poor water solubility and low bioavailability in vivo severely restrict the clinical application. To overcome these drawbacks, breviscapine solid dispersion tablets consisting of breviscapine, polyvinylpyrrolidone K30 (PVP K30), microcrystalline cellulose and crospovidone were appropriately prepared. In vitro dissolution profiles showed that breviscapine released percentage of solid dispersion tablets reached 90 %, whereas it was only 40 % for commercial breviscapine tablets. Comparative pharmacokinetic study between solid dispersion tablets and commercial products was investigated on the normal beagle dogs after oral administration. Results showed that the bioavailability of breviscapine was greatly increased by 3.45-fold for solid dispersion tablets. The greatly improved dissolution rate and bioavailability might be attributed to intermolecular hydrogen bonding reactions between PVP K30 and scutellarin. These findings suggest that our solid dispersion tablets can greatly improve the bioavailability as well as the dissolution rate of breviscapine.
    European Journal of Drug Metabolism and Pharmacokinetics 09/2013; 39(3). DOI:10.1007/s13318-013-0150-0 · 1.31 Impact Factor
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    ABSTRACT: Preparative HPLC was used to prepare ferulic acid, senkyunolide I and senkyunolide H from Ligusticum chuanxiong. The separation was conducted on a Shim-Pack Prep-ODS (20.0 mm x 250 mm, 5 microm) column with the mobile phase of methanol-0.2% glacial acetic acid (50:50)at the flow rate of 5 mL x min(-1). The detection wavelength was 278 nm, and the purity of each compound was detected by HPLC analysis. Spectral data analyses including UV, ESI-MS and NMR were used to identify their structures. This method is simple, fast, which is suitable for preparation of standard reference of ferulic acid, senkyunolide I and senkyunolide H from L. chuanxiong and can meet the requirement of new drug research and development.
    Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 06/2013; 38(12):1947-50.
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    ABSTRACT: This work aimed to improve the clinical application of Radix Ophiopogonis polysaccharide (ROP), a natural anti-myocardial ischemic fructan with Mw of 4.80 kDa, by mono-PEGylation. Three mono-PEGylated ROPs were prepared by a moderate coupling reaction between amino-terminated methoxy-PEG (20-, 30-, or 40-kDa) and excessive hydroxyl-activated ROP. After being fully characterized by proton nuclear magnetic resonance as well as high-performance gel permeation chromatography and anthrone-sulfuric acid colorimetry coupled assay, they were evaluated for pharmacokinetics and anti-myocardial ischemic activities in rats with coronary artery ligation. The results showed that mono-PEGylated ROPs were successfully and effectively prepared. Compared with ROP, the three mono-PEGylated ROPs showed approximately 32-, 85-, and 100-fold prolonged retention in systemic circulation with plasma half-lives reaching 16.1, 42.4, and 49.8 h, respectively. Studies on anti-myocardial ischemic effects of the conjugates showed that administrated at the same molar dose of 4 μmol/kg per injection as ROP, they could achieve comparable or even better therapeutic effects although their administration intervals were 2- to 6-fold longer than that of ROP. These findings confirm that PEGylation would be a promising approach to markedly reducing the injection-administered frequency of ROP and hence patient compliance without sacrifice of the therapeutic efficacy by significantly improving its pharmacokinetics.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 05/2013; 49(4). DOI:10.1016/j.ejps.2013.05.020 · 3.01 Impact Factor
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    ABSTRACT: The N-myc downstream-regulated gene 2 (NDRG2) is involved in cell apoptosis and survival. Although reported to be highly expressed in the cardiac tissue, the biological function of NDRG2 in the heart remains to be established. Insulin exerts protective effects against myocardial ischemia/reperfusion (I/R) injury through the PI3K/Akt pathway. Here, we examined the changes in phosphorylation of NDRG2, a novel substrate and phosphoprotein of Akt, in insulin-induced protection against myocardial I/R. Rat hearts were subjected to 30 min regional ischemia followed by reperfusion with or without insulin at the onset of reperfusion. Reperfusion with insulin inhibited myocardial apoptosis and reduced infarct size, as well as significantly up-regulated myocardial Akt and NDRG2 phosphorylation levels compared with the I/R group. These effects of insulin were blocked by pretreatment with the PI3K inhibitor wortmannin or Akt inhibitor. To further ascertain the role of NDRG2 in insulin-induced cardioprotection, cardiomyocytes were transduced with a lentivirus encoding shRNA targeting NDRG2 (loss-of-function), which rendered the cells more susceptible to I/R injury and significantly blunted the anti-apoptotic effect of insulin. Moreover, the NDRG2 shRNA lentivirus was tested in vivo, and NDRG2 knockdown aggravated myocardial I/R injury and attenuated the insulin-mediated cardioprotection against I/R injury. Taken together, these results suggest a novel role of PI3K/Akt/NDRG2 signaling in the cardioprotective effect of insulin.
    Archiv für Kreislaufforschung 05/2013; 108(3):341. DOI:10.1007/s00395-013-0341-5 · 5.96 Impact Factor

Publication Stats

529 Citations
249.18 Total Impact Points

Institutions

  • 2005–2015
    • Shanghai University of Traditional Chinese Medicine
      • • College of Chinese Materia Medica
      • • Department of Pharmacy
      Shanghai, Shanghai Shi, China
  • 2010–2014
    • Chongqing Medical University
      Ch’ung-ch’ing-shih, Chongqing Shi, China
  • 2005–2014
    • Fourth Military Medical University
      • • Department of Biochemistry and Molecular Biology
      • • Department of Anesthesiology
      Xi’an, Liaoning, China
  • 2013
    • Shanghai University
      Shanghai, Shanghai Shi, China
    • Hebei University
      Pao-ting-shih, Hebei, China
  • 2012
    • Chinese Academy of Sciences
      Peping, Beijing, China
  • 2011–2012
    • Kunming University of Science and Technology
      Yün-nan, Yunnan, China
    • Shandong University
      • Department of Neurology
      Jinan, Shandong Sheng, China