Acta Pharmacologica Sinica (ACTA PHARMACOL SIN )

Publisher: Zhongguo yao li xue hui; Shanghai yao wu yan jiu suo; Zhongguo ke xue yuan, Nature Publishing Group

Description

Acta Pharmacologica Sinica, published monthly, is the official journal of the Chinese Pharmacological Society and Shanghai Institute of Materia Medica, Chinese Academy of Sciences. APS was registered as an English international journal in 2000. APS has gained a well-earned reputation during the last two decades for its persisting in reporting researches of high scientific quality.The APS welcomes current original researches on all aspects of life sciences, both experimental and clinical, from any part of the world. Reviews based primarily on authors' own research of internationally important topics are especially welcome.

  • Impact factor
    2.35
    Show impact factor history
     
    Impact factor
  • 5-year impact
    2.52
  • Cited half-life
    6.20
  • Immediacy index
    0.60
  • Eigenfactor
    0.01
  • Article influence
    0.60
  • Website
    Acta Pharmacologica Sinica website
  • Other titles
    Acta pharmacologica Sinica (Online), APS, Acta pharmacologica Sinica, Zhongguo yao li xue bao
  • ISSN
    1671-4083
  • OCLC
    51169124
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Nature Publishing Group

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 6 months embargo
  • Conditions
    • Published source must be acknowledged and DOI cited
    • Must link to publisher version
    • Publisher's version/PDF cannot be used
    • On funding body's archive, author website and institutional repository
    • If funding agency rules apply, authors may post authors version to their relevant funding body's archive, 6 months after publication
    • Several Journals have paid open access options and licenses (see journal homepages)
    • Creative Commons Licenses available for selected titles.
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:To evaluate the effects of an Al(3+)- and Mg(2+)-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin in healthy humans.Methods:Two single-dose, open-label, randomized, crossover studies were conducted in 24 healthy male Chinese volunteers (12 per study). In Study 1, the subjects orally received nemonoxacin (500 mg) alone, or an antacid (containing 318 mg of Al(3+) and 496 mg of Mg(2+)) plus nemonoxacin administered 2 h before, concomitantly or 4 h after the antacid. In Study 2, the subjects orally received nemonoxacin (500 mg) alone, or nemonoxacin concomitantly with ferrous sulfate (containing 60 mg of Fe(2+)) or calcium carbonate (containing 600 mg of Ca(2+)).Results:Concomitant administration of nemonoxacin with the antacid significantly decreased the area under the concentration-time curve from time 0 to infinity (AUC0-∞) for nemonoxacin by 80.5%, the maximum concentration (Cmax) by 77.8%, and urine recovery (Ae) by 76.3%. Administration of nemonoxacin 4 h after the antacid decreased the AUC0-∞ for nemonoxacin by 58.0%, Cmax by 52.7%, and Ae by 57.7%. Administration of nemonoxacin 2 h before the antacid did not affect the absorption of nemonoxacin. Administration of nemonoxacin concomitantly with ferrous sulfate markedly decreased AUC0-∞ by 63.7%, Cmax by 57.0%, and Ae by 59.7%, while concomitant administration of nemonoxacin with calcium carbonate mildly decreased AUC0-∞ by 17.8%, Cmax by 14.3%, and Ae by 18.4%.Conclusion:Metal ions, Al(3+), Mg(2+), and Fe(2+) markedly decreased the absorption of nemonoxacin in healthy Chinese males, whereas Ca(2+) had much weaker effects. To avoid the effects of Al(3+) and Mg(2+)-containing drugs, nemonoxacin should be administered ≥2 h before them.
    Acta Pharmacologica Sinica 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:Osteocalcin, a biochemical marker of bone formation, has been suggested to be involved in the regulation of energy metabolism. The aim of this study was to investigate the possible association between serum osteocalcin and markers of glucose and lipid metabolism in a large sample of healthy Chinese women.Methods:A total of 2032 healthy Chinese women in Shanghai, aged 20-94 (including 1396 discovery-study subjects and 636 postmenopausal women for a reduplication analysis) were recruited. Their serum osteocalcin, calcium and the relevant measurements were analyzed. A Spearman correlation analysis was performed between osteocalcin and the other markers of energy metabolism including triglyceride, total cholesterol, fasting plasma glucose (FPG), serum insulin, body mass index and homeostasis model assessment-insulin resistance. Separate multiple regression analyses were performed with data from the discovery and reduplication subjects to determine whether serum osteocalcin concentration was an independent predictor of the glucose or lipid metabolism markers.Results:For the discovery-study subjects, serum osteocalcin was found to be negatively associated with weight (r=-0.08, P=0.002), BMI (-0.13, P<0.001) and FPG (r=-0.13, P=0.001). Similar results were also found in the reduplication subjects (weight: r=-0.19, P=0.016; BMI: r=-0.23, P=0.003; FPG: r=-0.28, P<0.001). In the multiple regression analysis, serum osteocalcin was revealed as a potential independent predictor for FPG (β=-0.07 and -0.210 for discovery and reduplication, respectively, P<0.01) and BMI (β=-0.127 and -0.299 for discovery and reduplication, respectively, P<0.01).Conclusion:Serum osteocalcin is negatively associated with weight BMI and FPG in healthy Chinese women. Therefore, osteocalcin might contribute to obesity and diabetes.
    Acta Pharmacologica Sinica 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:To explore the effects of noradrenaline (NA) on hepatic stellate cells (HSCs) in vitro and to determine the adrenoceptor (AR) subtypes and underlying mechanisms.Methods:The distribution and expressions of α1A-, α1B-, and α1D-ARs in HSC-T6 cells were analyzed using immunocytochemistry and RT-PCR. Cell proliferation was evaluated with MTT assay. The expression of HSC activation factors [transforming factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA)], extracellular matrix (ECM) secretion factors [tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen-Ι (ColΙ)] and PKC-PI3K-AKT signaling components (PKC, PI3K, and AKT) in the cells were detected by Western blotting and RT-PCR.Results:Both α1B- and α1D-AR were expressed in the membrane of HSC-T6 cells, whereas α1A-AR was not detected. Treatment of the cells with NA concentration-dependently increased cell proliferation (EC50=277 nmol/L), which was suppressed by the α1B-AR antagonist CEC or by the α1D-AR antagonist BMY7378. Furthermore, NA (0.001, 0.1, and 10 μmol/L) concentration-dependently increased the expression of TGF-β1, α-SMA, TIMP-1 and ColΙ, PKC and PI3K, and phosphorylation of AKT in HSC-T6 cells, which were suppressed by CEC or BMY7378, or by pertussis toxin (PT), RO-32-0432 (PKC antagonist), LY294002 (PI3K antagonist) or GSK690693 (AKT antagonist).Conclusion:NA promotes HSC-T6 cell activation, proliferation and secretion of ECM in vitro via activation of Gα-coupled α1B-AR and α1D-AR and the PKC-PI3K-AKT signaling pathway.
    Acta Pharmacologica Sinica 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:Pharmacodynamic analysis of intravenous recombinant urate oxidase produced by Escherichia coli was performed in healthy subjects using a pharmacokinetic/pharmacodynamic (PK/PD) model.Methods:A randomized, single-blind, placebo-controlled study was performed in 40 healthy Chinese subjects (4 groups of 10 subjects each, placebo 4:1 ratio) who received infusions of uricase (single doses of 0.1, 0.2, and 0.3 mg/kg; multiple doses of 0.2 mg·kg(-1)·d(-1) for 7 d). PK profiles were determined through plasma uricase activity, and PD profiles were established using uric acid levels in plasma and urine. The plasma PD parameter was estimated as changes in plasma uric acid levels as the effect in the indirect response model. Adverse events were also monitored.Results:A two-compartment PK model with constant iv input and first-order output was used to describe the kinetic process of plasma uricase. The low value (2.8 U/L) of drug concentration that achieved 50% of maximum effect (EC50) indicated that low plasma uricase concentrations were sufficient to produce pharmacological effects. A strong relationship (r(2)=0.9991) between the mean uric acid concentration in blood and the mean uric acid excretion rate in urine in the range of 11 to 30 h after single dosing was found. Infusions of uricase were well tolerated in all subjects.Conclusion:The PK/PD model predicted the effective dose to be 0.1 mg/kg in healthy subjects. The excretion rate of uric acid in urine may be used as a new index for pharmacological effects in further clinical trials.
    Acta Pharmacologica Sinica 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:Genome-wide association studies have identified several novel loci associated with serum uric acid concentrations in individuals of European descent. In the current study, we aimed to evaluate the associations between these loci and serum uric acid concentrations in a Chinese population.Methods:Fourteen single nucleotide polymorphisms (SNPs) mapped in or near 11 loci (PDZK1, GCKR, LRP2, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC17A3, SLC22A11, SLC22A12 and SF1) were genotyped in 2329 Chinese subjects in Shanghai. Serum biochemical parameters including uric acid concentrations were determined. All the variants were analyzed for gender differences since uric acid metabolism differed between genders.ResultsIn males after adjustments for age and BMI, GCKR rs780094, SLC2A9 rs11722228 and SF1 rs606458 were associated with the uric acid concentrations, which were statistically significant (P=0.016, 0.001 and 0.03, respectively), whereas SLC2A9 rs3775948 was marginally associated with the uric acid concentrations (P=0.071). In females, SLC22A12 rs506338 was also marginally associated with the uric acid concentrations (P=0.057). The meta-analysis for combined data from both males and females revealed that rs3775948 and rs606458 were associated with the uric acid concentrations (P=0.036 and 0.043, respectively). Furthermore, the gender significantly affected the association of rs11722228 with serum uric acid levels (P=0.012).Conclusion The SLC2A9 rs11722228, SF1 rs606458 and GCKR rs780094 variants modulate uric acid concentrations in Chinese males, while SF1 rs606458 and SLC2A9 rs3775948 are associated with the uric acid concentrations in both Chinese males and females.
    Acta Pharmacologica Sinica 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:TGR5 is a G protein-coupled receptor that is expressed in intestinal L-cells and stimulates glucagon-like peptide 1 (GLP-1) secretion. TGR5 may represent a novel target for the treatment of metabolic disorder. Here, we sought to design and synthesize a series of TGR5 agonists derived from the natural product betulinic acid.Methods:A series of betulinic acid derivatives were designed and synthesized. A cAMP assay was established using a HEK293 cell line expressing human TGR5. Luciferase reporter assay was established using HEK293 cells transfected with plasmids encoding human FXR and luciferase reporter. A human intestinal L-cell line NCI-H716 was used to evaluate the effects of the betulinic acid derivatives on GLP-1 secretion in vitro.Results:Biological data revealed that the 3-α-OH triterpenoids consistently show increased potency for TGR5 compared to their 3-β-OH epimers. 3-OH esterification increased the lipophilicity and TGR5 activity of 3-α betulinic derivatives and enhanced the activity differences between 3-α and 3-β derivatives. The 3-α-acyloxy betulinic acids also exhibited a significant dose-dependent GLP-1 secretion effect.Conclusion:This study demonstrates that highly lipophilic 3-epi-betulinic acid derivatives can be potent and selective TGR5 agonists with improved cellular efficacy, and our research here provides a new strategy for the design and development of potent TGR5 agonists.
    Acta Pharmacologica Sinica 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:To investigate the effects of pyrroloquinoline quinone (PQQ), an oxidoreductase cofactor, on high glucose-induced mouse endothelial cell damage in vitro.Methods:Mouse brain microvascular endothelial bEND.3 cells were exposed to different glucose concentrations (5.56, 25 and 40 mmol/L) for 24 or 48 h. The cell viability was examined using MTT assay. Flow cytometry was used to analyze the apoptosis and ROS levels in the cells. MitoTracker Green staining was used to examine the mitochondria numbers in the cells. Western blot analysis was used to analyze the expression of HIF-1α and the proteins in JNK pathway.Results:Treatment of bEND.3 cells with high glucose significantly decreased the cell viability, while addition of PQQ (1 and 10 μmol/L) reversed the high glucose-induced cell damage in a concentration-dependent manner. Furthermore, PQQ (100 μmol/L) significantly suppressed the high glucose-induced apoptosis and ROS production in the cells. PQQ significantly reversed the high glucose-induced reduction in both the mitochondrial membrane potential and mitochondria number in the cells. The high glucose treatment significantly increased the expression of HIF-1α and JNK phosphorylation in the cells, and addition of PQQ led to a further increase of HIF-1α level and a decrease of JNK phosphorylation. Addition of JNK inhibitor SP600125 (10 μmol/L) also significantly suppressed high glucose-induced apoptosis and JNK phosphorylation in bEND.3 cells.Conclusion:PQQ protects mouse brain endothelial cells from high glucose damage in vitro by suppressing intracellular ROS and apoptosis via inhibiting JNK signaling pathway.
    Acta Pharmacologica Sinica 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The chicken ovalbumin upstream promoter transcription factors (COUP-TFs), members of the nuclear receptor superfamily, consist of two highly homologous subtypes, COUP-TFI (EAR-3, NR2F1) and COUP-TFII (ARP-1, NR2F2). They are referred to as orphan receptors because the COUP-TF ligands have yet to be identified. Since the discovery of COUP-TFs in 1986, extensive studies have demonstrated their crucial functions in a variety of developmental processes, such as organogenesis, angiogenesis, and metabolic homeostasis. Recently, emerging evidence has highlighted that COUP-TFs, specifically COUP-TFII, play important roles in tumorigenesis. In this review, we will discuss the critical functions of COUP-TFII in the development of the tumor microenvironment, the progression of various cancers, and its underlying mechanisms.
    Acta Pharmacologica Sinica 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:To evaluate the biochemical features and activities of a glyco-engineered form of the anti-human epidermal growth factor receptor monoclonal antibody (EGFR mAb) cetuximab in vitro.Methods:The genes encoding the Chinese hamster bisecting glycosylation enzyme (GnTIII) and anti-human EGFR mAb were cloned and coexpressed in CHO DG44 cells. The bisecting-glycosylated recombinant EGFR mAb (bisec-EGFR mAb) produced by these cells was characterized with regard to its glycan profile, antiproliferative activity, Fc receptor binding affinity and cell lysis capability. The content of galactose-α-1,3-galactose (α-Gal) in the bisec-EGFR mAb was measured using HPAEC-PAD.Results:The bisec-EGFR mAb had a higher content of bisecting N-acetylglucosamine residues. Compared to the wild type EGFR mAb, the bisec-EGFR mAb exhibited 3-fold higher cell lysis capability in the antibody-dependent cellular cytotoxicity assay, and 1.36-fold higher antiproliferative activity against the human epidermoid carcinoma line A431. Furthermore, the bisec-EGFR mAb had a higher binding affinity for human FcγRIa and FcγRIIIa-158F than the wild type EGFR mAb. Moreover, α-Gal, which was responsible for cetuximab-induced hypersensitivity reactions, was not detected in the bisec-EGFR mAb.Conclusion:The glyco-engineered EGFR mAb with more bisecting modifications and lower α-Gal content than the approved therapeutic antibody Erbitux shows improved functionality in vitro, and requires in vivo validations.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:Fasudil, a selective Rho kinase (ROCK) inhibitor, has been shown to alleviate the severity of experimental autoimmune encephalomyelitis (EAE) via attenuating demyelination and neuroinflammation. The aim of this study was to investigate the effects of fasudil on interactions between macrophages/microglia and T cells in a mice EAE model.Methods:Mouse BV-2 microglia were treated with IFN-γ and fasudil. Cell viability was detected with MTT assay. BV-2 microglia polarization was analyzed using flow cytometry. Cytokines and other proteins were detected with ELISA and Western blotting, respectively. Mice were immunized with MOG35-55 to induce EAE, and then treated with fasudil (40 mg/kg, ip) every other day from d 3 to d 27 pi. Encephalomyelitic T cells were prepared from the spleen of mice immunized with MOG35-55 on d 9 pi.Results:Treatment of mouse BV-2 microglia with fasudil (15 μg/mL) induced significant phenotype polarization and functional plasticity, shifting M1 to M2 polarization. When co-cultured with the encephalomyelitic T cells, fasudil-treated BV-2 microglia significantly inhibited the proliferation of antigen-reactive T cells, and down-regulated IL-17-expressing CD4(+) T cells and IL-17 production. Furthermore, fasudil-treated BV-2 microglia significantly up-regulated CD4(+)CD25(high) and CD4(+)IL-10(+) regulatory T cells (Tregs) and IL-10 production, suggesting that the encephalomyelitic T cells had converted to Tregs. In EAE mice, fasudil administration significantly decreased both CD11b(+)iNOS(+) and CD11b(+)TNF-α(+) M1 microglia, and increased CD11b(+)IL-10(+) M2 microglia.Conclusion:Fasudil polarizes BV-2 microglia into M2 cells, which convert the encephalomyelitic T cells into Tregs in the mice EAE model.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:Metabolic syndrome (MS) and aging are low-grade systemic inflammatory conditions, and inflammation is a key component of endothelial dysfunction. The aim of this study was to investigate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) upon the vascular reactivity in aging MS rats.Methods:MS was induced in young male rats by adding 30% sucrose in drinking water over 6, 12, and 18 months. When the treatment was finished, the blood samples were collected, and aortas were dissected out. The expression of COX isoenzymes and PLA2 in the aortas was analyzed using Western blot analysis. The contractile responses of aortic rings to norepinephrine (1 μmol/L) were measured in the presence or absence of different NSAIDs (10 μmol/L for each).Results:Serum levels of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in control rats were remained stable during the aging process, whereas serum IL-6 in MS rats were significantly increased at 12 and 18 months. The levels of COX isoenzyme and PLA2 in aortas from control rats increased with the aging, whereas those in aortas from MS rats were irregularly increased with the highest levels at 6 months. Pretreatment with acetylsalicylic acid (a COX-1 preferential inhibitor), indomethacin (a non-selective COX inhibitor) or meloxicam (a COX-2 preferential inhibitor) decreased NE-induced contractions of aortic rings from MS rats at all the ages, with meloxicam being the most potent. Acetylsalicylic acid also significantly reduced the maximum responses of ACh-induced vasorelaxation of aortic rings from MS rats, but indomethacin and meloxicam had no effect.Conclusion:NSAIDs can directly affect vascular responses in aging MS rats. Understanding the effects of NSAIDs on blood vessels may improve the treatment of cardiovascular diseases and MS in the elders.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:Excess dietary fat intake can induce lipotoxicity in non-adipose tissues. The aim of this study was to observe the effects of dietary high-fat lard intake on thyroid in rats.Methods:Male Sprague-Dawley rats were fed a high-fat lard diet for 24 weeks, and then the rats were fed a normal control diet (acute dietary modification) or the high-fat lard diet for another 6 weeks. The serum lipid profile, total thyroxine (TT4), free thyroxine (FT4) and thyrotropin (TSH) levels were determined at the 12, 18, 24 and 30 weeks. High-frequency ultrasound scanning of the thyroid glands was performed at the 24 or 30 weeks. After the rats were sacrificed, the thyroid glands were collected for histological and immunohistochemical analyses.Results:The high-fat lard diet significantly increased triglyceride levels in both the serum and thyroid, and decreased serum TT4 and FT4 levels in parallel with elevated serum TSH levels. Ultrasonic imaging revealed enlarged thyroid glands with lowered echotexture and relatively heterogeneous features in the high-fat lard fed rats. The thyroid glands from the high-fat lard fed rats exhibited enlarged follicle cavities and flattened follicular epithelial cells under light microscopy, and dilated endoplasmic reticulum cisternae, twisted nuclei, fewer microvilli and secretory vesicles under transmission electron microscopy. Furthermore, the thyroid glands from the high-fat lard fed rats showed markedly low levels of thyroid hormone synthesis-related proteins TTF-1 and NIS. Acute dietary modification by withdrawal of the high-fat lard diet for 6 weeks failed to ameliorate the high-fat lard diet-induced thyroid changes.Conclusion:Dietary high-fat lard intake induces significant thyroid dysfunction and abnormal morphology in rats, which can not be corrected by short-term dietary modification.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:Ryanodine receptor 2 (RyR2) is a critical component of intracellular Ca(2+) signaling in vascular smooth muscle cells (VSMCs). The aim of this study was to investigate the role of RyR2 in abnormal vascular reactivity after hemorrhagic shock in rats.Methods:SD rats were hemorrhaged and maintained mean arterial pressure (MAP) at 40 mmHg for 30 min or 2 h, and then superior mesenteric arteries (SMA) rings were prepared to measure the vascular reactivity. In other experiments, SMA rings of normal rats and rat VSMCs were exposed to a hypoxic medium for 10 min or 3 h. SMA rings of normal rats and VSMCs were transfected with siRNA against RyR2. Intracellular Ca(2+) release in VSMCs was assessed using Fura-2/AM.Results:The vascular reactivity of the SMA rings from hemorrhagic rats was significantly increased in the early stage (30 min), but decreased in the late stage (2 h) of hemorrhagic shock. Similar results were observed in the SMA rings exposed to hypoxia for 10 min or 3 h. The enhanced vascular reactivity of the SMA rings exposed to hypoxia for 10 min was partly attenuated by transfection with RyR2 siRNA, whereas the blunted vascular reactivity of the SMA rings exposed to hypoxia for 3 h was partly restored by transfection with RyR2 siRNA. Treatment with the RyR agonist caffeine (1 mmol/L) significantly increased Ca(2+) release in VSMCs exposed to hypoxia for 10 min or 3 h, which was partially antagonized by transfection with RyR2 siRNA.Conclusion:RyR2-mediated Ca(2+) release contributes to the development of bi-phasic vascular reactivity induced by hemorrhagic shock or hypoxia.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:To investigate the anticancer effects of S115, a novel heteroaromatic thiosemicarbazone compound in vitro and in vivo.Methods:The anti-proliferative action of S115 was analyzed in 12 human and mouse cancer cell lines using MTT assay. Autograft and xenograft cancer models were made by subcutaneous inoculation of cancer cells into mice or nude mice. The mice were orally treated with S115 (2, 8, 32 mg·kg(-1)·d(-1)) for 7 d, and the tumor size was measured every 3 d. Cell apoptosis and cell cycle distribution were examined using flow cytometry, gene expression profile analyses, Western blots and RT-PCR.Results:The IC50 values of S115 against 12 human and mouse cancer cell lines ranged from 0.3 to 6.6 μmol/L. The tumor growth inhibition rate caused by oral administration of S115 (32 mg·kg(-1)·d(-1)) were 89.7%, 81.7%, 78.4% and 77.8%, respectively, in mouse model of B16 melanoma, mouse model of Colon26 colon cancer, nude mouse model of A549 lung cancer and nude mouse model of SK-OV-3 ovarian cancer. Furthermore, oral administration of S115 (7.5 mg·kg(-1)·d(-1)) synergistically enhanced the anticancer effects of cyclophosphamide, cisplatin, or 5-fluorouracil in mouse model of S180 sarcoma. Treatment of A549 human lung cancer cells with S115 (1.5 μmol/L) induced G0/G1 cell cycle arrest, and increased apoptosis. Furthermore, S115 downregulated the level of ubiquitin, and upregulated the level of Tob2 in A549 cells.Conclusion:S115 exerts anticancer effects against a variety of cancer cells in vitro and in grafted cancer models by inducing apoptosis, downregulating ubiquitin and upregulating Tob2.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:To investigate the metabolite changes caused by simvastatin or fenofibrate intervention in diet-induced hyperlipidemia rats using a GC-MS-based metabolomic profiling approach.Methods:SD rats were fed with high-lipid diet for 4 weeks to induce hyperlipidemia, then the rats were fed with normal diet, and orally administered with simvastatin (10 mg·kg(-1)·d(-1)) or fenofibrate (150 mg·kg(-1)·d(-1)) for 2 weeks. Blood samples were collected once a week, and potential biomarkers were examined using commercial assay kits and a metabolomic approach. The metabolomics data were analyzed using a multivariate statistical technique and a principal component analysis (PCA).Results:Oral administration of simvastatin or fenofibrate significantly decreased the plasma levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol and increased the plasma level of high-density lipoprotein (HDL) cholesterol in the hyperlipidemia rats. Plasma samples were scattered in the PCA scores plots in response to the diet and to the drugs administered. The main metabolites changed in the hyperlipidemia rats were cholesterol, creatinine, linoleic acid, β-hydroxybutyric acid, tyrosine, isoleucine and ornithine. The plasma level of creatinine was significantly lower in the simvastatin-treated rats than in the fenofibrate-treated rats. The plasma tyrosine concentration was declined following intake of high-lipid diet, which was reversed by fenobrate, but not by simvastatin.Conclusion:A series of potential biomarkers including tyrosine, creatinine, linoleic acid, β-hydroxybutyric acid and ornithine have been identified by metabolomic profiling, which may be used to identify the metabolic changes during hyperlipidemia progression.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:Liguzinediol is a novel derivative of ligustrazine isolated from the traditional Chinese medicine Chuanxiong (Ligusticum wallichii Franch), and produces significant positive inotropic effect in isolated rat hearts. In this study we investigated the effects of liguzinediol on a rat model of heart failure.Methods:To induce heart failure, male SD rats were injected with doxorubicin (DOX, 2 mg/kg, ip) once a week for 4 weeks. Then the rats were administered with liguzinediol (5, 10, 20 mg·kg(-1)·d(-1), po) for 2 weeks. Hemodynamic examination was conducted to evaluate heart function. Myocardial cell apoptosis was examined morphologically. The expression of related genes and proteins were analyzed using immunohistochemical staining and Western blot assays, respectively.Results:Oral administration of liguzinediol dose-dependently improved the heart function in DOX-treated rats. Electron microscopy revealed that liguzinediol (10 mg·kg(-1)·d(-1)) markedly attenuated DOX-induced injury of cardiomyocytes, and decreased the number of apoptotic bodies in cardiomyocytes. Furthermore, liguzinediol significantly decreased Bax protein level, and increased Bcl-2 protein level in cardiomyocytes of DOX-treated rats, led to an increase in the ratio of Bcl-2/Bax. Moreover, liguzinediol significantly decreased the expression of both cleaved caspase-3 and NF-κB in cardiomyocytes of DOX-treated rats. Administration of digitalis (0.0225 mg·kg(-1)·d(-1)) also markedly improved the heart function and the morphology of cardiomyocytes in DOX-treated rats.Conclusion:Liguzinediol improves the heart function and inhibits myocardial cell apoptosis in the rat model of heart failure, which is associated with regulating Bcl-2, Bax, caspase-3 and NF-κB expression.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases (PTPs) are considered next-generation drug targets. For instance, PTP1B is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type 1 diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTP1B, Src homology phosphotyrosyl phosphatase 2,(SHP2), lymphoid-specific tyrosine phosphatase (LYP), CD45, Fas associated phosphatase-1 (FAP-1), striatal enriched tyrosine phosphatases (STEP), mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1), phosphatases of regenerating liver-1 (PRL), low molecular weight PTPs (LMWPTP), and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:To develop a population pharmacokinetics model of oxcarbazepine in Chinese pediatric patients with epilepsy, and to study the interactions between oxcarbazepine and other antiepileptic drugs (AEDs).Methods:A total of 688 patients with epilepsy aged 2 months to 18 years were divided into model (n=573) and valid (n=115) groups. Serum concentrations of the main active metabolite of oxcarbazepine, 10-hydroxycarbazepine (MHD), were determined 0.5-48 h after the last dosage. A population pharmacokinetics (PPK) model was constructed using NLME software. This model was internally evaluated using Bootstrapping and goodness-of-fit plots inspection. The data of the valid group were used to calculate the mean prediction error (MPE), mean absolute prediction error (MAE), mean squared prediction error (MSE) and the 95% confidence intervals (95% CI) to externally evaluate the model.Results:The population values of pharmacokinetic parameters estimated in the final model were as follows: Ka=0.83 h-1, Vd=0.67 L/kg, and CL=0.035 L·kg(-1)·h(-1). The enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital) and newer generation AEDs (levetiracetam, lamotrigine, topiramate) increased the weight-normalized CL value of MHD by 17.4% and 10.5%, respectively, whereas the enzyme-inhibiting AED valproic acid decreased it by 3%. No significant association was found between the CL value of MHD and the other covariates. For the final model, the evaluation results (95% CI) were MPE=0.01(-0.07-0.10) mg/L, MAE=0.46 (0.40-0.51) mg/L, MSE=0.39 (0.27-0.51) (mg/L)(2).Conclusion:A PPK model of OXC in Chinese pediatric patients with epilepsy is established. The enzyme-inducing AEDs and some newer generation AEDs (lamotrigine, topiramate) could slightly increase the metabolism of MHD.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:Telekin, isolated from the Chinese herb Carpesium divaricatum, has shown anti-proliferation effects against various cancer cells, including hepatocellular carcinoma cells. In this study, we investigated the anti-proliferation mechanisms of telekin in human hepatocellular carcinoma HepG2 cells in vitro.Methods:HepG2 cells were treated with telekin. Cell viability was evaluated using MTT assay. Flow cytometry was used to measure cell cycle profiles, ROS level and apoptosis. The protein expression levels were analyzed with Western blotting.Results:Telekin (3.75-30 μmol/L) dose-dependently inhibited the viability of HepG2 cells and induced l apoptosis. Furthermore, the treatment induced cell cycle arrest at G2/M phase, accompanied by significantly increased the phosphorylation of Cdc25A and Cdc2, and decreased Cyclin B1 level. Moreover, the treatment significantly stimulated ROS production, and increased the phosphorylation of p38 and MAPKAPK-2 in the cells. Pretreatment with the antioxidant NAC (2.5, 5, and 10 mmol/L), or the p38 MAPK inhibitor SB203580 (2.5 and 5 μmol/L) dose-dependently attenuated these telekin-induced effects in the cells.Conclusion:Telekin suppresses hepatocellular carcinoma cells in vitro by inducing G2/M phase arrest via activating the p38 MAPK pathway.
    Acta Pharmacologica Sinica 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim:To discover novel ligands of estrogen receptor (ER) β using pharmacophore mapping and structure-based screening.Methods:A computer-aided strategy combining pharmacophore mapping and structure-based screening was used to screen the Maybridge and Enamine databases. Yeast two-hybrid (Y2H) assay was used to detect the activity and selectivity of the chosen compounds. The transcriptional activities of the chosen compounds were demonstrated with luciferase reporter assays. The anti-proliferative effects of ER antagonists against MCF-7 and MDA-MB-231 breast cancer cells were examined using MTT assay, and the mechanisms of action were analyzed with flow cytometry analysis and Western blotting.Results:Through in silico screen, 95 compounds were chosen for testing in Y2H assay, which led to 20 potent ligands, including 10 agonists, 8 antagonists and 2 partial agonists with EC50 or IC50 values at μmol/L. Furthermore, 6 agonists exhibited absolute selectivity for ERβ, and 3 agonists showed higher selectivity for ERβ. The agonists 1g and 1h (10, 25, and 50 μmol/L) dose-dependently increased ER transcriptional activities, whereas the antagonists 2a and 2d (10, 25, and 50 μmol/L) caused dose-dependent inhibition on the activities. The antagonists and partial agonists at 100 μmol/L suppressed the proliferation of ERα positive MCF-7 cells and ERβ positive MDA-MB-231 cells, but were more effective against MDA-MB-231 cells. Treatment of MDA-MB-231 cells with antagonists 2a and 2d (25 and 50 μmol/L) dose-dependently increased the population of cells in the S phase. Both 2a and 2d treatment dose-dependently decreased the expression levels of cyclin A and CDK2. Meanwhile, the downregulation of cyclin E was only caused by 2d, while 2a treatment did not cause significant changes in the protein levels of cyclin E.Conclusion:The selective ligands discovered in this study are promising drug candidates to be used as molecular probes to explore the differences between ERα and ERβ.
    Acta Pharmacologica Sinica 09/2014;