Publications by authors named "Yan-xin Liu"

35 Publications

SAF-248, a novel PI3Kδ-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma.

Acta Pharmacol Sin 2021 Mar 29. Epub 2021 Mar 29.

Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

PI3Kδ is expressed predominately in leukocytes and overexpressed in B-cell-related malignances. PI3Kδ has been validated as a promising target for cancer therapy, and specific PI3Kδ inhibitors were approved for clinical practice. However, the substantial toxicity and relatively low efficacy as a monotherapy in diffuse large B-cell lymphoma (DLBCL) limit their clinical use. In this study, we described a novel PI3Kδ inhibitor SAF-248, which exhibited high selectivity for PI3Kδ (IC = 30.6 nM) over other PI3K isoforms at both molecular and cellular levels, while sparing most of the other human protein kinases in the kinome profiling. SAF-248 exhibited superior antiproliferative activity against 27 human lymphoma and leukemia cell lines compared with the approved PI3Kδ inhibitor idelalisib. In particular, SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines (with GI values < 1 μM in 5 DLBCL cell lines). We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G phase arrest and apoptosis in DLBCL KARPAS-422, Pfeiffer and TMD8 cells. Its activity against the DLBCL cells was negatively correlated to the protein level of PI3Kα. Oral administration of SAF-248 dose-dependently inhibited the growth of xenografts derived from Pfeiffer and TMD8 cells. Activation of mTORC1, MYC and JAK/STAT signaling was observed upon prolonged treatment and co-targeting these pathways would potentiate the activity of SAF-248. Taken together, SAF-248 is a promising selective PI3Kδ inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.
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http://dx.doi.org/10.1038/s41401-021-00644-1DOI Listing
March 2021

Epidemiological survey of echinococcosis in Tibet Autonomous Region of China.

Infect Dis Poverty 2019 Apr 28;8(1):29. Epub 2019 Apr 28.

Henan Center for Diseases Control and Prevention, Zhengzhou, Shanghai, 450 000, Henan, China.

Background: The echinococcosis is prevalent in 10 provinces /autonomous region in western and northern China. Epidemiological survey of echinococcosis in China in 2012 showed the average prevalence of four counties in Tibet Autonomous Region (TAR) is 4.23%, much higher than the average prevalence in China (0.24%). It is important to understand the transmission risks and the prevalence of echinococcosis in human and animals in TAR.

Methods: A stratified and proportionate sampling method was used to select samples in TAR. The selected residents were examined by B-ultrasonography diagnostic, and the faeces of dogs were tested for the canine coproantigen against Echinococcus spp. using enzyme-linked immunosorbent assay. The internal organs of slaughtered domestic animals were examined by visual examination and palpation. The awareness of the prevention and control of echinococcosis among of residents and students was investigated using questionnaire. All data were inputted using double entry in the Epi Info database, with error correction by double-entry comparison, the statistical analysis of all data was processed using SPSS 21.0, and the map was mapped using ArcGIS 10.1, the data was tested by Chi-square test and Cochran-Armitage trend test.

Results: A total of 80 384 people, 7564 faeces of dogs, and 2103 internal organs of slaughtered domestic animals were examined. The prevalence of echinococcosis in humans in TAR was 1.66%, the positive rate in females (1.92%) was significantly higher than that in males (1.41%), (χ = 30.31, P < 0.01), the positive rate of echinococcosis was positively associated with age (χ = 423.95, P < 0.01), and the occupational populations with high positive rates of echinococcosis were herdsmen (3.66%) and monks (3.48%). The average positive rate of Echinococcus coproantigen in TAR was 7.30%. The positive rate of echinococcosis in livestock for the whole region was 11.84%. The average awareness rate of echinococcosis across the region was 33.39%.

Conclusions: A high prevalence of echinococcosis is found across the TAR, representing a very serious concern to human health. Efforts should be made to develop an action plan for echinococcosis prevention and control as soon as possible, so as to control the endemic of echinococcosis and reduce the medical burden on the population.
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http://dx.doi.org/10.1186/s40249-019-0537-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487032PMC
April 2019

Transforming Growth Factor-β Receptor III is a Potential Regulator of Ischemia-Induced Cardiomyocyte Apoptosis.

J Am Heart Assoc 2017 May 30;6(6). Epub 2017 May 30.

Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China

Background: Myocardial infarction (MI) is often accompanied by cardiomyocyte apoptosis, which decreases heart function and leads to an increased risk of heart failure. The aim of this study was to examine the effects of transforming growth factor-β receptor III (TGFβR3) on cardiomyocyte apoptosis during MI.

Methods And Results: An MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFβR3, and mitogen-activated protein kinase signaling were assessed by methylthiazolyldiphenyl-tetrazolium bromide assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunofluorescence, electron microscopy, and Western blotting. Our results demonstrated that TGFβR3 expression in the border region of the heart was dynamically changed during MI. After stimulation with HO, TGFβR3 overexpression in cardiomyocytes led to increased cell apoptosis and activation of p38 signaling, whereas TGFβR3 knockdown had the opposite effect. ERK1/2 and JNK1/2 signaling was not altered by TGFβR3 modulation, and p38 inhibitor (SB203580) reduced the effect of TGFβR3 on apoptosis, suggesting that p38 has a nonredundant function in activating apoptosis. Consistent with the in vitro observations, cardiac TGFβR3 transgenic mice showed augmented cardiomyocyte apoptosis, enlarged infarct size, increased injury, and enhanced p38 signaling upon MI. Conversely, cardiac loss of function of TGFβR3 by adeno-associated viral vector serotype 9-TGFβR3 short hairpin RNA attenuated the effects of MI in mice.

Conclusions: TGFβR3 promotes apoptosis of cardiomyocytes via a p38 pathway-associated mechanism, and loss of TGFβR3 reduces MI injury, which suggests that TGFβR3 may serve as a novel therapeutic target for MI.
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http://dx.doi.org/10.1161/JAHA.116.005357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669164PMC
May 2017

Arsenic trioxide and angiotensin II have inhibitory effects on HERG protein expression: Evidence for the role of PML SUMOylation.

Oncotarget 2017 Jul;8(28):45447-45458

Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P. R. China.

The human ether-a-go-go-related gene (HERG) channel is a novel target for the treatment of drug-induced long QT syndrome, which causes lethal cardiotoxicity. This study is designed to explore the possible role of PML SUMOylation and its associated nuclear bodies (NBs) in the regulation of HERG protein expression. Both arsenic trioxide (ATO) and angiotensin II (Ang II) were able to significantly reduce HERG protein expression, while also increasing PML SUMOylation and accelerating the formation of PML-NBs. Pre-exposure of cardiomyocytes to a SUMOylation chemical inhibitor, ginkgolic acid, or the silencing of UBC9 suppressed PML SUMOylation, subsequently preventing the downregulation of HERG induced by ATO or Ang II. Conversely, knockdown of RNF4 led to a remarkable increase in PML SUMOylation and the function of PML-NBs, further promoting ATO- or Ang II-induced HERG protein downregulation. Mechanistically, an increase in PML SUMOylation by ATO or Ang II dramatically enhanced the formation of PML and Pin1 complexes in PML-NBs, leading to the upregulation of TGF-β1 protein, eventually inhibiting HERG expression through activation of protein kinase A. The present work uncovered a novel molecular mechanism underlying HERG protein expression and indicated that PML SUMOylation is a critical step in the development of drug-acquired arrhythmia.
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http://dx.doi.org/10.18632/oncotarget.17563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542199PMC
July 2017

Manipulating PML SUMOylation via Silencing UBC9 and RNF4 Regulates Cardiac Fibrosis.

Mol Ther 2017 03 28;25(3):666-678. Epub 2017 Jan 28.

Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China. Electronic address:

The promyelocytic leukemia protein (PML) is essential in the assembly of dynamic subnuclear structures called PML nuclear bodies (PML-NBs), which are involved in regulating diverse cellular functions. However, the possibility of PML being involved in cardiac disease has not been examined. In mice undergoing transverse aortic constriction (TAC) and arsenic trioxide (ATO) injection, transforming growth factor β1 (TGF-β1) was upregulated along with dynamic alteration of PML SUMOylation. In cultured neonatal mouse cardiac fibroblasts (NMCFs), ATO, angiotensin II (Ang II), and fetal bovine serum (FBS) significantly triggered PML SUMOylation and the assembly of PML-NBs. Inhibition of SUMOylated PML by silencing UBC9, the unique SUMO E2-conjugating enzyme, reduced the development of cardiac fibrosis and partially improved cardiac function in TAC mice. In contrast, enhancing SUMOylated PML accumulation, by silencing RNF4, a poly-SUMO-specific E3 ubiquitin ligase, accelerated the induction of cardiac fibrosis and promoted cardiac function injury. PML colocalized with Pin1 (a positive regulator for TGF-β1 mRNA expression in PML-NBs) and increased TGF-β1 activity. These findings suggest that the UBC9/PML/RNF4 axis plays a critical role as an important SUMO pathway in cardiac fibrosis. Modulating the protein levels of the pathway provides an attractive therapeutic target for the treatment of cardiac fibrosis and heart failure.
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http://dx.doi.org/10.1016/j.ymthe.2016.12.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363217PMC
March 2017

[Investigation of soil - transmitted nematode infections in Xiding Township, Menghai County, Yunnan Province].

Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi 2016 May;29(1):93-95

Menghai Center for Disease Control and Prevention, Yunnan Province, China.

Objective: To understand the status of soil-transmitted nematode infections in Xiding Township, Menghai County, Yunnan Province, so as to provide the reference for formulating the strategy of soil-transmitted nematodosis control.

Methods: Soil-transmitted nematode eggs in feces were detected by the Kato-Katz method, and the eggs of were detected by the cellophane tape method in children. The soil samples were collected from vegetable, fruit and other crop fields of 15 residents randomly to detect hookworm.

Results: The stool samples from 1 002 residents were examined and the soil -transmitted nematode infection rate was 20.06% (201/1 002). The infection rates of hookworm, and were 18.96% (190 cases), 1.70% (17 cases) and 0.90% (9 cases) respectively. The percentages of people with light infection of hookworm, and were 97.37% (185/190), 88.24% (15/17) and 100% (9/9) respectively. No infection of was found. Fifteen soil samples were tested, and no hookworm was found in the soil.

Conclusions: The infection rate of soil-transmitted nematode in Xiding Township, Menghai County is high, but the infectiosity is light. The control and monitoring of soil-transmitted nematodosis should be strengthened in this area.
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http://dx.doi.org/10.16250/j.32.1374.2016070DOI Listing
May 2016

Formulation of intumescent flame retardant coatings containing natural-based tea saponin.

J Agric Food Chem 2015 Mar 10;63(10):2782-8. Epub 2015 Mar 10.

ΔSchool of Chemistry and Environment Engineering, Hunan City University, Yiyang 413000, Hunan, People's Republic of China.

Natural product tea saponin (TS), extracted from the nutshell of camellia (Camellia oleifera Abel, Theaceae), was introduced into intumescent flame retardant formulations as blowing agent and carbon source. The formulations of the flame retardant system were optimized to get the optimum proportion of TS, and intumescent flame retardant coatings containing tea saponin (TS-IFRCs) were then prepared. It was found that TS can significantly affect the combustion behavior and the thermal stability of TS-IFRCs evaluated by cone calorimetry and simultaneous thermal analyzer, respectively. It was shown that TS, degraded to water vapor and carbon at high temperatures, can combine with other components to form a well-developed char layer. The char layer was supposed to inhibit erosion upon exposure to heat and oxygen and enhance the flame retardancy of TS-IFRCs. In addition, the smoke release of TS-IFRCs was also studied, which provided a low amount of smoke production.
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http://dx.doi.org/10.1021/jf505898dDOI Listing
March 2015

Performance analysis of extracted rule-base multivariable type-2 self-organizing fuzzy logic controller applied to anesthesia.

Biomed Res Int 2014 21;2014:379090. Epub 2014 Dec 21.

Department of Mechanical Engineering and Innovation Center for Big Data and Digital Convergence, Yuan Ze University, Chungli 320, Taiwan ; Center for Dynamical Biomarkers and Translational Medicine, National Central University, Chung-Li 32001, Taiwan.

We compare type-1 and type-2 self-organizing fuzzy logic controller (SOFLC) using expert initialized and pretrained extracted rule-bases applied to automatic control of anaesthesia during surgery. We perform experimental simulations using a nonfixed patient model and signal noise to account for environmental and patient drug interaction uncertainties. The simulations evaluate the performance of the SOFLCs in their ability to control anesthetic delivery rates for maintaining desired physiological set points for muscle relaxation and blood pressure during a multistage surgical procedure. The performances of the SOFLCs are evaluated by measuring the steady state errors and control stabilities which indicate the accuracy and precision of control task. Two sets of comparisons based on using expert derived and extracted rule-bases are implemented as Wilcoxon signed-rank tests. Results indicate that type-2 SOFLCs outperform type-1 SOFLC while handling the various sources of uncertainties. SOFLCs using the extracted rules are also shown to outperform those using expert derived rules in terms of improved control stability.
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http://dx.doi.org/10.1155/2014/379090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283452PMC
August 2015

[Molecular mechanism of hydroxyurea enhances K562 cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2012 Apr;34(2):146-52

Institute of Basic Medical Sciences, CAMS and PUMC, Beijing, China.

Objective: To explore the molecular mechanism via which the chemotherapeutic drug hydroxyurea (HU) enhances K562 cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

Methods: Chronic myelogenous leukemia-derived K562 and SVT-35 cells were treated with recombinant soluble TRAIL (rsTRAIL) alone or combined with HU for a time course, and the cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-4-sulfophenyl-2H-tetrazolium-phenazine methosulphate assay. Western blot was performed to analyze the activation of apoptosis-related protein kinases and the expression of apoptosis inhibitor molecules.

Results: The survival rates of SVT-35 and K562 cells treated with 1 μg/ml rsTRAIL for 24 hours were 32% and 93%, respectively. HU significantly increased the sensitivity of K562 cells to rsTRAIL cytotoxicity. Combination of rsTRAIL and HU resulted in the phosphorylation of rat sarcoma (RAS), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase and in the significant reduction of apoptosis-inhibited molecule Fas associated death domain protein-like interleukin-1 beta-convening enzyme inhibitory protein and cellular inhibitor of apoptosis protein-1 in K562 cells.

Conclusions: HU enhanced K562 cell sensitivity to rsTRAIL is mediated by Ras-MEK-ERK signaling pathway. Expression of antiapoptotic proteins cellular Fas associated death domain protein-like interleukin-1 beta-convening enzyme inhibitory protein and cellular inhibitor of apoptosis protein-1 is also down-regulated during this process. These results may through light on the therapeutic study of human chronic myelogenous leukemia.
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http://dx.doi.org/10.3881/j.issn.1000-503X.2012.02.009DOI Listing
April 2012

Synthesis, structure-activity relationship and in vitro anti-mycobacterial evaluation of 13-n-octylberberine derivatives.

Eur J Med Chem 2012 Jun 21;52:151-8. Epub 2012 Mar 21.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Twenty-eight new 13-n-octylberberine derivatives were synthesized and evaluated for their activities against drug-susceptible Mycobacterium tuberculosis (M. tuberculosis) strain H(37)Rv. Among these compounds, compound 16e was the most effective anti-tubercular agent with a MIC value of 0.125 μg/mL. Importantly, compound 16e exhibited more potent effect against rifampicin (RIF)- and isoniazid (INH)-resistant M. tuberculosis strains than both RIF and INH, suggesting a new mechanism of action. Therefore, it has been selected as a drug candidate for further investigation, or as a chemical probe for identifying protein target and studying tuberculosis biology. We consider 13-n-octylberberine analogs to be a promising novel class of antituberculars against multi-drug-resistant (MDR) strains of M. tuberculosis.
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http://dx.doi.org/10.1016/j.ejmech.2012.03.012DOI Listing
June 2012

Synthesis and in vitro antitubercular evaluation of novel sansanmycin derivatives.

Bioorg Med Chem Lett 2011 Nov 16;21(22):6804-7. Epub 2011 Sep 16.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Tuberculosis (TB) is a major health problem worldwide. A series of novel sansanmycin derivatives were designed, semi-synthesized and evaluated for their activity against drug-susceptible Mycobacterium tuberculosis strain H(37)Rv with sansanmycin A (SSA) as the lead. Among these analogs tested, compound 1d possessing an isopropyl group at the amino terminal afforded an increased antimycobacterial activity with a MIC value of 8 μg/mL in comparison with SSA. Importantly, it was active for rifampicin- and isoniazid-resistant M. tuberculosis strain isolated from patients in China. These promising results offer an opportunity for further exploration of this novel class of analogs as antitubercular agents.
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http://dx.doi.org/10.1016/j.bmcl.2011.09.031DOI Listing
November 2011

[Combination of AD5-10 and epirubicin in treating rheumatoid arthritis].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2011 Aug;33(4):367-70

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Beijing, China.

Objective: To investigate the mechanism of anti-death receptor 5-10 (AD5-10) combined with epirubicin in treating rheumatoid arthritis (RA).

Methods: We detected the cell viability of the fibroblast-like synoviocytes (FLS) from RA patients with MTT. The expression level of apoptosis signaling pathways protein, p53, and p21 were evaluated with Western blot.

Results: We found that epirubicin, at different doses, could enhance the effect of AD5-10 on FLS, promoting the apoptosis of FLS. The expression levels of caspase-3, -8, -9, c-FLIP, Bcl-2, p53, and p21 in the FLS changed after epirubicin treatment.

Conclusion: Epirubicin may coordinate with AD5-10 in inducing FLS apoptosis through affecting the levels of p53, p21, c-FLIP, and Bcl-2.
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http://dx.doi.org/10.3881/j.issn.1000-503X.2011.04.004DOI Listing
August 2011

Synthesis, structure-activity relationship and in vitro biological evaluation of N-arylethyl isoquinoline derivatives as Coxsackievirus B3 inhibitors.

Bioorg Med Chem Lett 2011 Oct 8;21(19):5787-90. Epub 2011 Aug 8.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Currently, there is no approved antiviral drug for the infection caused by enteroviruses. A series of novel N-arylethyl isoquinoline derivatives defined with substituents on the ring A and C were designed, synthesized and evaluated in vitro for their activities against Coxsackievirus B3 (CVB3). The primary structure-activity relationship revealed that substituents on the ring A were not beneficial for the activity. Among these analogs synthesized, compound 7f bearing a methylenedioxy at the R(4) and R(5) positions afforded an anti-CVB3 activity and a reasonable selectivity index (SI=26.8); furthermore, 7f exhibited a moderate activity against enterovirus 71 (EV71) with SI value of 9.0. Thus it has been selected as an anti-enteroviral lead compound for further investigation.
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http://dx.doi.org/10.1016/j.bmcl.2011.08.002DOI Listing
October 2011

Synthesis, structure-activity relationship and biological evaluation of novel N-substituted matrinic acid derivatives as host heat-stress cognate 70 (Hsc70) down-regulators.

Bioorg Med Chem Lett 2011 Aug 23;21(16):4732-5. Epub 2011 Jun 23.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Oxymatrine (1) is a natural anti-hepatitis B virus (HBV) drug that down-regulates host heat-stress cognate 70 (Hsc70) expression through a mechanism different from that of nucleosides. Taking Hsc70 as a target against HBV, 26 novel N-substituted matrinic acid analogs were designed, synthesized and evaluated for their regulation of Hsc70 mRNA expression with 1 as the lead. The SAR analysis revealed that (i) the carboxyl group at the 11-position was required for activity; (ii) introducing of a substituent on the nitrogen atom at the 12-position of 3, especially substituted benzyl, might significantly improve the activity. Among these analogs, compound 9p possessing N-p-methoxylbenzyl afforded an increased anti-HBV effect in comparison with 1. We consider 9p a promising anti-HBV candidate.
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http://dx.doi.org/10.1016/j.bmcl.2011.06.071DOI Listing
August 2011

[Expression and tumoricidal activity of a human-mouse chimeric anti-DR5 antibody through a Furin/2A peptide].

Zhonghua Yi Xue Za Zhi 2011 Mar;91(10):707-10

Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China.

Objective: To express a full-length human-mouse chimeric anti-DR5 antibody from a single open reading frame with tumoricidal activity to various cancer cells.

Methods: The heavy and light chains of chimeric antibody were joined by the Furin and 2A (F/2A) self-cleavage peptide and cloned into a lentiviral vector of pWPXL. Then the HEK293 cells were infected with the constructed expression vector pWPXL-HF2AL. Western blot, enzyme-linked immunosorbent assay (ELISA) and MTS assay were used to detect the chimeric antibody expression, cleavage, binding affinity to the antigen and tumoricidal activity to various tumor cells.

Results: The recombinant chimeric antibody was successfully expressed from a single open reading frame in pWPXL-HF2AL construct. And it possessed a similar binding affinity to the parental murine counterpoint and strong tumoricidal activity to various cancer cells. For example, on the concentration of 3 µg/ml, it made the relative cells viability of HCT116, SMMC7721, A549 and U251 down to 20.6% ± 2.6%, 35.1% ± 2.7%, 76.1% ± 6.1% and 15.6% ± 2.0% respectively.

Conclusions: The human-mouse chimeric anti-DR5 antibody of F/2A peptide is successfully expressed. Possessing a strong tumoricidal activity in various cancer cells, it may provide a novel strategy for cancer biotherapy.
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March 2011

[Effect of miR-146a on IL-18 expression in mouse macrophage].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2011 May;27(5):477-9

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.

Aim: To investigate the effect of miR-146a on the Th1/Th2 cytokine expression in mouse RAW264.7 cell line and primary peritoneal macrophage.

Methods: miR-146a mimics, mimics negative control (NC mimics), inhibitor miR-146a and inhibitor negative control (NC inhibitor) were transfected into RAW264.7 cells and freshly isolated peritoneal macrophage. IL-18, IL-5 and IL-10 expressions in the cells were measured by real time PCR.

Results: MiR-146a mimics suppressed IL-18 expression (P<0.05), and miR-146a specific inhibitor increased IL-18 expression significantly (P<0.05). However, IL-5 and IL-10 expressions were not affected by both miR-146a mimics and miR-146a inhibitor transfections.

Conclusion: These data demonstrate at first time that miR-146a can regulate Th1 cytokine IL-18 expression, but not affect Th2 cytokine IL-5 and IL-10 expressions.
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May 2011

[Construction and stable expression of anti-human tumor necrosis factor-related apoptosis-inducing ligand receptor 2 chimeric antibody in CHO cells].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2011 Apr;27(4):415-8

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, CAMS, Beijing 100005, China.

Aim: To establish an human-mouse chimeric antibody against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (death receptor 5, DR5) in an eukaryotic cell line and analyse its tumoricidal activity.

Methods: The cDNAs encoding for the variable regions of heavy chain (V(H);) and light chain (V(L);) of AD5-10 were amplified by PCR and inserted into the human IgG heavy and light chain containing expression vector RpCI-neo, respectively. The recombinant plasmids were co-transfected into HEK293 and/or CHO cells. The production of anti-DR5 human-mouse chimeric antibody (hmAD5-10) and the antibody affinity for DR5 were identified by ELISA and Western blot assay. The tumoricidal activity of hmAD5-10 was demonstrated by MTS assay. The stable expression cells were selected and cultured in serum-free medium.

Results: Two stable CHO cells CHO-A5 and CHO-B11 with the chimeric antibody hmAD5-10 expression were established, in which the production of hmAD5-10 were reached at (0.36±0.11) mg/L and (0.16±0.01) mg/L, respectively. The hmAD5-10 secreted from the cells can well bind with DR5 and kill the cultured leukemia SVT35 cells by apoptosis remarkably.

Conclusion: The human-mouse chimeric antibody hmAD5-10 was successfully expressed in the eukaryotic cells and resulted tumor cell death by apoptosis. This study lays a fundamental basis for the potential application of the recombinant chimeric antibody in cancer therapy.
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April 2011

[Killing effects of controllable expression of tumor necrosis factor-related apoptosis-inducing ligand from mesenchymal stem cells on hepatocellular carcinoma cells].

Zhonghua Yi Xue Za Zhi 2011 Mar;91(8):544-8

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.

Objective: To study the controllable expression of soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in mesenchymal stem cells and evaluate its potential tumoricidal effects in cancer therapy.

Methods: The controllable TRAIL expression vector of Ad-Tet-TRE-TRAIL was established in an adenovirus vector for transfection into murine mesenchymal stem cells. The controllable expression and secretion of TRAIL were detected by Western blot and enzyme-linked immunosorbent assay. The viability of hepatocellular carcinoma cells was determined by MTT assay. The tumoricidal activity of TRAIL was determined by Annexin-V/PI staining and flow cytometry.

Results: The murine expression model of TRAIL was successfully established in the presence of doxycycline. The secreted TRAIL in cell culture medium could efficaciously suppress the growth of human hepatocellular carcinoma SMMC-7402 by induced apoptosis. The cell viability of SMMC-7402 was 66.5% ± 4.8% and 42.9% ± 6.5% at post-treatment versus 97.3% ± 2.2% and 99.4% ± 4.7% in the control group at 24 h and 48 h.

Conclusion: The controllable TRAIL expression mediated by mesenchymal stem cells kills human hepatocellular carcinoma cells effectively. And it may provide a novel therapeutic strategy for hepatocellular carcinoma.
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March 2011

Structural and functional analysis of the N-terminal region of death receptor 5.

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2011 Feb;33(1):33-8

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences,CAMS and PUMC, Beijing 100005, China.

Objective: To investigate the structure and function of the N-terminal region (NTR) of death receptor 5 (DR5).

Methods: A series of deletions of the DR5 extracellular domain (DR5-ECD) proteins were expressed in E.coli. and purified by affinity chromatography. The binding ability of these deletant proteins to AD5-10, a mouse anti-human DR5 monoclonal antibody, was evaluated by immunoblotting and ELISA.

Results: Recombinant DR5-ECD proteins containing the NTR were recognized and bound by AD5-10, while the other deletant proteins without the NTR failed to interact with AD5-10.

Conclusion: There is an AD5-10 targeting site in the NTR of DR5, which may play a role in developing novel immunotherapies for cancers.
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http://dx.doi.org/10.3881/j.issn.1000-503X.2011.01.008DOI Listing
February 2011

[Analysis of HSP70 mRNA level and association between linked microsatellite loci and heat tolerance traits in dairy cows].

Yi Chuan 2010 Sep;32(9):935-41

College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.

The objective of this study was to investigate the variation of HSP70 mRNA level in dairy cows and relationships of its closely linked microsatellite loci with heat tolerance traits. Blood samples were collected from ten healthy Holstein cows with the same age and milking stage at different temperatures-humid-index (THI) (86.2, high temperature; 70.9, critical high temperature, and 56.8, optimum temperature). The mRNA levels of HSP70 of lymphocytes in peripheral blood were analyzed using real-time RT-PCR. The mRNA level of HSP70 was increased with the THI; the mRNA level of HSP70 at high temperature was higher than others (P<0.01). This indicated that the bovine HSP70 gene may act as a potential can-didate gene for response to heat shock. Genetic variation of three microsatellite loci BMS468, BM1258, and BM1815, which were closely linked to HSP70 gene on chromosome 23, was analyzed in 160 Holstein cows with non-denaturing poly-acrylamide gel electrophoresis. The association between these microsatellite loci and heat tolerance traits were analyzed by least square linear model. The results showed that 134 bp/128 bp at BMS468 and 186 bp/148 bp at BM1815 were the most favorable genotypes for HTC, red cell potassium, and decrement rate of milk yield in high temperature (P<0.05); 101 bp/99 bp at BM1258 was the most favorable genotype for decrement rate of milk yield in high temperature (P<0.05).
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http://dx.doi.org/10.3724/sp.j.1005.2010.00935DOI Listing
September 2010

[Relationships of three microsatellite loci with GSH-Px, SOD and Na+/K+-ATP enzyme activities and daily milk yield in different seasons in Holstein cows].

Yi Chuan 2010 Apr;32(4):381-6

College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.

Genetic variation of three microsatellite loci BMS2258, SOD1, and BM723, which were closely correlated with GSH-Px, SOD, and Na+/K+-ATPase genes, was analyzed in 130 Holstein cows by PCR and nondenaturing polyacrylamide gel-electrophoresis. Polymorphic information content, effective number of alleles and heterozygosity of these microsatellite loci were determined. Relationships of the three microsatellite loci with enzyme activities and daily milk yields in Holstein cows were analyzed by least squares linear model. The results showed significant correlations of the three microsatellite loci with their corresponding enzyme activities and daily milk yield in summer and fall (Plt;0.05). The least square means of GSH-Px activities and daily milk yields for BMS2258 (182 bp/164 bp), SOD activities for SOD1 (148 bp/148 bp), and daily milk yields for SOD1 (148 bp/146 bp), Na+/K+-ATPase activities and daily milk yields for BM723 (161 bp/111 bp) were relatively higher. These genotypes were the most favorable genotypes for enzyme activity and daily milk yields in summer and fall, which could be references for marker assisted selection in heat resistance traits in dairy cattle.
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http://dx.doi.org/10.3724/sp.j.1005.2010.00381DOI Listing
April 2010

[Impact of heavy snow storm and freezing rain disasters on soil fauna in Chinese fir plantation in southern China].

Ying Yong Sheng Tai Xue Bao 2009 Jan;20(1):65-70

Huitong Experimental Station of Forest Ecology, Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang 110016, China.

In January 2008, southern China suffered an unusual heavy snowstorm and freezing rain over a large area for almost a month long. This catastrophic event was the worst one in past 50 years, which brought the area a serious impact on the infrastructure, ecology, and environment. To understand the long-term impact of this catastrophic event on the forest ecosystems in this area, a field investigation was conducted on the soil fauna in a pure Chinese fir plantation and a mixed Chinese fir plantation-alder plantation in Huitong County of Hunan Province on March 23, 2008, the date 40 days after the heavy snowstorm and freezing rain. With the abundance and community composition as the main parameters and the monitoring data from the two plantations on March 23, 2007 as the reference, the flexibility and resistance of soil fauna to the disturbances of the catastrophic event was preliminarily evaluated. The results showed that there was a significant deviation of soil fauna communities in the two plantations from the reference. An outbreak increase in microfauna nematode abundance was found from 12216.9 ind x m(-2) to 118343.9 ind x m(-2) in pure Chinese fir plantation and from 25435.9 ind x m(-2) to 84573.0 ind x m(-2) in mixed Chinese fir plantation-alder plantation, while a 27.0% and 85.6% decrease of macrofauna abundance was found in the two plantations, respectively, compared with the reference. Mesofauna abundance also had a significant decrease in litter layer but not in soil. The abundance recovery displayed a trend from quick rate for microfauna to slow rate for macrofauna, which indicated that the soil fauna functional groups, in terms of body size, could be used as a vulnerable indicator in evaluating disturbance event and post-disturbance recovery. By using community ordinations, no shift in soil fauna community composition was detected 40 days after the catastrophic event, suggesting that the community composition of soil invertebrate had a high resistance to catastrophic snowstorm and freezing rain disturbances.
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January 2009

[Construction and expression of anti-tumor necrosis factor related apoptosis-inducing ligand receptor death receptor 5 chimeric antibody in eukaryotic cells].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2008 Dec;30(6):690-5

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, CAMS and PUMC, Beijing 100005, China.

Objective: To construct the human/mouse chimeric antibody of a functional anti-death receptor 5 (DR5) antibody. Methods The viable region of light chain (VL) and viable region of heavy chain (VH) genes of anti-DR5 antibody were amplified and cloned into the light- and heavy-chain expression vectors respectively, then the recombinant plasmids were co-transfected into dihydrofolate reductase(-) Chinese hamster ovary cell (CHO-dhfr(-)) for expression. The positive clone was screened by the two selective genes (neo and dhfr). The humanization and specificity of chimeric antibody was identified by ELISA and Western blotting, and the tumoricidal activity of the expressed chimeric antibody was detected by tetrazolium salt phenazine methosulfate assay.

Results: The expression vectors stably expressed chimeric antibody in CHO-dhfr(-). In the cell supernatant of the F4' clone, the human IgG heavy constant region and light constant region were identified. Moreover, the secreted chimeric antibody retained the binding capacity to the antigen (DR5) and decreased the cell viability of Jurkat and HCT116 cells to 73.15% and 77.30% in vitro respectively.

Conclusion: The human/mouse anti-DR5 chimeric antibody has been successfully expressed in eukaryotic cells and shows tumoricidal activity, which establishes a foundation for the future research of humanized antibody medicine.
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December 2008

[Effects of human telomerase reverse transcriptase promoter and survivin promoter in targeted tumor gene therapy].

Zhonghua Yi Xue Za Zhi 2008 Feb;88(7):475-9

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.

Objective: To investigate the effects of human telomerase reverse transcriptase (hTERT) promoter and survivin promoter in tumor-specific gene therapy.

Methods: hTERT promoter and survivin promoter were obtained by PCR using Jurkat genomic DNA. Recombinant adeno-associated virus (AAV) vectors containing exogenous TRAIL gene and hTERT promoter or survivin promoter were constructed and designated as rAAV-hTERT-TRAIL (h/TRAIL) or rAAV-survivin-TRAIL (s/TRAIL). rAAV particles were obtained after packing and purification and the virus titer was calculated by real-time PCR. Human hepatocellular carcinoma (HCC) cells of the lines SMMC-7721, BEL-7402, HepG2, and Hep3B, and primary human hepatocytes (PHHs) were transfected with h/TRAIL or s/TRAIL. Flow cytometry was used to detect the expression of the reporter gene enhanced green fluorescent protein (EGFP), so as to examine the activity of the two promoters. MTT method was used to detect the activity of the cells. Fifteen BalB/C mice underwent subcutaneous injection of SMMC-7721 cells so as to establish tumor models and then were randomly divided into 3 groups to undergo intra-tumor injection of h/TRAIL, s/TRAIL, or PBS. The growth of tumor was observed for 5 weeks, and then peripheral blood samples were collected to examine the serum AST and ALT levels. TUNEL was used to detect the apoptosis if the tumor cells.

Results: All the SMMC-7721, BEL-7402, HepG2, and Hep3B cells driven by both h/TRAIL and s/TRAIL showed EGFP expression, however, no fluorescence could be seen in the PHHs transfected with h/TRAIL and s/ TRAIL. MTT method showed that 72 hours after the transfection of h/TRAIL and s/TRAIL the survival rates of the SMMC-7721, BEL-7402, and HepG2 cells all decreased, however, the survival rate of the Hep3B cells and PHHs did not changed significantly. The size of the subcutaneous tumor of the mice of the h/ TRAIL group was 625 mm3, significantly smaller than that of the PBS group (1500 mm3, P <0.05), however, the tumor size of the s/TRAIL group was 1117 mm3, not significantly different from that of the PBS group (P >0.05). The AST and ALT levels of all mice did not change significantly 5 weeks after the intratumor injection.

Conclusion: Tumor-specific promoters are promising candidates in targeted tumor gene therapy.
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February 2008

Postischemic administration of Z-Ligustilide ameliorates cognitive dysfunction and brain damage induced by permanent forebrain ischemia in rats.

Pharmacol Biochem Behav 2008 Jan 24;88(3):213-21. Epub 2007 Aug 24.

Department of Pharmacology, Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University West China School of Pharmacy, Chengdu, PR China 610041.

Previous studies have demonstrated that Z-Ligustilide (LIG), a characterized phthalide constituent present in numerous medical Umbelliferae plants, has significant neuroprotective effects in transient forebrain ischemia and permanent cerebral focal ischemia. The present study further investigated the effect of LIG on chronic cerebral hypoperfusion. Male Wistar rats were subjected to permanent ligation of both common carotid arteries (2VO). On Days 8-12 postsurgery, rat cognition was assessed in the Morris water maze. Rats with significantly impaired acquisition of spatial information were randomly allocated to three groups and orally administered LIG (10 or 40 mg/kg/day) or volume-matched vehicle on Days 13-40 post-2VO surgery. The sham-operated group served as controls. After long-term treatment with LIG, the impaired animals' behavioral, biochemical, and histopathological features were examined. Compared to the sham-operated group, significant cognitive impairment was observed in the vehicle-treated group 40 days after 2VO. Shortened mean escape latency was detected in the Morris water maze in rats treated with LIG (p<0.01 vs. vehicle-treated group) during the same trial days. Chronic 2VO-induced pathological changes included neuronal loss and an increase of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the hippocampus. These effects were prevented with LIG treatment (p<0.01 vs. vehicle-treated group). LIG also significantly reduced malondialdehyde levels and increased superoxide dismutase activity in ischemic brain tissue (p<0.05 and p<0.01 vs. vehicle-treated group). In addition, LIG significantly increased choline acetyltransferase activity and inhibited acetylcholinesterase activity in ischemic brain tissues (p<0.05 and p<0.01 vs. vehicle-treated group). The present data demonstrate that LIG significantly prevented chronically hypoperfused cognitive deficits and brain damage at least partly through an antioxidant effect and improved cholinergic activity. The present findings suggest that LIG may have therapeutic potential in treating vascular dementia and cerebrovascular insufficiency.
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http://dx.doi.org/10.1016/j.pbb.2007.08.006DOI Listing
January 2008

[Effects of Cunninghamia lanceolata-broadleaved tree species mixed leaf litters on active soil organic matter].

Ying Yong Sheng Tai Xue Bao 2007 Jun;18(6):1203-7

Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang 110016, China.

With incubation test, this paper studied the effects of Cunninghamia lanceolata leaf litter and its mixture with the litters of main broadleaved tree species in subtropical China, such as Alnus cremastogyne, Kalopanax septemlobus and Michelia macclurei on active soil organic matter. The results showed that adding leaf litters into soil could significantly increase soil microbial biomass C and N, respiration rate and dissolved organic C, and mixed leaf litters were more effective than C. lanceolata leaf litter in increasing soil dissolved organic C. By the end of the incubation, the increment of soil microbial biomass C and N, respiration rate, and dissolved organic C in treatments C. lanceolata leaf litter and C. lanceolata-broadleaved tree species mixed leaf litters was 49% and 63%, 35% and 75%, 65% and 100%, and 66% and 108%, respectively, compared with control. The addition of leaf litters had no significant effects on soil microbial quotient and microbial biomass C/N ratio.
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June 2007

[Identification of binding proteins to the PDZ domain of ERBIN].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2007 Jun;29(3):307-11

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, CAMS and PUMC, Beijing 100005, China.

Objective: To identify the binding proteins to PDZ domain of ERBIN.

Methods: Using PDZ domain of ERBIN as the bait, yeast two-hybrid technology was employed to screen the human lymphocyte leukemia cells MATCHMAKER cDNA library. The protein interaction was identified by immunoprecipitation.

Results: A PDZ-binding protein, TAX1, was identified.

Conclusion: TAX1 is a novel binding protein to PDZ domain of ERBIN.
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June 2007

Neuroprotective effect of Z-ligustilide against permanent focal ischemic damage in rats.

Biol Pharm Bull 2007 Feb;30(2):309-12

Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, China.

The present study investigated the effect of Z-Ligustilide (LIG), a characterized 3-n-alkyphthalide derivative existed in many medical Umbelliferae plants, on permanent focal ischemic brain injury in rats. Focal cerebral ischemia was induced by the occlusion of middle cerebral artery (MCA) for 24 h. LIG (20, or 80 mg/kg), orally administered at 2 h after ischemia, reduced the cerebral infarct volumes by 48.29% and 84.87% respectively compared to control group as visualized by 2,3,5-triphenyltetrazolium chloride (TTC) staining (p<0.01). Treatment with LIG could dose-dependently reduce brain swelling by 68.62% and 82.08% (p<0.01), and significantly improve behavioral deficits (p<0.01). In addition, LIG at the above used doses had no significant effect on rat body temperature. These data, along with previous findings in our lab demonstrating the neuroprotective effects of LIG in transient cerebral ischemia, suggest that LIG may be a potential neuroprotective agent for the treatment of ischemic stroke in future.
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http://dx.doi.org/10.1248/bpb.30.309DOI Listing
February 2007

[Mechanisms of sensitization by 8-chloro-adenosine of human tumor cells to TRAIL-induced apoptosis].

Zhonghua Zhong Liu Za Zhi 2005 Oct;27(10):586-90

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.

Objective: To study the effect of 8-chloro-adenosine (8-Cl-Ado) on the sensitivity of human hepatoma and breast cancer cell lines to TRAIL-induced apoptosis in vitro and its mechanisms.

Methods: Recombinant soluble TRAIL (rsTRAIL) or 8-Cl-Ado was used to treat hepatoma cell line BEL-7402 and breast cancer cell line MCF-7 in vitro. MTT assay was used to evaluate cell viability. The effect of cotreatment with rsTRAIL and 8-Cl-Ado was analyzed. NF-kappaB activity reporter plasmid was designed to measure the activity of transcription factor NF-kappaB. After transient transfection with the reporter plasmid, which contains NF-kappaB-responsive elements, into the cell lines, cells were treated with rsTRAIL and/or 8-Cl-Ado, then the activity of the reporter gene luciferase was determined. Different kinds of caspase inhibitors were used to measure the effect of caspases in the rsTRAIL and/or 8-Cl-Ado induced apoptosis.

Results: 8-Cl-Ado could greatly enhance sensitivity of BEL-7402 and MCF-7 cells to reTRAIL. Treatment with 8-Cl-Ado and rsTRAIL inactivated transcription factor NF-kappaB and induced apoptosis in BEL-7402, but not in MCF-7. Caspase family inhibitor could not prevent apoptosis induced by 8-Cl-Ado and rsTRAIL in BEL-7402 cells, however, it could block apoptosis in MCF-7 cells, indicating that two different apoptosis pathways in MCF-7 and BEL-7402 might exist, one was caspase dependent and the other caspase independent. Moreover, all of the inhibitors of caspse-3, -8 and -9 could not block apoptosis induced by the co-treatment.

Conclusion: 8-chloro-adenosine can enhance the sensitivity of human hepatoma cell line BEL-7402 and breast cancer cell line MCF-7 to rsTRAIL, even though MCF-7 is TRAIL-resistant. 8-Cl-Ado combined with rsTRAIL can trigger different signal pathways in MCF-7 and BEL-7402, which are caspase dependent and independent, respectively.
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October 2005

[Establishment of high-throughput drug screening model targeting retinoic acid receptor in cells].

Yao Xue Xue Bao 2005 Oct;40(10):908-11

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.

Aim: To screen new drug for the treatment of acute promyelocytic leukemia, psoriasis and acne, high-throughput drug screening cell models marked by green fluorescent protein (GFP) have been established.

Methods: Eight repeats of retinoic acid response element (RARE) were synthesized and cloned into a GFP expression vector. This construct was stably transfected into cells in vitro. Stable and sensitive cell clones with high copy numbers of RARE were selected by retinoic acid (RA) using fluorescence-activated cell sorting (FACS).

Results: A cell line has been chosen to be high-throughput drug screening cell model. This model was shown with low background, high sensitive and good reproducibility, and was convenient and inexpensive.

Conclusion: This drug screening cell model can be used for retinoic acid receptor target high-throughput drug screening.
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October 2005