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Biomedical subjects

Ji Zhang

Publications and source records attributed to Ji Zhang.

At least 55 records · Page 3Linked to original sources
PubMed2005

Dinuclear macrocyclic polyamine zinc(II) complexes: syntheses, characterization and their interaction with plasmid DNA.

The syntheses, characteristics of dinuclear macrocyclic polyamine zinc complexes and their interaction with plasmid DNA are reported. The two cyclen (1,4,7,10-tetraazacyclododecane) moieties are bridged by rigid and flexible linkages. The crystal structures of Zn2C27H43N8O15Cl4 [5c.(ClO4)3.2H2O] and Zn2C30H43N10O13Cl3 [5e.(ClO4)3.H2O] have been determined. The complexes crystallize in the monoclinic space group C2/c and P2(1)/c with the following unit cell parameters: 5c.(ClO4)3.2H2O: a=32.568(4)A, b=14.8593(17)A, c=19.443(2)A, alpha=90.00 degrees , beta=119.435(4) degrees , gamma=90.00 degrees , Dc=1.551 mg/m3, FW=956.71, F(000)=3932; 5e.(ClO4)3.H2O: a=15.807(2)A, b=16.756(2)A, c=16.161(2)A, alpha=90.00 degrees , beta=97.062(4) degrees , gamma=90.00 degrees , Dc=1.546 mg/m3, FW=988.83, F(000)=2032. The distance between the two Zn(II) ions is about 4.0 A. The structures show that two zinc ions can synergistically interact with the substrate DNA. With this novel structural characteristics, the dinuclear macrocyclic polyamine Zn(II) complexes via the synergetic effect between the two zinc ions can catalyze the cleavage of plasmid DNA (pUC18) with unprecedented speed at physiological conditions.

Crystallography, X-Ray↗
PubMed2005

A comparison of nonlinear mixed-model analyses for a pediatric pharmacokinetic study.

Nonlinear mixed models are important tools for analyzing repeated measures data. In particular, these models are used for population pharmacokinetic analyses for estimating population pharmacokinetic parameters. As more clinical studies are performed for the advancement of treatment of pediatric patients, methodology is needed for comparing results from pharmacokinetic studies in pediatric patients and adult control groups. These pediatric studies introduce complexities to the design and analysis, including how analysis of sparse data affects the limitations of model selection. A case study is presented demonstrating that good communication with regulatory agencies and appropriate selection of analysis models are integral parts of completing population analyses for timely approval and labeling of drugs for treating pediatric patients.

Adult↗
PubMed2005

6-Hydroxydopamine-induced glutathione alteration occurs via glutathione enzyme system in primary cultured astrocytes.

AIM: To define the role of enzymes involved in glutathione metabolism in 6-hydroxydopamine (6-OHDA)-induced glutathione alteration in primary cultured astrocytes. METHODS: Total glutathione (GSx) levels were determined using the modified enzymatic microtiter plate assay. The mRNA levels of gamma-glutamylcysteine synthetase (gammaGCS), gamma-glutamyltransferase (gammaGT), glutathione peroxidase (GPx), GR(glutathione reductase), and glutathione transferases (GST) were determined using RT-PCR. gammaGT activity was determined using gammaGT assay kits. RESULTS: In primary cultured astrocytes, 6-OHDA induced a significant elevation of cellular GSx levels after treatment for 24 h. However, the GSx levels decreased after 24 h and the values were even lower than the value in the control group without 6-OHDA at 48 h. RT-PCR data showed that the mRNA levels of gammaGCS, the rate-limiting enzyme of gamma-L-glutamyl-L-cysteinylglycine (GSH) synthesis, were increased by 6-OHDA after treatment for 24 h and 48 h; the mRNA levels of GPx, GR, and GST did not alter in 6-OHDA-treated astrocytes after treatment for 24 h and 48 h; and 6-OHDA increased the mRNA levels and the activity of gammaGT after treatment for 48 h, which induced a decrease in GSx levels, despite the up-regulation of gammaGCS after exposure to 6-OHDA for 48 h. CONCLUSION: The change in gammaGCS correlated with the increase in GSH levels induced by 6-OHDA after treatment for 24 h. GSx levels decreased because of increased gammaGT mRNA levels and gammaGT activity induced by 6-OHDA after treatment for 48 h.

Animals↗
PubMed2005

Protein phosphatase 5 is required for ATR-mediated checkpoint activation.

In response to DNA damage or replication stress, the protein kinase ATR is activated and subsequently transduces genotoxic signals to cell cycle control and DNA repair machinery through phosphorylation of a number of downstream substrates. Very little is known about the molecular mechanism by which ATR is activated in response to genotoxic insults. In this report, we demonstrate that protein phosphatase 5 (PP5) is required for the ATR-mediated checkpoint activation. PP5 forms a complex with ATR in a genotoxic stress-inducible manner. Interference with the expression or the activity of PP5 leads to impairment of the ATR-mediated phosphorylation of hRad17 and Chk1 after UV or hydroxyurea treatment. Similar results are obtained in ATM-deficient cells, suggesting that the observed defect in checkpoint signaling is the consequence of impaired functional interaction between ATR and PP5. In cells exposed to UV irradiation, PP5 is required to elicit an appropriate S-phase checkpoint response. In addition, loss of PP5 leads to premature mitosis after hydroxyurea treatment. Interestingly, reduced PP5 activity exerts differential effects on the formation of intranuclear foci by ATR and replication protein A, implicating a functional role for PP5 in a specific stage of the checkpoint signaling pathway. Taken together, our results suggest that PP5 plays a critical role in the ATR-mediated checkpoint activation.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

[Constructing standard allelic ladders for four short tandem repeat loci and employing them in a population study on Han Nationality of Chengdu in China].

OBJECTIVE: To solve the problems in the accuracy and standardization of short tandem repeats-polymerase chain reaction (STR-PCR) typing, the authors adopted the molecular clone technology in producing the standard allelic ladders of D1S1676, D2S2735, D11S1977 and D22S444 loci and applied them in a population study on the Hans in Chengdu, China. METHODS: PCR was used to produce several different allelic fragments of these loci. PCR products were eluted from the gel and re-amplified by PCR. The purified allelic fragments were then blunt-end subcloned individually into the pGEMR-T plasmid vectors and the recombinant were transfected into competent E.coli DH5alpha TM cells. The results of sequencing confirmed that the size and the construction of the inserts were correct. The recombinant plasmids DNA with the inserts were then used as template for re-amplification to generate the four loci standard ladders. RESULTS: The authors succeeded in producing large quantity of standard allelic ladder of these four loci, with which the genetic polymorphisms of these loci in Chengdu Han population of China were studied. CONCLUSION: This method is of high value for forensic DNA typing to construct standard ladders. D1S1676, D2S2735 loci are robust for forensic analysis in Chinese Han population, whereas the value of D11S1977 and D22S444 loci is limited.

Alleles↗
PubMed2005

[Genetic polymorphisms of fifteen short tandem repeat loci in Chengdu Han population].

OBJECTIVE: To acquire the population genetic data of fifteen short tandem repeat (STR) loci in Chengdu Han population. METHODS: A total of 210 EDTA-blood specimens were collected from the unrelated individuals in Chengdu Han population. The DNA samples were extracted with Chelex method and amplified by multiplex PCR technique. The PCR products were analyzed by an automatic genetic analyzer; the relative fragment's lengths of PCR products were calculated by gene scan analysis software and afterward genotyped by genotype software. RESULTS: Fifteen STR loci of the 210 samples showed a successful result of genotyping. The heterozygosities of the fifteen STR loci in Chengdu Han population were found to be 0.529-0.881; the combined exclusion probability and discrimination power for the fifteen STR loci in Chengdu Han population were determined to be 0.999998 and 7.3 x 10 (-17); respectively. CONCLUSION: The distinct genotype of fifteen STR loci and the sex of sample could be unveiled just through PCR and electrophoresis once, and a higher measured value could be obtained for both the combined discrimination power and the exclusion probability; the fifteen STR loci can meet the needs of the parentage testing and personal identification in forensic medicine.

Asian People↗
PubMed2005

[Study of Five STR Loci in A Chinese Han Population.].

To understanding the allele structure and genetic polymorphisms at five STR loci in Chinese Han population, and construct a preliminary database, EDTA-blood specimens were collected from unrelated individuals. DNA samples were extracted with Chelex method and were amplified by PCR technique. The PCR products were analyzed using both PAGE horizontal electrophoresis with discontinuous buffer system and automated fluorescence detection approach. As a result, three STRs consist of simple repeat motifs, while two STR contain a complex repeat structure. The STR polymorphisms at all of the five loci have been observed in Chinese Han population. In a word, the obtained data are beneficial to understanding the population genetics of the five STR loci in Chinese Han population. As a simple approach, the PAGE horizontal electrophoresis can be employed for typing the five STR markers.

Alleles↗
PubMed2005

[Studies on the chemical constituents of the essential oil of Artemisia dracunculus].

OBJECTIVE: To analyse the chemical constituents of Artemisia dracunculus. METHOD: The essential oil from A. dracunculus was extracted by steam distillation and the chemical constituents were analysed by capillary GC-MS method. The relative content of each component was calculated by area normalization. RESULT: 36 peaks were separated and all of them were identified. The main chemical components were 3,7-dimethyl-1,3,7-octatriene (38.43%), 1S-alpha-pinene (36.96%), 1-methoxy-4-(2-Propenyl)-benzene (8.57%), limonene (6.33%), 1R-alpha-pinene (3.40%), etc. CONCLUSION: The study provided solid and scientific proof for the further exploitation and utilization of A. dracunculus.

Artemisia↗
PubMed2005

Effect of caspase 9 related signaling molecules on the apoptosis of human vascular endothelial cell induced by homocysteine.

OBJECTIVE: To understand the role of mitochondria associated signaling pathway in the apoptosis of human vascular endothelial cell induced by homocysteine (Hcy). METHODS: The mRNA and protein expression levels of the up-stream signaling molecules of caspase 3, Bcl 2, caspase 9, and cytosolic cytochrome-c, were investigated. The in vitro cultured human umbilical vein endothelial cells with homocysteine at different concentrations were incubated for 24 h. The expressions of Bcl 2 and caspase 9 at mRNA and protein levels were analyzed by reverse transcription-polymerase chain reaction(RT-PCR) and Western blot. Cytochrome-c in cytoplasm was also detected by Western blot. RESULTS: The expression levels of three signaling molecules were all down-regulated by homocysteine at both mRNA and protein levels in a dose-dependent manner. CONCLUSION: Homocysteine could affect the formation of apoptosome through repressing the expression of Bcl 2 gene and release of cytochrome-c from mitochondria. Decreasing of apoptosome could disturb the activation of caspase 9. The results also indicate that the mitochondria pathway is not the major signaling pathway involved in Hcy-induced apoptosis.

Apoptosis↗
PubMed2005

[Analysis of gene expression profile of G1/S transition in gastric cancer cell cycle].

OBJECTIVE: To detect the variation of gene expression profile of G1/S transition and elucidate the role of related genes regulating cell cycle from G1 to S phase in gastric cancer. METHODS: Nocodazole-thymidine and double thymidine methods were used to synchronize gastric cells at G2/M and G1/S point, cDNA microarray chips was applied to examine the gene expression profile at G1 early and late phase, S early and late phase during the cell cycle, hierarchy analysis was conducted by a professional software package. RESULTS: A total of 2001 genes were detected available, 959 genes appeared to be upregulated or downregulated, including 147 genes upregulated at G1 late phase. These 147 genes are involved in DNA metabolism, transcription and translation,posttranslational modification, ubiquitination, signal transduction etc, which all affected cell cycle from different aspects. CONCLUSION: Complex multiple gene processes, such as DNA metabolism, transcription and translation, posttranslational modification, ubiquitination, signal transduction etc,are implicated in and also essential for G1/S transition during gastric cancer cell cycle, part of these genes are significantly associate with overproliferation in gastric cancer.

Cell Division↗
PubMed2005

[Mechanisms of fenretinide-triggered apoptosis in leukemic cells].

The retinoid N-4-hydroxyphenyl retinamide (4-HPR also known as fenretinide), a synthetic derivative of all trans retinoic acid (ATRA), has shown as an efficient chemopreventive, chemotherapeutic agent and a potent inducer of apoptosis in various cancer cell types in vitro, including leukemic cells. However the mechanisms by which 4-HPR has the apoptotic effects is not completely elucidated. This study was aimed to investigate the effect of 4-HPR on several leukemic cells and explore its mechanisms of effect on U937 cells. The cell growth and proliferation experiments were performed [corrected] cell apoptosis was detected by annexin V; reactive oxygen species (ROS) and mitochondrial transmembrane potential (DeltaPsim) were determined; protein [corrected] expression was detected by Western blot. The results showed that 4-HPR inhibited the proliferation of U937 cells in a dose- and time-dependent manner. 4-HPR markedly [corrected] induced apoptosis in U937 cells, triggered the generation of ROS, induced the loss of mitochondrial transmembrane potential, decreased the expression of procaspase-8 and procaspase-3. Pretreatment of L-ascorbic acid suppressed the generation of ROS, disruption of mitochondrial potential, activation of caspases and apoptosis. It is concluded that the generation of ROS followed by the disruption of mitochondrial transmembrane potential plays an important role on 4-HPR-induced apoptosis in leukemic cells, suggesting that 4-HPR may be one of mitochondrial-targeted agents with clinical potential in treating cancer.

Antineoplastic Agents↗
PubMed2005

[Study on sterols and triterpenes from the stems of Akebia quinata].

The ethanol extract from Akebia quinata was seperated by dichloromethane, n-butanol in sequence. Six compounds were isolated and identified as beta-sitosterol (I), delta(5,22) stigmasterol (II), oleanolic acid (III), hederagenin (IV), daucosterol (V), delta(5,22) stigmasterol-3-O-beta-D-glycopyranoside (VI). Compound VI was isolated from Akebia plants for the first time.

Glucosides↗
PubMed2005

[Study on the relationship between polymorphisms of Cyp1A1, GSTM1, GSTT1 genes and the susceptibility to acute leukemia in the general population of Hunan province].

OBJECTIVE: Based on the distribution of genetic polymorphisms regarding phase I metabolic enzyme cytochrome P450 1A1 (CYP1A1) and phase II metabolic enzymes glutathione S-transferase GSTM1 and GSTT1 genotypes in acute leukemia patients and health controls among general population of Hunan in China, this study was to explore the relationship between these gene polymorphisms and the susceptibility to acute leukemia. METHODS: Using case-control methodology, we studied 204 healthy controls and 232 patients with acute leukemia, of which 112 patients were suffering acute lymphoblastic leukemia (ALL) and 120 with acute non-lymphoblastic leukemia (ANLL). The frequencies of the genotypes were detected by PCR and PCR-RFLP techniques. RESULTS: The variation frequencies of CYP1A1 gene (Msp I polymorphisms, site 3801T-C variation) in ALL and ANLL groups were 74.1% and 70.8% respectively which were higher than 63.3% appeared in the healthy controls. However, the differences between patients (ALL or ANLL) and healthy controls were not statistically significant (P > 0.05 for both). The null genotype of GSTM1 (GSTM1 -/-) in ALL group was 60.7%, which was not significantly different from the controls (55.4%). However, GSTM1 -/- genotype in ANLL group was 68.3%, significantly different from the controls (P < 0.05). The null genotypes among GSTT1 (GSTT1 -/-) in ALL, ANLL and control group were 50.9%, 55.0% and 49.0% but their differences were not statistically significant (P > 0.05). The incidences of GSTM1 -/- and GSTT1 -/- combined genotype in ALL, ANLL and control group were 33.0%, 40.0% and 27.5%, of which the difference between ANLL group and control group was statistically significant (P < 0.05) and CYP1A1 gene heterozygous mutation type or homozygous mutation type combined with GSTM1 -/- and GSTT1 -/- increased the risk of ANLL (OR value 1.890, 95% CI: 1.084-3.295). CONCLUSION: These results indicated that both the variation of CYP1A1 gene or GSTT1 -/- genotype alone might not be associated with the susceptibility of acute leukemia while GSTM1 -/- genotype alone or combined with GSTT1 -/- or the 3801 T-C variation of CYP1A1 gene were correlated with ANLL. These findings suggest that GSTM1 - / - genotype alone or in combination with other defective genotypes might serve as risk factors to the etiology of ANLL.

Case-Control Studies↗
PubMed2004

Differential type 4 cAMP-specific phosphodiesterase (PDE4) expression and functional sensitivity to PDE4 inhibitors among rats, monkeys and humans.

It has been suggested that the rat is relatively more susceptible to toxicity induced by inhibitors for type 4 cAMP-specific phosphodiesterase (PDE4). In this study designed to elucidate possible biochemical basis for the higher susceptibility, we compared PDE4 expression levels and their functional relevance among rats, monkeys and humans. In several toxicologically relevant tissues and blood leukocytes, the mRNA expression levels of PDEs 4A, 4B, 4C and 4D were significantly higher in rats than in humans. We confirmed that higher PDE4 expression levels were correlated with a higher enzyme activity level in rat leukocytes. The PDE4 enzyme activity level of leukocytes in monkeys fell between that of rats and humans. Functionally, the potencies of the PDE4 inhibitors rolipram, SB 207499 and SCH 351591 in inhibiting tumor necrosis factor production from leukocytes were in the following order: rat > monkey > human. In addition, rolipram was about 10-fold more potent in rats than in humans in inhibiting phenylephrine-induced contraction of renal artery. These inhibitors were confirmed to be highly selective for PDE4 in comparison to all other PDE families, and to inhibit rat and human PDE4s with identical potencies. Taken together, these results suggest that the higher susceptibility of rats to PDE4 inhibitor-induced toxicity might be due to their higher expression levels of PDE4, and that PDE4 inhibitors may be safer in humans than in monkeys and, particularly, rats.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

Differential inhibitor sensitivity between human recombinant and native photoreceptor cGMP-phosphodiesterases (PDE6s).

Human photoreceptor cGMP-phosphodiesterases (PDE6s) are important reagents in PDE inhibitor discovery. However, recombinant human PDE6s have not been expressed, and isolation of native human PDE6s is highly difficult. In this study, the catalytic subunit(s) of human rod and cone PDE6s (PDE6alphabeta and PDE6alpha', respectively) were co-expressed or expressed separately as catalytically active enzymes. Sildenafil inhibited both the recombinant PDE6s in a dose-dependent manner with Ki values of 94 and 98 nM, respectively. These Ki values were four-fold higher than that (25 nM) of a human native PDE6 preparation. Similarly, 3-isobutyl-1-methylxanthine (IBMX)'s Ki values for the recombinant PDE6s were five- to eight-fold higher than that of the native enzyme. However, E4021 and zaprinast exhibited much (30-80-fold) lower potencies for the recombinant PDE6s than for the native enzyme. Additional PDE5 inhibitors representing other structural classes and possessing different selectivity against native PDE6 also showed different potencies against the recombinant and native PDE6s. In particular, one class of xanthine analogues exhibited significantly (5-15-fold) higher potencies for the recombinant PDE6s than for the native enzyme. Our data demonstrates that the recombinant and native PDE6s exhibit differential sensitivity to inhibitors, and cautions the use of recombinant catalytic subunits of PDE6 in drug discovery or in structural/functional studies.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein.

Imatinib (STI571, Gleevec) is a tailored drug for chronic myelogenous leukemia (CML), whereas arsenic compounds were used as ancient remedies for CML with certain efficacy. The aim of this study was to investigate the potential benefit of combination therapy with imatinib and arsenic sulfide (As(4)S(4)). Analysis of cell proliferation and clonogenic ability showed that As(4)S(4) and imatinib exerted synergistic effects on both K562 cells and fresh CML cells. The effective concentrations on fresh CML cells were pharmacokinetically available in vivo but had much less inhibitory effect on CD34(+) cells from the nonleukemic donors. Examination of cell cycles showed that As(4)S(4) induced G(2)/M arrest whereas imatinib induced G(1) arrest. Using a number of parameters such as morphology, annexin V/propidium iodide (PI), mitochondrial transmembrane potential, caspase-3 activity, and Fas/Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through the mitochondrial pathway. The 2 drugs also exhibited a synergistic effect in targeting BCR-ABL protein. While As(4)S(4) triggered its degradation and imatinib inhibited its tyrosine kinase activity, combined use of the 2 led to lower protein/enzymatic activity levels of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of imatinib and As(4)S(4) combination on CML.

Antineoplastic Agents↗
PubMed2004

Induction of lysosomal and plasma membrane-bound sialidases in human T-cells via T-cell receptor.

Among the three isoenzymes of neuraminidase (Neu) or sialidase, Neu-1 has been suggested to be induced by cell activation and to be involved in IL (interleukin)-4 biosynthesis in murine T-cells. In the present study, we found that antigen-induced airway eosinophilia, a typical response dependent on Th2 (T-helper cell type 2) cytokines, as well as mRNA expression of Th2 cytokines, including IL-4, are suppressed in Neu-1-deficient mice, thereby demonstrating the in vivo role of murine Neu-1 in regulation of Th2 cytokines. To elucidate the roles of various sialidases in human T-cell activation, we investigated their tissue distribution, gene induction and function. Neu-1 is the predominant isoenzyme at the mRNA level in most tissues and cells in both mice and humans, including T-cells. T-cells also have significant levels of Neu-3 mRNAs, albeit much lower than those of Neu-1, whereas the levels of Neu-2 mRNAs are minimal. In human T-cells, both Neu-1 and Neu-3 mRNAs are significantly induced by T-cell-receptor stimulation, as is sialidase activity against 4-methylumbelliferyl- N -acetylneuramic acid (a substrate for both Neu-1 and Neu-3) and the ganglioside G(D1a) [NeuAcalpha2-3Galbeta1-3GalNAcbeta1-4(NeuAcalpha2-3)Galbeta1-4Glcbeta1-cer] (a substrate for Neu-3, but not for Neu-1). The expression of the two sialidase genes may be under differential regulation. Western blot analysis and enzymic comparison with recombinant sialidases have revealed that Neu-3 is induced as a major isoform in activated cells. The induction of Neu-1 and Neu-3 in T-cells is unique. In human monocytes and neutrophils stimulated with various agents, the only observation of sialidase induction has been by IL-1 in neutrophils. Functionally, a major difference has been observed in Jurkat T-cell lines over-expressing Neu-1- and Neu-3. Upon T-cell receptor stimulation, IL-2, interferon-gamma, IL-4 and IL-13 are induced in the Neu-1 line, whereas in the Neu-3 line the same cytokines are induced, with the exception of IL-4. Taken together, these results suggest an important immunoregulatory role for both Neu-1 and Neu-3 in humans.

Animals↗