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4. Novel Synthesis and Structural Characterization of a High-Affinity Paramagnetic Kinase Probe for the Identification of Non-ATP Site Binders by Nuclear Magnetic Resonance

Author

Desiree H.H. Tsao, Arthur Lee, Lori Krim Gavrin, Franklin J. Moy, Zhang Bao Xu, John C. McKew, Lidia Mosyak, Elizabeth Kieras, Wayne Stochaj, and Annette Sievers

Subjects
Models, Molecular, Binding Sites, Magnetic Resonance Spectroscopy, Molecular Structure, Protein Conformation, Kinase, Chemistry, Electron Spin Resonance Spectroscopy, Crystallography, X-Ray, Pyrazolopyrimidine, Paramagnetism, chemistry.chemical_compound, Adenosine Triphosphate, Nuclear magnetic resonance, Drug Discovery, Humans, Molecular Medicine, Spin Labels, Protein Kinase Inhibitors, Protein Kinases, Protein Binding, Proto-oncogene tyrosine-protein kinase Src
Abstract

To aid in the pursuit of selective kinase inhibitors, we have developed a unique ATP site binder tool for the detection of binders outside the ATP site by nuclear magnetic resonance (NMR). We report here the novel synthesis that led to this paramagnetic spin-labeled pyrazolopyrimidine probe (1), which exhibits nanomolar inhibitory activity against multiple kinases. We demonstrate the application of this probe by performing NMR binding experiments with Lck and Src kinases and utilize it to detect the binding of two compounds proximal to the ATP site. The complex structure of the probe with Lck is also presented, revealing how the probe fits in the ATP site and the specific interactions it has with the protein. We believe that this spin-labeled probe is a valuable tool that holds broad applicability in a screen for non-ATP site binders.

Published
2009

5. Catalytic Domain Crystal Structure of Protein Kinase C-θ (PKCθ)

Author

Christina Benander, William S. Somers, Laura Lin, Mark Stahl, Diane Joseph-McCarthy, Karl Malakian, Rita Greco, Stephane Olland, Lori Fitz, Lidia Mosyak, Robert M. Czerwinski, Zhang-Bao Xu, Scott Wolfrom, and Divya Chaudhary

Subjects
Molecular Sequence Data, Drug design, Biology, Crystallography, X-Ray, Biochemistry, Substrate Specificity, medicine, Humans, Transferase, Staurosporine, Amino Acid Sequence, Molecular Biology, Protein Kinase C, Protein kinase C, chemistry.chemical_classification, Binding Sites, Kinase, Cell Biology, Peptide Fragments, Protein Structure, Tertiary, Cell biology, Isoenzymes, Kinetics, Enzyme, chemistry, Protein kinase domain, Protein Kinase C-theta, Phosphorylation, Sequence Alignment, medicine.drug
Abstract

A member of the novel protein kinase C (PKC) subfamily, PKCθ, is an essential component of the T cell synapse and is required for optimal T cell activation and interleukin-2 production. Selective involvement of PKCθ in TCR signaling makes this enzyme an attractive therapeutic target in T cell-mediated disease processes. In this report we describe the crystal structure of the catalytic domain of PKCθ at 2.0-A resolution. Human recombinant PKCθ kinase domain was expressed in bacteria as catalytically active phosphorylated enzyme and co-crystallized with its subnanomolar, ATP site inhibitor staurosporine. The structure follows the classic bilobal kinase fold and shows the enzyme in its active conformation and phosphorylated state. Inhibitory interactions between conserved features of staurosporine and the ATP-binding cleft are accompanied by closing of the glycine-rich loop, which also maintains an inhibitory arrangement by blocking the phosphate recognition subsite. The two major phosphorylation sites, Thr-538 in the activation loop and Ser-695 in the hydrophobic motif, are both occupied in the structure, playing key roles in stabilizing active conformation of the enzyme and indicative of PKCθ autocatalytic phosphorylation and activation during bacterial expression. The PKCθ-staurosporine complex represents the first kinase domain crystal structure of any PKC isotypes to be determined and as such should provide valuable insight into PKC specificity and into rational drug design strategies for PKCθ selective leads.

Published
2004

6. Two N-Terminal Domains of Kv4 K+ Channels Regulate Binding to and Modulation by KChIP1

Author

Laura Lin, Mark Stahl, William S. Somers, Karen C. Carroll, Zhang-Bao Xu, Pranab K. Chanda, KeWei Wang, Karl Malakian, Robert Scannevin, Flora Jow, Meggin Taylor, Lydia Mosyak, Wade Edris, Alan H. Katz, Jennifer Megules, Stephane Olland, Kenneth J. Rhodes, Mark R. Bowlby, Weixin Xu, Qiang Lu, and David C. Kopsco

Subjects
Models, Molecular, Patch-Clamp Techniques, Potassium Channels, Neuroscience(all), Crystallography, X-Ray, Cell Line, Membrane Potentials, Calcium-binding protein, Animals, Humans, Amino Acid Sequence, K channels, Binding Sites, Chemistry, General Neuroscience, Calcium-Binding Proteins, Cell Membrane, Mutagenesis, Kv Channel-Interacting Proteins, Structural framework, Protein Structure, Tertiary, Transport protein, N-terminus, Protein Subunits, Shal Potassium Channels, Terminal (electronics), Biochemistry, Potassium Channels, Voltage-Gated, Mutagenesis, Site-Directed, Oocytes, cardiovascular system, Biophysics, Protein Binding
Abstract

The family of calcium binding proteins called KChIPs associates with Kv4 family K + channels and modulates their biophysical properties. Here, using mutagenesis and X-ray crystallography, we explore the interaction between Kv4 subunits and KChIP1. Two regions in the Kv4.2 N terminus, residues 7–11 and 71–90, are necessary for KChIP1 modulation and interaction with Kv4.2. When inserted into the Kv1.2 N terminus, residues 71–90 of Kv4.2 are also sufficient to confer association with KChIP1. To provide a structural framework for these data, we solved the crystal structures of Kv4.3N and KChIP1 individually. Taken together with the mutagenesis data, the individual structures suggest that that the Kv4 N terminus is required for stable association with KChIP1, perhaps through a hydrophobic surface interaction, and that residues 71–90 in Kv4 subunits form a contact loop that mediates the specific association of KChIPs with Kv4 subunits.

Published
2004

7. Molecular determinants of ERα and ERβ involved in selectivity of 16α-iodo-17β estradiol

Author

Heather A. Harris, Zhang-Bao Xu, Barry S. Komm, Rayomand J Unwalla, Barbara Stauffer, and Ramesh A. Bhat

Subjects
Chemistry, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Mutant, Estrogen receptor, Alpha (ethology), Cell Biology, Biochemistry, Molecular biology, Transactivation, Endocrinology, Molecular Medicine, Receptor, Molecular Biology, Estrogen receptor alpha, Transcription factor, Estrogen receptor beta
Abstract

The two known estrogen receptors, ER alpha and ER beta, are hormone inducible transcription factors that have distinct roles in regulating cell proliferation and differentiation. The natural ligand, 17 beta-estradiol (E2), binds with high affinity to both ER alpha and ER beta. However, a close analogue, 16 alpha-iodo-17 beta-estradiol (16 alpha IE2) showed about 10-fold selectivity for ER alpha over ER beta. From X-ray studies, it has been shown that the ligand-binding domains (LBD) of the two receptors are strikingly similar, and that only two changes fall within the binding cavity (ER alpha Leu384 to ER beta Met336, and ER alpha Met421 to ER beta Ile373). To understand the molecular basis for the ER alpha selectivity of 16 alpha IE2, mutants and chimeras of ER alpha and ER beta were generated, and ligand-binding and transactivation functions were studied. The ER alpha Leu384 Met mutant behaved like ER alpha WT in the presence of 16 alpha IE2; whereas the profile of the ER alpha Met421 Ile mutant was similar to that of ER beta WT. The ER beta mutant Ile373 Met behaved like ER alpha with 16 alpha IE2. The results clearly demonstrate the role of ER alpha Met421 in the ER alpha selectivity of 16 alpha IE2.

Published
2004

8. Synthesis and Structure−Activity Relationship of N-Substituted 4-Arylsulfonylpiperidine-4-hydroxamic Acids as Novel, Orally Active Matrix Metalloproteinase Inhibitors for the Treatment of Osteoarthritis

Author

Rebecca Cowling, Michele A. Sharr, Jerauld S. Skotnicki, Zhang Bao Xu, Venkatesan Aranapakam, Vincent Sandanayaka, G. Jin, Arie Zask, Mila Du, John W. Ellingboe, Joseph Mcdevitt, Jannie Lea Baker, Jeff Tillett, Loran M. Killar, Jamie Marie Davis, Thomas Walter, Weiguang Zhao, Amy Sung, George Theodore Grosu, John F. DiJoseph, and Levin Jeremy Ian

Subjects
Male, Models, Molecular, Matrix metalloproteinase inhibitor, Administration, Oral, ADAM17 Protein, Matrix Metalloproteinase Inhibitors, Matrix metalloproteinase, Crystallography, X-Ray, Hydroxamic Acids, Chemical synthesis, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Dogs, Piperidines, Oral administration, Matrix Metalloproteinase 13, Osteoarthritis, Drug Discovery, Animals, Humans, Structure–activity relationship, Protease Inhibitors, Sulfones, chemistry.chemical_classification, Binding Sites, Hydroxamic acid, biology, Metalloendopeptidases, Haplorhini, Matrix Metalloproteinases, Rats, ADAM Proteins, Cartilage, Enzyme, chemistry, Biochemistry, Enzyme inhibitor, biology.protein, Molecular Medicine, Biological Assay, Cattle, Rabbits, Dialysis
Abstract

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.

Published
2003

9. Identification of Potent and Selective MMP-13 Inhibitors

Author

Mary Geck, Zhang-Bao Xu, Rajeev Hotchandani, Jeremy I. Levin, Junjun Wu, Xuemei Du, Thomas S. Rush, J.S. Skotnicki, Elisabeth Collins, and Frank Lovering

Subjects
Models, Molecular, Matrix metalloproteinase inhibitor, Clinical Biochemistry, Administration, Oral, Pharmaceutical Science, Articular cartilage, Pharmacology, Matrix metalloproteinase, Crystallography, X-Ray, Biochemistry, Substrate Specificity, Drug Discovery, Amino Acids, Chelating Agents, media_common, chemistry.chemical_classification, biology, Chemistry, General Medicine, Zinc, Enzyme inhibitor, Molecular Medicine, Selectivity, Drug, media_common.quotation_subject, In Vitro Techniques, Matrix Metalloproteinase Inhibitors, Sensitivity and Specificity, Inhibitory Concentration 50, Structure-Activity Relationship, Pharmacokinetics, Matrix Metalloproteinase 13, Animals, Structure–activity relationship, Protease Inhibitors, Chelation, Collagenases, Molecular Biology, Benzofurans, Organic Chemistry, In vitro, Protein Structure, Tertiary, Rats, Bioavailability, Cartilage, Enzyme, Drug Design, biology.protein, Cattle, Explant culture
Abstract

A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 microM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model.

Published
2005

10. The discovery of anthranilic acid-based MMP inhibitors. Part 3: incorporation of basic amines

Author

J.S. Skotnicki, Zhang-Bao Xu, T. Wehr, Mila T. Du, Roy A. Black, C. E. Roth, Li Di, James M. Chen, Jeremy I. Levin, Michele A. Sharr, C.J March, R. Cowling, John F. DiJoseph, S. Skala, Kendall M. Mohler, Amy Sung, Mary M. Sherman, Frances C. Nelson, Loran M. Killar, and G. Jin

Subjects
Models, Molecular, Magnetic Resonance Spectroscopy, Stereochemistry, Clinical Biochemistry, Interleukin-1beta, Pharmaceutical Science, ADAM17 Protein, Matrix Metalloproteinase Inhibitors, Hydroxamic Acids, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Mice, Structure-Activity Relationship, In vivo, Drug Discovery, Matrix Metalloproteinase 13, Osteoarthritis, Anthranilic acid, Animals, ortho-Aminobenzoates, Collagenases, Amines, Enzyme Inhibitors, Molecular Biology, chemistry.chemical_classification, Hydroxamic acid, Binding Sites, biology, Organic Chemistry, Metalloendopeptidases, Sulfonamide, Rats, Piperazine, ADAM Proteins, Enzyme, chemistry, Matrix Metalloproteinase 9, Enzyme inhibitor, biology.protein, Molecular Medicine, Matrix Metalloproteinase 1, Interleukin-1
Abstract

Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.

Published
2001

14. Catalytic Domain Crystal Structure of Protein Kinase C-θ (PKCθ).

Author

Zhang-Bao Xu, Chaudhary, Divya, Olland, Stephane, Wolfrom, Scott, Czerwinski, Robert, Malakian, Karl, Lin, Laura, Stahl, Mark L., Joseph-McCarthy, Diane, Benander, Christina, Fitz, Lori, Greco, Rita, Somers, William S., and Mosyak, Lidia

Subjects
*PROTEIN kinases, *T cells, *ADENOSINE triphosphate, *ENZYMES, *PROTEIN kinase C, *PROTEINS, *PHOSPHORYLATION, *CATALYSTS
Abstract

A member of the novel protein kinase C (PKC) subfamily, PKCθ, is an essential component of the T cell synapse and is required for optimal T cell activation and interleukin-2 production. Selective involvement of PKCθ in TCR signaling makes this enzyme an attractive therapeutic target in T cell-mediated disease processes. In this report we describe the crystal structure of the catalytic domain of PKCθ at 2.0-Å resolution. Human recombinant PKCθ kinase domain was expressed in bacteria as catalytically active phosphorylated enzyme and co-crystallized with its subnanomolar, ATP site inhibitor staurosporine. The structure follows the classic bilobal kinase fold and shows the enzyme in its active conformation and phosphorylated state. Inhibitory interactions between conserved features of staurosporine and the ATP-binding cleft are accompanied by closing of the glycine-rich loop, which also maintains an inhibitory arrangement by blocking the phosphate recognition subsite. The two major phosphorylation sites, Thr-538 in the activation loop and Ser-695 in the hydrophobic motif, are both occupied in the structure, playing key roles in stabilizing active conformation of the enzyme and indicative of PKCθ autocatalytic phosphorylation and activation during bacterial expression. The PKCθ-staurosporine complex represents the first kinase domain crystal structure of any PKC isotypes to be determined and as such should provide valuable insight into PKC specificity and into rational drug design strategies for PKCθ selective leads. [ABSTRACT FROM AUTHOR]

Published
2004
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15. The intramolecular nitrile oxide cycloaddition (INOC) route to the ergot alkaloids: Use of the isoxazoline to γ-amino alcohol conversion in the total synthesis of (+)-paliclavine

Author

Wang B.C, Chen Yon-Yih, Alan P. Kozikowski, and Zhang Bao Xu

Subjects
Allylic rearrangement, Nitrile, Intramolecular reaction, Stereochemistry, Reducing agent, Organic Chemistry, Paliclavine, Total synthesis, Biochemistry, Cycloaddition, chemistry.chemical_compound, chemistry, Intramolecular force, Drug Discovery
Abstract

A total synthesis of the ergot alkaloid paliclavine ( 20 ), in optically active form is described. The synthesis scheme is based on the intramolecular dipolar cycloaddition reaction of a nitrile oxide to a neighboring olefinic appendage bearing an allylic asymmetric center. The extent of diastereofacial selection in the intramolecular nitrile oxide cycloaddition (INOC) reaction was found to be marginal. A single-crystal X-ray analysis has established the complete stereostructure of the isoxazoline 15 prepared from the “major” INOC product. The dependence of the reduction stereochemistry of the isoxazolinium salt 15a on the nature of the reducing agent is discussed.

Published
1984

16. The INOC approach to the hydroazulenone ring system - a potential entry tot he guaianolides and pseudoguaianolides

Author

Zhang bao Xu, B. B. Mugrage, B. C. Wang, and Alan P. Kozikowski

Subjects
chemistry.chemical_compound, Nitrile, Stereochemistry, Chemistry, Intramolecular force, Organic Chemistry, Drug Discovery, Oxide, Ring (chemistry), Biochemistry, System a, Cycloaddition
Abstract

The intramolecular nitrile oxide cycloaddition reaction has been examined as a method for preparing the hydroazulene ring system.

Published
1983

17. An improved method for the synthesis of anomerically allylated C-glycopyranosides and C-glycofuranosides

Author

Alan P. Kozikowski, Kirk L. Sorgi, B.C. Wang, and Zhang-bao Xu

Subjects
carbohydrates (lipids), chemistry.chemical_compound, chemistry, Organic Chemistry, Drug Discovery, Organic chemistry, lipids (amino acids, peptides, and proteins), Glycosyl, Improved method, Biochemistry, Zinc bromide
Abstract

The reaction of glycosyl acetates with allyltrimethylsilane in the presence of zinc bromide has been investigated as a new method for C-glycoside construction.

Published
1983

18. [Determination of 2,4-dihydroxybenzophenone in mouse brain by high performance liquid chromatography].

Author

Wang YC, Sun Y, Cui R, Li YL, and Zhang BX

Subjects
Animals, Chromatography, High Pressure Liquid, Mice, Benzophenones chemistry, Brain Chemistry
Abstract

Objective: To optimize and establish the experimental methods for the determination of 2,4-dihydroxybenzophenone (BP-1) in mouse brain., Methods: BP-1 was determined by high performance liquid chromatography (HPLC) and separated by Waters Symmetry C18 (4.6 mm×250 mm, 5 μm) using isocratic elution, and the sample preparation conditions were optimized by orthogonal experiment design. The mobile phase was methanol-water (volume ratio 3:1) containing 3% (volume fraction) acetic acid (pH 3.40) at a flow rate of 1.0 mL/min, and ultraviolet (UV) detection wavelength was set at 290 nm. Retention time was used for qualitative analysis and internal standard method for quantitative analysis., Results: Under the optimized experimental conditions, the calibration curve was linear with a correlation coefficient of 0.999 8 over the concentration range of 0.2-10.0 mg/L. The recoveries of BP-1 were between 96.8% and 104.5%. The intra-day and inter-day precision of BP-1 were 3.5%-5.7% and 4.5%-6.4%, respectively. The extraction recoveries of BP-1 at three concentrations (0.5, 2.0, 8.0 mg/L) in the mouse brain were 90.5%, 89.5%, and 97.7%, and the matrix effect of BP-1 at these three concentrations were 102.9%, 102.7%, and 90.9%, respectively., Conclusion: The method is simple, accurate, and suitable for determination of the contents of BP-1 in mouse brain.

Published
2015

19. [Protective effect of 2,4-dihydroxybenzophenone on cocaine-induced hepatotoxicity and neurotoxicity in mice].

Author

Wu XY, Xue R, Liu X, Jia FL, Ruan M, and Zhang BX

Subjects
Animals, Antioxidants therapeutic use, Male, Mice, Mice, Inbred ICR, Benzophenones therapeutic use, Chemical and Drug Induced Liver Injury prevention & control, Cocaine toxicity, Neurotoxicity Syndromes prevention & control
Abstract

Objective: To investigate the protective effect of 2,4-dihydroxybenzophenone(BP-1) on acute hepatotoxicity and neurotoxicity induced by cocaine in mice, and its possible mechanism., Methods: Male ICR mice were pretreated with BP-1(100,200,400 mg/kg, ig, 4 d), cocaine(75 mg/kg) was injected 30 minutes after BP-1 administration on day 4.Twenty-four hours after the injection of cocaine, the serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were assayed by HITACHI-7170A automatic analyzer. The content of malondialdehyde (MDA) and the content of reduced glutathione (GSH) and oxidized glutathione (GSSG) were examined, and the ratio of GSH/GSSG was calculated, and histopathological analyses were also made. Male ICR mice were pretreated with BP-1(100,200,400 mg/kg, ig, 3 d), cocaine(20 mg/kg) was injected 30 minutes after BP-1 administration on day 3.The locomotor activity during 0-180 minutes of mice was recorded individually for each animal immediately after cocaine injection., Results: After the administration of cocaine, compared with corresponding solvent group, the activities of ALT [(1 571±1 161) IU/L vs. (30±16) IU/L, P<0.05], AST [(408±226) IU/L vs. (101±12) IU/L, P<0.05] and LDH [(3 963±1 431) IU/L vs. (1 935±287) IU/L, P<0.05] were significantly increased; the ratio of GSH/GSSG [(5.11±0.63) vs. (6.88±1.13),P<0.05] was decreased and the content of MDA [(1.97±1.36) μ mol/g vs. (0.07±0.06) μmol/g, P<0.01] was significantly increased. With the pretreatment of BP-1, compared with cocaine treatment group, the serum ALT [(112±96 )IU/L, (54±20) IU/L, (35±15) IU/L, P<0.05],AST [(130±33) IU/L,(107±5) IU/L, (99±9) IU/L, P<0.05] and LDH [(1 667±564) IU/L, (1 507±365) IU/L, (1 249±349) IU/L, P<0.01] were significantly decreased, the ratios of GSH/GSSG [(7.33±1.84), (9.28±0.67), (10.5±1.20), P<0.05] were increased and the contents of MDA [(1.82±1.19)μmol/g, (0.49±0.31)μmol/g, (0.35±0.30) μmol/g, P<0.05] were decreased. Significant amelioration in liver histopathology was also presented in the BP-1 treatment groups. The BP-1 pretreated mice showed significant reduction in activity counts evoked by cocaine (20 mg/kg), and shorten the time for activity counts to become normal., Conclusion: BP-1 has protective effect on acute hepatotoxicity and neurotoxicity of mice induced by cocaine. Its mechanisms might be associated with its antioxidant activity.

Published
2012

20. Protective effects of 5-methoxypsoralen against acetaminophen-induced hepatotoxicity in mice.

Author

Liu WX, Jia FL, He YY, and Zhang BX

Subjects
5-Methoxypsoralen, Administration, Oral, Alanine Transaminase blood, Animals, Antioxidants administration & dosage, Antioxidants toxicity, Aspartate Aminotransferases blood, Biomarkers blood, Chemical and Drug Induced Liver Injury blood, Chemical and Drug Induced Liver Injury etiology, Chemical and Drug Induced Liver Injury pathology, Cytoprotection, Disease Models, Animal, Dose-Response Relationship, Drug, Glutathione metabolism, Glutathione Disulfide metabolism, L-Lactate Dehydrogenase blood, Liver metabolism, Liver pathology, Male, Malondialdehyde metabolism, Methoxsalen administration & dosage, Methoxsalen pharmacology, Methoxsalen toxicity, Mice, Mice, Inbred C57BL, Oxidative Stress drug effects, Acetaminophen, Antioxidants pharmacology, Chemical and Drug Induced Liver Injury prevention & control, Liver drug effects, Methoxsalen analogs & derivatives
Abstract

Aim: To investigate the hepatic protective effects of 5-methoxypsoralen (5-MOP) and to learn if 5-MOP causes hepatotoxicity at protective doses., Methods: C57BL/6J mice were administrated orally with 5-MOP at doses of 12.5, 25 and 50 mg/kg body weight respectively every morning for 4 d before given acetaminophen (APAP) subcutaneously at a dose of 500 mg/kg. The 5-MOP alone group was treated with 5-MOP orally at a dose of 50 mg/kg body weight for 4 d without APAP. Twenty-four hours after APAP administration, blood samples of mice were analyzed for serum enzyme alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH) levels, and malondialdehyde (MDA), reduced glutathione (GSH) and oxidized glutathione (GSSG) of liver tissues were measured and histopathologic changes of the liver were observed., Results: Compared with the vehicle control group, the serum levels (IU/L) of ALT, AST and LDH were all increased significantly in APAP group (8355 ± 3940 vs 30 ± 21, P < 0.05; 6482 ± 4018 vs 146 ± 58, P < 0.05; 24627 ± 10975 vs 1504 ± 410, P < 0.05). Compared with APAP group, the serum ALT levels (IU/L) (1674 ± 1810 vs 8355 ± 3940, P < 0.05; 54 ± 39 vs 8355 ± 3940, P < 0.05; 19 ± 9 vs 8355 ± 3940, P < 0.05), AST levels (IU/L) (729 ± 685 vs 6482 ± 4108, P < 0.05; 187 ± 149 vs 6482 ± 4108, P < 0.05; 141 ± 12 vs 6482 ± 4108, P < 0.05) and LDH levels (IU/L) (7220 ± 6317 vs 24 627 ± 10 975, P < 0.05; 1618 ± 719 vs 24 627 ± 10 975, P < 0.05; 1394 ± 469 vs 24 627 ± 10 975, P < 0.05) were all decreased drastically in the three-dosage 5-MOP pretreatment groups. Pretreatment of 5-MOP could attenuate histopathologic changes induced by APAP, including hepatocellular necrosis and infiltration of inflammatory cells, and the effect was dose-dependent. MDA levels (nmol/mg) were decreased by 5-MOP in a dose-dependent manner (0.98 ± 0.45 vs 2.15 ± 1.07, P > 0.05; 0.59 ± 0.07 vs 2.15 ± 1.07, P < 0.05; 0.47 ± 0.06 vs 2.15 ± 1.07, P < 0.05). The pretreatment of 5-MOP could also increase the GSH/GSSG ratio (3.834 ± 0.340 vs 3.306 ± 0.282, P > 0.05; 5.330 ± 0.421 vs 3.306 ± 0.282, P < 0.05; 6.180 ± 0.212 vs 3.306 ± 0.282, P < 0.05). In the group treated with 5-MOP but without APAP, the serum enzyme levels, the liver histopathologic manifestation, and the values of MDA and GSH/GSSG ratio were all normal., Conclusion: 5-MOP can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity and possesses an antioxidative activity, and does not cause liver injury at the protective doses.

Published
2012
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21. Protective effects of 2,4-dihydroxybenzophenone against acetaminophen-induced hepatotoxicity in mice.

Author

He YY, Zhang BX, and Jia FL

Subjects
Animals, Benzophenones pharmacology, Glutathione metabolism, Humans, Liver drug effects, Liver enzymology, Male, Malondialdehyde metabolism, Mice, Mice, Inbred C57BL, Oxidative Stress, Acetaminophen toxicity, Analgesics, Non-Narcotic toxicity, Benzophenones therapeutic use, Chemical and Drug Induced Liver Injury drug therapy, Chemical and Drug Induced Liver Injury prevention & control, Liver pathology
Abstract

Aim: To examine the effects of 2,4-dihydroxybenzophenone (BP-1), a benzophenone derivative used as an ultraviolet light absorbent, on acetaminophen (APAP)-induced hepatotoxicity in C57BL/6J mice., Methods: Mice were administered orally with BP-1 at doses of 200, 400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP (350 mg/kg body weight) was given subcutaneously. Twenty four hours after APAP intoxication, the serum enzyme including serum alaine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) were measured and liver histopathologic changes were examined., Results: BP-1 administration dramatically reduced serum ALT, AST and LDH levels. Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner. Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment, and glutathione depletion was ameliorated obviously., Conclusion: BP-1 can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity, and reduction of oxidative stress might be part of the protection mechanism.

Published
2011
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22. [The hepatoprotective effect of aqueous extracts from Ficus hirta on N, N-dimethylformamide induced acute liver injury in mice].

Author

Lv YJ, Jia FL, Ruan M, and Zhang BX

Subjects
Alanine Transaminase blood, Animals, Aspartate Aminotransferases blood, Chemical and Drug Induced Liver Injury blood, Dimethylformamide poisoning, Dose-Response Relationship, Drug, Female, L-Lactate Dehydrogenase blood, Liver drug effects, Liver enzymology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Plant Extracts isolation & purification, Plant Extracts therapeutic use, Plant Roots chemistry, Plants, Medicinal chemistry, Protective Agents therapeutic use, Random Allocation, Chemical and Drug Induced Liver Injury prevention & control, Ficus chemistry, Liver pathology, Plant Extracts pharmacology, Protective Agents pharmacology
Abstract

Objective: To investigate the effect of aqueous extract from Ficus hirta on N, N-Dimethylformamide (DMF) induced liver injury in mice., Methods: C57BL/6 mice and ICR mice were randomly divided into 5 groups: negative control group, positive control group and three treated groups respectively. Treated groups were administered orally with 100, 200, 300 g/kg Ficus hirta aqueous extract per day respectively for 5 days. On the 4th day, 2. 3 g/kg DMF was given by intraperitoneal injection to all C57BL/6 mice except negative control group, while for ICR, DMF was administration at a 2.75 g/kg dose. 48h after DMF injection, serum samples were collected to determine the activities of ALT, AST and LDH and the pathological changes of liver tissue were analyzed under microscope., Results: Compared with the positive control, the activities of ALT, AST and LDH were significantly reduced and the liver injury obviously attenuated in treated groups., Conclusion: The aqueous extract of Ficus hirta has an obvious protective effect against DMF-induced acute liver injury in mice.

Published
2008

23. [Effect of roots of Ficus hirta on cocaine-induced hepatotoxicity and active components].

Author

Cai QY, Chen HB, Cai SQ, Zhao ZZ, Ruan M, Jia FL, Ou T, and Zhang BX

Subjects
Alanine Transaminase blood, Animals, Aspartate Aminotransferases blood, Catalase metabolism, Chemical and Drug Induced Liver Injury, Cocaine, Drugs, Chinese Herbal isolation & purification, Ficusin isolation & purification, Ficusin pharmacology, Liver drug effects, Liver enzymology, Liver pathology, Liver Diseases blood, Male, Mice, Mice, Inbred ICR, Random Allocation, Drugs, Chinese Herbal pharmacology, Ficus chemistry, Liver Diseases prevention & control, Plant Roots chemistry, Plants, Medicinal chemistry
Abstract

Objective: To investigate the protective effect of the roots of F. hirta against the cocaine-induced hepatotoxicity and it's active components., Method: Cocaine hydrochloride was subcutaneously injected to make male ICR mice liver wounded. Male ICR mice were randomly ig administered with the F. hirta decoction. The dose groups are 100, 200, 300 g x kg(-1) herb materials per body weight. Cocaine hydrochloride was subcutaneously injected into the mice after the administration. The serum ALT, AST activity and the activity of CAT in liver homogenate were assayed, and liver change of pathomorphism was evaluated to prove the effect of the F. hirta decoction on cocaine-induced hepatotoxicity. And the activity of psoralean which was separated from the F. hirta decoction by bioassay-guided fractionation, was proofed in the same method., Result: We find that the F. hirta decoction shows a distinct effect on reducing serum transferase. The serum transferase and the content CAT in liver homogenate were dose-related reduced, and the histopathological examination found a significantly change of the liver tissues. And the psoralean, qua the mainly component, shows the same effect., Conclusion: F. hirta has the protective effect against the cocaine-induced hepatotoxicity. Psoralean is the basis.

Published
2007

24. [Study on the use of haemoglobin denaturation test as an alternative to Draize eye irritation test].

Author

Liao Y, Wang X, Zhang LS, Li GM, and Zhang BX

Subjects
Animal Testing Alternatives methods, Animals, Conjunctiva drug effects, Cornea drug effects, Humans, Product Surveillance, Postmarketing, Protein Denaturation, Quality Control, Sensitivity and Specificity, Cosmetics toxicity, Hemoglobins, Irritants toxicity, Toxicity Tests methods
Abstract

Objective: To use haemoglobin denaturation test (HD test) as an alternative to Draize eye irritation test (Draize test)., Methods: Fourteen cosmetic ingredients were tested by HD test. The results were compared with two kinds of scores in Draize test, i.e. Maximum average Draize total score (MAS) and Score of 24 h after application (S24)., Results: The correlation coefficient between RDC50 and MAS and that between RDC50 and S24 were 0.926 and 0.921 respectively, while that between 1%lambdamax and MAS, and between 1%lambdamax and S24 were 0.881 and 0.791 respectively. The results showed that RDC50 had a higher correlation with Draize test than 1%lambdamax did, but in the use of RDC50 some information of data would be lost. On the other hand, 1%lambdamax, which had a greater correlation with corneal score in the three component scores of the Draize test, could be used for assessing water-insoluble chemicals., Conclusion: The results showed that HD test could be used as an effective alternative to Draize eye irritation test.

Published
2004

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