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He J.-H.,Wenzhou University | He J.-H.,Hunter Biotechnology Inc. | Gao J.-M.,Wenzhou University | Huang C.-J.,Wenzhou University | And 2 more authors.
Neurotoxicology and Teratology | Year: 2014

The zebrafish is increasingly used as a vertebrate animal model for in vivo drug discovery and for assessing chemical toxicity and safety. Numerous studies have confirmed that zebrafish and mammals are similar in their physiology, development, metabolism and pathways, and that zebrafish responses to toxic substances are highly predictive of mammalian responses. Developmental and reproductive toxicity assessments are an important part of new drug safety profiling. A significant number of drug candidates have failed in preclinical tests due to their adverse effect on development and reproductivity. Compared to conventional mammal testing, zebrafish testing for assessing developmental and reproductive toxicity offers several compelling experimental advantages, including transparency of embryo and larva, higher throughput, shorter test period, lower cost, smaller amount of compound required, easier manipulation and direct compound delivery. Toxicity and safety assessments using zebrafish have also been accepted by the FDA and EMEA for investigative new drug (IND) approval. © 2014 Elsevier Inc.

Chen J.-B.,Tongji University | Gao H.-W.,Tongji University | Zhang Y.-L.,Tongji University | Zhang Y.,Hunter Biotechnology Inc. | And 3 more authors.
Scientific Reports | Year: 2014

Environmental pollution by emerging contaminants, e.g. pharmaceuticals, has become a matter of widespread concern in recent years. We investigated the membrane transport of diclofenac and its toxic effects on gene expression and the development of zebrafish embryos. The association of diclofenac with the embryos conformed to the general partition model at low concentration, the partition coefficient being 0.0033 ml per embryo. At high concentration, the interaction fitted the Freundlich model. Most of the diclofenac remained in the extracellular aqueous solution with less than 5% interacting with the embryo, about half of which was adsorbed on the membranes while the rest entered the cytoplasm. Concentrations of diclofenac over 10.13 μM were lethal to all the embryos, while 3.78 μM diclofenac was teratogenic. The development abnormalities at 4 day post treatment (dpt) include shorter body length, smaller eye, pericardial and body edema, lack of liver, intestine and circulation, muscle degeneration, and abnormal pigmentation. The portion of the diclofenac transferred into the embryo altered the expression of certain genes, e.g. down-regulation of Wnt3a and Gata4 and up-regulation of Wnt8a. The alteration of expression of such genes or the regulation of downstream genes could cause defects in the cardiovascular and nervous systems.

Yang R.,National Institutes for Food and Drug Control | Lao Q.-C.,Hunter Biotechnology Inc. | Yu H.-P.,Hunter Biotechnology Inc. | Zhang Y.,Hunter Biotechnology Inc. | And 5 more authors.
Journal of Applied Toxicology | Year: 2015

A number of recent reports suspected that Tween-80 in injectable medicines, including traditional Chinese medicine injections could cause life-threatening anaphylactoid reaction, but no sound conclusion was drawn. A drug-induced anaphylactoid reaction is hard to be assayed in vitro and in conventional animal models. In this study, we developed a microplate-based quantitative in vivo zebrafish assay for assessing anaphylactoid reaction and live whole zebrafish mast cell tryptase activity was quantitatively measured at a wavelength of 405nm using N-benzoyl-dl-arginine p-nitroanilide as a substrate. We assessed 10 batches of Tween-80 solutions from various national and international suppliers and three Tween-80 impurities (ethylene glycol, 2-chloroethanol and hydrogen peroxide) in this model and found that three batches of Tween-80 (nos 2, 20080709 and 20080616) and one Tween-80 impurity, hydrogen peroxide (H2O2), induced anaphylactoid reactions in zebrafish. Furthermore, we found that H2O2 residue and peroxide value were much higher in Tween-80 samples 2, 20080709 and 20080616. These findings suggest that H2O2 residue in combination with oxidized fatty acid residues (measured as peroxide value) or more likely the oxidized fatty acid residues in Tween-80 samples, but not Tween-80 itself, may induce anaphylactoid reaction. High-throughput zebrafish tryptase assay developed in this report could be used for assessing safety of Tween-80-containing injectable medicines and potentially for screening novel mast cell-modulating drugs. © 2014 John Wiley & Sons, Ltd.

Li J.-L.,CAS Shanghai Institute of Materia Medica | Zhou J.,Hunter Biotechnology Inc. | Chen Z.-H.,CAS Shanghai Institute of Materia Medica | Guo S.-Y.,Hunter Biotechnology Inc. | And 3 more authors.
Journal of Natural Products | Year: 2015

(Chemical Equation Presented). Six new C21 steroidal glycosides, cynotophyllosides A-F (1-6), together with 16 known compounds, were isolated from the roots of Cynanchum otophyllum. The structures of the new compounds were elucidated by spectroscopic analysis and chemical methods. The three major components, otophylloside F (15), otophylloside B (17), and rostratamine 3-O-β-d-oleandropyranosyl-(1→4)-β-d-cymaropyranosyl-(1→4)-β-d-cymaropyranoside (18), suppressed the seizure-like locomotor activity caused by pentylenetetrazole in zebrafish. Preliminary structure-activity relation studies revealed that a pregnene skeleton with a C-12 ester group (ikemaoyl > cinnamoyl > hydroxy > p-hydroxybenzoyl) and a C-3 sugar chain consisting of three 2,6-dideoxysaccharide units is essential for this suppressive activity. © 2015 American Chemical Society and American Society of Pharmacognosy.

Zhang Y.,Hunter Biotechnology Inc. | Guo S.-Y.,Hunter Biotechnology Inc. | Deng Z.-P.,Shanghai University of Traditional Chinese Medicine | Li C.-Q.,Hunter Biotechnology Inc.
Chinese Journal of New Drugs | Year: 2016

In this review, we discuss the advantages of zebrafish models and introduce their applications in target organ toxicity studies of Chinese herbs, especially for acute toxicity, hepatotoxicity, cardiovascular toxicity, kidney toxicity and neurotoxicity tests. The advantages and particular value of zebrafish in toxic target organ studies of Chinese herbs are highlighted. This new vertebrate model may become a powerful tool for toxicity studies and safety assessment of Chinese herbs. Copyright © 2016 by the Editorial Board of Chinese Journal of Contemporary Neurology and Neurosurgery

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