National Shanghai Center for New Drug Safety Evaluation and Research

Shanghai, China

National Shanghai Center for New Drug Safety Evaluation and Research

Shanghai, China

Time filter

Source Type

Sun Y.,Shanghai JiaoTong University | Shi N.,Shanghai Pudong New District Zhoupu Hospital | Li H.,National Shanghai Center for New Drug Safety Evaluation and Research | Liu K.,Shanghai Pudong New District Zhoupu Hospital | And 3 more authors.
Cellular Signalling | Year: 2014

Although ghrelin receptors have been demonstrated to be widely expressed in the central nervous system and peripheral tissues of mammals, it is still unknown whether ghrelin functions in cerebellar Purkinje neurons. In this study, we identified a novel functional role for ghrelin in modulating P-type Ca2+ channel (P-type channel) currents (IBa) as well as action-potential firing in rat Purkinje neurons. Our results show that ghrelin at 0.1μM reversibly decreased IBa by ~32.3%. This effect was growth hormone secretagogue receptor 1a (GHS-R1a)-dependent and was associated with a hyperpolarizing shift in the voltage-dependence of inactivation. Intracellular application of GDP-β-S and pretreatment with pertussis toxin abolished the inhibitory effects of ghrelin. Dialysis of cells with the peptide QEHA (but not the scrambled peptide SKEE), and a selective antibody raised against the G-protein αo subunit both blocked the ghrelin-induced response. Ghrelin markedly increased protein kinase A (PKA) activity, and intracellular application of PKI 5-24 as well as pretreatment of the cells with the PKA inhibitor KT-5720 abolished ghrelin-induced IBa decrease, while inhibition of PKC had no such effects. At the cellular level, ghrelin induced a significant increase in action-potential firing, and blockade of GHS-R1a by BIM-28163 abolished the ghrelin-induced hyperexcitability. In summary, these results suggest that ghrelin markedly decreases IBa via the activation of GHS-R1a, which is coupled sequentially to the activities of Go-protein βγ subunits and the downstream PKA pathway. This could contribute to its physiological functions, including the spontaneous firing of action potentials in cerebellar Purkinje neurons. © 2014 Elsevier Inc.


Wu C.,Fudan University | Feng C.,Centers for Disease Control and Prevention | Qi X.,Fudan University | Wang G.,Centers for Disease Control and Prevention | And 4 more authors.
Chemosphere | Year: 2013

Pyrethroid insecticides are extensively and increasingly applied in agricultural and residential environments in China. Children's exposure to pesticides attracted global concerns because of their particular vulnerability. Several studies have reported residual pyrethroid levels in urine both in adults and in children. However, few published data focused on very young infants. The study aimed to assess exposure to pyrethroid insecticides in young infants and investigate the potential influence factors on pyrethroid exposure levels. Data on pyrethroids exposure was based on questionnaire items and measurement of urinary metabolite levels among 481 infants. We detected pyrethroid metabolites of 3-phenoxybenzoic acid (3-PBA), cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (cis-DCCA and trans-DCCA) in urine using a gas chromatography-mass spectrometry method. Median values for urinary pyrethroid metabolites in these infants were 0.39μgL-1 for 3-PBA, 0.18μgL-1 for cis-DCCA, 0.92μgL-1 for trans-DCCA, respectively. About 60.9% of the infants had urinary concentrations of three pyrethroid metabolites that were above the level of 0.10μgL-1 (limit of detection, LOD). These findings of the urinary metabolites were comparable or slightly higher than those children from the other countries. From questionnaire, we learned that more than 70% of households reported that they or family members had applied mosquito repellents in infants. Above data indicated the need to assess the potential adverse effects of pyrethroids exposure on infants in order to take adequate measures to protect them from pesticide exposures during early childhood. © 2012 Elsevier Ltd.


Li R.,Zhejiang Academy of Agricultural Sciences | He L.,National Shanghai Center for New Drug Safety Evaluation and Research | Wei W.,Zhejiang Academy of Agricultural Sciences | Hao L.,Southwest University for Nationalities | And 3 more authors.
Food Control | Year: 2015

In this study, chlorpyrifos residue levels in field crops of rice, maize and soybean were investigated according to the "Guideline on Pesticide Residue Trials" of China. On the basis of the residual results, human dietary risks were further evaluated. Chlorpyrifos residues of harvest grains were firstly prepared by QuEChERS method and analyzed using Gas Chromatography Tandem Mass Spectrometry (GC-MS/MS). Dietary risks were assessed by a deterministic approach. The median residues in field trials of rice, maize and soybean were 0.617, 0.0227 and 0.0136 mg kg-1, respectively. The highest residues in field trials of rice, maize and soybean were 3.23, 0.114 and 0.102 mg kg-1, respectively. Chronic intake assessment indicated that only 39.0% of acceptable daily intake (ADI, 0-0.01mg kg bw-1day-1) was consumed through rice, maize and soybean. The acute hazard indexes (aHI) of adults was 26.1% of acute reference dose (ARfD, 0-0.1 mg kg bw-1) and aHI of children was 63.5% of ARfD in dietary exposure assessment through rice, maize and soybean consumption. Single pathway risk assessment indicated that chlorpyrifos application on field crops in manner of the good agricultural practices didn't pose public health risks. © 2014 Elsevier Ltd.


Wang Y.,National Shanghai Center for New Drug Safety Evaluation and Research | Wang Y.,Shanghai Institute of Pharmaceutical Industry | Tang N.,National Shanghai Center for New Drug Safety Evaluation and Research | Hui T.,National Shanghai Center for New Drug Safety Evaluation and Research | And 6 more authors.
Journal of Applied Toxicology | Year: 2013

Circulating microRNA (miRNA) expression profiles have been reported to be promising biomarkers for drug-induced liver injury in preclinical and clinical practice. Proper normalization is critical for accurate miRNAs expression analysis. Herein, using SYBR green quantitative real-time PCR (RT-qPCR), we evaluated the expression stability of six candidate reference genes including two commonly used small RNAs (U6, 5S) and four miRNAs (let-7a, miR-92a, miR-103 and miR-16) in plasma of rats with acetaminophen-induced hepatotoxicity. Data were analysed using geNorm, Normfinder, BestKeeper and comparative delta-Ct statistical models, and the results consistently show that miR-103 is the most stably expressed reference gene. Whereas the commonly used housekeeping genes 5S or U6 are all not suitable normalizers, because 5S exhibits extensive variability in expression and U6 has a low expression level across the plasma samples. Then the effect of reference genes on normalization of plasma miR-122 was assessed; when normalized to the most stable reference gene there were significant differences between the acetaminophen-treated group and the vehicle group. However, when the data were normalized to a less stably expressed gene, miR-16, a biased result was obtained. Therefore, we recommend that miR-103 as suitable reference gene for plasma miRNAs analysis for acetaminophen-induced liver injury. Data presented in this paper are crucial to successful biomarker discovery and validation for the diagnosis of the early stage of acetaminophen hepatotoxicity. © 2013 John Wiley & Sons, Ltd.


Huang P.-C.,National Shanghai Center for New Drug Safety Evaluation and Research | Zhou C.-H.,National Shanghai Center for New Drug Safety Evaluation and Research | Chang Y.,National Shanghai Center for New Drug Safety Evaluation and Research
Chinese Journal of New Drugs | Year: 2016

DNA double strand breaks (DSBs) are the most serious DNA damage types in the cell. DSBs can activate cell's DNA damage response (DDR) mechanism and then the histone H2AX be rapidly phosphorylated (phosphorylated histone H2AX is called the γ-H2AX). Subsequently, γ-H2AX gathered in double-stranded breaks and formed a large number of γ-H2AX foci. Therefore, γ-H2AX foci tested in the cell can be used for evaluation of double-stranded DNA rupture, which can be used to evaluate the genetic toxicity of the mutagenic capability. At home and abroad at present, there are many detection methods of γ-H2AX foci, including Western blotting, immunofluorescence staining microscopic method, whole-cell enzyme-linked immune assay and flow cytometry assay. Each method has its advantages and disadvantages. This paper will be focused on new progress in γ-H2AX detection methods in recent years at home and abroad, and summarize the operation steps, statistical parameters, advantages and disadvantages between different test methods, and analyze the application of γ-H2AX assay in the field of genetic toxicology. © 2016, Chinese Journal of New Drugs Co. Ltd. All right reserved.


Li R.,Institute of Quality and Standard for Agro products | He L.,National Shanghai Center for New Drug Safety Evaluation and Research | Zhou T.,Agriculture and Agri Food Canada | Ji X.,Institute of Quality and Standard for Agro products | And 3 more authors.
Analytical and Bioanalytical Chemistry | Year: 2014

A rapid, specific, and sensitive method based on modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) coupled to gas chromatography tandem mass spectrometry (GC-MS/MS) was developed and validated for simultaneous determination of chlorpyrifos (CP) and its metabolite 3,5,6-trichloro-2- pyridinol (TCP) in duck muscle. The residues of CP and TCP were extracted by acidified acetonitrile. The fat layer of the extract was removed under-20 °C, then the organic layer was evaporated. The analytes were derivatized by N-(tert-butyldimethylsilyl)-Nmethyltrifluoroacetamide (MTBSTFA) and cleaned up by a mixture of 150 mg MgSO4, 25 mg graphitized carbon black (GCB), and 50mg N-propylethylenediamine (PSA) to remove interference. The final extract was analyzed by GC-MS/MS. Recovery values at the spiking concentrations ranged from 86.2 to 92.3 % for CP and from 74.8 to 81.8 % for TCP, with relative standard deviations (RSDs) lower than 9.5 and 12.3, respectively. The correlation coefficients of CP (from 2 to 2,000 μg/kg) and TCP (from 1 to 1,000 μg/kg) were equal to or higher than 0.998. The limits of detection (LODs) were 0.3 and 0.15 μg/kg, and the limits of quantification (LOQs) were 1.0 and 0.5 μg/kg for CP and TCP in duck muscle, respectively. The average intra- and inter-day accuracy ranged from 84.6 to 91.2 % for CP and 75.6 to 82.3 % for TCP, and the intra- and inter-day precisions were from 5.8 to 8.2 % for CP and 6.5 to 11.9 % for TCP. Furthermore, the CP and TCP residues in duck muscle samples were detected for dietary risk assessment using the validated method.


Zhang Y.,Soochow University of China | Li H.,National Shanghai Center for New Drug Safety Evaluation and Research | Pu Y.,Soochow University of China | Gong S.,Soochow University of China | And 3 more authors.
Journal of Pineal Research | Year: 2015

Although melatonin receptors are widely expressed in the mammalian central nervous system and peripheral tissues, there are limited data regarding the functions of melatonin in cerebellar Purkinje cells. Here, we identified a novel functional role of melatonin in modulating P-type Ca2+ channels and action-potential firing in rat Purkinje neurons. Melatonin at 0.1 μm reversibly decreased peak currents (IBa) by 32.9%. This effect was melatonin receptor 1 (MTR1) dependent and was associated with a hyperpolarizing shift in the voltage dependence of inactivation. Pertussis toxin pretreatment, intracellular application of QEHA peptide, and a selective antibody raised against the Gβ subunit prevented the inhibitory effects of melatonin. Pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitors abolished the melatonin-induced decrease in IBa. Surprisingly, melatonin responses were not regulated by Akt, a common downstream target of PI3K. Melatonin treatment significantly increased protein kinase C (PKC) activity 2.1-fold. Antagonists of PKC, but not of protein kinase A, abolished the melatonin-induced decrease in IBa. Melatonin application increased the membrane abundance of PKCδ, and PKCδ inhibition (either pharmacologically or genetically) abolished the melatonin-induced IBa response. Functionally, melatonin increased spontaneous action-potential firing by 53.0%; knockdown of MTR1 and blockade of P-type channels abolished this effect. Thus, our results suggest that melatonin inhibits P-type channels through MTR1 activation, which is coupled sequentially to the βγ subunits of Gi/o-protein and to downstream PI3K-dependent PKCδ signaling. This likely contributes to its physiological functions, including spontaneous firing of cerebellar Purkinje neurons. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


He L.,National Shanghai Center for New Drug Safety Evaluation and Research | Hao L.,Southwest University for Nationalities | Fu X.,National Shanghai Center for New Drug Safety Evaluation and Research | Huang M.,National Shanghai Center for New Drug Safety Evaluation and Research | And 2 more authors.
BMC Nephrology | Year: 2015

Background: Hyperlipidemia is thought to be a major risk factor for the progression of renal diseases in diabetes. Recent studies have shown that lipid profiles are commonly abnormal early on type 2 diabetes mellitus (T2DM) with diabetic nephropathy. However, the early effects of triglyceride and cholesterol abnormalities on renal injury in type 1 diabetes mellitus (T1DM) are not fully understood and require reliable animal models for exploration of the underlying mechanisms. Hamster models are important tools for studying lipid metabolism because of their similarity to humans in terms of lipid utilization and high susceptibility to dietary cholesterol and fat. Methods: Twenty-four male Golden Syrian hamsters (100-110 g) were rendered diabetes by intraperitoneal injections of streptozotocin (STZ) on consecutive 3 days at dose of 30 mg/kg, Ten days after STZ injections, hamsters with a plasma Glu concentration more than 12 mmol/L were selected as insulin deficient ones and divided into four groups (D-C, D-HF, D-HC, and D-HFHC), and fed with commercially available standard rodent chow, high-fat diet, high-cholesterol diet, high-fat and cholesterol diet respectively, for a period of four weeks. Results: After an induction phase, a stable model of renal injury was established with the aspects of early T1DM kidney disease, These aspects were severe hypertriglyceridemia, hypercholesterolemia, proteinuria with mesangial matrix accumulation, upgraded creatinine clearance, significant cholesterol and triglyceride deposition, and increasing glomerular surface area, thickness of basement membrane and mesangial expansion. The mRNA levels of sterol regulatory element binding protein-1c, transforming growth factors-β, plasminogen activator inhibitor-1, tumor necrosis factor-α and interleukin-6 in the D-HFHC group were significantly up-regulated compared with control groups. Conclusions: This study presents a novel, non-transgenic, non-surgical method for induction of renal injury in hamsters, which is an important complement to existing diabetic models for pathophysiological studies in early acute and chronic kidney disease, especially hyperlipidemia. These data suggest that both severe hypertriglyceridemia and hypercholesterolemia can accelerate renal injury in the early development of T1DM. © 2015 He et al.; licensee BioMed Central.


PubMed | Shanghai Key Laboratory of Veterinary Biotechnology and National Shanghai Center for New Drug Safety Evaluation and Research
Type: Journal Article | Journal: Journal of the American Association for Laboratory Animal Science : JAALAS | Year: 2016

To evaluate the effects of transportation on oxidative stress in cynomolgus monkeys, we measured serum levels of reduced glutathione (GSH), malondialdehyde, and protein carbonyl (PC) and the activities of total antioxidant capacity (TAOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase in cynomolgus macaques before transportation (day 0), on the day of arrival (day 1), and on days 7, 14, and 21 after transportation. Compared with that on day 0, TAOC and catalase activities on days 1, 7, and 14 after transportation were significantly decreased, reached their nadirs on day 7, and increased thereafter to reach their pretransportation levels by day 21 after transportation. Compared with day 0 levels, mean SOD activity and GSH concentration were decreased significantly on day 1; they thereafter increased to reach their pretransportation measures by day 7 after transportation. In contrast, PC and malondialdehyde concentrations in serum and the activity of GSH-Px were increased on day 1 compared with day 0 and thereafter decreased to reach their pretransportation levels by day 14 after transportation. In summary, GSH, TAOC, catalase, and SOD levels decreased and malondialdehyde, PC, and GSH-Px concentrations increased in cynomolgus macaques after transportation. These results suggest that transportation might imbalance oxidant and antioxidant levels to create excess oxidative stress in cynomolgus macaques. Therefore, cynomolgus macaques should have at least 21 d to recover after transportation and regain their healthy status.


PubMed | State Key Laboratory Breeding Base for Zhejiang Sustainable Plant Pest Control, National Shanghai Center for New Drug Safety Evaluation and Research and Southwest University for Nationalities
Type: | Journal: BMC nephrology | Year: 2015

Hyperlipidemia is thought to be a major risk factor for the progression of renal diseases in diabetes. Recent studies have shown that lipid profiles are commonly abnormal early on type 2 diabetes mellitus (T2DM) with diabetic nephropathy. However, the early effects of triglyceride and cholesterol abnormalities on renal injury in type 1 diabetes mellitus (T1DM) are not fully understood and require reliable animal models for exploration of the underlying mechanisms. Hamster models are important tools for studying lipid metabolism because of their similarity to humans in terms of lipid utilization and high susceptibility to dietary cholesterol and fat.Twenty-four male Golden Syrian hamsters (100-110g) were rendered diabetes by intraperitoneal injections of streptozotocin (STZ) on consecutive 3days at dose of 30mg/kg, Ten days after STZ injections, hamsters with a plasma Glu concentration more than 12mmol/L were selected as insulin deficient ones and divided into four groups (D-C, D-HF, D-HC, and D-HFHC), and fed with commercially available standard rodent chow, high-fat diet, high-cholesterol diet, high-fat and cholesterol diet respectively, for a period of four weeks.After an induction phase, a stable model of renal injury was established with the aspects of early T1DM kidney disease, These aspects were severe hypertriglyceridemia, hypercholesterolemia, proteinuria with mesangial matrix accumulation, upgraded creatinine clearance, significant cholesterol and triglyceride deposition, and increasing glomerular surface area, thickness of basement membrane and mesangial expansion. The mRNA levels of sterol regulatory element binding protein-1c, transforming growth factors-, plasminogen activator inhibitor-1, tumor necrosis factor- and interleukin-6 in the D-HFHC group were significantly up-regulated compared with control groups.This study presents a novel, non-transgenic, non-surgical method for induction of renal injury in hamsters, which is an important complement to existing diabetic models for pathophysiological studies in early acute and chronic kidney disease, especially hyperlipidemia. These data suggest that both severe hypertriglyceridemia and hypercholesterolemia can accelerate renal injury in the early development of T1DM.

Loading National Shanghai Center for New Drug Safety Evaluation and Research collaborators
Loading National Shanghai Center for New Drug Safety Evaluation and Research collaborators