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Effect of methylamphetamine on action potential and delayed rectifier potassium current in guinea-pig ventricular myocytes

Yanming ZHOU ; Ruobing LIANG ; Xiuli ZHAO ; Minghui ZHANG ; Feng WU ; Bo ZHU

Chinese Journal of Pharmacology and Toxicology.2010;24(6):449-454. doi:10.3867/j.issn.1000-3002.2010.06.001

OBJECTIVE To explore the mechanism of methylamphetamine (MA) on heart toxicity. METHODS The effects of MA on delayed rectifier potassium current (IK) and action potential (AP) were analyzed in isolated decreased AP from 121.6 to 106.0 mV and delayed the action potential duration (APD), but had no effect on the resting potential. The 10%, 25%, 50%, 75% and 90% of APD (APD10, APD25, APD50, APD75 and APD90)inhibited the membrane potential of rapidly activating delayed rectifier potassium current (IKr) and slowly activating delayed rectifier potassium current (IKs), downward shifted the Ⅰ -Ⅴ curve, but had no effect on the curve shape and could be partly recovered after flushing. The tail current IKr was blocked concentration-dependently after simiarly inhibited by MA. CONCLUSION MA has inhibitory effects on Ik and AP in ventricular myocytes,which may be one of the possible electrophysiological mechanisms of the cardiac damage caused by MA.

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Pre-clinical pharmacokinetics of recombinant heat shock protein 65-mucin 1 fusion protein vaccine

Jing BAI ; Xiao SUN ; Lun OU ; Xiuwen LIU ; Zhongming TANG ; Haifeng SONG

Chinese Journal of Pharmacology and Toxicology.2010;24(3):168-173. doi:10.3867/j.issn.1000-3002.2010.03.002

OBJECTIVE To study the pharmacokinetics of heat shock protein 65-mucin 1 (HSP65-MUC1) recombinant fusion protein vaccine in Macaca mulatta monkeys and tumor-bearing mice. METHODS HSP65-MUC1 was labeled by radioactive isotope 125I. M. mulatta monkeys were randomly divided into sc and iv administration groups. Simultaneously, sc administration group was designed as a multiple dose group in which M. mulatta monkeys were sc given [ 125I] HSP65-MUC1 40 μg·g-1, once every 2 weeks for a total of 3 times. Size exclusion chromatography ( SEC) was used to determine concentrations of HSP65-MUC1 in serum samples. The tumor-bearing mice were randomly divided into 0.5, 1.5, 4, 8 and 24 h groups. Mice were sc given [125I] HSP65-MUC1 550 μg·kg-1, tissues were collected and tissue distribution of [125I] HSP65-MUC1 in tumor-bearing mice was studied using trichloroacetic acid (TCA) precipitation method. RESULTS The absolute bioavailability of [125I]HSP65-MUC1 was 38.33% after M. mulatta monkeys were sc given [125I]HSP65-MUC1. In multiple dose group, concentrations of [125I]HSP65-MUC1 after the third dose administration was compared to that of the first dose administration. The accumulation factor (AUC3/AUC1) was 1.17 ±0.25. Distribution of [ 125I]HSP65-MUC1 was significantly different compared with general polypeptide and protein drugs after sc in tumor-bearing mice. The concentration in lymph nodes was the highest. The concentration in other immune tissues, such as thymus and spleen, were not relatively high, but their declined tendency was slow after reaching the peak concentration (cmax ). However, the concentrations in the serum and some other tissues with a large blood volume, such as the heart, liver, and lung, were relatively low and declined quickly after reaching cmax. Its level in the tumor was not very high. [125 I] HSP65-MUC1 was excreted mainly by the kidneys. CONCLUSION The bioavailability of [125I]HSP65-MUC1 is 38.33% after sc administration in M. mulatta. After multiple-dose administration, the vaccine does not accumulate in the body, whose concentration is the highest in lymph nodes after [1251] HSP65-MUC1 was sc given in tumor-bearing mice, but is not very high in tumor. Besides, the vaccine declined tendency is slow after reaching cmax in immune tissues such as thymus and spleen compared with other tissues with a large blood volume.

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Effect of Angong Niuhuang Wan, cinnabar and realgar against lipopolysaccharide-mediated neurotoxicity

Feng ZHANG ; Jie LIU ; Jingshan SHI

Chinese Journal of Pharmacology and Toxicology.2010;24(3):161-167. doi:10.3867/j.issn.1000-3002.2010.03.001

OBJECTIVE To investigate the role of cinnabar and realgar in Angong Niuhuang Wan (AGNH) -produced neuroprotection against lipopolysaccharide ( LPS) -mediated neuronal damage and further explore the corresponding mechanisms. METHODS Primary rat midbrain neuron-glia cultures were used as an in vitro model to investigate effects of AGNH on LPS-mediated degeneration of dopamine (DA) neurons. The experiment was divided into normal control group, LPS model group, LPS + cinnabar (4 and 40 mg·L-1) groups, LPS + realgar (4 and 40 mg·L-1 ) groups and LPS + AGNH (40 and 400 mg·L-1 ) group. Drugs were added 30 min before LPS treatment. After 7 d, dopaminergic neurotoxicity was assessed through the quantification of tyrosine hydroxylase (TH)-positive neurons and morphological analysis of TH-positive neurons; the activation of microglia was evaluated using OX-42 antibody; the gene expression of tumor necrosis factor-α (TNF-α) and induced nitric oxide synthase (iNOS) mRNA in microglia was performed by real-time RT-PCR analysis, and the release of TNF-α and nitric oxide (NO) in the supernatant of neuron-glia cultures was determined respectively by the ELISA and Griess reagent. RESULTS Compared with normal control group, DA neurons in LPS model group decreased by 40% (P <0.05) , microglial activation was induced, the expression of TNF-α mRNA and iNOS mRNA in microglia increased 9 and 2 times, respectively ( P < 0. 05 ) , and subsequent production of TNF-α and NO in the supernatant of neuron-glia cultures increased 20 and 30 times, respectively (P<0.05). Compared with LPS model group, AGNH 400 mg·L-1 and realgar 40 mg·L-1 significantly attenuated LPS-mediated DA neuronal loss by 40% and 30% , respectively (P<0.05) and inhibited activation of microglia and expression of TNF-α mRNA by 61% and 52% (P <0.05). iNOS mRNA was reduced by 58% and 51% (P <0.05 ) in microglia. The subsequent release of TNF-α was reduced by 55% and 43% (P<0.05) and NO reduced by 53% and 34% (P<0.05) in the supernatant of neuron-glia cultures. Cinnabar had no inhibitory effect on LPS-induced changes. CONCLUSION AGNH protects LPS-induced neurotoxicity through its anti-inflammatory properties and realgar might be the key contributor to the neuroprotective action of AGNH, while cinnabar fails to show any neuroprotection.

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Inhibitory effect of berberine on differentiation of rat bone marrow mesenchymal stem cells to adipocytes

Daohua XU ; Wei YANG ; Chenhui ZHOU ; Yuyu LIU ; Bilian XU

Chinese Journal of Pharmacology and Toxicology.2011;25(1):1-6. doi:10.3867/j.issn.1000-3002.2011.01.001

OBJECTIVE To investigate the effect of berberine on differentiation of rat bone marrow mesenchymal stem cells (MSCs) to adipocytes and its mechanism. METHODS Rat MSCs were isolated and cultured, adipocytic differentiation was induced with adipogenesis-inducing medium (AIM). Cells were assigned into 6 groups:normal control, AIM group, AIM+berberine 0.1, 0.3, 1 and 3 μmol·L-1 groups, respectively. Morphology characteristics of mesenchymal stem cells were observed under an inverted microscope and adipocyte levels were analyzed by oil O staining. Alkaline phosphatase (ALP) activity was detected using p-nitrophenyl phosphate as a substrate. The cell survival was determined by MTT assay. Expressions of peroxisome proliferator activated receptor γ (PPARγ), fatty acid binding protein (aP2) and CCAAT enhancer-binding protein α (C/EBPα) mRNA were detected by semiquantitative RT-PCR. RESULTS Compared with normal control group, MSCs adipogenic differentiation, PPARγ, aP2 and C/EBPα mRNA expression significantly increased in AIM group (P<0.01), ALP activity in AIM group significantly decreased (P<0.01). Compared with AIM group, berberine inhibited MSCs adipogenic differentiation (P<0.01) and berberine 0.1, 0.3, 1 and 3 μmol·L-1 increased ALP activity by 26%, 54%, 81% and 122%, respectively. Berberine 3 μmol·L-1 significantly downregulated PPARγ expression (0.91±0.10 vs 1.34±0.06) (P<0.01), aP2 (1.05±0.10 vs 1.53±0.09) (P<0.01) and C/EBPα mRNA (1.24±0.06 vs 1.54±0.09) (P<0.01). Berberine had no effect on proliferation of MSCs. CONCLUSION Berberine inhibits differentiation of MSCs into adipocytes, which might be closely related to the downregulation of PPARγ, aP2 and C/EBPα mRNA.

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Effect of lead exposure on function of blood-cerebrospinal fluid barrier and ZO-1 and occludin protein expression in vitro

Xinqin LIU ; Gang ZHENG ; Peng SU ; Yupeng CAO ; Yang LIU ; Mingchao LIU

Chinese Journal of Pharmacology and Toxicology.2017;31(6):615-620. doi:10.3867/j.issn.1000-3002.2017.06.017

OBJECTIVE To establish an in vitro blood-cerebrospinal fluid barrier (BCB) model to investigate the underlying mechanism of lead-induced BCB injuries.METHODS The in vitro BCB model was established by Z310 cells.Different concentrations of Pb(AC)2 (2.5,5.0 and 10.0 mmol·L-1) were used for 24,48 and 72 h.Transendothelial electrical resistance (TEER) and flux of FITC-dextran were performed to determine the permeability of the in vitro BCB model.Western blotting and immunofluorescence methods were used to observe the expression of tight junction protein ZO-1 and occludin.RESULTS Compared with control group,Pb(AC)2 2.5,5.0 and 10.0 mmol· L-1 exposure for 48 h to Z310 cells had no significant effect on survival rate and density.TEER in different groups was gradually increasing.At the 12th day after Pb(AC)2 exposure,the values of TEER and flux of FITC-dextran in Pb(AC)2 5 and 10 mmol· L-1 groups were significantly decreased (P＜0.05).Western blotting and immunofluorescence images showed that the expression of ZO-1 and occludin were significantly decreased (P＜0.05) after Pb(AC)2 exposure for 48 h.CONCLUSION Lead exposure can cause the breakdown of BCB barriers,and this effect may be mediated by reducing the expression of ZO-1 and occludin proteins.

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Reseach progress in long non-coding RNA and its toxicology

Danyan ZHANG ; Longlue JIA ; Jiangfeng GUO

Chinese Journal of Pharmacology and Toxicology.2017;31(6):696-700. doi:10.3867/j.issn.1000-3002.2017.06.029

A large number of studies have shown that long non-coding RNAs (IncRNAs) display abnormallity in organisms exposed to toxic chemicals,carcinogens and heavy metals.In this paper,the relationships between IncRNAs and microRNAs (miRNAs),the expressions of IncRNAs in organisms exposed to different exogenous toxic chemicals and the related toxicological mechanism are reviewed in order to provide reference for biological monitoring with IncRNAs in environmental toxicology.

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High-content screening in studies of toxicology and its application in drug-induced hepatotoxicity

Shuai GE ; Naping TANG ; Lijie FU ; Jing MA

Chinese Journal of Pharmacology and Toxicology.2017;31(6):689-695. doi:10.3867/j.issn.1000-3002.2017.06.028

Drug-induced liver injury(DILI) is one of the major causes of termination of drug development.The establishment of a high-throughput test system to predict potential clinical hepatotoxicity is a valuable approach in the pharmaceutical industry.The high-content imaging-based in vitro assays allow simultaneous detection of cellular multiple parameters in the system.The real-time monitoring of multiple signaling pathways can shed light on many mechanisms of cell injury,with high sensitivity and specificity.Many types of liver cell models have been applied to high-content screening(HCS) so far.This paper introduceds the HCS technology and reviews the data of hepatotoxicity obtained from HCS technology in recent years.At the same time,we discuss the application of this technology in exploring the mechanism of hepatotoxicity and the potential of HCS technology in studying DILI and mechanisms.

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Anti-leukemia effect and toxicity of arsenic trioxide: a review

Yong ZHANG ; Xianxian WU ; Haiying ZHANG ; Zhimin DU

Chinese Journal of Pharmacology and Toxicology.2017;31(6):675-681. doi:10.3867/j.issn.1000-3002.2017.06.026

Arsenic trioxide (As2O3) has been considered a poison,which is also known as an old drug and has recently been re-introduced as a new medicine.As2O3 shows potent effect on many types of cancers,especially on a specific types of leukemia-acute promyelocytic leukemia (APL).This poison drug As2O3 is effective against all stages of APL and has been approved by the Food and Drug Administration (FDA) of the United States for the treatment of APL.However,the clinical use of As2O3 has been limited by its toxicities,especially cardiotoxicity.This review focuses on the therapeutic effect on APL and the side effect during treatment.

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Absorption, distribution and excretion of 2-fluorine-6-trifl-uoromethylpyridine in rats by radioactivity isotope tracing method

Lihong LIN ; Yang YU ; Xiaolei LI ; Na LI ; Yanan PANG

Chinese Journal of Pharmacology and Toxicology.2017;31(6):670-674. doi:10.3867/j.issn.1000-3002.2017.06.025

OBJECTIVE To study the absorption,distribution and excretion of 2-fluorine-6-trifluoromethylpyridine (JJBD) in rats.METHODS [14C] Radioactivity isotope tracing method was used.Male SD rats were ig given a single dose of JJBD 10 and 100 mg·kg-1 (radioactivity:3.7 GBq·kg-1).Concentrations of rat plasma,tissue,feces,urine and bile were determined with a liquid scintillation counting (LSC) analyzer.Toxicokinetics (TK) parameters were fitted using WinNonlin.RESULTS TK parameters of JJBD 10 and 100 mg · kg-1 in male SD rats were as follows:area under the curve (AUC（0-t）) was 22 548±1579 and (203 395±27 586) h·iμg Eq.·L-1,half time (t1/2) was 15.8±1.0 and (14.1±0.9) h,peak time (Tmax) was 4.0±3.0 and (6.0±5.0) h,peak concentration (Cmax) was 1450±355 and (7776±1703) μg Eq.·L-1.JJBD was mainly distributed in fat,livers,kidneys,stomachs and intestinal walls.The concentration of JJBD in most of the tissues reached peak values after 4 h.However,JJBD couldn't be detected in the muscle,thymus gland,brain,gonad or spleen.Excretion rate of JJBD was 43.1％ in urine,29.7％ in feces and 9.97％ in cleaning solution within 0-168 h.JJBD could be excreted through bile at a rate of 28.1％ within 0-72 h.CONCLUSION JJBD can be absorbed immediately and excreted slowly in SD rat.There is no accumulation risk.The distribution of JJBD in vivo is very extensive,but cannot go through the blood-brain barrier.JJBD is mostly excreted through feces and urine.

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Effect and mechanism of zinc oxide nanoparticle on cardiac development of zebrafish embryos

Cheng XU ; Chunlan ZHANG ; Wentao SHAO ; Aihua GU

Chinese Journal of Pharmacology and Toxicology.2017;31(6):655-660. doi:10.3867/j.issn.1000-3002.2017.06.023

OBJECTIVE To explore the toxic effects of zinc oxide nanoparticls (ZnO-NPs) on cardiac development of zebrafish embryos and rat myocardial cell lines (H9c2),as well as potential molecular mechanisms.METHODS ZnO-NPs were characterized.Zebrafish embryos were exposed to different doses of ZnO-NPs (0,0.5,2.5,5.0 and 10.0 mg· L-1) for 24 to 96 h at 4 h post fertilization (4 hpf).The embryo mortality was observed.The expressions of notochord homeobox (noto),T-box 6 (tbx16),T,brachyury homolog a(ta),and tbx6 which were related to cardiac mesoderm were investigated using real-time PCR at 17 hpf.The heart rate and number of cardiomyocytes of embryos [[Tg (cmlc2:nucdsRed)] exposed to 0,2.5 and 5 mg· L-1 ZnO-NPs were detected at 72 hpf.Rat myocardial cell lines (H9c2) were treated with ZnO-NPs (0.1,0.5,1.0,5.0 and 10.0 mg· L-1) for 24 h.Cell viability was measured with Alamar Blue method.Mitochondrial ultrastructure was observed by transmission electron microscopy.Cellular ATP was detected using chemiluminescence,and oxygen consumption rate (OCR) was examined with Seahorse instrument.RESULTS The particle size of ZnO-NPs was (331 ±3)nm.The ZnO-NPs LC50 of zebrafish embryos at 48 hpf was 21.81 mg· L-1.The mRNA expressions of noto,ta and tbx6 were reduced after ZnO-NPs 2.5 mg· L-1 treatment at 17 hpf.The heart rate of 72 hpf zebrafish was 153 min-1 in the ZnO-NPs 5 mg· L-1 group,12.6％ lower than that in the cell vehicle group (P＜0.01),and the number of cardiomyocytes decreased by 15.5％ (P＜0.01) compared with the cell vehicle group.Reduced cell viability and mitochondrial vacuolation were observed in H9c2 after ZnO-NPs 0.5 mg· L-1 exposure.Compared with the cell vehicle group,the cell ATP decreased by 25.7％ (P＜0.05),and OCR decreased by 27.2％ (P＜0.01).CONCLUSION Low-dose ZnO-NPs exposure has effect on the cardiac development of zebrafish,mainly due to reduced heart rate and decreased number of cardiomyocytes.These changes may be related to the decreased expressions of cardiac development-related genes and the impairment of mitochondrial structure and function.

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