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.

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.

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.

Abnormal aggregation of α-synuclein(α-Syn) is thought to be a key event in the pathogenesis of Parkinson disease (PD). In recent years, it was shown that above 90% of α-Syn deposited in Lewy bodies in brain tissues from patients with PD is phosphorylated, which suggested that α-Syn phosphorylation be connected with the occurrence of PD. Several kinds of phosphokinases can make α-Syn phosphorylated, however the precise roles of these phosphokinases in PD are less clear.

Exosomes are extracellular nanoparticles secreted by multiple types of cells,which are enriched for some bioactive molecules,such as proteins,messcge RNA(mRNA),micro RNA(miRNA), DNA and lipid. These molecules are documented to be involved in the process of intercellular material exchange and signal communication,thus affecting the function of cells. Also,exosomes are considered to participate in tumor angiogenesis,cancer progression and metastasis,but the mechanism remains obscure. Exosomes are of great value for the diagnosis and treatment of tumor. The correlations between exosomes and tumorigenesis and tumor metastasis as well as their clinical applications are summarized in this review.

Emotional and cognitive disorders (EACD),such as depression and anxiety,have become very common in today′s society,seriously affecting human lives and health. Neural plasticity can reflect the anti-stress ability of the nervous system to the internal and external stimulation,and is capable of dynamic changes in structure or function to adapt to environmental changes,as is often manifested in the process of compensation and repair of nerve injuries. EACD is often accompanied by macroscopic and cellular morphological changes in brain tissues and functions. Thus,studies on the mechanisms of neural plasticity will contribute to the treatment of EACD. In this paper ,the role of neural plasticity in the active components of Chinese herbal medicine(ACCHM) is reviewed. The effects of ACCHM on 5-hydroxytryptamine(5-HT)system,and the antioxidant activities and neurotrophic effects of ACCHM are described. ACCHM can affect neural plasticity,playing a neuroprotective role by improving 5-HT levels,reducing oxidative stress in brain cells,and increasing the expression of brain derived neurotrophic factor(BDNF). In summary,one ACCHM could affect neural plasticity through one or more mechanisms. There are interactions between different mechanisms of the same ACCHM. Different ACCHM can play a synergistic effect on the enhancement of neural plasticity because of their different mechanisms.

OBJECTIVE To investigate the toxicological effect of patulin(PAT)on the growth of human normal liver cells L-02 and its possible mechanisms. METHODS After cells were treated with PAT 1.25, 2.5,5,10 and 20μmol·L-1 for 24 or 48 h,cell viability was examined using MTT assay. L-02 cells were treated with PAT 5 and 10 μmol · L- 1 for 24 h ,respectively. Cytomorphology and mitochondrial membrane potential (MMP) were observed under a fluorescence microscope. Apoptosis,MMP and reactive oxygen species (ROS)were analyzed by flow cytometry. Mitochondria apoptosis pathways were detected by Western blotting. RESULTS PAT exhibited a strong inhibitory effect on L-02 in a concentration-dependent and time-dependent manner. IC50 of PAT treatment for 24 or 48 h was 6.61 and 2.78 μmol · L-1,respectively. MMP was decreased,while the percentage of low MMP cells increased from(9.2±2.3)%in controls to(23.4±4.5)%( PAT 5μmol·L-1)and(47.1±5.5)%(PAT 10μmol·L-1), respectively. Compared to untreated cells,the early apoptosis population increased from(3.8±1.1)%to(29.8±4.5)%( PAT 5μmol·L-1)and (24.1±6.2)%(PAT 10μmol·L-1)(P<0.01),respectively. Further?more,the accumulation of ROS was also observed. The effect of PAT on ROS and cell viabilities could be attenuated by glutathione. CONCLUSION PAT can significantly inhibit the growth of L-02 and induce apoptosis via ROS-dependent mitochondria pathways.

OBJECTIVE To compare the liver toxicity of matrine and oxymatrine ,and to explore their toxic mechanism. METHODS Thirty ICR mice were randomly divided into normal control ,matrine 200 mg · kg-1 and oxymatrine 200 mg · kg-1 groups,10 mice per group. After single ig administration of corresponding drugs or water, animal mortality was calculated at the 15th day. The content of glutamic-pyruvic transami?nase(GPT),glutamic-oxalacetic transamin(GOT),alkaline phosphatase(ALP)and lactate dehydroge?nase (LDH) in serum were detected. Histopathological changes of the liver were examined by HE stain. The content of superoxide dismutase(SOD)and glutathione(GSH)in liver homogenates were detected by ELISA. Hepatocyte apoptosis was detected by Tunel stain. RESULTS The mortality rate of mice in two groups was 80% and 0,respectively. GPT,GOT and ALP contents of dead mice in matrine group were significantly higher than that in normal control group(P<0.05). In oxymatrine group,only the content of ALP was increased(P<0.05). Four of the eight dead mice in matrine group exhibited liver cell necrosis(P<0.05),while only 1/10 mice in oxymatrine group had a mild liver cell necrosis(P>0.05). The content of SOD and GSH of dead mice in matrine group was lower than that in control group(P<0.05,P<0.01). The content of GSH in oxymatrine group was also decreased(P<0.05). The apoptosis rate of liver cells in dead mice in matrine group was increased(P<0.05). CONCLUSION A large dose of matrine and oxymatrine can produce liver toxicity. At an equal dosage,the liver toxicity of matrine is significantly higher than that of oxymatrine. The toxic mechanism is related to oxidative stress and apoptosis.

OBJECTIVE To analyze trimethylation of genome-wide histone H3 lysine 4(H3K4met3) induced by silicon dioxide(SiO2)through chromatin immunoprecipitation linked to microarrays(ChIP-chip)in lung fibroblast(LF)of rats. METHODS A primary co-culture model of rat alveolar macrophages (AM)and LF in vitro. AM were exposed to 100 mg · L-1 free SiO2 for 24 h,before LF were collected and the phenotype of LF was determined after transdifferentiation by immunohistochemistry. ChIP-chip was used to profile the variations of trimethylation in H3K4 of lung fibroblasts in CpG island regions. ChIP-qPCR was used to validate the microarray results. The mRNA expression of nfib and kpna3 was analyzed by qRT-PCR. RESULTS Totally 1815 (518 increased and 1297 decreased) genes of H3K4met3 displayed significant differences in SiO2 100 mg·L-1 group compared with control group(Cy3/Cy5 value>2.0 or <0.5,NimbleScan V2.5 software). The results of ChIP-qPCR were quite consistent with those of microarray. CONCLUSION There are significant differences in methylation of genome-wide H3K4 between SiO2 100 mg·L-1 group and control group. These novel candidate genes may become potential biomarkers or new interfered targets.

Polyunsaturated fatty acids (PUFAs) are important structural fatty acids of biological membrane. They play important roles in regulation of lipid metabolism,stimulation of growth and development,protection a gainst cancer,retardation of aging,immuno-regulation, cardiovascular health,and bodymass loss. In recent years, researchers have found t hat ω-6 PUFAs can promote tumor angiogenesis,while ω-3 PUFAs have the properties of inhibiting tumor angiogenesis. This review focuses on the effects of these two types of fatty acids on tumors,especially on the regulation of tumor angiogenesis.