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1.
Fish Shellfish Immunol ; 96: 152-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794843

RESUMO

C-type lectins are Ca2+-dependent carbohydrate-binding proteins containing one or more carbohydrate-recognition domains (CRDs). C-type lectins play crucial roles in innate immunity, including nonself-recognition and pathogen elimination. In the present study, two C-type lectins (designated ReCTL-1 and ReCTL-2) were identified from the shrimp Rimicaris exoculata which dwells in deep-sea hydrothermal vents. The open reading frames of ReCTL-1 and ReCTL-2 encoded polypeptides of 171 and 166 amino acids respectively, which were both composed of a signal peptide and a single CRD. The key motifs determining the carbohydrate binding specificity of ReCTL-1 and ReCTL-2 were respectively Glu-Pro-Ala (EPA) and Gln-Pro-Asn (QPN), which were firstly discovered in R. exoculata. ReCTL-1 and ReCTL-2 displayed similar pathogen-associated molecular pattern (PAMP) binding features and they bound three PAMPs-ß-glucan, lipopolysaccharide and peptidoglycan-with relatively high affinity. In addition, both could efficiently recognize and bind Gram-positive bacteria, Gram-negative bacteria and fungi. However, ReCTL-1 and ReCTL-2 exhibited different microbial agglutination activities: ReCTL-1 agglutinated Staphylococcus aureus and Saccharomyces cerevisiae, while ReCTL-2 agglutinated Micrococcus luteus, Vibrio parahaemolyticus and V. fluvialis. Both ReCTL-1 and ReCTL-2 inhibited the growth of V. fluvialis. All these results illustrated that ReCTL-1 and ReCTL-2 could function as important pattern-recognition receptors with broad nonself-recognition spectra and be involved in immune defense against invaders, but their specificities are not the same. In addition, the two ReCTLs possessed different carbohydrate binding specificities from each other and from the classical pattern: ReCTL-1 with an EPA motif bound d-galactose and l-mannose, while ReCTL-2 with a QPN motif bound d-fucose and N-acetylglucosamine.

2.
J Toxicol Sci ; 44(11): 777-788, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708534

RESUMO

Loss of cognitive function due to arsenic exposure is a serious health concern in many parts of the world, including China. The present study aims to determine the molecular mechanism of arsenic-induced neurotoxicity and its consequent effect on downstream signaling pathways of mouse N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Drinking water containing 0, 25, 50 or 100 mg/L arsenite was provided each day to mother mice throughout gestation period until postnatal day (PND) 35 to expose the newborn mice to arsenite during early developmental period. The effect of arsenite in the expressions of different components of NMDAR (NR1, NR2A, NR2B) and AMPAR (GluR1, GluR2, GluR3), including calcium/calmodulin-dependent protein kinase II (CaMKII) and phosphorylated-CaMKII (p-CaMKII), at PND 7, 14, 21 and 35 was estimated and analyzed from the hippocampus of mice. A significant inhibition in the protein and mRNA expressions of NR1, NR2A, NR2B and GluR1 was observed in mice exposed to 50 mg/L arsenite since PND 7. Down regulation of GluR2 and GluR3 both at mRNA and protein levels was observed in mice exposed to 50 mg/L arsenite till PND 14. Moreover, both CaMKII as well as p-CaMKII expressions were significantly limited since PND 7 in 50 mg/L arsenite exposed mice group. Findings form this study suggested that the previously reported impairment in learning and memorizing abilities in later stage due to early life arsenite exposure is associated with the alterations of NMDARs, AMPARs, CaMKII and p-CaMKII expressions.

3.
Neurotoxicology ; 75: 233-244, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31585129

RESUMO

Brain edema caused by subacute poisoning with 1,2-dichloroethane (1,2-DCE) has gained much attention during recent years, but its underlying mechanism is poorly understood. As an intermediate metabolite of 1,2-DCE in vivo, 2-chloroethanol (2-CE) can be transformed into chloroacetaldehyde and reactive oxygen species (ROS) through cytochrome P450 2E1 (CYP2E1) mediated metabolism. In previous studies, it was found that CYP2E1 expression is enhanced in the brain of mice treated with 1,2-DCE. This study was designed to verify the roles of CYP2E1 overexpression in 2-CE induced cytotoxicity in rat astrocytes, and the contribution of specific signaling molecules to the upregulation of CYP2E1 expression caused by 2-CE. The results of this study demonstrate that treatment with 2-CE can enhance CYP2E1 protein and mRNA levels, cause an increase in ROS and MDA levels, and higher percentages of apoptotic cells in rat astrocytes. Pretreatment with either diallyl sulfide or vitamin C, the inhibitor of CYP2E1 or scavenger of ROS, respectively, can suppress the levels of CYP2E1 expression, ROS and MDA, ameliorate cell apoptosis, and attenuate phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in these cells. Additionally, pretreatment with the inhibitor of either ERK1/2 or transcriptional factor specificity protein 1 (SP1) can suppress the CYP2E1 expression, and alleviate the oxidative damage caused to these cells. In conclusion, our findings demonstrate that CYP2E1 overexpression plays a crucial role in 2-CE induced oxidative damage of rat astrocytes, and that CYP2E1 expression is upregulated partially through the activation of the ERK1/2 and SP1 signaling pathways by ROS generated during CYP2E1-mediated 2-CE metabolism. This study provides novel information that can be used in elucidating the mechanism by which 1,2-DCE induces brain edema.

4.
Cells ; 8(9)2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461951

RESUMO

We previously reported that expression of matrix metalloproteinase-9 (MMP-9) mRNA and protein was upregulated during 1,2-dichloroethane (1,2-DCE) induced brain edema in mice. We also found that the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway resulted in MMP-9 overexpression and nuclear factor-κB (NF-κB) activation in mice treated with 1,2-DCE. In this study, we further hypothesized that inflammatory reactions mediated by the p38 MAPK/ NF-κB signaling pathway might be involved in MMP-9 overexpression, blood-brain barrier (BBB) disruption and edema formation in the brain of 1,2-DCE-intoxicated mice. Our results revealed that subacute poisoning by 1,2-DCE upregulates protein levels of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), interleukin-1ß (IL-1ß), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS) and p-p65 in mouse brains. Pretreatment with an inhibitor against p38 MAPK attenuates these changes. Moreover, pretreatment with an inhibitor against NF-κB attenuates alterations in brain water content, pathological indications notable in brain edema, as well as mRNA and protein expression on levels of MMP-9, VCAM-1, ICAM-1, iNOS, and IL-1ß, tight junction proteins (TJs), GFAP and Iba-1 in the brain of 1,2-DCE-intoxicated mice. Furthermore, pretreatment with an inhibitor against MMP-9 obstructs the decrease of TJs in the brain of 1,2-DCE-intoxicated mice. Lastly, pretreatment with an antagonist against the IL-1ß receptor also attenuates changes in protein levels of p-p38 MAPK, p-p65, p-IκB, VCAM -1, ICAM-1, IL-1ß, and Iba-1 in the brain of 1,2-DCE-intoxicated-mice. Taken together, findings from the current study indicate that the p38 MAPK/ NF-κB signaling pathway might be involved in the activation of glial cells, and the overproduction of proinflammatory factors, which might induce inflammatory reactions in the brain of 1,2-DCE-intoxicated mice that leads to brain edema.

5.
Front Pharmacol ; 9: 1317, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524279

RESUMO

This study was designed to explore the role of cytochrome P4502E1 (CYP2E1) expression in the course of brain edema induced by subacute poisoning with 1,2-dichloroethane (1,2-DCE). Mice were randomly divided into five groups: the control group, the 1,2-DCE poisoned group, and the low-, medium- and high-dose diallyl sulfide (DAS) intervention groups. The present study found that CYP2E1 expression levels in the brains of the 1,2-DCE-poisoned group were upregulated transcriptionally; in contrast, the levels were suppressed by DAS pretreatment in the intervention groups. In addition, the expression levels of both Nrf2 and HO-1 were also upregulated transcriptionally in the brains of the 1,2-DCE-poisoned group, while they were suppressed dose-dependently in the intervention groups. Moreover, compared with the control group, MDA levels and water contents in the brains of the 1,2-DCE-poisoned group increased, whereas NPSH levels and tight junction (TJ) protein levels decreased significantly. Conversely, compared with the 1,2-DCE- poisoned group, MDA levels and water contents in the brains of the intervention groups decreased, and NPSH levels and TJ protein levels increased significantly. Furthermore, pathological changes of brain edema observed in the 1,2-DCE-poisoned group were markedly improved in the intervention groups. Collectively, our results suggested that CYP2E1 expression could be transcriptionally upregulated in 1,2-DCE-poisoned mice, which might enhance 1,2-DCE metabolism in vivo, and induce oxidative damage and TJ disruption in the brain, ultimately leading to brain edema.

6.
Neurotoxicology ; 69: 296-306, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30081051

RESUMO

Accumulated data have revealed that subacute poisoning of 1,2-dichloroethane (1,2-DCE), an industrial solvent used in some countries can cause encephalopathy, in which brain edema is the main pathological change. However, the underlying mechanisms are unclear. In the present study, we hypothesized that the p38 MAPK (p38) signaling pathway could be activated in 1,2-DCE-intoxicated mice, which in turn stimulates transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), and then enhances the expression of proinflammatory factors, including matrix metalloproteinase-9 (MMP-9), finally leading to blood-brain barrier (BBB) disruption and brain edema formation. Our results revealed that brain water content and BBB permeability increased significantly in the intoxicated mice. Meanwhile, the levels of phosphorylated p38 (p-p38) and inhibitory κBα (p-IκB), as well as the expression levels of MMP-9, c-jun, c-fos, and p65, also increased markedly in the brains of intoxicated mice. Conversely, the protein levels of ZO-1, occludin and claudin-5 in these mice decreased markedly, but their JAM-1 protein levels increased dramatically. Our results revealed that p-p38 levels in the brains of intoxicated mice were suppressed by pretreatment with a p38 inhibitor. In response to suppressed p-p38 levels, the brain water contents and DNA binding activities of NF-κB and AP-1, as well as the expression levels of MMP-9, c-jun, c-fos, p65, p-IκB and JAM-1, decreased, whereas the protein levels of ZO-1, occludin and claudin-5 increased markedly. Taken together, our findings indicated that the p38 signaling pathway might be activated and involved in the course of brain edema in 1,2-DCE-intoxicated mice.


Assuntos
Edema Encefálico/induzido quimicamente , Edema Encefálico/enzimologia , Dicloretos de Etileno/toxicidade , Metaloproteinase 9 da Matriz/biossíntese , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Feminino , Regulação Enzimológica da Expressão Gênica , Metaloproteinase 9 da Matriz/genética , Camundongos , Transdução de Sinais/fisiologia
7.
Cells ; 7(8)2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087244

RESUMO

Subacute poisoning of 1,2-dichloroethane (1,2-DCE) has become a serious occupational problem in China, and brain edema is its main pathological consequence, but little is known about the underlying mechanisms. As the metabolite of 1,2-DCE, 2-chloroethanol (2-CE) is more reactive, and might play an important role in the toxic effects of 1,2-DCE. In our previous studies, we found that matrix metalloproteinases-9 (MMP-9) expression was enhanced in mouse brains upon treatment with 1,2-DCE, and in rat astrocytes exposed to 2-CE. In the present study, we analyzed the association of nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) with MMP-9 overexpression in astrocytes treated with 2-CE. MMP-9, p65, c-Jun, and c-Fos were significantly upregulated by 2-CE treatment, which also enhanced phosphorylation of c-Jun, c-Fos and inhibitor of κBα (IκBα), and nuclear translocation of p65. Furthermore, inhibition of IκBα phosphorylation and AP-1 activity with the specific inhibitors could attenuate MMP-9 overexpression in the cells. On the other hand, inhibition of p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway suppressed the activation of both NF-κB and AP-1 in 2-CE-treated astrocytes. In conclusion, MMP-9 overexpression induced by 2-CE in astrocytes could be mediated at least in part through the p38 signaling pathway via activation of both NF-κB and AP-1. This study might provide novel clues for clarifying the mechanisms underlying 1,2-DCE associated cerebral edema.

8.
Mol Carcinog ; 57(11): 1566-1576, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30035324

RESUMO

Ferroptosis is a recently recognized form of regulated cell death driven by lipid-based reactive oxygen species (ROS) accumulation. However, the molecular mechanisms of ferroptosis regulation are still largely unknown. Here we identified a novel miRNA, miR-9, as an important regulator of ferroptosis by directly targeting GOT1 in melanoma cells. Overexpression of miR-9 suppressed GOT1 by directly binding to its 3'-UTR, which subsequently reduced erastin- and RSL3-induced ferroptosis. Conversely, suppression of miR-9 increased the sensitivity of melanoma cells to erastin and RSL3. Importantly, anti-miR-9 mediated lipid ROS accumulation and ferroptotic cell death could be abrogated by inhibiting glutaminolysis process. Taken together, our findings demonstrate that miR-9 regulates ferroptosis by targeting GOT1 in melanoma cells, illustrating the important role of miRNA in ferroptosis.


Assuntos
Aspartato Aminotransferase Citoplasmática/genética , Regulação Neoplásica da Expressão Gênica , Ferro/metabolismo , Melanoma/genética , Melanoma/metabolismo , MicroRNAs/genética , Interferência de RNA , Regiões 3' não Traduzidas , Carbolinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Melanoma/patologia , Modelos Biológicos , Piperazinas/metabolismo
9.
Fish Shellfish Immunol ; 78: 238-247, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29678793

RESUMO

Galectins are ß-galactoside binding lectins that play crucial roles in innate immunity in vertebrates and invertebrates through their conserved carbohydrate-recognition domains (CRDs). In the present study, single- and four-CRD-containing galectins were identified in oyster Crassostrea gigas (designated CgGal-2 and CgGal-3). The open reading frames (ORFs) of CgGal-2 and CgGal-3 encode polypeptides of 200 and 555 amino acids, respectively. All CRDs of CgGal-3 include two consensus motifs essential for ligand-binding, and a novel motif is present in CgGal-2. Pathogen-associated molecular pattern (PAMP) profiles were determined for recombinant rCgGal-2 and rCgGal-3, and rCgGal-2 displayed low binding affinity for PAMPs, while rCgGal-3 bound various PAMPs including glucan, lipopolysaccharide (LPS), and peptidoglycan (PGN) with relatively high affinity. Furthermore, rCgGal-2 and rCgGal-3 exhibited different microbe binding profiles; rCgGal-2 bound to Gram-negative bacteria (Escherichia coli and Vibrio vulnificus) and fungi (Saccharomyces cerevisiae and Pichia pastoris), while rCgGal-3 bound to these microbes but also to Gram-positive bacteria (Micrococcus luteus). In addition, rCgGal-3 possessed microbial agglutinating activity and coagulation activity against fungi and erythrocytes, respectively, but rCgGal-2 lacked any agglutinating activity. Carbohydrate binding specificity analysis showed that rCgGal-3 specifically bound D-galactose. Furthermore, rCgGal-2 and rCgGal-3 functioned as opsonin participating in the clearance against invaders in C. gigas. Thus, CgGal-2 with one CRD and CgGal-3 with four CRDs are new members of the galectin family involved in immune responses against bacterial infection. Differences in the organisation and amino acid sequences of CRDs may affect their specificity and affinity for nonself substances.


Assuntos
Crassostrea/genética , Galectina 2/genética , Galectina 3/genética , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Sequência de Aminoácidos , Animais , Crassostrea/imunologia , Fungos/fisiologia , Galectina 2/química , Galectina 2/imunologia , Galectina 3/química , Galectina 3/imunologia , Perfilação da Expressão Gênica , Bactérias Gram-Negativas/fisiologia , Bactérias Gram-Positivas/fisiologia , Filogenia , Alinhamento de Sequência
10.
Front Neurosci ; 12: 12, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29410610

RESUMO

The aim of this study was to explore changes in intracellular ATP generation and tight junction protein expression during the course of brain edema induced by subacute poisoning of 1,2-dichloroethane (1,2-DCE). Mice were exposed to 1.2 g/m3 1,2-DCE for 3.5 h per day for 1, 2, or 3 days, namely group A, B, and C. Na+-K+-ATPase and Ca2+-ATPase activity, ATP and lactic acid content, intracellular free Ca2+ concentration and ZO-1 and occludin expression in the brain were measured. Results of present study disclosed that Ca2+-ATPase activities in group B and C, and Na+/K+-ATPase activity in group C decreased, whereas intracellular free Ca2+ concentrations in group B and C increased significantly compared with control. Moreover, ATP content decreased, whereas lactic acid content increased significantly in group C compared with control. On the other hand, expressions of ZO-1 and occludin at both the protein and gene levels in group B and C decreased significantly compared with control. In conclusion, findings from this study suggest that calcium overload and depressed expression of tight junction associated proteins, such as ZO-1 and occludin might play an important role in the early phase of brain edema formation induced by subacute poisoning of 1,2-DCE.

11.
Metallomics ; 9(10): 1394-1412, 2017 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-28901367

RESUMO

Arsenic exposure through drinking water can impair the learning and memory ability of children in China and other countries. Synaptic plasticity plays a key role in the process of learning and memory. Alterations in the expression of presynaptic and postsynaptic proteins can be used to evaluate synaptic plasticity, and further to evaluate impairment in learning and memory ability. Thereby, the aim of this study was to explore the mechanisms underlying arsenic neurotoxicity by focusing on alterations in the hippocampal synapses of mouse offspring induced by developmental arsenite exposure. Mother mice and their offspring were exposed to 0, 25, 50 or 100 mg L-1 arsenite via drinking water from the first day of gestation until postnatal day (PND) 35. The spatial learning and memory ability of PND 35 mice was evaluated using a Morris water maze. The levels of speciated arsenicals in the brain of PND 7, 14, 21 and 35 mice were analyzed by hydride generation coupled with atomic absorption spectrophotometry. Synaptic structure and protein expression of postsynaptic density protein-95 (PSD-95) and synaptophysin (SYP) in the hippocampus of PND 7, 14, 21 and 35 mice were examined. The findings from this study disclosed that the spatial learning ability of mice could be impaired by exposure to 25 mg L-1 arsenite; however spatial memory ability could not be impaired until exposure to 100 mg L-1 arsenite. The thickness of the postsynaptic density (PSD) decreased, whereas the width of the synaptic cleft widened significantly in arsenite exposure groups. Moreover, protein expression of both PSD-95 and SYP decreased significantly in arsenite exposure groups. In conclusion, the results of this study demonstrated that developmental arsenite exposure could depress the expression of synaptic proteins, subsequently cause alteration in synaptic structures, and finally contribute to arsenite-induced deficits in spatial learning and memory ability in mouse offspring.


Assuntos
Arsenitos/toxicidade , Encéfalo/patologia , Hipocampo/patologia , Plasticidade Neuronal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Sinapses/patologia , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória/efeitos dos fármacos , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
12.
Front Cell Neurosci ; 11: 218, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769771

RESUMO

2-Chloroethanol (2-CE) is one of the reactive metabolites of 1,2-DCE in vivo, which might contribute to brain edema formation induced by 1,2-dichloroethane (1,2-DCE) poisoning. Thus, the purpose of this study was to explore the roles of mitogen-activated protein kinase (MAPK) signal pathways in upregulation of matrix metalloproteinase-9 (MMP-9) in 2-CE exposed rat astrocytes. Expression of p38 MAPK (p38), extracellular signal regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and MMP-9 at both protein and gene levels in rat astrocytes were determined using western blot and real-time RT-PCR methods. The results showed that both protein and mRNA levels of MMP-9 in 2-CE exposed astrocytes significantly increased. Meanwhile, protein levels of phosphorylated p38 (p-p38), ERK1/2 (p-ERK1/2) and JNK1/2 (p-JNK1/2) in 2-CE exposed astrocytes also significantly increased. In addition, both protein and mRNA levels of MMP-9 significantly decreased in response to reduced protein levels of p-p38, p-ERK1/2 and p-JNK1/2 achieved by supplement with their specific inhibitors, indicating that activation of MAPK signal pathways might play an important role in upregulation of MMP-9 expression at the transcriptional level in 2-CE exposed astrocytes. Furthermore, since pretreatment of n-acetyl-l-cysteine (NAC), a powerful antioxidant amino acid, could attenuate the elevated levels of MMP-9, p-p38, p-ERK2 and p-JNK1/2 in 2-CE exposed astrocytes, activation of MAPK signal pathways in 2-CE exposed astrocytes could be mediated partially by reactive oxygen species (ROS), which was most likely generated in the metabolism of 2-CE.

13.
Toxicol In Vitro ; 37: 50-60, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27596522

RESUMO

The aim of this study was to explore the mechanisms that contribute to 1,2-dichloroethane (1,2-DCE) induced brain edema by focusing on alteration of mitochondrial function and glutamate metabolism in primary cultured astrocytes induced by 2-chloroethanol (2-CE), a metabolite of 1,2-DCE in vivo. The cells were exposed to different levels of 2-CE in the media for 24h. Mitochondrial function was evaluated by its membrane potential and intracellular contents of ATP, lactic acid and reactive oxygen species (ROS). Glutamate metabolism was indicated by expression of glutamine synthase (GS), glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) at both protein and gene levels. Compared to the control group, exposure to 2-CE could cause a dose dependent damage in astrocytes, indicated by decreased cell viability and morphological changes, and supported by decreased levels of nonprotein sulfhydryl (NPSH) and inhibited activities of Na+/K+-ATPase and Ca2+-ATPase in the cells. The present study also revealed both mitochondrial function and glutamate metabolism in astrocytes were significantly disturbed by 2-CE. Of which, mitochondrial function was much vulnerable to the effects of 2-CE. In conclusion, our findings suggested that mitochondrial dysfunction and glutamate metabolism disorder could contribute to 2-CE-induced cytotoxicity in astrocytes, which might be related to 1,2-DCE-induced brain edema.


Assuntos
Astrócitos/efeitos dos fármacos , Dicloretos de Etileno/toxicidade , Ácido Glutâmico/metabolismo , Mitocôndrias/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Compostos de Sulfidrila/metabolismo
14.
Wei Sheng Yan Jiu ; 45(2): 179-83, 188, 2016 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-27301210

RESUMO

OBJECTIVE: To explore the expression of CYP2E1 in the liver of mice and its effects on liver injury induced by 1,2-dichloroethane (1, 2-DCE). METHODS: (1) Thirty-two female mice were randomly divided into four groups, which were control group, low dose group, medium dose group and high dose group. Mice were exposed to 1,2-DCE through respiratory for 4 h per day for 10 days. At the end of exposure, the mice were sacrificed, their blood and liver were collected rapidly. Pathological analysis was examined. Activity of ALT and AST in serum and activity of CYP2E1 in liver were mice were randomly divided into six groups, ie simple control group, corn oil control group, inhibitor control group, simple poisonous group, low and high dose diallyl sulfide (DAS) intervention groups. Mice were treated orally with DAS in corn oil 4 hours before 1, 2-DCE exposure. The examination indicators were as aforementioned. RESULTS: (1) Compared to control group, activity of ALT in serum of mice in the high dose group and expression of CYP2E1 in the liver of mice in medium and high dose group increased significantly. In addition, the histological observation suggested obvious liver damage in medium and high dose group. (2) CYP2E1 protein expression and activity in liver and ALT in serum decreased significantly in DAS-intervention groups compared to simple poisonous group. Along with the changes of CYP2E1 and ALT, pathological changes of liver damage was better. CONCLUSION: Our results suggested that expression of CYP2E1 and oxidative damage in the liver could be induced by 1,2-DCE exposure, and CYP2E1 inhibitors can reduce the hepatic tissue damage caused by DCE.


Assuntos
Compostos Alílicos/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Citocromo P-450 CYP2E1/metabolismo , Dicloretos de Etileno/toxicidade , Sulfetos/farmacologia , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Feminino , Exposição por Inalação , Camundongos
15.
Environ Toxicol ; 31(11): 1430-1438, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25926354

RESUMO

The aim of this study was to explore the roles of cytochrome P450 2E1 (CYP2E1) in 1,2-dichloroethane (1,2-DCE)-induced liver damage. Two parts were included in this study: first, effect of 1,2-DCE on microsomal expression of CYP2E1, and second, potential of an inhibitor of CYP2E1 to reduce 1,2-DCE-induced liver damage. In part one, mice were exposed to 0, 0.225, 0.45, or 0.9 g/m3 1,2-DCE for 10 days, 3.5 h per day through static inhalation. In part two, mice were divided into blank control, solvent control, inhibitor control, 1,2-DCE-poisoned group, and low or high intervention group. In part one, compared to the control, serum alanine aminotransferase (ALT) activities and hepatic malondialdehyde (MDA) levels in 0.9 g/m3 1,2-DCE group, and microsomal CYP2E1 protein expression and activity in both 0.45 and 0.9 g/m3 1,2-DCE groups increased significantly; conversely, hepatic nonprotein sulfhydryl (NPSH) levels in both 0.45 and 0.9 g/m3 1,2-DCE groups and hepatic SOD activities in 0.9 g/m3 1,2-DCE group decreased significantly. In part two, microsomal CYP2E1 protein expression and activity decreased significantly in both low and high intervention groups compared to 1,2-DCE-poisoned group. Along with the changes of CYP2E1, hepatic MDA levels and serum ALT activities decreased; conversely, hepatic NPSH levels and SOD activities increased significantly in high intervention group. Taken together, our results suggested that 1,2-DCE could enhance CYP2E1 protein expression and enzymatic activity, which could cause oxidative damage in liver, serving as an important mechanism underlying 1,2-DCE-induced liver damage. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1430-1438, 2016.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Citocromo P-450 CYP2E1/fisiologia , Dicloretos de Etileno/toxicidade , Fígado/efeitos dos fármacos , Alanina Transaminase/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP2E1/metabolismo , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Malondialdeído/metabolismo , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Testes de Toxicidade
16.
Mol Neurobiol ; 53(10): 6786-6798, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-26660114

RESUMO

Lead exposure can cause cognitive dysfunction in children, thus it still raises important public health concerns in China and other countries. However, the underlying molecular mechanisms are still not well defined. In this study, we aimed to elucidate the mechanisms underlying lead neurotoxicity by focusing on alterations of synaptic proteins in the mouse hippocampus at the early life. Mother mice and their offspring were exposed to 0, 0.5, 1.0, and 2.0 g/L lead via drinking water from the first day of gestation until postnatal day (PND) 40. Synaptic ultrastructure and expressions of postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS) and synaptophysin (SYP) at both protein and gene levels in the hippocampus were analyzed. The results revealed that developmental lead exposure caused a diminished postsynaptic density in the hippocampus. Moreover, the protein levels of PSD-95, nNOS, and SYP decreased significantly due to developmental lead exposure. On the other hand, the messenger RNA (mRNA) levels of PSD-95 and SYP decreased significantly in PND 40 mice exposed to lead. Collectively, developmental lead exposure might result in decreased protein and gene expressions of both presynaptic and postsynaptic proteins. Our findings raised a possibility that alterations of synaptic proteins in the hippocampus induced by lead exposure at the early life might serve an important role for the subsequent intellectual impairments, e.g., deficits in spatial learning and memory ability at later ages shown in our recently published paper.


Assuntos
Hipocampo/metabolismo , Chumbo/toxicidade , Proteínas do Tecido Nervoso/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Sinapses/metabolismo , Animais , Feminino , Imunofluorescência , Hipocampo/ultraestrutura , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura
17.
Front Neurosci ; 10: 593, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28101000

RESUMO

This study was to explore the mechanisms underlying 1,2-dichloroethane (1,2-DCE) induced brain edema by focusing on alteration of matrix metalloproteinase-2 (MMP-2) in rat astrocytes induced by 2-chloroethanol (2-CE), an intermediate metabolite of 1,2-DCE in vivo. Protein and mRNA levels of MMP-2, and the phosphorylated protein levels of p38 MAPK (p-p38), extracellular signal regulated protein kinase (p-ERK1/2) and c-Jun N-terminal kinase (p-JNK1/2) in astrocytes were examined by immunostaining, western blot or real-time RT-PCR analysis. Findings from this study disclosed that protein levels of MMP-2 were upregulated by 2-CE in astrocytes. Meanwhile, protein levels of p-p38, p-ERK1/2 and p-JNK1/2 were also increased apparently in the cells treated with 2-CE. Moreover, pretreatment of astrocytes with SB202190 (inhibitor of p38 MAPK), U0126 (inhibitor of ERK1/2) or SP600125 (inhibitor of JNK1/2) could suppress the upregulated expression of p-p38, p-ERK1/2, and p-JNK1/2. In response to suppressed protein levels of p-p38 and p-JNK1/2, the protein levels of MMP-2 also decreased significantly, indicating that activation of MAPK signal pathways were involved in the mechanisms underlying 2-CE-induced upregulation of MMP-2 expression.

18.
Toxicology ; 325: 189-99, 2014 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-25242007

RESUMO

The aim of this study was to explore the mechanisms of lead neurotoxicity by focusing on the alteration of D-serine metabolism in the hippocampus of mice at the early life. Mother mice and their offspring were exposed to 0, 0.5, 1.0 and 2.0 g/L lead in lead acetate via drinking water from the first day of gestation until the postnatal day (PND) 40. Morris water maze was used to measure the spatial learning and memory ability of PND 40 mice. Expressions of serine racemase (SR), D-amino acid oxidase (DAAO), alanine-serine- cysteine transporter-1 (asc-1) and subunits of N-methyl-D-aspartate receptor (NMDAR) in the hippocampus of PND 10, 20 and 40 mice were examined by western blot and real time RT-PCR. Findings from this study disclosed that the spatial learning ability of mice tested by place trial could be significantly impaired by 0.5 g/L lead exposure, and the spatial memory ability tested by probe trail could be impaired by 1.0 g/L lead exposure. Exposure to 2.0 g/L lead in the water could significantly inhibit the protein and mRNA expression of SR; conversely enhance the expression of DAAO protein and mRNA in the hippocampus during the early developmental stages. However, the protein expressions of DAAO and asc-1 in the hippocampus were significantly enhanced by 0.5 g/L lead exposure at different developmental stages. On the other hand, the protein and mRNA expressions of both NR1 and NR2A were inhibited significantly by 1.0 g/L lead exposure since PND 10, and by 0.5 g/L lead exposure since PND 20. Noteworthy, the protein expression of NR2B was inhibited significantly by 0.5 g/L lead exposure in PND 10 mice, and by 1.0 g/L lead exposure in PND 20 mice, but there was no significant group difference in PND 40 mice. Meanwhile, expressions of asc-1 and NR2B mRNA were not affected obviously by lead exposure. In conclusion, chronic lead exposure during brain development might affect D-serine metabolism by enhancing its degradation, which might be related to the inhibited expression of NMDAR subunits, and furthermore contribute to deficits in learning and memory ability in mice.


Assuntos
Hipocampo/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo na Infância/etiologia , Compostos Organometálicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Serina/metabolismo , Fatores Etários , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , D-Aminoácido Oxidase/genética , D-Aminoácido Oxidase/metabolismo , Relação Dose-Resposta a Droga , Feminino , Idade Gestacional , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Intoxicação do Sistema Nervoso por Chumbo na Infância/genética , Intoxicação do Sistema Nervoso por Chumbo na Infância/metabolismo , Intoxicação do Sistema Nervoso por Chumbo na Infância/fisiopatologia , Memória/efeitos dos fármacos , Camundongos , Gravidez , RNA Mensageiro/metabolismo , Racemases e Epimerases/genética , Racemases e Epimerases/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Aprendizagem Espacial/efeitos dos fármacos
19.
Neurotoxicol Teratol ; 44: 105-12, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24964198

RESUMO

The aim of this study was to explore the effects of 1,2-dichloroethane (1,2-DCE) on expression of aquaporins (AQPs) and matrix metalloproteinases (MMPs) in the process of brain edema formation. Two parts were included in this study, establishment of animal model of brain edema, and mechanism of brain edema induced by subacute exposure to 1,2-DCE. In part one, mice were exposed to 0, 1.1, 1.2 or 1.3g/m(3) 1,2-DCE, 3.5h per day for 3days. Pathological analysis and water content detection in the brain were examined. In part two, mice were exposed to 1.2g/m(3) 1,2-DCE, 3.5h per day for 1, 2 or 3days, named group D, E and F, respectively. Expression of AQP4, MMP2 and MMP9 in the brain was determined by immunochemical staining, western blot and real time PCR. According to the results of part one, the 1.2g/m(3) dose was chosen for part two, a follow-up time-course study. In part two, protein expression of MMP2 and MMP9 in group F, and AQP4 in group E and F significantly increased compared to the control. Similarly, mRNA levels of AQP4 in group F, and MMP9 in group E and F significantly increased. Our results suggested that exposure to 1,2-DCE might up-regulate the expression of AQP4 protein and MMP9 mRNA at the early phase of brain edema, and AQP4 may play an important role in the brain edema formation.


Assuntos
Aquaporina 4/metabolismo , Edema Encefálico/metabolismo , Dicloretos de Etileno/toxicidade , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/induzido quimicamente , Modelos Animais de Doenças , Dicloretos de Etileno/administração & dosagem , Feminino , Camundongos , Síndromes Neurotóxicas , RNA Mensageiro/metabolismo
20.
Artigo em Chinês | MEDLINE | ID: mdl-22096850

RESUMO

OBJECTIVE: To explore the effects of 1,2-dichloroethane (1,2-DCE) on the behavior and the brain neurotransmitter levels in mice. METHODS: Thirty mice were randomly divided into four groups, which were control group and groups of low, middle and high exposure (225, 450 and 900 mg/m3) to 1,2-DCE for 10 days (3.5 h a day) by inhalation. After the last exposure, the open field test was performed immediately. After exposure all mice were killed and the brain tissues were taken up rapidly. The levels of aspartate (Asp), glutamate (Glu) and gamma-aminobutyric acid (GABA) in the brain were detected by high performance liquid chromatography (HPLC). RESULTS: Levels of Asp and Glu in all exposure groups increased with doses. As compared to the control group, levels of Glu in all exposure groups increased significantly (P < 0.05). Levels of GABA in the low exposure group were significantly lower than those in control group, but those in the high exposure group were significantly higher than those in control group. The results of the open field test showed that effect of low exposure to 1,2-DCE on the behavior was stimulant, but the high exposure to 1,2-DCE inhibited behavior of exploration, excitement and sport. CONCLUSIONS: Subacute exposure to 1,2-DCE could result in the change of amino acid neurotransmitter content and ratio in the brain, thereby change the behavior of mice appeared, which might be the mechanism of neurotoxicity caused by 1,2-DCE in part.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Dicloretos de Etileno/toxicidade , Neurotransmissores/metabolismo , Animais , Ácido Aspártico/análise , Feminino , Ácido Glutâmico/análise , Camundongos , Camundongos Endogâmicos , Ácido gama-Aminobutírico/análise
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