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1.
Neuron ; 100(1): 183-200.e8, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30269986

RESUMO

Acute infection, if not kept in check, can lead to systemic inflammatory responses in the brain. Here, we show that within 2 hr of systemic inflammation, PDGFRß mural cells of blood vessels rapidly secrete chemokine CCL2, which in turn increases total neuronal excitability by promoting excitatory synaptic transmission in glutamatergic neurons of multiple brain regions. By single-cell RNA sequencing, we identified Col1a1 and Rgs5 subgroups of PDGFRß cells as the main source of CCL2. Lipopolysaccharide (LPS)- or Poly(I:C)-treated pericyte culture medium induced similar effects in a CCL2-dependent manner. Importantly, in Pdgfrb-Cre;Ccl2fl/fl mice, LPS-induced increase in excitatory synaptic transmission was significantly attenuated. These results demonstrate in vivo that PDGFRß cells function as initial sensors of external insults by secreting CCL2, which relays the signal to the central nervous system. Through their gateway position in the brain, PDGFRß cells are ideally positioned to respond rapidly to environmental changes and to coordinate responses.


Assuntos
Quimiocina CCL2/metabolismo , Inflamação/metabolismo , Neuroimunomodulação/fisiologia , Pericitos/metabolismo , Animais , Colágeno Tipo I/biossíntese , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/fisiologia , Pericitos/citologia , Proteínas RGS/biossíntese , Receptor beta de Fator de Crescimento Derivado de Plaquetas/biossíntese , Transmissão Sináptica/fisiologia
2.
Zhongguo Zhong Yao Za Zhi ; 43(13): 2784-2788, 2018 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-30111032

RESUMO

To study the effect of serum containing Xihuang pill on the proliferation of human breast cancer cell lines MDA-MB-435 and MCF-7 and the gene and protein expressions of Bcl-2, Bax, TP53, in order to explore the effect and mechanism of Xihuang pill in resisting breast cancer. The serum of the rats was prepared by the method of MTT assay. The expressions of Bcl-2 and Bax were detected by RT-PCR. The serum levels of Bcl-2 and Bax and the mRNA expression of TP53 were detected by immunofluorescence. The rats with serum containing Xihuang pill could inhibit the proliferation of MDA-MB-435 cells and MCF-7 cells (P<0.05). The serum containing Xihuang pill increased TP53 and Bax in MDA-MB-435 cells (P<0.05), and the ratio of Bcl-2/Bax was decreased (P<0.05). Meanwhile, the serum containing Xihuang pill could up-regulate the mRNA expression of Bax in MCF-7 cells and decrease the expression of Bcl (P<0.05), but there was no significant difference between the expression of TP53mRNA and Bax protein expressions after the treatment of MCF-7 cells with Xihuang pill serum. Serum containing Xihuang pill can induce the apoptosis of human breast cancer cells, and the mechanism of estrogen receptor-negative breast cancer cell apoptosis may be induced by up-regulating the mRNA expression of TP53, which can induce the expression of Bax and promote the metastasis of Bax to mitochondria, and ultimately play the role of inducing apoptosis.


Assuntos
Apoptose , Neoplasias da Mama , Animais , Proliferação de Células , Medicamentos de Ervas Chinesas , Humanos , Células MCF-7 , Ratos , Proteína X Associada a bcl-2
3.
Chronic Dis Transl Med ; 3(1): 60-66, 2017 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29063057

RESUMO

OBJECTIVE: To analyze the clinical epidemiological characteristics of patients with gallbladder carcinoma recruited from 17 hospitals in five northwestern provinces of China (Shaanxi Province, Gansu Province, Qinghai Province, Ningxia Hui Autonomous Region, and Xinjiang Uygur Autonomous Region) from 2009 to 2013, and to summarize the clinical diagnosis and treatment data of gallbladder carcinoma. METHODS: Clinical information of 2379 patients with gallbladder carcinoma from 17 hospitals in five northwestern provinces of China was retrospectively collected and analyzed using the "Questionnaire for Gallbladder Carcinoma Patients in Northwestern Area of China." All information was verified with EpiData software and analyzed with SPSS 13.0 software. RESULTS: (1) Gallbladder carcinoma accounted for 2.7% (2379/86,609) of all biliary tract diseases during the study period, which was significantly higher than that from 1986 to 1998 (P < 0.001). (2) Gallbladder carcinoma was more prone to occur in elderly women. The male:female incidence ratio was 1.0:2.1, the average age of onset of disease was 63.7 ± 11.3 years, and the incidence was higher in farmers than in other occupational groups. (3) A total of 57.2% (1360/2379) of patients with gallbladder carcinoma also had gallstones. (4) Abdominal pain (1796/2379, 75.5%) and jaundice (727/2379, 30.6%) were the most common clinical manifestations, 81.2% (1527/1881) were positive in those receiving B ultrasound examinations and 90.7% (1567/1727) were positive in those undergoing computed tomography, and 64.5% (1124/1742) of patients with gallbladder carcinoma were positive for carbohydrate antigen (CA) 19-9. (5) The pathological type of gallbladder carcinoma was mainly moderately and poorly differentiated adenocarcinoma with a high degree of malignancy. At admission, 55.1% (1091/1981) of patients had stage IV cancer among patients with TNM staging information; 55.9% (1331/2379) had lymphatic metastasis, 29.7% (706/2379) had bile duct metastasis, and 53.1% (1263/2379) had liver metastasis. (6) A total of 283 patients (283/2379, 11.9%) had incidentally detected gallbladder carcinoma. (7) The rate of radical surgical resection was 30.4% (723/2379). CONCLUSION: The proportion of gallbladder carcinoma in biliary tract diseases in the northwestern area of China was significantly higher from 2009 to 2013 than from 1986 to 1998. Gallbladder carcinoma was common in older women and mainly diagnosed at an advanced stage. Compared with other surveys in different regions, the rate of metastasis in this survey was high, leading to a low resection rate. Populations at high risk should undergo B-ultrasound examinations at regular follow-up intervals to increase the rate of early diagnosis of gallbladder carcinoma.

4.
Nature ; 530(7588): 98-102, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26808898

RESUMO

Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders. Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression. Here we report that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wild-type monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wild-type monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviours. Notably, we succeeded in generating five F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wild-type monkeys of similar age. Together, these results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/psicologia , Modelos Animais de Doenças , Mutação em Linhagem Germinativa/genética , Hereditariedade/genética , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Animais , Animais Geneticamente Modificados , Ansiedade/genética , Ansiedade/psicologia , Transtorno Autístico/metabolismo , Transtorno Autístico/fisiopatologia , Encéfalo/metabolismo , Cognição/fisiologia , Feminino , Humanos , Locomoção/genética , Locomoção/fisiologia , Macaca fascicularis , Masculino , Fenótipo , Comportamento Social , Injeções de Esperma Intracitoplásmicas , Transgenes/genética
5.
Nat Neurosci ; 17(3): 391-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24464043

RESUMO

Sensory experience is critical to development and plasticity of neural circuits. Here we report a new form of plasticity in neonatal mice, where early sensory experience cross-modally regulates development of all sensory cortices via oxytocin signaling. Unimodal sensory deprivation from birth through whisker deprivation or dark rearing reduced excitatory synaptic transmission in the correspondent sensory cortex and cross-modally in other sensory cortices. Sensory experience regulated synthesis and secretion of the neuropeptide oxytocin as well as its level in the cortex. Both in vivo oxytocin injection and increased sensory experience elevated excitatory synaptic transmission in multiple sensory cortices and significantly rescued the effects of sensory deprivation. Together, these results identify a new function for oxytocin in promoting cross-modal, experience-dependent cortical development. This link between sensory experience and oxytocin is particularly relevant to autism, where hypersensitivity or hyposensitivity to sensory inputs is prevalent and oxytocin is a hotly debated potential therapy.


Assuntos
Plasticidade Neuronal/fisiologia , Ocitocina/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Animais Recém-Nascidos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ocitocina/administração & dosagem , Ocitocina/farmacologia , Privação Sensorial/fisiologia , Transdução de Sinais/fisiologia , Córtex Somatossensorial/crescimento & desenvolvimento , Córtex Somatossensorial/metabolismo , Transmissão Sináptica/fisiologia
6.
Chem Biol Interact ; 207: 7-15, 2014 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-24211618

RESUMO

Combinations of antioxidants are believed to be more effective than single antioxidant because when antioxidants are combined they support each other synergistically to create a magnified effect. Discovering the enhancer effects or synergies between bioactive components is valuable for resisting oxidative stress and improving health benefits. The aim of this study was to investigate a possible cooperation of natural antioxidant caffeic acid phenethyl ester (CAPE) with synthetic antioxidant Trolox in the model systems of chemical generation of free radicals, lipid peroxidation of microsomes and radiation-induced oxidative injury in L929 cells. Based on the intermolecular interaction between CAPE and Trolox, the present study shows a synergistic effect of CAPE and Trolox in combination on elimination of three different free radicals and inhibition of lipid peroxidation initiated by three different systems. CAPE and Trolox added simultaneously to the L929 cells exerted an enhanced preventive effect on the oxidative injury induced by radiation through decreasing ROS generation, protecting plasma membrane and increasing the ratios of reduced glutathione/oxidized glutathione and the expression of key antioxidant enzymes mediated by nuclear factor erythroid 2 p45-related factor 2 (Nrf2). Our results showed for the first time that administration of CAPE and Trolox in combination may exert synergistic antioxidant effects, and further indicate that CAPE and Trolox combination functions mainly through scavenging ROS directly, inhibiting lipid peroxidation and promoting redox cycle of GSH mediated by Nrf2-regulated glutathione peroxidase and glutathione reductase expression.


Assuntos
Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Cromanos/farmacologia , Raios gama , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Álcool Feniletílico/análogos & derivados , Animais , Compostos de Bifenilo/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Depuradores de Radicais Livres/farmacologia , Dissulfeto de Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos da radiação , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/efeitos da radiação , Álcool Feniletílico/farmacologia , Picratos/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Espectrofotometria Ultravioleta , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
7.
J Appl Toxicol ; 33(1): 71-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21818760

RESUMO

Phosgene is a poorly water-soluble gas penetrating the lower respiratory tract which can induce acute lung injury characterized by a latent phase of fatal pulmonary edema. Pulmonary edema caused by phosgene is believed to be a consequence of oxidative stress and inflammatory responses. Ethyl pyruvate (EP) has been demonstrated to have anti-inflammatory and anti-oxidative properties in vivo and in vitro. The potential therapeutic role of EP in phosgene-induced pulmonary edema has not been addressed so far. In the present study, we aim to investigate the protective effects of EP on phosgene-induced pulmonary edema and the underlying mechanisms. Rats were administered with EP (40 mg kg(-1)) and RAW264.7 cells were also incubated with it (0, 2, 5 or 10 µm) immediately after phosgene (400 ppm, 1 min) or air exposure. Wet-to-dry lung weight ratio (W:D ratio), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production, cyclooxygenase2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, and mitogen-activated protein kinases activities (MAPKs) were measured. Our results showed that EP treatment attenuated phosgene-induced pulmonary edema and decreased the level of NO and PGE(2) dose-dependently. Furthermore, EP significantly reduced COX-2 expression, iNOS expression and MAPK activation induced by phosgene. Moreover, specific inhibitors of MAPKs reduced COX-2 and iNOS expression induced by phosgene. These findings suggested that EP has a protective role against phosgene-induced pulmonary edema, which is mediated in part by inhibiting MAPK activation and subsequently down-regulating COX-2 and iNOS expression as well as decreasing the production of NO and PGE(2).


Assuntos
Pulmão/efeitos dos fármacos , Fosgênio/toxicidade , Substâncias Protetoras/farmacologia , Edema Pulmonar/prevenção & controle , Piruvatos/farmacologia , Animais , Líquido da Lavagem Broncoalveolar/química , Linhagem Celular , Substâncias para a Guerra Química/toxicidade , Ciclo-Oxigenase 2/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/patologia , Ratos , Ratos Sprague-Dawley
8.
Exp Toxicol Pathol ; 65(3): 311-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22030112

RESUMO

The mechanism of phosgene-induced acute lung injury (ALI) remains unclear and it is still lack of effective treatments. Previous study indicated that oxidative stress was involved in phosgene-induced ALI. Caffeic acid phenethyl ester (CAPE) has been proved to be an anti-inflammatory agent and a potent free radical scavenger. The purpose of this study was to investigate the protective effects of CAPE on phosgene-induced ALI and identify the mechanism, in which oxidative stress and inflammation were involved. The phosgene was used to induce ALI in rats. The results showed that after phosgene exposure, total protein content in BALF was not significantly changed. The increase of MDA level and SOD activity induced by phosgene was significantly reduced by CAPE administration, and the decrease of GSH level in BALF and lung were significantly reversed by CAPE. CAPE also partially blocked the translocation of NF-κB p65 to the nucleus, but it had little effect on the phosphorylation of p38 MAPK. In conclusion, CAPE showed protective effects on lung against phosgene-induced ALI, which may be related with a combination of the antioxidant and anti-inflammatory functions of CAPE.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Poluentes Atmosféricos/toxicidade , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Ácidos Cafeicos/uso terapêutico , Fosgênio/toxicidade , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Western Blotting , Líquido da Lavagem Broncoalveolar/química , Ácidos Cafeicos/administração & dosagem , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/imunologia , Masculino , Malondialdeído/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Fator de Transcrição RelA/metabolismo
9.
Exp Toxicol Pathol ; 63(6): 527-33, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20510595

RESUMO

Tert-butyl hydroperoxide (t-BHP) can induce cell injury by forming free radical intermediates. Peroxisome proliferator-activated receptor (PPAR)-γ is a ligand-activated transcription factor belonging to nuclear hormone receptor superfamily, and is involved in oxidative stress response. Thiazolidinedione rosiglitazone is a potent PPARγ agonist. The main aim of this study was to investigate the protective effect of rosiglitazone on QZG cells from t-BHP-induced toxicity. MTT assay showed that t-BHP treatment resulted in decreased cell viability in a concentration dependent manner. Under 400 µM t-BHP treatment, QZG cell displayed significant loss of viability and dramatic morphological changes characterized by changing in shape from triangle to spherical, disappearance of cell cilia, swollen mitochondrial and typical apoptotic alteration such as condensation of chromatin, and appearance of crescent under light microscopy and electronic microscopy, respectively. Flow cytometry analysis indicated that 30.90±1.70% QZG cells were undergoing apoptosis compared to that of the control cells (2.80±0.85%, P<0.05). There was substantial population of the cells undergoing necrosis (28.5.%). 25 µM rosiglitazone treatment inhibited the t-BHP-induced cell toxicity significantly by restoring the cell viability, reducing cell population undergone apoptosis to normal level (3.5%) and ameliorating t-BHP-induced pathological changes. Real-time RT-PCR results showed that 400 µM t-BHP caused dramatic down-regulation of PPARγ expression in QZG cells, whereas combining treatment with 25 µM rosiglitazone resistant to PPARγ expression to normal level partially. Overall, our results indicate that rosiglitazone has protective effect against t-BHP-induced QZG cell injury. The protective effect of rosiglitazone is involved in its regulation on the function of PPARγ.


Assuntos
Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , terc-Butil Hidroperóxido/toxicidade , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Interpretação Estatística de Dados , Citometria de Fluxo , Humanos , Microscopia Eletrônica de Transmissão , Microscopia de Contraste de Fase , PPAR gama/biossíntese , Rosiglitazona
10.
Inhal Toxicol ; 22(11): 889-95, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20569121

RESUMO

Phosgene inhalation results in acute lung injury (ALI) mostly, pulmonary edema and even acute respiratory distress syndrome, but there is no specific antidote. Inflammatory cells play an important role in the ALI caused by phosgene. Intercellular adhesion molecule-1 (ICAM-1) is a critical factor for inflammatory organ injury. We hypothesized that pentoxifylline (PTX), an inhibitor of leukocyte activation, would have a protective effect on experimental phosgene-induced lung injury rats by inhibiting ICAM-1. To prove this hypothesis, we used rat models of phosgene (400 ppm x 1 min)-induced injury to investigate: (1) the time course of lung injury (control 1, 3, 6, 12, 24, and 48 h group), including pathological changes in hematoxylin and eosin staining and transmission electron microscope, myeloperoxidase (MPO) activity by colorimetric method and ICAM-1 protein level detected by western blot, (2) At 3 h after phosgene exposure, protective effects of different dosages of PTX (50 mg/kg and 100 mg/kg) administration were evaluated by MPO activity, ICAM-1 differential expression and WBC count in bronchoalveolar lavage fluid. The results showed that inflammatory cells emerged out of lung blood vessels at 3 h after phosgene exposure. The MPO activity of lung tissue increased significantly from 3 to 48 h after phosgene exposure (P < 0.05) and ICAM-1 expression presented a similar change, especially at 3 h and 24 h (P < 0.05). After pretreatment and treatment with PTX (100 mg/kg), significant protective effects were shown (P < 0.05). These data supported our hypothesis that PTX reduced phosgene-induced lung injury, possibly by inhibiting ICAM-1 differential expression.


Assuntos
Molécula 1 de Adesão Intercelular/biossíntese , Lesão Pulmonar/metabolismo , Lesão Pulmonar/prevenção & controle , Pentoxifilina/farmacologia , Pentoxifilina/uso terapêutico , Fosgênio/toxicidade , Animais , Exposição por Inalação/efeitos adversos , Lesão Pulmonar/induzido quimicamente , Masculino , Peroxidase/antagonistas & inibidores , Peroxidase/metabolismo , Fosgênio/administração & dosagem , Ratos , Ratos Sprague-Dawley
11.
Inhal Toxicol ; 22(7): 535-42, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20384467

RESUMO

Previous studies indicated that oxidative stress was involved in phosgene-induced acute lung injury (ALI) and many antioxidants had been used to prevent ALI. N-acetylcysteine (NAC) had been used to protect ALI induced by various types of oxidative stress. Considering the limited information of NAC on phosgene-induced ALI, the purpose of this study was to elucidate the molecular mechanisms of phosgene-induced ALI and the protective effects of NAC. This study discovered that intraperitoneal administration of NAC significantly alleviated phosgene-induced pulmonary edema, as confirmed by decreased lung wet to dry weight ratio and oxidative stress markers. The content of l-gamma-glutamyl-l-cysteinyl-glycine (glutathione; GSH) and the ratio of the reduced and disulfide forms (GSH/GSSG), significant indicators of the antioxidative ability, were apparently inhibited by phosgene exposure. However, both indicators could be reversed by NAC administration, indicating that dysregulation of redox status of glutathione might be the cause of phosgene-induced ALI. The nuclear factor (NF)-E2-related factor 2 (Nrf2), which has been proven to up-regulate the expression of glutathione reductase (GR), was obviously decreased by phosgene exposure. However, NAC administration elevated Nrf2 expression significantly. In conclusion, these data provided the first evidences showing that it was the transcriptional factor Nrf2 that connected phosgene-induced ALI with GSH metabolism. NAC protected against oxidative stress through acting on this newly disclosed Nrf2/GR/GSH pathway, by which NAC elevated the biosynthesis of protective GSH to repair and reconstitute the defense system destroyed by phosgene.


Assuntos
Acetilcisteína/uso terapêutico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/prevenção & controle , Fator 2 Relacionado a NF-E2/biossíntese , Fosgênio/toxicidade , Regulação para Cima/fisiologia , Acetilcisteína/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Glutationa/antagonistas & inibidores , Glutationa/fisiologia , Glutationa Redutase/antagonistas & inibidores , Glutationa Redutase/fisiologia , Masculino , Fator 2 Relacionado a NF-E2/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Regulação para Cima/efeitos dos fármacos
12.
Chem Biol Interact ; 184(3): 328-37, 2010 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-20100471

RESUMO

Oleanolic acid (OA) is a natural triterpenoid, which has been used in Chinese medicine for the treatment of liver disorders for many years. Its pharmacological activities have been the focus of intense research in recent years. However, there is little research on the antioxidant activities of OA. In the present study, we aim to investigate whether OA produces its protective effects mainly through antioxidant mechanisms and whether OA plays as an antioxidant through quenching reactive oxygen species (ROS), inhibiting lipid peroxidation or stimulating cellular antioxidant defenses. In the in vitro antioxidant activity-assessing models, OA acted as not only a free radical-scavenger through direct chemical reactions but also a biological molecule, which may enhance the antioxidant defenses. tert-Butyl hydroperoxide (tBHP) induced ROS generation, damaged plasma membrane and decreased cell viability and the expression of key antioxidant enzymes and MAP kinases in QZG cells. OA ameliorated the oxidative injury induced by tBHP through increasing the generation of antioxidant (glutathione) and the expression of key antioxidant enzymes mediated by nuclear factorerythroid 2 p45-related factor 2 (Nrf2), in which process, activation of JNK and ERK, but not p38, was involved. The present study, for the first time, investigated the antioxidant activities of OA systematically. OA probably functions mainly through indirect biological effect and protects QZG cells against cytotoxicity induced by tBHP through increasing the generation of antioxidant and the expression of oxidative stress sensitive transcription factor-Nrf2, and MAP kinases, mainly JNK and ERK. These findings may significantly better the understanding of OA and advance therapeutic approaches to the diseases which are associated with oxidative stress.


Assuntos
Depuradores de Radicais Livres/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleanólico/farmacologia , Animais , Células Cultivadas , Glutationa/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Microssomos Hepáticos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , terc-Butil Hidroperóxido/toxicidade
13.
Inhal Toxicol ; 21(4): 374-80, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19235614

RESUMO

Secreted phospholipase A(2) of group IIA (sPLA(2)-IIA) has been involved in a variety of inflammatory diseases, including acute lung injury. However, the specific role of sPLA(2)-IIA in phosgene-induced acute lung injury remains unidentified. The aim of the present study was to investigate the correlation between sPLA(2)-IIA activity and the severity of phosgene-induced acute lung injury. Adult male rats were randomly exposed to either normal room air (control group) or a concentration of 400 ppm phosgene (phosgene-exposed group) for there are 5 phosgene-exposed groups altogether. For the time points of 1, 3, 6, 12 and 24 h post-exposure, one phosgene-exposed group was sacrificed at each time point. The severity of acute lung injury was assessed by Pa(O2)/F(IO2) ratio, wet-to-dry lung-weight ratio, and bronchoalveolar lavage (BAL) fluid protein concentration. sPLA(2)-IIA activity in BAL fluid markedly increased between 1 h and 12 h after phosgene exposure, and reached its highest level at 6 h. Moreover, the trend of this elevation correlated well with the severity of lung injury. These results indicate that sPLA(2)-IIA probably participates in phosgene-induced acute lung injury.


Assuntos
Substâncias para a Guerra Química/toxicidade , Fosfolipases A2 do Grupo II/biossíntese , Pneumopatias/induzido quimicamente , Pneumopatias/enzimologia , Fosgênio/toxicidade , Animais , Gasometria , Líquido da Lavagem Broncoalveolar , Permeabilidade Capilar/efeitos dos fármacos , Fosfolipases A2 do Grupo II/genética , Interleucina-10/biossíntese , Pulmão/patologia , Pneumopatias/patologia , Masculino , Tamanho do Órgão , Oxigênio/sangue , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/biossíntese
14.
Inhal Toxicol ; 20(9): 805-12, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18645720

RESUMO

Acute lung injury (ALI) induced by phosgene increases risk of serious edema and mortality. Increased permeability of the microvascular endothelium is implicated in the progression of ALI, but the processing interaction and time course activity of the vascular regulators in exudation are still not understood. The main aim of this study was to investigate the time course and potential role for vascular endothelial growth factor (VEGF), its receptors, and some vascular function regulators related to increased vascular permeability of lung induced by phosgene. Sprague Dawley rats were randomly divided into seven groups according to time post phosgene exposure (control, and 1, 3, 6, 12, 24, and 48 h groups). Lung tissue was removed to evaluate VEGF isoforms, fms-like tyrosine kinase receptor 1 (Flt-1), and kinase insert domain containing region (KDR/Flk-1) by reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Blood samples were collected for measurement of plasma endothelin-1 (ET-1) and nitric oxide (NO) level. The results showed that the mRNA and protein expression profile of the VEGF system after phosgene exposure was time dependent. The VEGF system expression in lung tissue was related closely to the level of ET-1 and NO. In conclusion, increased permeability of the lung microvascular endothelium induced by phosgene was primarily a result of differential expression of VEGF and its receptors, and was related to the level of ET-1 and NO. The results suggest that the cooperation of VEGF system, ET-1, and NO plays a critical role, and all those parameters emerge as time dependent in the early phase of the permeability process induced by phosgene exposure.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Pneumopatias/induzido quimicamente , Pulmão/efeitos dos fármacos , Fosgênio/toxicidade , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Endotelina-1/sangue , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/ultraestrutura , Ensaio de Imunoadsorção Enzimática , Expressão Gênica/efeitos dos fármacos , Pulmão/irrigação sanguínea , Pneumopatias/sangue , Pneumopatias/patologia , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/ultraestrutura , Óxido Nítrico/sangue , Circulação Pulmonar/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
15.
Inhal Toxicol ; 18(1): 71-7, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16326403

RESUMO

Phosgene inhalation can induced pulmonary edema formation. The purpose of this study was to investigate cell of apoptosis in pulmonary edema mice induced by phosgene. Fifty-two BALB/c mice were random divided into a negative group and a positive group with 26 mice in each. Mice were exposed for 5 min to air and phosgene in the negative group and in the positive one, respectively. The dose of phosgene was 539 ppm. After 4 h of exposure, all mice were anesthetized. Lungs were analyzed for lung wet/dry weight ratio and pathological alternation. The method of isolation and culture of alveolar type II cells (ATII cells) was established to observe their apoptosis by electron microscope and flow cytometry. Apoptosis of lung cells was observed by DNA gel electrophoresis and TUNEL. The lung wet/dry weight ratio was significantly higher in the positive group (6.42 +/- 1.00) than in the negative group (4.25 +/- 0.47, p < 0.05). A large amount of fluid effusion was observed in the alveolus of mice induced by phosgene. Alveolar type II cells were identified by tannic acid staining and electron microscope. The apoptotic signs in alveolar type II cells, alveolar type I cells, eosinophils, macrophages, symphocytes, and ciliated cells were viewed under electron microscope in positive group. The ratio of apoptosis cells (40.26 +/- 7.74) in positive was higher than that (1.58 +/- 1.01, p < 0.001) in the negative group by flow cytometry. DNA ladder alternation was seen through DNA gel electrophoresis. Apoptosis of epithelia and vascular endothelia in lung were found by TUNEL. These results indicate that there is success in establishing a model of pulmonary edema and method of isolation and culture of AT II cells in BALB/c mice. Phosgene can induce apoptosis of cells in the lungs of BALB/c mice, and this indicates that pulmonary edema is related to apoptosis of lung cells in mice, induced by phosgene.


Assuntos
Apoptose/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Fosgênio/toxicidade , Alvéolos Pulmonares/efeitos dos fármacos , Animais , Células Cultivadas , Citometria de Fluxo , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Tamanho do Órgão/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/patologia
16.
Di Yi Jun Yi Da Xue Xue Bao ; 25(8): 983-5, 990, 2005 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-16109555

RESUMO

OBJECTIVE: To study apoptosis of pulmonary epithelial cells and endothelial cells in mice with pulmonary edema induced by phosgene exposure. METHODS: Thirty-two mice were divided into normal group and phosgene group with 16 mice in each group. The mice in phosgene group were exposed to phosgene (11.9 mg/L) for 5 min and those in the control group to air. Four hours after exposure, alveolar type II cells were isolated and cultured to observe their apoptosis by electron microscope and flow cytometry. The lung tissues were also taken for DNA gel electrophoresis and TUNEL assay. RESULTS: Apoptotic bodies were observed in alveolar type II cells under electron microscope in phosgene group, which had higher cell apoptosis rate than the control group [(40.26+/-7.74)% vs (1.58+/-1.01)%, P<0.001] as determined by flow cytometry. Ladder-like DNA fragmentation pattern was observed in DNA gel electrophoresis in phosgene group with apoptosis of the pulmonary epithelial and endothelial cells observed by TUNEL. CONCLUSIONS: Phosgene can induce pulmonary epithelial and endothelial cell apoptosis in mice, suggesting that the mechanism of phosgene-induced pulmonary edema involves apoptosis of the lung cells.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/patologia , Fosgênio/toxicidade , Alvéolos Pulmonares/patologia , Edema Pulmonar/patologia , Animais , Substâncias para a Guerra Química/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Edema Pulmonar/induzido quimicamente , Distribuição Aleatória
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