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1.
Brain Struct Funct ; 226(8): 2665-2673, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34373950

RESUMO

Increasing evidence suggests that genetic factors play a key role in the development of Parkinson's disease (PD). The variant rs11240572 in the PARK16 gene locus is strongly associated with PD. However, its effect on the pathogenesis of PD is yet to be clarified. The objective of the study was to explore the effect of the PARK16 rs11240572 variant on brain structure in PD patients. A total of 51 PD patients were enrolled in the study and genotyped for the rs11240572 variant. Clinical assessments and MRI scans were conducted across all participants. Voxel-based morphometry (VBM) was used to investigate gray matter volume (GMV) of the whole brain between these two groups. Correlation analysis was performed to identify the relationships between GMV and clinical features. There were 17 rs11240572-A variant carriers and 34 non-carriers, with no significant demographic differences between these two groups. Compared with non-carriers, rs11240572-A carriers showed increased GMV in the left caudate nucleus and putamen, but decreased GMV in the left superior temporal gyrus and supramarginal gyrus. In non-carriers, left basal ganglia GMV was positively correlated with UPDRS III (r = 0.365, p = 0.034) and bradykinesia (r = 0.352, p = 0.042), but negatively correlated with MMSE (r = - 0.344, p = 0.047), while in carriers negative correlation between basal ganglia GMV and MMSE was also observed (r = - 0.666, p = 0.004). Moreover, the GMV of left temporoparietal cortex was positively associated with cognitive function in both groups (carriers, r = 0.692, p = 0.002; non-carriers, r = 0.879, p < 0.001). When reducing the sample size of non-carriers to the level of the carrier sample, similar correlations were observed in both groups. Our study showed that the PARK16 rs11240572 variant affects the brain structure of patients with PD, especially in the basal ganglia and temporoparietal cortex. This indicated that this variant might play an important role in the pathogenesis of PD.


Assuntos
Encéfalo/anatomia & histologia , Doença de Parkinson , Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/genética
2.
Front Aging Neurosci ; 12: 580853, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250763

RESUMO

BACKGROUND: Excessive aggregation of α-synuclein is the key pathophysiological feature of Parkinson's disease (PD). Rapid eye movement sleep behavior disorder (RBD) is also associated with synucleinopathies and considered as a powerful predictor of PD. Growing evidence suggests the diminished clearance of α-synuclein may be partly attributable to poor interstitial fluid drainage, which can be reflected by magnetic resonance imaging (MRI)-visible enlarged perivascular space (EPVS). However, the effect of MRI-visible EPVS on iRBD and PD, and their correlation with clinical characteristics remain unclear. OBJECTIVE: To evaluate the clinical and neuroimaging significance of MRI-visible EPVS in iRBD and PD patients. METHODS: We enrolled 33 iRBD patients, 82 PD (with and without RBD) patients, and 35 healthy controls (HCs), who underwent clinical evaluation and 3.0 Tesla MRI. Two neurologists assessed MRI-visible EPVS in centrum semiovale (CSO), basal ganglia (BG), substantia nigra (SN), and brainstem (BS). Independent risk factors for iRBD and PD were investigated using multivariable logistic regression analysis. Spearman analysis was used to test the correlation of MRI-visible EPVS with clinical characteristics of patients. RESULTS: iRBD patients had significantly higher EPVS burdens (CSO, BG, SN, and BS) than PD patients. Higher CSO-EPVS and BS-EPVS burdens were independent risk factors for iRBD. Furthermore, higher CSO-EPVS and SN-EPVS burdens were positively correlated with the severity of clinical symptom in iRBD patients, and higher BG-EPVS burden was positively correlated with the severity of cognitive impairment in PD patients. CONCLUSION: iRBD and PD patients have different MRI-visible EPVS burdens, which may be related with a compensatory mechanism in glymphatic system. Lower MRI-visible EPVS burden in PD patients may be a manifestation of severe brain waste drainage dysfunction. These findings shed light on the pathophysiologic relationship between iRBD and PD with respect to neuroimaging marker of PD.

3.
CNS Neurosci Ther ; 26(1): 117-125, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278861

RESUMO

AIMS: Cognitive impairment is a common symptom in the trajectory of Parkinson's disease (PD). However, the pathological underpinning is not fully known. We aimed to explore the critical structural alterations in the process of cognitive decline and its relationships with the dopaminergic deficit and the level of related cerebrospinal fluid (CSF) proteins. METHODS: Ninety-four patients with PD and 32 controls were included in this study. Neuropsychological tests were performed at baseline and after 28 months to identify which patients had normal cognition and which ones developed PD-MCI after follow-up ("converters"). Gray matter atrophy was assessed in cross-sectional and longitudinal analyses, respectively. The associations between altered GMV with dopamine transporter (DAT) results and the level of CSF proteins were assessed. RESULTS: Among the 94 patients with normal cognition at baseline, 24 (mean age, 63.1 years) developed PD-MCI after 28 months of follow-up, and 70 (mean age, 62.3 years) remained nonconverters. The converters showed significant right temporal atrophy at baseline and extensive atrophy in temporal lobe at follow-up. Progressive bilateral frontal lobe atrophy was found in the converters. Baseline right temporal atrophy was correlated with the striatal dopaminergic degeneration in the converters. No correlation was found between the right temporal atrophy and the alterations of CSF proteins. CONCLUSION: Early atrophy in temporal lobes and progressive atrophy in frontal lobes might be a biomarker for developing multidomain impairment of cognition and converting to PD-MCI. Furthermore, cognition-related temporal atrophy might be associated with dopaminergic deficit reflected by DAT scan but independent of CSF proteins in patients with PD who convert to PD-MCI.


Assuntos
Encéfalo/patologia , Disfunção Cognitiva/patologia , Doença de Parkinson/patologia , Idoso , Atrofia , Proteínas do Líquido Cefalorraquidiano/líquido cefalorraquidiano , Disfunção Cognitiva/psicologia , Corpo Estriado/patologia , Estudos Transversais , Progressão da Doença , Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Substância Cinzenta/patologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/psicologia , Lobo Temporal/patologia
4.
Inflamm Res ; 64(7): 513-26, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26033389

RESUMO

OBJECTIVE AND DESIGN: Cigarette smoke (CS)-induced inflammation is critical in chronic obstructive pulmonary disease (COPD). However, the role of acetylation at histone 3 lysine 9 (H3K9) in COPD inflammation remains unclear. The present study assessed the effect of acetylation of H3K9 on transcription both in rat lungs and in macrophages. METHODS: Sprague-Dawley rats were exposed to CS for either 6 or 12 weeks and rat lungs were collected. Rat macrophages were subjected to 20 % cigarette smoke extract (CSE) for 48 h. RESULTS: CS increased MCP-1 and IL-8 expressions at both mRNA and protein levels in rat lungs after 6 and 12 weeks; increased TNF-α and MMP9 expressions at both levels were noted only after 12 weeks. CSE increased these genes expression in macrophages after 48 h exposure. Increased abundance of acetylated H3K9 protein in rat lungs and in macrophages were associated with decreased expression of histone deacetylase-1(HDAC1). Chromatin immunoprecipitation demonstrated increased level of acetylated H3K9 on promoter regions of these genes both in vivo and in vitro. Knockdown of HDAC1 increased these genes mRNA expression. CONCLUSIONS: CS increased H3K9 acetylation and subsequently altered the expression of pro-inflammatory mediators and protease genes through HDAC1 depression in CS-induced rat lungs and in macrophages.


Assuntos
Citocinas/metabolismo , Histona Desacetilase 1/biossíntese , Histonas/química , Lisina/química , Fumaça/efeitos adversos , Tabaco , Acetilação , Animais , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Técnicas de Silenciamento de Genes , Histona Desacetilase 1/genética , Exposição por Inalação/efeitos adversos , Interleucina-8/biossíntese , Interleucina-8/genética , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Células RAW 264.7/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
5.
COPD ; 11(5): 582-90, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24766333

RESUMO

Cigarette smoke has been shown to cause chronic inflammation of the lungs, eventually leading to chronic obstructive pulmonary disease (COPD). Additionally, recent studies have suggested that mesenchymal stem cells (MSCs) can mediate local inflammatory responses in the lungs. Thus, the aim of the present study was to test the effects of rat MSCs (rMSCs) on inflammation of the lungs and destructive pulmonary function induced by cigarette smoke in rats. Rats were exposed to cigarette smoke for 7 weeks. rMSCs were cultured in vitro and infused intratracheally into cigarette smoke-exposed rats. The total and differential cell counts in the bronchoalveolar lavage fluid (BALF), histological changes, pro-inflammatory cytokines, transforming growth factor-ß1 (TGF-ß1) expression, and pulmonary function were evaluated. Additionally, human peripheral blood mononuclear cells and human MSCs were cocultured in vitro to detect cytokines and TGF-ß1 levels. We found that rMSC administration resulted in downregulation of pro-inflammatory cytokines in the lungs while increasing TGF-ß1 expression, reducing total inflammatory cell numbers in the BALF, and improving pulmonary histopathology and airflow obstruction. Coculture revealed that human MSCs mediated an anti-inflammatory effect partly via upregulation of TGF-ß1. These findings suggested that MSCs may have therapeutic potential in cigarette smoke-induced inflammation and airflow obstruction, partly via upregulation of TGF-ß1.


Assuntos
Inflamação/induzido quimicamente , Leucócitos Mononucleares/imunologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Fumaça/efeitos adversos , Tabaco/efeitos adversos , Fator de Crescimento Transformador beta1/imunologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Técnicas de Cocultura , Citocinas/imunologia , Humanos , Inflamação/imunologia , Mediadores da Inflamação/imunologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/imunologia , Traqueia
6.
J Cell Biochem ; 114(2): 323-35, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22949406

RESUMO

Progressive pulmonary inflammation and emphysema have been implicated in the progression of chronic obstructive pulmonary disease (COPD), while current pharmacological treatments are not effective. Transplantation of bone marrow mesenchymal stem cells (MSCs) has been identified as one such possible strategy for treatment of lung diseases including acute lung injury (ALI) and pulmonary fibrosis. However, their role in COPD still requires further investigation. The aim of this study is to test the effect of administration of rat MSCs (rMSCs) on emphysema and pulmonary function. To accomplish this study, the rats were exposed to cigarette smoke (CS) for 11 weeks, followed by administration of rMSCs into the lungs. Here we show that rMSCs infusion mediates a down-regulation of pro-inflammatory mediators (TNF-α, IL-1ß, MCP-1, and IL-6) and proteases (MMP9 and MMP12) in lung, an up-regulation of vascular endothelial growth factor (VEGF), VEGF receptor 2, and transforming growth factor (TGFß-1), while reducing pulmonary cell apoptosis. More importantly, rMSCs administration improves emphysema and destructive pulmonary function induced by CS exposure. In vitro co-culture system study of human umbilical endothelial vein cells (EA.hy926) and human MSCs (hMSCs) provides the evidence that hMSCs mediates an anti-apoptosis effect, which partly depends on an up-regulation of VEGF. These findings suggest that MSCs have a therapeutic potential in emphysematous rats by suppressing the inflammatory response, excessive protease expression, and cell apoptosis, as well as up-regulating VEGF, VEGF receptor 2, and TGFß-1.


Assuntos
Lesão Pulmonar , Transplante de Células-Tronco Mesenquimais , Receptores de Fatores de Crescimento do Endotélio Vascular , Fator de Crescimento Transformador beta , Fator A de Crescimento do Endotélio Vascular , Animais , Modelos Animais de Doenças , Enfisema/induzido quimicamente , Enfisema/terapia , Regulação da Expressão Gênica , Humanos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/terapia , Células-Tronco Mesenquimais , Pneumonia/induzido quimicamente , Pneumonia/terapia , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/terapia , Ratos , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fumar/efeitos adversos , Produtos do Tabaco/toxicidade , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Zhonghua Jie He He Hu Xi Za Zhi ; 33(3): 188-92, 2010 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-20450637

RESUMO

OBJECTIVE: To study the role of phosphorylation of c-Jun NH2-terminal kinase (JNK) in asthmatic airway remodeling and to explore the effect of glucocorticoids on IL-1beta, JNK and airway remodeling. METHODS: Forty-eight 4 - 6 week old male SD rats were randomly divided into 4 groups with 12 rats in each group: the control group, the asthma group, the budesonide (BUD) group, and the dexamethasone (DXM) group. The asthma airway remodeling models were made by intra-peritoneal injection of ovalbumin (OVA) on days 1 and 8 and inhalation of OVA every other day for 12 weeks since day 15. The BUD group underwent inhalation of BUD 30 min before every inhalation; the DXM group received intra-peritoneal injection of DXM 30 min before every inhalation; while the control group received normal saline instead of OVA. The histopathology and ultrastructural changes of pulmonary tissues were observed by light microscope and transmission electron microscope (TEM). The total bronchial wall thickness (Wat) and the airway smooth muscle thickness (Wam) were measured by image analysis system. The concentrations of IL-1beta in serum and BALF were tested by sandwich ELISA. The protein expressions of P-JNK and P-c-Jun were detected by immunohistochemistry technique. Lung tissue extracts were analyzed for phosphorylation of JNK by Western blot. Linear correlation analysis was used to evaluate correlations between Wat and P-JNK protein (mA), Wam and P-JNK protein (mA), P-JNK protein (mA) and levels of IL-1beta in serum, P-JNK protein (mA) and levels of IL-1beta in BALF. RESULTS: In the asthma group, HE-staining showed inflammatory cell infiltration around bronchi and mucous gland hyperplasia. TEM examination showed airway smooth muscle and collagen fiber proliferation, and widening of intercellular distance. The Wat and Wam of the asthma group were significantly higher than those of the control group, while the thickness of airway wall in the glucocorticoid intervention groups became significantly decreased. The concentrations of IL-1beta in serum and BALF of the asthma group [(81 +/- 4) ng/L, (331 +/- 15) ng/L] were significantly higher than those of the control group [(53 +/- 6) ng/L, (130 +/- 9) ng/L] (t = -8.62 and t = -24.10, both P < 0.01). Mean absorbance values (by immunohistochemistry) of P-JNK and P-c-Jun in the asthma group were significantly higher than those of the control group, and the mean absorbance values of P-JNK and P-c-Jun in the BUD and DXM groups were significantly lower than those of the asthma group, but higher than those of the control group (F = 223.59 and F = 76.53, both P < 0.01). Absorbance (by Western blot) of P-JNK in the control, asthma, BUD, and DXM groups were (1.00 +/- 0.00), (1.66 +/- 0.16), (1.18 +/- 0.12), and (1.29 +/- 0.14), respectively; that of the asthma group was significantly higher than that of the control group, while absorbance of P-JNK in the BUD and the DXM groups were significantly lower than that of the asthma group, but higher than that of the control group (F = 17.84, P < 0.05). Strong positive correlations were found between Wat or Wam and P-JNK (mA) (r = 0.700 and r = 0.769, P < 0.01, respectively, n = 48). Strong positive correlations were also found between P-JNK (mA) and concentration of IL-1beta in serum or BALF (r = 0.689 and r = 0.805, P < 0.01, respectively, n = 48). CONCLUSION: Phosphorylation of JNK is closely related to asthma airway remodeling. Glucocorticoids can inhibit phosphorylation of JNK, one mechanism of which may be down-regulation of IL-beta expression.


Assuntos
Remodelação das Vias Aéreas , Asma/metabolismo , Asma/fisiopatologia , Glucocorticoides/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Animais , Budesonida/farmacologia , Dexametasona/farmacologia , Interleucina-1beta/metabolismo , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
9.
Zhonghua Er Ke Za Zhi ; 46(7): 535-9, 2008 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-19099816

RESUMO

OBJECTIVE: To study the role of c-Jun N-terminal kinase (JNK) signal transduction pathway in the course of asthma airway remodeling, to explore whether IL-1beta participates in asthma airway remodeling mediated by JNK signal transduction pathway. METHODS: Totally 72 male Sprague-Dawlay rats (6 - 8 weeks old, weighing about 120 g) were randomly divided into control groups (36 rats) and asthma groups (36 rats). The rats were sensitized for inducing asthma by intraperitoneal injection of ovalbumin and AL(OH)3 and were repeatedly exposed to aerosolized ovalbumin for 4, 8, 12 weeks (A4, A8, or A12 group), each had 12 rats, and correspondingly control rats were intraperitoneally injected with 0.9% NaCl, then were repeatedly exposed to 0.9% NaCl for 4, 8, 12 weeks (C4, C8, or C12 group), each had 12 rats. The ultrastructural changes of pulmonary tissues were observed by transmission electron microscope (TEM). The total bronchial wall thickness (Wat) and the airway smooth muscle thickness (Wam) were measured by an image analysis system. The concentrations of IL-1beta in serum and bronchoalveolar lavage fluid (BALF) were tested by a "sandwich" ELISA. The protein expressions of P-JNK and P-c-Jun were detected by immunohistochemical technique. Lung tissue extracts were analyzed for phosphorylation of JNK by Western blotting. Linear correlation analysis showed the correlation between Wat and P-JNK protein, Wam and P-JNK protein, levels of IL-1beta in serum and P-JNK protein, levels of IL-1beta in BALF and P-JNK protein. RESULTS: In asthma groups, TEM showed alveolar septal proliferation and alveolus type II epithelial cells swelling. Wat and Wam in all asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), and compared with group A4 and group A8, Wat and Wam of group A12 significantly increased (P < 0.01). The concentrations of IL-1beta in serum and BALF of asthma groups were all significantly higher than those of the corresponding control groups (P < 0.01, respectively), and compared with group A4 and group A8, the concentrations of IL-1beta in BALF of group A12 significantly increased (P < 0.01 or P < 0.05), but the levels of IL-1beta in serum were not significantly different among them (P > 0.05). Mean absorbance values (by immunohistochemistry) of P-JNK and P-c-Jun in asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), and compared with group A4 and group A8, those of group A12 significantly increased (P < 0.01 or P < 0.05). The absorbance (by Western Blot) of P-JNK in A4, A8, A12 group was significantly higher than that in C4, C8, C12 groups (P < 0.01, respectively), and compared with group A4, that of P-JNK of A12 significantly increased (P < 0.01), and compared with group A8, there was no significant difference (P > 0.05). Strong positive correlations were found between Wat or Wam and P-JNK (r = 0.823 and r = 0.818, P < 0.01, respectively, n = 68) and between P-JNK and concentration of IL-1beta in serum or BALF (r = 0.717 and r = 0.803, P < 0.01, respectively, n = 68). CONCLUSIONS: The expression of P-JNK and its downstream P-c-Jun in rats of asthma airway remodeling is increased, which implicates that JNK signal transduction pathway plays an important role in the course of asthma airway remodeling. IL-1beta participates in asthma airway remodeling possibly partly through activating JNK signal transduction pathway.


Assuntos
Remodelação das Vias Aéreas , Asma/metabolismo , Asma/fisiopatologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Animais , Interleucina-1beta/sangue , Masculino , Ratos , Ratos Sprague-Dawley
10.
Zhonghua Yi Xue Za Zhi ; 87(25): 1767-72, 2007 Jul 03.
Artigo em Chinês | MEDLINE | ID: mdl-17919386

RESUMO

OBJECTIVE: To study role of external signal regulated kinase (ERK) and transforming growth factor beta(1) (TGF-beta1) in asthma airway remodeling and to explore the regulation of glucocorticoids on ERK, TGF-beta1, and airway remodeling. METHODS: Thirty SD rats were randomly divided into 3 equal groups: control group; asthma group, undergoing intra-peritoneal injection of ovalbumin (OVA) on days 1 and 8 and inhalation of OVA every other day for 8 weeks since day 15 to establish chronic asthma models; dexamethasone (DM) intervention group, undergoing intra-peritoneal injection of DM 30 min before every inhalation instigation; and control group, receiving normal saline instead of DM. 1 - 2 hours after the last instigation the left lungs were taken out. The total bronchial wall thickness (Wat) and smooth muscle thickness (Wam) were measured by image analysis system. Phosphorylated ERK (P-ERK) was detected by immunohistochemistry. 1 - 2 hours after the last instigation blood samples were collected from the femoral artery. The concentration of transforming growth factor (TGF)-beta1 in the serum was measured by sandwich ELISA. Rat airway epithelial cells were cultured, stimulated with platelet-derived growth factor-BB (PDGF-BB, 1, 10, 25, or 50 microg/L), U0126 (specific inhibitor of phosphorylation of ERK), or budesonide (BUD). Western blotting was used to detect the P-ERK level. The level of TGF-beta1 in the cell culture supernatant was detected by sandwich ELISA. RESULTS: The Wat and Wam of the asthma group was significantly higher than those of the control group (both P < 0.01), and the Wat and Wam of the DM group were both significantly lower than those of the asthma group (both P < 0.01). The mean optical density of P-ERK and concentration of TGF-beta1 in the serum of the asthma group were 31.1 +/- 2.2 and 28.1 +/- 7.4 microg/L respectively, both significantly higher than those of the control group (12.8 +/- 2.4 and 13.6 +/- 2.7 microg/L respectively, both P < 0.01), and the mean optical density of P-ERK and concentration of TGF-beta1 in the serum of the DM group were 18.7 +/- 3.1 and 15.0 +/- 3.2 microg/L respectively, both significantly lower than those asthma group (both P < 0.01). In the PDGF-BB (25 microg/L) stimulated cells marked phosphorylation of ERK occurred 15 min later, the level of P-ERK remained high up to 8 hour later, and the maximal activation occurred at the period of 2 h - 4 h later, 6.5 +/- 0.4 times that of the control value (P < 0.01). The phosphorylation levels of ERK depended on the concentration of PDGF-BB and the maximal level phosphorylation was detected with the concentration of PDGF-BB of 50 microg/L, which was 4.1 +/- 0.3 times that of the control value (P < 0.01). U0126 and BUD inhibited the phosphorylation of ERK in the cells stimulated by PDGF-BB of the concentration of 25 microg/L. there was no difference in the level of TGF-beta1 in the cell culture supernatant among different groups. CONCLUSION: Phosphorylation of ERK and TGF-beta1 have an important role in asthma airway remodeling; PDGF-BB does not induce normal rat airway epithelial cells to product or release TGF-beta1 by phosphorylation of ERK. Glucocorticoids can inhibit phosphorylation of ERK.


Assuntos
Asma/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glucocorticoides/uso terapêutico , Fator de Crescimento Transformador beta1/sangue , Animais , Asma/sangue , Asma/metabolismo , Becaplermina , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/fisiopatologia , Butadienos/farmacologia , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Glucocorticoides/administração & dosagem , Injeções Intraperitoneais , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/fisiopatologia , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteínas Proto-Oncogênicas c-sis , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
11.
Zhonghua Er Ke Za Zhi ; 45(4): 288-92, 2007 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-17706067

RESUMO

OBJECTIVE: Airway remodeling in asthma makes treatment of asthma very difficult, and study of its pathogenesis becomes very important. The present study aimed to explore the role of external signal regulated kinase (ERK) signal transduction pathway in airway remodeling in rats asthma model and regulatory effects of glucocorticoids on ERK signal transduction pathway and airway remodeling. METHODS: Totally 80 male Sprague-Dawlay rats (6-8 weeks old, weighing about 120 g) were randomly divided into control groups (30 rats), asthma groups (30 rats) and treated groups [including a group intervened with dexamethasone (DM group) and budesonide (BUD group), each had 10 rats]. The rats were sensitized for inducing asthma by intraperitoneal injection of ovalbumin and Al (OH)(3) and were repeatedly exposed to aerosolized ovalbumin for 4, 8, or 12 weeks [respectively called 4, 8 or 12 wk asthma group (A4, A8 or A12 group), each had 10 rats]; and correspondingly control rats were intraperitoneally injected with 0.9% NaCl, then were repeatedly exposed to 0.9% NaCl for 4, 8, or 12 weeks [respectively called 4, 8 or 12 wk control group (C4, C8 or C12 group), each had 10 rats]; DM group rats were repeatedly exposed to aerosolized ovalbumin for 8 wk, and BUD group rats for 12 wk. Total bronchial wall thickness (Wat) and smooth muscle thickness (Wam) were measured by an image analysis system. Concentrations of PDGF-AB in serum were measured by sandwich ELISA. Phospho-ERK (P-ERK) and c-Fos were detected by immunohistochemical technique; lung tissue extracts were analyzed for phosphorylation of ERK by Western blotting. RESULTS: Wat and Wam in all asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), those of the treated groups were significantly lower than asthma groups (P < 0.01). The concentrations of PDGF-AB in serum of asthma groups [(228 +/- 18) pg/ml, (293 +/- 77) pg/ml, (225 +/- 66) pg/ml for A4, A8, A12 groups, respectively] were all significantly higher than those of the control groups [(160 +/- 14) pg/ml, (165 +/- 29) pg/ml and (164 +/- 27) pg/ml for C4, C8, C12 group, respectively] (P < 0.01 or P < 0.05); the value of DM group [(157 +/- 46) pg/ml] was significantly lower than that of the group A8 (P < 0.01), no significant difference was found when the values of BUD group [(208 +/- 40) pg/ml] was compared with that of A12 group (P > 0.05). Mean absorbance values (by immunohistochemistry) of P-ERK and c-Fos in asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), DM group had a significantly lower value than group A8 (P < 0.01), BUD group had a significantly lower value than group A12 (P < 0.01); absorbance (by Western blot) of P-ERK in A4, A8, A12 group was significantly higher than that in C4 and C8 group, the value of DM group was significantly lower than that of group A8 (P < 0.01), and that of BUD group (1.8 +/- 0.2) was significantly lower than that of group A12 (P < 0.01). CONCLUSION: Asthmatic rats have higher concentrations of PDGF-AB in serum and phosphorylation of ERK and c-Fos; glucocorticoids inhibit phosphorylation of ERK and c-Fos in asthmatic rats, and to some extent also inhibit Wat and Wam.


Assuntos
Asma/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glucocorticoides/farmacologia , Transdução de Sinais , Animais , Asma/tratamento farmacológico , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Masculino , Fosforilação , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley
12.
Zhonghua Er Ke Za Zhi ; 44(12): 937-40, 2006 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-17254466

RESUMO

OBJECTIVE: Eosinophilic airway inflammation is one of the basic characteristics of allergic asthma. Toll-like receptor is one of the most important innate immunity pattern recognition receptors. Glucocorticoids (GCS) are still the most effective treatment for asthma. However, few reports of studies on regulatory mechanism of GCS on the innate immunity system are available. The mechanism of effects of GCS on TLR4 is unclear. The present study aimed at understanding the effect of dexamethasone (DXM) on change of TLR4 and mechanism of regulatory effect of TLR4 on eosinophil (EOS) apoptosis. METHODS: Twenty-seven Sprague-Dawley (SD) rats (age 28 to 42 days, body weight 120 to 180 gram) were randomly divided into the control group, asthma group and DXM group with 9 in each. Asthma model rats were sensitized with the mixture of ovalbumin (OVA, 1 mg) and Al (OH)(3), 100 mg on day 1 and day 8, repeatedly exposed to aerosolized OVA after day 15, once a day for three days and continued for 30 minutes at every time. During the sensitization stage, 100 microg/ml DXM were prepared with DXM group for every other day, and the same doses DXM were prepared for every day on the stage of challenge. The histopathological changes of lung tissues were observed with light microscope (LM). EOS and other inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted; the concentrations of OVA-sIgE in serum were measured by using "sandwich" ELISA; The expressions of TLR4 mRNA were determined by in situ hybridization, the apoptosis of EOS was detected by TUNEL. RESULTS: (1) LM showed many inflammatory cells infiltration around the bronchi and blood vessels, bronchus mucus increased, airway epithelium damage and desquamation, and airway mucous plugs in asthma group, whereas DXM group showed significantly milder changes. (2) Inflammationary cells count in BALF of asthma group was significantly higher as compared to control group (P < 0.01); compared with asthma group, the total cell count, EOS absolute count and EOS% were all significantly decreased in DXM group [(2.14 +/- 0.10) x 10(9)/L, (4.78 +/- 1.23) x 10(7)/L, (2.17 +/- 0.25)%]. (3) Levels of OVA-sIgE in serum of asthma group [(83.40 +/- 6.80) microg/ml] were significantly higher than those of the control group [(14.38 +/- 4.25) microg/ml] (P < 0.01), while those of DXM group [(45.02 +/- 7.47) microg/ml] were significantly lower than asthma group (P < 0.0 1). (4) There were no significant differences in TLR4 mRNA detected by in situ hybridization between control group (24.71 +/- 0.85) and asthma group (25.81 +/- 3.56) (P > 0.05); but it significantly increased in DXM group (29.86 +/- 3.92) as compared to asthma group. (5) The percentages of apoptotic EOS in asthma group [(7.39 +/- 1.93)%] were significantly lower than those in control group [(9.06 +/- 1.52)%] (P < 0.01); and significantly higher in DXM group [(13.33 +/- 1.09)%] than in asthma group (P < 0.01). There were significantly positive correlations between TLR4 mRNA and the percentage of apoptotic EOS (r = 0.612, P < 0.01). CONCLUSION: DXM can decrease OVA-sIgE level, induce EOS apoptosis, which may correlate with the activation of TLR4 signal transduction.


Assuntos
Asma/imunologia , Dexametasona/farmacologia , Eosinófilos/imunologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Asma/induzido quimicamente , Líquido da Lavagem Broncoalveolar/citologia , Glucocorticoides/farmacologia , Imunoglobulina E/sangue , Pulmão/patologia , Ovalbumina , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/imunologia
13.
Ai Zheng ; 24(12): 1498-502, 2005 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-16351800

RESUMO

BACKGROUND & OBJECTIVE: CHOP regimen is the standard treatment for patients with diffuse large B-cell lymphoma. Rituximab, an anti-CD20 monoclonal antibody, is effective in treating diffuse large B-cell lymphoma. This study was conducted to compare the efficacy of rituximab plus CHOP and CHOP alone on newly diagnosed patients with diffuse large B-cell lymphoma, and analyze their toxicities. METHODS: A total of 72 newly diagnosed patients with diffuse large B-cell lymphoma were divided into 2 groups prospectively with concurrent control: 34 received CHOP plus rituximab (375 mg/m2, 2 days before each course) (combination group), 38 received CHOP alone. Each course lasted 3 weeks. All cases were evaluated after 6 courses. RESULTS: The total response rate in combination group was 93.8% (30/32), among which complete remission was seen in 23 patients and partial remission was seen in 7 patientsû while the total response rate in CHOP group was 75.0% (27/36), among which complete remission was seen in 19 patients and partial remission was seen in 8 patients. The therapeutic efficacy was significantly better in combination group than in CHOP group (P<0.05). The 1-year progression-freely and overall survival rates were significantly higher in combination group than in CHOP group (81.2% vs. 52.8%, 93.8% vs. 75.0%, P<0.05). The major adverse events in combination group were infusion-related response which could be well tolerated, and hematological toxicities which were similar to those in CHOP group. CONCLUSIONS: Rituximab increases the therapeutic efficacy of CHOP regimen on newly diagnosed patients with diffuse large B-cell lymphoma, without a clinically significant increase in toxicity. Rituximab plus CHOP can be used as a first-line therapy of diffuse large B-cell lymphoma.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Antígenos CD20/imunologia , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Prospectivos , Indução de Remissão , Rituximab , Taxa de Sobrevida , Vincristina/administração & dosagem , Vincristina/efeitos adversos
14.
World J Gastroenterol ; 8(2): 294-7, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11925610

RESUMO

AIM: To characterize the biochemical and immunological properties of an experimental ISCOMS vaccine prepared from a novel therapeutic polypeptide based on T cell epitopes of HBsAg, and a heptatis B-ISCOMS was prepared and investigated. METHODS: An immunostimulating complexes(ISCOMS)-based vaccine containing a novel therapeutic hepatitis B polypeptide was prepared by dialysis method, and its formation was visualized by electron microscopy and biochemically verified by SDS-polyacrylamide gel electrophoresis. Amount of the peptide within ISCOMS was determined by Bradford assay, and specific CTL response was detected by ELISPOT assay. RESULTS: Typical cage-like structures of submicroparticle with a diameter of about 40nm were observed by electron microscopy. Results from Bradford assay showed that the level of peptide incorporation was about 0.33g.L(-1). At the paralleled position close to the sixth band of the molecular weight marker(3480kDa) a clear band was shown in SDS-PAGE analysis, indicating successful incorporation of polypeptide into ISCOMS. It is suggested that ISCOMS delivery system could efficiently improve the immunogenicity of polypeptide and elicit specific immune responses in vivo by the results of ELISPOT assay, which showed that IFN-gamma producing cells(specific CTL responses) were increased(spots of ISCOMS-treated group: 47+/-5, n =3; control group: 5+/-2, n =3). CONCLUSION: ISCOMS-based hepatitis B polypeptide vaccine is successfully constructed and it induces a higher CTL response compared with short polypeptides vaccine in vivo.


Assuntos
Vacinas contra Hepatite B , ISCOMs , Peptídeos/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Feminino , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Citotóxicos/imunologia
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