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1.
Stroke ; 39(3): 983-90, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18239163

ABSTRACT

BACKGROUND AND PURPOSE: Ischemic postconditioning has been found to decrease brain infarct area and spinal cord ischemic injury. In this study, we tested the hypothesis that ischemic postconditioning reduces global cerebral ischemia/reperfusion-induced structural and functional injury in rats. METHODS: Ten-minute global ischemia was induced by 4-vessel occlusion in male Sprague-Dawley rats. The animals underwent postconditioning consisting of 3 cycles of 15-second/15-second (Post-15/15), 30-second/30-second (Post-30/30), or 60-second/15-second (Post-60/15) reperfusion/reocclusion or 15-second/15-second reperfusion/reocclusion applied after a 45-second reperfusion (Post-45-15/15). RESULTS: Ten minutes of ischemia and 7 days of reperfusion destroyed 85.8% of CA1 hippocampal neurons and 64.1% of parietal cortical neurons. Three cycles of Post-15/15, Post-30/30, and Post-45-15/15 reperfusion/reocclusion markedly reduced neuronal loss after 7 days or 3 weeks of reperfusion and diminished the deficiency in spatial learning and memory. After reperfusion, a period of hyperperfusion followed by hypoperfusion was observed, both of which were blocked by postconditioning. The cytosolic level of cytochrome c increased significantly after 48 hours of reperfusion, and this was inhibited by Post-15/15, Post-30/30, and Post-45-15/15. However, 3 cycles of 60-second/15-second reperfusion/reocclusion failed to protect against neuronal damage, behavioral deficit, or cytochrome c translocation. CONCLUSIONS: Our data provide the first evidence that an appropriate ischemic postconditioning strategy has neuroprotective effects against global cerebral ischemia/reperfusion injury and a consequent behavioral deficit and that these protective effects are associated with its ability to improve disturbed cerebral blood flow and prevent cytochrome c translocation.


Subject(s)
Brain Ischemia/pathology , Brain Ischemia/physiopathology , Ischemic Preconditioning , Reperfusion Injury/pathology , Reperfusion Injury/physiopathology , Animals , Brain Ischemia/psychology , Cell Count , Cerebrovascular Circulation , Cytochromes c/metabolism , Cytoprotection , Cytosol/metabolism , Hippocampus/metabolism , Hippocampus/pathology , Ischemic Preconditioning/methods , Male , Maze Learning , Memory , Neurons/metabolism , Neurons/pathology , Parietal Lobe/pathology , Rats , Rats, Sprague-Dawley , Reperfusion Injury/psychology , Swimming , Time Factors
2.
Eur J Pharmacol ; 547(1-3): 125-35, 2006 Oct 10.
Article in English | MEDLINE | ID: mdl-16956605

ABSTRACT

PDE4 (phosphodiesterase-4) plays a critical role in pathogenesis of allergic asthma and chronic obstructive pulmonary disease (COPD). PDE4 inhibitors are presently under clinical development for the treatment of asthma and/or COPD. Ciclamilast, a new PDE4 inhibitor, is a piclamilast (RP 73401) structural analogue, but has a more potent inhibitory effect on PDE4 and inflammation in the airway tissues and less side effects than that of piclamilast. In this study, we elucidate primarily on the roles of compound on PDE4 enzyme in physiological and pathological processes in a mouse model of asthma. The sensitized/challenged mice were reexposed to ovalbumin and airway response to inhaled methacholine was monitored. Orally administration of ciclamilast, in a dose-dependent manner, significantly inhibited changes in lung resistance and lung dynamic compliance, as well as upregulation of cAMP-PDE activity, increase of PDE4D mRNA expression, but not PDE4B from lung tissue in the murine model. In addition, the compound dose-dependently reduced mRNA expression of eotaxin, tumor necrosis factor (TNF)-alpha and interleukin (IL)-4, but slightly increased mRNA expression of interferon (IFN)-gamma from lung tissue. Further, levels of eotaxin, TNF-alpha and IL-4, and eosinophil and neutrophil accumulation in bronchoalveolar lavage fluid were also significantly reduced. Pathological examination, goblet cell hyperplasia and inflammatory cells infiltration in lung tissue were suppressed by treatment with ciclamilast. A significant correlation was observed between the increases in PDE4D mRNA expression and airway hyperresponsiveness. These studies confirm that inhibitory effect of ciclamilast on airway hyperresponsiveness includes its inhibiting PDE4D mRNA expression, down-modulating PDE4 activity, anti-inflammation and anti-mucus hypersecretion, and ciclamilast may have therapeutic potential for the treatment of asthma.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Asthma/prevention & control , Benzamides/pharmacology , Bronchial Hyperreactivity/prevention & control , Bronchitis/prevention & control , Phosphodiesterase Inhibitors/pharmacology , Pyridines/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/genetics , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Allergens/administration & dosage , Allergens/immunology , Animals , Anti-Inflammatory Agents/pharmacology , Asthma/genetics , Asthma/immunology , Bronchial Hyperreactivity/genetics , Bronchial Hyperreactivity/immunology , Bronchitis/genetics , Bronchitis/immunology , Bronchoalveolar Lavage Fluid/chemistry , Chemokines/genetics , Chemokines/metabolism , Cyclic AMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cytokines/genetics , Cytokines/metabolism , Dexamethasone/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Eosinophilia/pathology , Eosinophilia/prevention & control , Female , Gene Expression/genetics , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Isoenzymes/metabolism , Lung/drug effects , Lung/metabolism , Lung/pathology , Methacholine Chloride/administration & dosage , Methacholine Chloride/immunology , Mice , Mice, Inbred BALB C , RNA, Messenger/genetics , RNA, Messenger/metabolism
3.
Life Sci ; 79(22): 2077-85, 2006 Oct 26.
Article in English | MEDLINE | ID: mdl-16875702

ABSTRACT

Phosphodiesterase 4 (PDE4) isozyme plays important roles in inflammatory and immunomodulatory cells. In this study, piclamilast, a selective PDE4 inhibitor, was used to investigate the role of PDE4 in respiratory function and inflammation in a murine asthma model. Sensitized mice were challenged with aerosolized ovalbumin for 7 days, piclamilast (1, 3 and 10 mg/kg) and dexamethasone (2 mg/kg) were orally administered once daily during the period of challenge. Twenty-four hours after the last challenge, airway hyperresponsiveness to methacholine was determined by whole-body plethysmography, airway inflammation and mucus secretion by histomorphometry, pulmonary cAMP-PDE activity by HPLC, cytokine levels in bronchoalveolar lavage fluid and their mRNA expression in lung by ELISA and RT-PCR, respectively. In control mice, significant induction of cAMP-PDE activity was parallel to the increases of hyperresponsiveness, inflammatory cells, cytokine levels, mRNA expression as well as goblet cell hyperplasia. However, piclamilast dose-dependently and significantly improved airway resistance and dynamic compliance, and the maximal effect was similar to that of dexamethasone. Piclamilast treatment dose-dependently and significantly prevented the increase in inflammatory cell number and goblet cell hyperplasia, as well as production of cytokines, including eotaxin, TNFalpha and IL-4. Piclamilast exerted a weaker inhibitory effect than dexamethasone on eosinophils and neutrophils, had no effect on lymphocyte accumulation. Moreover, piclamilast inhibited up-regulation of cAMP-PDE activity and cytokine mRNA expression; the maximal inhibition of cAMP-PDE was greater than that exerted by dexamethasone, and was similar to dexamethasone on cytokine mRNA expression. This study suggests that inhibition of PDE4 by piclamilast robustly improves the pulmonary function, airway inflammation and goblet cell hyperplasia in murine allergenic asthma.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Asthma/drug therapy , Asthma/physiopathology , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Phosphodiesterase Inhibitors/therapeutic use , Animals , Cyclic AMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4 , DNA Primers , Disease Models, Animal , Interferon-gamma/genetics , Interleukin-4/genetics , Lung/pathology , Mice , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/genetics
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 23(2): 222-6, 2006 Apr.
Article in Chinese | MEDLINE | ID: mdl-16604504

ABSTRACT

OBJECTIVE: To investigate single nucleotide polymorphisms (SNPs) and the distribution of their haplotypes in caspase-8, -10 genes in Zhejiang Han nationality in China. METHODS: PCR, denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing were used to detect the SNPs in the 2nd-5th exons of caspase-10 gene, the 8th-10th exons of caspase-8 and their flanking sequences. Expectation Maximization (EM) algorithm was used for haplotype frequencies analysis and pairwise linkage disequilibrium (LD) test. RESULTS: (1) Two SNPs, A2823G and A12799G, were identified in caspase-10 gene, located in exon 2 and exon 5 respectively. A12799G was newly found with low informativeness. Three SNPs were identified in caspase-8 gene; A43466G, G51484A and G52951A were located in exon 8, exon 9 and intron 9, respectively. They do not change the primary structure of the encoded protein. (2) Linkage equilibrium was observed between A2823G in caspase-10 gene and the three sites in caspase-8 gene. A43466G and G52951A, and G51484A and G52951A in caspase-8 gene were also in linkage equilibrium. Their coefficients of disequilibrium were near 0. Whereas strong linkage disequilibrium was observed between A43466G and G51484A, because its coefficient of disequilibrium was near 1. (3) A total of 11 haplotypes were estimated within A2823G in caspase-10 gene and three sites in caspase-8 gene. A-2823/A-43466/G-51484/G-52951 was the main haplotype with a frequency of 0.3811. A-2823/A-43466/G-51484/A-52951 was the second haplotype with a frequency of 0.2536. The polymorphism information content of their haplotypes was 0.7106. CONCLUSION: The SNPs of caspase-8, -10 genes in Han Chinese of Zhejiang could be parsed into at least three different haplotype blocks. The polymorphism information content can be improved by using haplotype analysis of several SNPs.


Subject(s)
Caspase 10/genetics , Caspase 8/genetics , Polymorphism, Single Nucleotide , Alleles , Base Sequence , China/ethnology , DNA/analysis , Ethnicity/genetics , Gene Frequency , Haplotypes , Humans
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 21(6): 633-5, 2004 Dec.
Article in Chinese | MEDLINE | ID: mdl-15584000

ABSTRACT

OBJECTIVE: To investigate the single nucleotide polymorphisms (SNPs) and the distribution of their haplotypes in caspase-3 gene in Zhejiang Han nationality in China. METHODS: Denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing were used to detect the SNPs in the regulatory region and the exons 2-7 and their flanking sequences in caspase-3 gene. Expectation maximization (EM) algorithm was used for haplotype frequencies analysis and pairwise linkage disequilibrium test. RESULTS: (1) Three SNPs were identified in caspase-3 gene; the three sites C829A, A17532C and C20541T were located in 5' regulatory region, intron 4 and 3' regulatory region, respectively. (2) Strong linkage disequilibrium was found among these SNPs; site A17532C and C20541T were in complete linkage disequilibrium. (3) C-829/A-17532/C-20541 (54.3%) was the main haplotype of Zhejiang Han nationality. CONCLUSION: The above findings indicated there is strong linkage disequilibrium among the three SNPs in caspase-3 gene in Han nationality of Zhejiang province and the main haplotype of Han nationality is obviously different from that of North American.


Subject(s)
Asian People/genetics , Caspases/genetics , Haplotypes , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Caspase 3 , China/ethnology , DNA Mutational Analysis , Gene Frequency , Genotype , Humans , Introns
6.
Zhonghua Bing Li Xue Za Zhi ; 33(6): 513-7, 2004 Dec.
Article in Chinese | MEDLINE | ID: mdl-15634445

ABSTRACT

OBJECTIVE: To develop a protocol for gene rearrangement study in non-Hodgkin's lymphoma (NHL) by PCR-directed gel-scan method and to set up quantitative criteria for IgH gene rearrangement which can be applied in the follow up of lymphoma patients. METHODS: IgH gene rearrangement studies were carried out in 96 cases of B-cell NHL. The detection rate of clonality was evaluated. Sixty-five cases of IgH gene rearranged cases proven by FR3A-directed PCR and PAGE and 8 cases of benign lymphoid tissues (5 cases of reactive lymphoid hyperplasia, 3 cases of chronic tonsillitis), 5 cases of normal peripheral blood mononuclear cells were analyzed by gel-scan method and the proportion of h1/h2 (heights of peak1 and peak2 of gel-scan) was calculated. RESULTS: The detection rate of IgH gene clonality was up to 68% using primer FR3A in the 96 B-cell NHL cases. The detection rate was up to 61% using primer FR2A. With a combination of primers FR3A and FR2A, the detection rate increased to 83%. Gel-scan curve showed that the value of h1/h2 was greater than 3 in all the 65 cases with IgH gene rearranged. In the 8 benign lymphoid tissue cases showed h1/h2 < 1.5, 5 cases with normal peripheral blood mononuclear cells showed a bell-shaped curve. CONCLUSIONS: In the gel-scan curve of gene rearrangement studies in non-Hodgkin's lymphoma samples, the value of h1/h2 greater than 3 represents a true clonal proliferation. The peaks with relative heights less than 1.5 may not be significant and likely represent polyclonal cell population. A value between 1.5 and 3 however requires clinical follow-up. The success rate of rearrangement studies in B-cell NHL can be increased by using a combination of primers FR3A and FR2A.


Subject(s)
Gene Rearrangement, B-Lymphocyte, Heavy Chain , Genes, Immunoglobulin , Immunoglobulin Heavy Chains/genetics , Lymphoma, B-Cell/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , DNA Primers , Electrophoresis, Gel, Two-Dimensional , Female , Humans , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell, Marginal Zone/genetics , Lymphoma, B-Cell, Marginal Zone/immunology , Lymphoma, B-Cell, Marginal Zone/pathology , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Polymerase Chain Reaction
7.
Zhonghua Xue Ye Xue Za Zhi ; 25(10): 583-7, 2004 Oct.
Article in Chinese | MEDLINE | ID: mdl-15634589

ABSTRACT

OBJECTIVE: To investigate the rate of dual rearrangements of lymphocytic antigen receptor genes in non-Hodgkin lymphomas (NHL) and its pathogenesis and pathologic significance. METHODS: PCR analysis of monoclonal, polyclonal and dual rearrangements of IgH and TCR gamma, TCR beta genes was carried out in 125 cases of NHL to evaluate the rate of dual rearrangements, immunohistochemistry was performed for a Ki67 protein expression in 117 cases and the proliferation index was calculated. The relationship between antigen receptor gene rearrangements and proliferation index was analyzed. RESULTS: Combination of the two pairs of IgH gene primers with the multiplex PCR for TCR gamma and TCR beta gene revealed dual rearrangements in 8% (8/96) of B-NHL, 17% (5/29) of T-NHL. In B cell NHL, IgH gene monoclonal, dural and polyclonal rearrangements were identified in 65, 8 and 15 cases respectively, while in T-cell NHL, they were in 15, 5 and 9 cases, respectively. There was no significant difference between proliferation index and monoclonal, dual, polyclonal rearrangements in both B-NHL and T-NHL by One-way test. CONCLUSION: Dual rearrangements in NHL are not rare and have no relationship with proliferation index.


Subject(s)
Gene Rearrangement , Lymphoma, Non-Hodgkin/pathology , Receptors, Antigen/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Carrier Proteins/genetics , Cell Proliferation , Child , Female , Genes, T-Cell Receptor gamma/genetics , Humans , Immunohistochemistry , Ki-67 Antigen/metabolism , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/pathology , Lymphoma, Non-Hodgkin/genetics , Lymphoma, Non-Hodgkin/metabolism , Lymphoma, T-Cell/genetics , Lymphoma, T-Cell/metabolism , Lymphoma, T-Cell/pathology , Male , Middle Aged , Polymerase Chain Reaction , Young Adult
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