RESUMO
Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is influenced by genetic factors. The genetic signal rs10516526 in the glutathione S-transferase C-terminal domain containing (GSTCD) gene is a highly significant and reproducible signal associated with lung function and COPD on chromosome 4q24. In this study, comprehensive bioinformatics analyses and experimental verifications were detailly implemented to explore the regulation mechanism of rs10516526 and GSTCD in COPD. The results suggested that low expression of GSTCD was associated with COPD (p = 0.010). And C-Jun and CREB1 transcription factors were found to be essential for the regulation of GSTCD by rs80245547 and rs72673891. Moreover, rs80245547T and rs72673891G had a stronger binding ability to these transcription factors, which may promote the allele-specific long-range enhancer-promoter interactions on GSTCD, thus making COPD less susceptible. Our study provides a new insight into the relationship between rs10516526, GSTCD, and COPD.
RESUMO
Ulcerative colitis (UC), a bowel disease with signiï¬cant morbidity, is associated with inflammation. In this study, the effect of Qingchang Huashi granule (QCHS) on UC and its underlying mechanisms were explored using both animal and cell culture experiments. A rat UC model was induced with trinitro-benzene-sulfonic acid (TNBS), concentrations of the cytokines IL-1α, IL-6, IL-8, IL-1ß, and TNF-α were signiï¬cantly up-regulated and the concentrations of IL-4, IL-10, and IL-13 were signiï¬cantly down-regulated compared with the control group (P < 0.05). In contrast, the QCHS and salicylazosulfapyridine (SASP) groups reversed these modulations (P < 0.05). A UC cell model in HT-29 cells was generated using TNF-α combined with lipopolysaccharide treatment. Cells treated with QCHS were used to investigate the possible mechanisms. The expression of apoptosis-related proteins, including Bax/Bcl-2, caspase-3, caspase-9, Fas/Fas-L, and Rafl in the QCHS and SASP groups, were significantly lower than that in the control group in both animal and cell experiments (P < 0.05). In addition, the in vitro results indicate changes in these indicators mediate the MEK/ERK signaling pathways via SGK1. Our results suggested that QCHS could be beneficial in preventing UC progression as an alternative drug for UC treatment.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/enzimologia , Medicamentos de Ervas Chinesas/uso terapêutico , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Inativação Gênica , Células HT29 , Humanos , Proteínas Imediatamente Precoces/metabolismo , Lipopolissacarídeos , Masculino , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-DawleyRESUMO
BACKGROUND: Heterogeneity of COPD results in different therapeutic effects for different patients receiving the same treatment. COPD patients need to be individually treated according to their own characteristics. The purpose of this study was to explore the differences in different CT phenotypic COPD by molecular metabolites through the use of metabolomics. METHODS: According to the characteristics of CT imaging, 42 COPD patients were grouped into phenotype E (n=20) or phenotype M (n=24). Each COPD patient received tiotropium bromide powder for inhalation for a therapeutic period of 3 months. All subjects were assigned into phenotype E in pre-therapy (EB, n=20), phenotype E in post-therapy (EA, n=20), phenotype M in pre-therapy (MB, n=22), phenotype M in post-therapy (MA, n=22), or normal control (N, n=24). The method of metabolomics based on 1H nuclear magnetic resonance (1H-NMR) was used to compare the changes in serum metabolites between COPD patients and normal controls and between different phenotypes of COPD patients in pre- and post-therapy. RESULTS: Patients with COPD phenotype E responded better to tiotropium bromide than patients with COPD phenotype M in terms of pulmonary function and COPD assessment test scores. There were differences in metabolites in COPD patients vs normal control people. Differences were also observed between different COPD phenotypic patients receiving the treatment in comparison with those who did not receive treatment. The changes of metabolites involved lactate, phenylalanine, fructose, glycine, asparagine, citric acid, pyruvic acid, proline, acetone, ornithine, lipid, pyridoxine, maltose, betaine, lipoprotein, and so on. These identified metabolites covered the metabolic pathways of amino acids, carbohydrates, lipids, genetic materials, and vitamin. CONCLUSION: The efficacy of tiotropium bromide on COPD phenotype E is better than that of phenotype M. Metabolites detected by 1H-NMR metabolomics have potentialities of differentiation of COPD and healthy people, discrimination of different COPD phenotypes, and giving insight into the individualized treatment of COPD.
Assuntos
Espectroscopia de Ressonância Magnética/métodos , Metabolômica/métodos , Fenótipo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Adulto , Idoso , Broncodilatadores/administração & dosagem , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Valores de Referência , Testes de Função Respiratória , Medição de Risco , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
Background: Previous studies have suggested that ß2-adrenergic receptor (ADRB2) is associated with COPD. However, the role of genetic polymorphisms in ADRB2 on COPD has not been evaluated yet. Methods: In this study, SNaPshot genotyping, luciferase assay, chromatin immunoprecipitation and real-time polymerase chain reaction were adopted to investigate the association between ADRB2 genetic polymorphisms and COPD, comprehensively. Results: One single nucleotide polymorphism (rs12654778), located upstream of ADRB2, showed a significant association with COPD by the logistic regression analysis after adjusting for age, sex and smoking history (p=0.04) in 200 COPD patients and 222 controls from southwest Chinese population. Furthermore, the luciferase assay indicated that rs12654778-A allele reduced the relative promoter activity by ~26% compared with rs12654778-G allele (p=0.0034). The chromatin immunoprecipitation analysis demonstrated that rs12654778 modulated the binding affinity of transcription factor neurofibromin 1. In addition, a significantly reduced expression of ADRB2 in COPD patients was observed, compared with normal controls (p=0.017). Conclusion: Our findings suggest a previously unknown mechanism linking allele-specific effects of rs12654778 on ADRB2 expression to COPD onset, for the first time.
Assuntos
Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Receptores Adrenérgicos beta 2/genética , Adulto , Idoso , Sítios de Ligação , Estudos de Casos e Controles , Linhagem Celular , Distribuição de Qui-Quadrado , China , Feminino , Volume Expiratório Forçado , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neurofibromina 1/metabolismo , Razão de Chances , Fenótipo , Regiões Promotoras Genéticas , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptores Adrenérgicos beta 2/metabolismo , Fatores de Risco , Capacidade VitalRESUMO
BACKGROUND: Metabolomics is the global unbiased analysis of all the small-molecule metabolites within a biological system. Metabolic profiling of different high-resolution computed tomography (HRCT) phenotypes of COPD patients before and after treatment may identify discriminatory metabolites that can serve as biomarkers and therapeutic agents. PATIENTS AND METHODS: 1H nuclear magnetic resonance spectroscopy (1H-NMR)-based metabolomics was performed on a discovery set of plasma samples from 50 patients with stable COPD. Patients were assigned into two groups on the basis of HRCT findings including phenotype E (n=22) and phenotype M (n=28). After budesonide-formoterol treatment (160/4.5 µg ×2 inhalations twice daily for 3 months), clinical characteristics and metabolites were then compared between phenotype E pretreatment and posttreatment, phenotype M pretreatment and posttreatment, phenotype E pretreatment and phenotype M pretreatment, and phenotype E posttreatment and phenotype M posttreatment. RESULTS: Inhaled budesonide-formoterol therapy for both phenotype E (emphysema without bronchial wall thickening) and phenotype M (emphysema with bronchial wall thickening) was effective. However, phenotype E and phenotype M were different in response to therapy. Patients with phenotype M in response to therapeutic effects were significantly greater compared with phenotype E. Certain metabolites were identified, which were closely related to the treatment and phenotype. Metabolic changes in phenotype E or phenotype M after treatment may be involved with adenosine diphosphate (ADP), guanosine, choline, malonate, tyrosine, glycine, proline, l-alanine, l-valine, l-threonine leucine, uridine, pyruvic acid, acetone and metabolism disturbance. Metabolic differences between phenotype E and phenotype M in pretreatment and posttreatment covered glycine, d-glucose, pyruvic acid, succinate, lactate, proline, l-valine and leucine. CONCLUSION: Bronchial wall thickening in COPD may be an indicator for predicting the better response to the treatment with bronchodilator and corticosteroid. The identification of metabolic alterations provides new insights into different HRCT phenotypes and therapeutic assessment of COPD.
Assuntos
Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Combinação Budesonida e Fumarato de Formoterol/uso terapêutico , Pulmão/efeitos dos fármacos , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tomografia Computadorizada por Raios X , Administração por Inalação , Idoso , Biomarcadores/metabolismo , Estudos Transversais , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Resultado do TratamentoRESUMO
Peripheral muscle dysfunction is an important complication in patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to explore the relationship between the levels of peroxisome proliferator-activated receptor α (PPARα) mRNA expression and the respiratory function and ultrastructure of mitochondria in the vastus lateralis of patients with COPD. Vastus lateralis biopsies were performed on 14 patients with COPD and 6 control subjects with normal lung function. PPARα mRNA levels in the muscle tissue were detected by real-time PCR. A Clark oxygen electrode was used to assess mitochondrial respiratory function. Mitochondrial number, fractional area in skeletal muscle cross-sections, and Z-line width were observed via transmission electron microscopy. The PPARα mRNA expression was significantly lower in COPD patients with low body mass index (BMIL) than in both COPD patients with normal body mass index (BMIN) and controls. Mitochondrial respiratory function (assessed by respiratory control ratio) was impaired in COPD patients, particularly in BMIL. Compared with that in the control group, mitochondrial number and fractional area were lower in the BMIL group, but were maintained in the BMIN group. Further, the Z-line became narrow in the BMIL group. PPARα mRNA expression was positively related to mitochondrial respiratory function and volume density. In COPD patients with BMIN, mitochondria volume density was maintained, while respiratory function decreased, whereas both volume density and respiratory function decreased in COPD patients with BMIL. PPARα mRNA expression levels are associated with decreased mitochondrial respiratory function and volume density, which may contribute to muscle dysfunction in COPD patients.
Assuntos
Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , PPAR alfa/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , RNA Mensageiro/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Doença Pulmonar Obstrutiva Crônica/genéticaRESUMO
BACKGROUND: Heme oxygenase-1 (HO-1) plays a protective role as an antioxidant in the lung, and HO-1 gene promoter polymorphism has been shown to be associated with the severity and prognosis of COPD patients. N-acetylcysteine (NAC), an antioxidant/mucous modifier, has shown an uncertain benefit in COPD patients. We hypothesized that this polymorphism could be associated with the effectiveness of oral NAC. METHODS: A total of 368 patients with COPD were recruited and the polymorphisms of their HO-1 gene promoter were classified into three subclasses according to the number of (GT)n repeats, as previously reported: class S (<27 (GT)n repeats), class M (27-32 (GT)n repeats), and class L (>32 (GT)n repeats). These subjects were then classified as L+ group (with the L allele: L/L, L/M, L/S) and L- group (without the L allele: M/M, M/S, S/S). All the patients were allocated to standard therapy plus NAC 600 mg bid over a 1-year period and were observed over that year. RESULTS: The L- group saw improvements in forced expiratory volume in 1 second (FEV1) (from 1.44±0.37 to 1.58±0.38, P=0.04) and FEV1% predicted (from 56.6±19.2 to 59.7±17.2, P=0.03). No improvement was found in forced vital capacity of each group and the decline of forced vital capacity in both of the groups was not statistical significant. The number of yearly COPD exacerbations of the L- group was 1.5±0.66 which was lower than the 2.1±0.53 of the L+ group (P<0.01). For the changes of St George's Respiratory Questionnaire (SGRQ) score, only the activity score of the L- group was more significant than that of the L+ group (P=0.02). The improvement of the outcome of 6-minute walking distance test in L- group (from 290.1±44.9 meters to 309.7±46.9 m) was higher than that in the L+ group (from 289.7±46.2 m to 300.3±44.2 m) (P=0.03). CONCLUSION: A 600 mg bid oral NAC treatment for 1-year on COPD patients without the L allele can improve the FEV1, FEV1% predicted, the SGRQ activity score, and the result of 6-minute walking distance test, and the exacerbation rate of the L allele carrier in COPD patients is much higher than in the COPD patients without the L allele.
Assuntos
Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Heme Oxigenase-1/genética , Repetições de Microssatélites/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Administração Oral , Idoso , Alelos , DNA/genética , Relação Dose-Resposta a Droga , Feminino , Genótipo , Heme Oxigenase-1/metabolismo , Humanos , Masculino , Doença Pulmonar Obstrutiva Crônica/diagnósticoRESUMO
BACKGROUND: The role of the antioxidant N-acetylcysteine (NAC) in the treatment of chronic obstructive pulmonary disease (COPD) has not been clarified as yet. In early studies, we found that the proportion of smokers with COPD having extremely slow/slow microsomal epoxide hydrolase (EPHX1) enzyme activity is significantly higher than that in healthy smokers. The purpose of this study was to evaluate whether different EPHX1 enzyme activity is related to differential therapeutic effects of treatment with NAC in COPD. METHODS: A total of 219 patients with COPD were randomly allocated to an extremely slow/slow EPHX1 enzyme activity group (n=157) or a fast/normal EPHX1 enzyme activity group (n=62) according to their EPHX1 enzyme activity. Both groups were treated with NAC 600 mg twice daily for one year. The main study parameters, including forced expiratory volume in one second (FEV1), St George's Respiratory Questionnaire (SGRQ), and yearly exacerbation rate, were measured at baseline and at 6-month intervals for one year. RESULTS: Both FEV1 and SGRQ symptom scores were improved after treatment with NAC in the slow activity group when compared with the fast activity group. Further, changes in FEV1 and SGRQ symptom score in patients with mild-to-moderate COPD were more significant than those in patients with severe-to-very severe COPD. The yearly exacerbation rates were reduced in both groups, but the reduction in the slow activity group was significantly lower than in the fast activity group. CONCLUSION: NAC treatment in COPD patients with extremely slow/slow EPHX1 enzyme activity improves FEV1 and the SGRQ symptom score, especially in those with mild-to-moderate COPD, and polymorphism in the EPHX1 gene may have a significant role in differential responses to treatment with NAC in patients with COPD.
Assuntos
Acetilcisteína/administração & dosagem , Antioxidantes/administração & dosagem , Epóxido Hidrolases/genética , Pulmão/efeitos dos fármacos , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Idoso , Progressão da Doença , Esquema de Medicação , Epóxido Hidrolases/metabolismo , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Farmacogenética , Fenótipo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Espirometria , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To explore the relationship between the mRNA expression level of mitochondrial cytochrome oxidase and the maternal inheritance of asthma. METHODS: From January to December 2009, 220 asthma patients, 162 patient kins and 260 healthy subjects were recruited from Departments of Respiratory Critical Care Medicine and Pediatric Medicine at First Affiliated Hospital, Kunming Medical College. Lung function tests were performed and serum IgE level measured. The polymorphism of mitochondrial cytochrome oxidase gene polymorphisms was detected by direct sequencing. And the peripheral level of COX mRNA was measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: No significant difference existed in age, gender among 3 groups. For 3 groups, the first second forced expiratory volume (FEV1)/forced vital capacity (FVC) were 90.6 ± 6.2, 92.3 ± 2.3, 102.3 ± 2.3 and FEV1 percentage of expected value (FEV1%) were (82.9 ± 10.8)%, (94.8 ± 5.4)% and (98.3 ± 8.6)% respectively. The lung function was not significant difference among three groups. The mRNA expression level of mitochondrial cytochrome oxidase in peripheral blood were 0.357 ± 0.217, 0.637 ± 0.473 and 0.975 ± 0.260 in the asthma, kin and control groups respectively. No significant difference existed in the expression level of COX3 mRNA among 3 groups (F = 21.45, P = 0.012). The serum level of lgE was the highest for the asthma patients. And it was significantly higher in the asthma group than that in the control group ((283.6 ± 62.4) vs (52.3 ± 13.7) µg/L, F = 48.31, P < 0.05). Moreover, the serum level of IgE was significantly higher in the kin group than that in the control group ((116.4 ± 57.5) vs (52.3 ± 13.7) µg/L, F = 20.45, P < 0.05). However, there was a negative correlation between the mRNA expression level of mitochondrial cytochrome oxidase and the serum level of IgE among 3 groups. CONCLUSIONS: The down-regulated mRNA expressin of mitochondrial cytochrome oxidase may participate in allergic inflammation by regulating the level of IgE. And the maternal inheritance of asthma is in effect.
Assuntos
Asma/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Predisposição Genética para Doença , RNA Mensageiro/genética , Humanos , RNA Mitocondrial , Testes de Função Respiratória , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: To conduct a preliminary proteomic study of chronic obstructive pulmonary disease (COPD) with peripheral skeletal muscle atrophy. METHODS: A total of 16 COPD patients and 8 aged-matched persons because of bone fractures were recruited in First Hospital Affiliated to Kunming Medical College from February to July in 2010. According to body mass index, fat free mass index, quadriceps femoris perimeter and quadriceps femoris active contraction, they were divided into those with muscle atrophy (group A, n = 8) and those without (group B, n = 8). There were 6 males and 2 females with an average age of (70 ± 8) years in the group A and 5 males and 3 females with an average age of (74 ± 8) years in the group B. And the control group had 6 males and 2 females with an average age of (72 ± 6) years. All samples of total quadriceps protein were separated by two-dimensional gel electrophoresis. The abnormal protein points on electrophoresis were compared by PDQuest image software. And the differential protein expression was detected. Then the corresponding peptide quality fingerprint spectrum was analyzed by mass spectrometer. Finally the differential protein points were partially detected by a search of database. RESULTS: The two-dimensional gel electrophoresis yielded an excellent profile of resolution and repeatability. And 12 proteins likely to cause skeletal muscle atrophy in COPD were identified. Among them, 8 proteins belonged to structural proteins (actin alpha cardiac muscle isoform CRA_c, myosin regulatory light chain 2, ventricular/cardiac muscle isoform, myoglobin isoform myosin heavy polypeptide 7 cardiac muscle beta isoform CRA_c, actin, alpha skeletal muscle, actin alpha cardiac muscle isoform CRA_b, hemoglobin alpha 1 globin chain & myosin light chain 6B) and 4 proteins were of functional proteins (chain A, crystal structure of human enolase; troponin T, slow skeletal muscle isoform alpha, carbonate anhydrase, troponin T & slow skeletal muscle isoform b). CONCLUSIONS: COPD patients are often accompanied with obvious peripheral skeletal muscle atrophy. It may be caused by quantitative or qualitative changes of peripheral skeletal structural and functional proteins.
Assuntos
Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Feminino , Humanos , Masculino , Atrofia Muscular/complicações , Proteoma/análise , Proteômica , Doença Pulmonar Obstrutiva Crônica/complicaçõesRESUMO
BACKGROUND AND OBJECTIVE: Adrenergic ß2 receptors (ADRB2) play an important role in regulating pulmonary function. Many previous studies have investigated possible associations between polymorphisms in the ADRB2 gene and asthma, but have yielded conflicting results. Furthermore, little is known regarding the possible role of the Arg19Cys polymorphism in susceptibility to asthma among Chinese. METHODS: This case-control association study involved 238 patients with asthma and 265 healthy subjects from a Han population in southwest China. For all subjects, the 5' leader cistron Arg19Cys, Arg16Gly and Gln27Glu polymorphisms in the ADRB2 gene were characterized by direct sequencing. Genotype, allele and haplotype frequencies were determined. In addition, to evaluate the association between the ADRB2 polymorphisms and lung function, bronchodilator response to inhaled ß2 agonists (400 µg of albuterol) was assessed in the asthmatic patients. RESULTS: There were no significant differences in genotype or allele frequencies for the three ADRB2 polymorphisms between the two cohorts. The Arg19/Arg16/Gln27 haplotype was more frequent among asthmatic patients than control subjects (odds ratio 2.24, 95% confidence interval (CI): 1.05-4.73, P=0.04). Moreover, the Arg19/Cys19 genotype was associated with a lower FEV1% (mean difference -4.5, 95% CI: -12.5 to 3.6, P=0.02) and FEV1/FVC (mean difference 8.9, 95% CI: 8.5-9.4, P=0.01). The bronchodilator response to albuterol was also marginally lower in individuals who were homozygous for the Arg19 genotype (mean difference 4.2, 95% CI: 3.7-4.8, P=0.03). CONCLUSIONS: The Arg19/Cys19 genotype was an independent risk factor for lower FEV1% and FEV1/FVC. Asthmatic patients with the Arg19/Arg19 genotype showed decreased responsiveness to albuterol. Furthermore, the Arg19/Arg16/Gln27 haplotype may contribute to increased susceptibility to asthma in the Chinese population.
Assuntos
Povo Asiático/genética , Asma/etnologia , Asma/genética , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 2/genética , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Albuterol/uso terapêutico , Arginina , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Estudos de Casos e Controles , China/epidemiologia , Feminino , Volume Expiratório Forçado , Regulação da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Glutamina , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaAssuntos
Glutationa S-Transferase pi/genética , Doença Pulmonar Obstrutiva Crônica/genética , Povo Asiático/genética , Predisposição Genética para Doença , Humanos , Metanálise como Assunto , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/etnologia , População Branca/genéticaRESUMO
BACKGROUND: Recent studies have proposed that the serine protease inhibitor E2 (SERPINE2) was a novel susceptibility gene for chronic obstructive pulmonary disease (COPD) in Caucasians. However, this issue still remained controversial. Additional evidences from populations with different environments and/or genetic backgrounds, such as East Asian, would be helpful to elucidate the issue. METHODS: In this study, five proposed causal SNPs in SERPINE2 were genotyped in 327 COPD patients and 349 controls, all of which belonged to the Han population sampled from Southwest China. The frequency of each SNP was compared both individually and in combination between patients and controls. The potential relationship between these SNPs and severity of COPD was also investigated. RESULTS: Three SNPs (rs3795877, rs6747096, and rs3795879) showed complete linkage disequilibrium (r2 = 1), and the minor allele frequencies were 13.0% and 12.9% in case and control cohorts, respectively, with no significant difference observed (P = 0.96). We also failed to observe any significant correlation between these SNPs and COPD severity (P = 0.67). The other two SNPs (rs7579646 and rs840088) also presented a similar pattern. Moreover, four major haplotypes were observed in our sample but none showed a significant difference between case and control groups (P > 0.1). CONCLUSION: Our results failed to obtain the evidence that these SNPs in SERPINE2 contributed to the COPD susceptibility in the Han Chinese population.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Doença Pulmonar Obstrutiva Crônica/genética , Receptores de Superfície Celular/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Povo Asiático , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Nexinas de Proteases , Serpina E2RESUMO
OBJECTIVE: To observe the efficacy of combination therapy with inhaled salmeterol/fluticasone and tiotropium in reducing the frequency of acute episodes of symptom exacerbation and improving lung function and health status in chronic obstructive pulmonary disease (COPD). METHODS: One hundred and twenty-six patients (M/F: 92/34) with COPD were treated in a randomised, parallel-group, controlled study with salmeterol/fluticasone (50/250 microg) twice daily and tiotropium 18 microg once daily (n = 33, M/F: 23/10); salmeterol/fluticasone (50/250 microg) twice daily (n = 32, M/F: 24/8); or tiotropium 18 microg once daily (n = 32, M/F: 23/9) for 12 months. Patients in the blank control group (n = 29, M/F: 22/7) did not receive any inhaled anticholinergic drugs, long-acting beta(2) agonists or glucocorticoid therapy. Intention-to-treat analysis (n = 161) and per-protocol analysis (n = 126, age 45 - 71 years) were performed. RESULTS: Three active treatments significantly improved symptoms and health status. The use of rescue medication in the combination group [1 (0 - 7) time, 95% CI] was significantly decreased compared with those in the blank group [2 (0 - 29) times], salmeterol/fluticasone alone [2 (0 - 13) times], tiotropium alone [1 (0 - 11) time], F = 4.914, P < 0.01. The frequency of exacerbations in the combination group was (0.7 +/- 0.5) time, significantly lower than that in the blank group [(1.5 +/- 0.9) times], salmeterol/fluticasone alone [(1.2 +/- 0.6) times], and tiotropium alone [(1.1 +/- 0.5) times], F = 8.513, P < 0.01. The FEV(1) in the combination group after the trial was (1.19 +/- 0.03) L, significantly improved compared to that before treatment (1.09 +/- 0.04) L, a 9.5% increase, which was greater than the blank (0.9%), tiotropium alone (8.2%) and salmeterol/fluticasone alone (6.3%), t = -5.024 to -15.58, P < 0.01. CONCLUSION: Combination therapy with salmeterol/fluticasone and tiotropium leads to better control of symptoms and improved lung function, with no greater risk of side-effects, as compared to salmeterol/fluticasone or tiotropium alone in the treatment of COPD.
Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/análogos & derivados , Androstadienos/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Derivados da Escopolamina/uso terapêutico , Administração por Inalação , Idoso , Albuterol/administração & dosagem , Albuterol/uso terapêutico , Androstadienos/administração & dosagem , Quimioterapia Combinada , Feminino , Fluticasona , Humanos , Masculino , Pessoa de Meia-Idade , Xinafoato de Salmeterol , Derivados da Escopolamina/administração & dosagem , Brometo de TiotrópioRESUMO
OBJECTIVE: To study the diagnostic and prognostic value of procalcitonin (PCT), common inflammatory markers combining with scores for estimating organ failure of infection related organs (SOFA) in patients with sepsis in early stage. METHODS: Patients were observed continuously in a perspective study with diagnostic tests. According to the definition of ACCP/SCCM Consensus Conference, patients were classified into 5 groups, including non-systemic inflammatory response syndrome (SIRS) (control) group, SIRS group, sepsis group, severe sepsis group and septic shock group. Indexes of inflammation, SOFA and concentration of PCT were determined at 24 hours, and their correlation was analyzed. RESULTS: Two hundred and eight patients were enrolled, including 59 in non-SIRS group, 57 in SIRS group, 52 in sepsis group, 28 in severe sepsis group and 12 in septic shock group. PCT concentrations were positively correlated with the severity of sepsis. Spearman's correlation coefficient was 0.909 (P=0.000). According to the receiver operating characteristic curves (ROC-curves) analysis principle, ROC curves were drawn and areas under these curves (AUC) was calculated. In the diagnosis of sepsis, AUC values were 0.936+/-0.020 for PCT, 0.973+/-0.011 for SOFA (both P=0.000). The best cutoff values in the diagnosis of sepsis were 0.375 microg/L for PCT, and 3. 5 for SOFA score. The Youden index of PCT and SOFA scores was 0.808 and 0.801, respectively. Binary Logistic regression analysis confirmed that PCT and SOFA score were highly correlated with sepsis (OR=84.794,10.761, respectively, both P=0.000) after eliminating confusion factors including age and C-reactive protein (CRP) etc.. PCT and SOFA score could be used to predict the incidence of sepsis. SOFA score was the best prognostic indicator of sepsis (OR=2.084, P=0.0002). CONCLUSION: The traditional inflammatory markers and CRP are useful parameters to differentiate SIRS from non-SIRS, but are not reliable indicators for the early diagnosis in patients with sepsis. PCT is more specific indicator in early diagnosis of sepsis to differentiate from SIRS. PCT combining with SOFA score can be used to predict the incidence of sepsis. SOFA score can be used to define objectively the severity of sepsis according to PCT level and is helpful for estimation of prognosis in patients with sepsis.
Assuntos
Biomarcadores/sangue , Calcitonina/sangue , Precursores de Proteínas/sangue , Sepse/diagnóstico , Peptídeo Relacionado com Gene de Calcitonina , Diagnóstico Precoce , Humanos , Prognóstico , Estudos Prospectivos , Sepse/sangueRESUMO
BACKGROUND: Recent studies have suggested that susceptibility to chronic obstructive pulmonary disease (COPD) might be related to the length polymorphism of (GT)(n) repeat in the 5'-flanking region of heme oxygenase-1 (HOX-1) gene. However, there has been no research about the relationship between the polymorphism of HOX-1 gene and severity of COPD. METHODS: The polymorphism of HOX-1 gene in 452 patients with COPD from Han population in Southwest China was analysed by fragment analysis. The frequencies of the HOX-1 genotype were compared with the stage of COPD of each patient. RESULTS: The HOX-1 genotypes were classified into two groups: group I were individuals with class L allele (the number of GT = 32 repeats), and group II were those without class L allele (the number of GT < 32 repeats). The genotypic frequency of the HOX-1 group I was significantly higher than group II in the very severe COPD patients (36.8% vs 22.4%, P < 0.01, OR = 2.0, 95% CI 1.3 - 3.1), while the genotypic frequency of the HOX-1 group II was lower in the mild COPD (16.0% vs 26.0%, P = 0.02, OR = 0.5, 95% CI 0.3 - 0.9). However, in moderate and severe stages COPD, there were similar genotypic frequencies between HOX-1 group I and group II. CONCLUSIONS: Genetic polymorphism in HOX-1 is associated with the severity of COPD in Southwest China. COPD patients with class L allele may be susceptible to develop very severe COPD. Conversely, the COPD patients without class L allele may be more easily stabilized on mild COPD.
Assuntos
Heme Oxigenase-1/genética , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/enzimologia , Adulto , Idoso , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologiaRESUMO
Recent studies have proposed that susceptibility to chronic obstructive pulmonary disease (COPD) might be related with the polymorphisms of some genes encoding antioxidant enzymes, such as heme oxygenase-1 (HOX-1) and microsomal epoxide hydrolase (mEPH). We examined these polymorphisms in 256 patients with COPD and 266 healthy smokers from Han population in Southwest China. The frequencies of each allele were compared both individually and in combination between patients and controls. Polymorphisms of HOX-1 gene could be grouped into three classes: S (
Assuntos
Epóxido Hidrolases/genética , Heme Oxigenase-1/genética , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Alelos , China , Primers do DNA/química , Éxons , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Reação em Cadeia da Polimerase , Análise de Sequência de DNARESUMO
OBJECTIVE: To investigate the relationship between the polymorphism of beta 2 adrenergic receptor (beta 2 AR) at loci 16, 27 and the nocturnal asthma phenotype. METHODS: Forty-nine asthmatic patients were divided into nocturnal asthmatic group (n = 25) and non-nocturnal asthmatic group(n = 24) by their peak expiratory flow rates (PEFR). The genotypes at loci 16, 27 of beta 2 AR were delineated by PCR product sequencing. Then the relationships of beta 2 AR genotypes with the PEFR, FEV1 and the situation of drug use in the two groups were analyzed. RESULTS: By the criteria of overnight decrements in PEFR, the nocturnal asthma group had a mean overnight decrement in PEFR of 33.6%, compared to 7.0% for the non-nocturnal asthma group (P < 0.001). The mean values of daytime baseline percent predicted forced expiratory volume in 1 s (FEV1) were 73.7% and 85.8% for the nocturnal and non-nocturnal cohorts, respectively (P < 0.001). The frequency of the Gly16 allele was 56.0% in the nocturnal group, compared to 22.9% in the non-nocturnal group (P < 0.05). The results from comparison of the two cohorts as to homozygosity for Gly16, homozygosity for Arg16, or heterozygosity were also consistent with the segregation of Gly16 with nocturnal asthma. There was no significant difference in the frequency of polymorphisms at locus 27 (Gln27 or Glu27). CONCLUSION: The Gly16 polymorphism of beta 2 AR appears to be associated with nocturnal asthma.