RESUMEN
We hypothesized that the adipose-derived mesenchymal stem cells (ADMSCs), which secrete high amounts of soluble molecules, such as soluble tumor necrosis factor receptor 1 (sTNFR1), may ameliorate sepsis-induced acute lung injury (ALI). A total of 120 male adult Sprague-Dawley rats were separated into four groups: the sham control (SC), sepsis induced by cecal ligation and puncture (CLP), CLP-ADMSCs, and CLP-sTNFR1 small interfering RNA (siRNA) groups; CLP groups underwent CLP and then received 1 × 106 ADMSCs with or without knockdown of sTNFR1 intravenously at 1 hr after surgery. Rats were killed at 3, 6, 24, and 48 hr after the SC or CLP procedures. 5-Ethynyl-2'-deoxyuridine-labeled ADMSCs extensively colonized the lungs at 6, 24, and 72 hr after injection. The lung wet/dry (W/D) weight ratios in the CLP group were higher than those in SC group; however, ADMSCs ameliorated the W/D weight ratios following CLP, and this effect was abolished by sTNFR1 siRNA treatment. The levels of serum sTNFR1 and interleukin-10 (IL-10) were higher in the CLP-ADMSCs group and lower in the SC group than in other groups; interestingly, these levels were higher in CLP and CLP-sTNFR1 siRNA groups than in SC group. Tumor necrosis factor-α and IL-6 levels increased significantly after CLP, and ADMSCs could alleviate these changes, but the effect was weakened by sTNFR1 siRNA treatment. The lung cell apoptosis and edema levels were consistent with IL-6 levels among all groups. Therapeutically administered ADMSCs secrete sTNFR1, which most likely protects against ALI in septic rats by ameliorating inflammation and lung edema.
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Human UDP-glucuronosyltransferase 1A1 (UGT1A1) is a unique enzyme involved in bilirubin conjugation. We previously characterized the hepatic expression of transcription factors affecting UGT1A1 expression during development. Accordingly, in this study, we characterized the ontogenetic expression of hepatic UGT1A1 from the perspective of epigenetic regulation. We observed significant histone-3-lysine-4 dimethylation (H3K4me2) enrichment in the adult liver and histone-3-lysine-27 trimethylation (H3K27me3) enrichment in the fetal liver, indicating that dynamic alterations of histone methylation were associated with ontogenetic UGT1A1 expression. We further showed that the transcription factor hepatocyte nuclear factor 1α (HNF1A) affects histone modifications around the UGT1A1 locus. In particular, we demonstrated that by recruiting HNF1A the cofactors mixed-lineage leukemia 1, the transcriptional coactivator p300, and nuclear receptor coactivator 6 aggregate at the UGT1A1 promoter, thereby regulating histone modifications and subsequent UGT1A1 expression. In this study, we proposed new ideas for the developmental regulation of metabolic enzymes via histone modifications, and our findings will potentially contribute to the development of age-specific therapies.
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Regulación Enzimológica de la Expresión Génica/fisiología , Glucuronosiltransferasa/genética , Código de Histonas/fisiología , Histonas/metabolismo , Hígado/crecimiento & desarrollo , Adulto , Anciano , Bilirrubina/metabolismo , Metilación de ADN/fisiología , Epigénesis Genética/fisiología , Femenino , Feto , Glucuronosiltransferasa/metabolismo , Células Hep G2 , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Hígado/enzimología , Masculino , Persona de Mediana Edad , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Coactivadores de Receptor Nuclear/metabolismo , Regiones Promotoras Genéticas/genética , Factores de Transcripción p300-CBP/metabolismoRESUMEN
PURPOSE: Complete or partial inactivity of UGT1A1, the unique enzyme responsible for bilirubin glucuronidation, is commonly associated with hyperbilirubinemia. We investigated the dynamic expression of UGT1A1, and that of the transcription factors (TFs) involved in its developmental regulation, during human hepatic growth in Han Chinese individuals. METHODS: Eighty-eight prenatal, pediatric, and adult liver samples were obtained from Han Chinese individuals. Quantitative real-time polymerase chain reaction was used to evaluate mRNA expression of UGT1A1 and TFs including PXR, CAR, HNF1A, HNF4A, PPARA, etc. UGT1A1 protein levels and metabolic activity were determined by western blotting and high-performance liquid chromatography. Direct sequencing was employed to genotype UGT1A1*6 (211GËA) and UGT1A1*28 (TA6ËTA7) polymorphisms. RESULTS: UGT1A1 expression was minimal in prenatal samples, but significantly elevated during pediatric and adult stages. mRNA and protein levels and metabolic activity were prominently increased (120-, 20-, and 10-fold, respectively) in pediatric and adult livers compared to prenatal samples. Furthermore, expression did not differ appreciably between pediatric and adult periods. Dynamic expression of TFs, including PXR, CAR, HNF1A, HNF4A, and PPARA, was consistent with UGT1A1 levels at each developmental stage. A pronounced correlation between expression of these TFs and that of UGT1A1 (P < 0.001) was observed. Moreover, UGT1A1*6 and UGT1A1*28 polymorphisms reduced levels of UGT1A1 by up to 40-60 %. CONCLUSIONS: Hepatic expression of transcription factors is associated with developmental regulation of UGT1A1 in the Han Chinese population. Moreover, UGT1A1 polymorphisms are associated with reduced expression of UGT1A1 mRNA and protein, as well as enzyme activity.
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Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Factores de Transcripción/genética , Adulto , Anciano , Pueblo Asiatico/genética , Preescolar , Femenino , Genotipo , Edad Gestacional , Humanos , Lactante , Masculino , Persona de Mediana Edad , Polimorfismo Genético , ARN Mensajero/metabolismoRESUMEN
BACKGROUND To observe and demonstrate therapeutic effects and side effects of two selective COX-2 inhibitors, imrecoxib and celecoxib, on patients with axial spondyloarthritis (axSpA) and observe the correlation between imaging scores and serum DKK-1 levels. MATERIAL AND METHODS Sixty patients with axSpA were randomly assigned to receive 200 mg imrecoxib or 200 mg celecoxib twice daily. Fifty-one patients who completed follow-up were included in the study. At baseline, week 4, and week 12, the clinical parameters, inflammatory markers (ESR, CRP), and adverse reactions were recorded. Serum DKK-1 levels were investigated by enzyme-linked immunosorbent assay. Radiographic scores were calculated by sacroiliac joint SPARCC (Spondyloarthritis Research Consortium of Canada) score method at baseline serum DKK-1 levels and week 12. RESULTS Patients in the imrecoxib group (n=25) and patients in the celecoxib group (n=26) were improved at week 4. At week 12, all clinical parameters and inflammatory markers were improved in the two groups and the differences was not statistically significant. Serum DKK-1 levels were decreased and the differences were not statistically significant. Serum DKK-1 levels in patients in the imrecoxib group at baseline were negatively correlated with all study parameters, while those in the celecoxib group had correlations with BASFI (r=-0.048, p=0.027) and Schober test (r=0.437, p=0.048), without any correlation with other clinical parameters or inflammatory markers. CONCLUSIONS Patients experienced significant improvement in disease activity, functional parameters, and inflammatory markers when treated with selective COX-2 inhibitors for 12 weeks, and the efficacy of imrecoxib was not inferior to celecoxib. Selective COX-2 inhibitors imrecoxib and celecoxib had no obvious effects on serum DKK-1 levels.
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Celecoxib/uso terapéutico , Péptidos y Proteínas de Señalización Intercelular/sangre , Pirroles/uso terapéutico , Espondiloartritis/sangre , Espondiloartritis/tratamiento farmacológico , Sulfuros/uso terapéutico , Biomarcadores/metabolismo , Celecoxib/efectos adversos , Celecoxib/farmacología , Demografía , Estudios de Seguimiento , Humanos , Inflamación/patología , Pirroles/efectos adversos , Pirroles/farmacología , Espondiloartritis/diagnóstico por imagen , Sulfuros/efectos adversos , Sulfuros/farmacología , Resultado del TratamientoRESUMEN
This study was designed to investigate effects of pargyline on histone methylation in the promoter and enhancer regions and transcription of cytochrome P450 3A4/3A7 (CYP3A4/3A7) gene. Human primary fetal liver cells were isolated, cultured and randomly divided into several groups including control, solvent, pargyline low, middle, high dose (treated with 0.6, 1.2, 2.4 mmol·L(−1)). HepG2 cells were cultured and treated with 0.03, 0.3, 3 mmol·L(−1) pargyline. After 48 hours, total RNAs were prepared from the cells to determine the expression of CYP3A m RNA in primary fetal cells and HepG2 cells with real-time quantative PCR (qPCR). HepG2 cells were cultured and then treated with 3 mmol·L(−1) pargyline for 48 hours. The chromatin immunoprecipitation (ChIP) assay was performed with dimethylation of histone H3 at lysine 4 (H3K4me2), and IgG antibodies respectively. The precipitated DNA was resuspended and used for qPCR. Primers were used to detect different regions of CYP3A4/3A7 promoter and enhancer. Occupancy of H3K4me2 was shown as percent of input DNA relative to control cells. The results suggested that pargyline has an effect on primary fetal liver cells and HepG2 cells proliferation. The level of CYP3A7 was markedly enhanced in human primary fetal liver cells by treatment with 1.2, 2.4 mmol·L(−1) of pargyline (P < 0.05, P < 0.01) and the levels of CYP3A4/3A7 were remarkably enhanced by treatment with 3 mmol·L(−1) of pargyline in HepG2 cells (P < 0.001) compared with solvent control. Occupancy of H3K4me2 on human CYP3A4 promoter (−362 to +53) and enhancer segment (−7 836 to −6 093) harbored the overlapping hepatocyte nuclear factors 4A (HNF4A) binding site compared with a negative control. Occupancy of H3K4me2 on human CYP3A7 promoter (−163 to +103) and enhancer segment (−4 054 to −3 421, −6 265 to −6 247) overlapped with glucocorticoid receptor (GR) binding site. In conclusion, the enriched H3K4me2 in the promoter and enhancer regions was induced by pargyline with HNF4A or GR binding site in CYP3A4/3A7 gene to activate the corresponding genes.
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Citocromo P-450 CYP3A/genética , Elementos de Facilitación Genéticos , Histonas/metabolismo , Metilación , Pargilina/farmacología , Regiones Promotoras Genéticas , Sitios de Unión , Células Cultivadas , Sistema Enzimático del Citocromo P-450 , ADN , Células Hep G2 , Hepatocitos/efectos de los fármacos , Humanos , Receptores de GlucocorticoidesRESUMEN
BACKGROUND: The purpose of the study was to investigate the effects of the pregnane X receptor (PXR)*1B polymorphisms on CYP3A4 enzyme activity and postoperative fentanyl consumption in Chinese patients undergoing gynecological surgery. METHODS: A total of 287 females of Han ethnicity, aged 20 to 50 years old, ASA I or II, scheduled to abdominal total hysterectomy or myomectomy under general anesthesia were enrolled. The analgesic model used was fentanyl consumption via patient-controlled intravenous analgesia (PCIA) in the post-operative period. Additionally, pain was assessed using a visual analog score (VAS). Pain scores, occurrence of adverse reactions and consumption of fentanyl were recorded during the 24 h postoperative period. The enzyme activity of CYP3A4 was evaluated by measuring the plasma ratio of 1'-hydroxymidazolam to midazolam 1 h after intravenous administration of 0.1 mg/kg midazolam. PXR genotyping was performed by direct DNA sequencing and the PXR * 1B haplotype was analyzed via PHASE V.2.1 software. RESULTS: The polymorphism frequency of PXR11156A > C/11193 T > C and 8055C > T were 49.6 and 49.3%, and the rate of PXR * 1B haplotype was 48.8% in our study. None of the pain scores, consumption of fentanyl 24 h post-operatively or enzyme activity of CYP3A4, showed differences among different genotypes. CONCLUSIONS: PXR11156A > C, PXR11193T > C, PXR8055C > T or the PXR * 1B haplotype do not appear to be important factors contributing to CYP3A4 activity and interindividual variations in postoperative fentanyl consumption in Han female patients undergoing gynecological surgery. TRIAL REGISTRATION: The DNA samples were obtained since 2007 to 2010 year in our hospital, there was no registration at that time. So this section is not applicable to our research.
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Pueblo Asiatico/genética , Fentanilo/administración & dosificación , Dolor Postoperatorio/prevención & control , Receptores de Esteroides/genética , Adulto , Alelos , Analgesia Controlada por el Paciente , China , Citocromo P-450 CYP3A/metabolismo , ADN/química , ADN/aislamiento & purificación , ADN/metabolismo , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Genotipo , Procedimientos Quirúrgicos Ginecológicos , Haplotipos , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptor X de PregnanoRESUMEN
Inflammation, demyelination, oligodendrocyte (OLG) death, and axonal degeneration are primary characteristics of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). OLGs generate myelin sheaths that surround axons, while damage to OLGs leads to demyelination and neurological functional deficit. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to effectively ameliorate clinical signs in EAE. Its therapeutic mechanism has, however, not been completely elucidated. In the present study, we found that MAT retarded the disease process, attenuated the clinical severity of EAE rats, ameliorated inflammation and demyelination, and suppressed the apoptosis of OLGs in the central nervous system (CNS) of EAE rats. In addition, MAT markedly blocked increased expression of the proNGF-p75(NTR) death signaling complex, which is known to mediate OLG death in EAE animals. At the same time, MAT also prevented a decrease in the levels of NGF and its receptor TrkA, which together mediate the cell survival pathway and differentiation of OLGs. ProNGF, NGF, and the downstream effector proteins play an important role in the growth, differentiation, and apoptosis of OLGs as well as the reparative response to neuronal damage. These findings thus indicate that MAT improves clinical severity of EAE in part by reducing OLG apoptosis via restoring the ratios of proNGF:NGF and the respective receptors p75(NTR):TrkA in vivo. Taken together, these results suggest that MAT may be a promising agent for MS treatment based on its protective effect on OLGs.
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Alcaloides/farmacología , Encefalomielitis Autoinmune Experimental/prevención & control , Factores de Crecimiento Nervioso/metabolismo , Precursores de Proteínas/metabolismo , Quinolizinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Axones/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/prevención & control , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Fármacos Neuroprotectores/farmacología , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Oligodendroglía/patología , Fitoterapia/métodos , Ratas Wistar , Sophora/química , MatrinasRESUMEN
OBJECTIVE: To determine whether ABCB1 gene polymorphisms affect the time course of action of rocuronium in Chinese patients. METHODS: This study included 105 unrelated Chinese patients undergoing general anesthesia with propofol, fentanyl, and rocuronium. Neuromuscular monitoring was performed with calibrated acceleromyography. Patients were allowed to recover spontaneously from the neuromuscular block. The time interval between the first maximum depression of the train of four (TOF) and spontaneous recovery TOF ratio of 0.25/0.7/0.8/0.9 was recorded. The Sequenom MassArray® single-nucleotide polymorphism (SNP) detection technology was used to detect the genotypes of the ABCB1 rs12720464, rs1055302. Demographic and non-genetic clinical data were also collected. RESULTS: In the present study, the mean time to spontaneous recovery of TOF ratio 0.8/0.9 in ABCB1 rs12720464 GG genotype was longer compared to that observed in ABCB1 rs12720464 AG genotype (56.77 ± 14.23 minutes vs. 49.50 ± 10.49 minutes, and 62.58 ± 18.16 minutes vs. 53.20 ± 12.56 minutes, respectively, p < 0.05). Further, the time to spontaneous recovery of TOF 0.7/0.8/0.9 in ABCB1 rs1055302 GG genotype was longer than that in ABCB1 rs1055302 AG genotype (52.00 ± 12.10 minutes vs. 44.83 ± 7.38 minutes, 55.96 ± 13.92 minutes vs. 46.83 ± 7.67 minutes, 61.66 ± 17.70 minutes vs. 49.50 ± 8.44 minutes, respectively, p < 0.05). CONCLUSION: In Chinese patients who were administered a single dose of rocuronium, the genetic variants ABCB1 rs12720464, and rs1055302 contribute to the individual< variability of time course of action.
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Androstanoles/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacología , Polimorfismo de Nucleótido Simple , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Pueblo Asiatico/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , RocuronioRESUMEN
AIMS: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a neurometabolic disease in which the degradation of γ-aminobutyric acid (GABA) is impaired. The purpose of this study was to report two novel ALDH5A1 mutations responsible for SSADH deficiency in a Chinese family and the prenatal diagnosis of an at-risk fetus with DNA sequencing. RESULTS: Genetic analysis of ALDH5A1, in a child with SSADH deficiency, parents, and 10 weeks' gestation at-risk fetus and 100 healthy unrelated volunteers, was performed. The coding sequence and the intron/exon junctions of ALDH5A1 were analyzed by bidirectional DNA sequencing. The proband was identified to have a compound heterozygous mutations with c.496T>C (p.W166R) and c.589G>A (p.V197M). Each of his parents carried a deleterious mutation. DNA sequencing of chorionic villus revealed the fetus was a carrier, but not affected, and this was confirmed after birth by genetic analysis of umbilical cord blood and urine organic acid analysis. A study in 2003 described 35 mutations of ALDH5A1 in 54 unrelated families, and the current study and systematic literature review identified nine additional novel mutations in eight unrelated families bringing the total number of unique mutations of ALDH5A1 resulting in SSADH deficiency to 44, and the 44 mutations occur from exon 1 to exon 10. No mutational hotspots or prevalent mutations were observed, and all mutations appeared vital for the function of SSADH. CONCLUSIONS: Two novel ALDH5A1 mutations likely responsible for SSADH deficiency were identified, and DNA sequencing provided an accurate diagnosis for an at-risk fetus whose sibling had SSADH deficiency.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Mutación Missense , Diagnóstico Prenatal , Succionato-Semialdehído Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Pueblo Asiatico/genética , Secuencia de Bases , China , Secuencia Conservada , Análisis Mutacional de ADN , Discapacidades del Desarrollo/enzimología , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Lactante , Masculino , Embarazo , Succionato-Semialdehído Deshidrogenasa/genéticaRESUMEN
Neuro-axonal injury in the central nervous system (CNS) is one of the major pathological hallmarks of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has recently been shown to effectively suppress EAE through an anti-inflammatory mechanism. However, whether MAT can also protect myelin/axons from damage is not known. In the present study we show that, while untreated rats developed severe clinical disease, CNS inflammatory demyelination, and axonal damage, these clinical and pathological signs were significantly reduced by MAT treatment. Consistently, MAT treatment reduced the concentration of myelin basic protein in serum and downregulated expression of ß-amyloid (Aß) and B-site APP cleaving enzyme 1 (BACE-1) in the CNS. Further, the CNS of MAT-treated rats exhibited increased expression of brain-derived neurotrophic factor (BDNF), an important factor for neuronal survival and axonal growth. Together, these results demonstrate that MAT effectively prevented neuro-axonal injury, which can likely be attributed to inhibiting risk factors such as BACE-1 and upregulating neuroprotective factors such as BDNF. We conclude that this novel natural reagent, MAT, which effectively protects neuro-axons from CNS inflammation-induced damage, could be a potential candidate for the treatment of neurodegenerative diseases such as MS.
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Alcaloides/farmacología , Axones/efectos de los fármacos , Axones/patología , Sistema Nervioso Central/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inflamación/prevención & control , Extractos Vegetales/farmacología , Quinolizinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Axones/metabolismo , Biomarcadores/análisis , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Ensayo de Inmunoadsorción Enzimática , Fabaceae/química , Femenino , Técnicas para Inmunoenzimas , Inflamación/inmunología , Inflamación/patología , ARN Mensajero/genética , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , MatrinasRESUMEN
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by immune-mediated neuroinflammation, demyelination and neurodegeneration of the central nervous system (CNS). While matrine (MAT), a monomer that is used in traditional Chinese medicine as an anti-inflammatory treatment, delayed onset and ameliorated severity of EAE, the underlying mechanisms have not been fully elucidated. In this study, we investigated the relationship between the clinical effect of MAT and the levels of certain important chemokines/chemokine receptors. Our results showed that attenuated severity of EAE resulting from MAT treatment was positively correlated with the reduction of CCL2 and CXCL10 levels in the periphery and the CNS; both of these chemokines play a crucial role in the recruitment and accumulation of inflammatory cells, especially monocytes/macrophages and T cells, into the CNS. The levels of their corresponding receptors, CCR2 and CXCR3, were also significantly reduced after MAT treatment. Taken together, our data indicate that MAT may be an effective immunomodulatory therapeutic approach for MS/EAE by countering the immune cell recruitment mechanisms.
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Alcaloides/farmacología , Quimiocinas/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Quinolizinas/farmacología , Receptores de Quimiocina/metabolismo , Animales , Quimiocinas/genética , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnicas para Inmunoenzimas , ARN Mensajero/genética , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Quimiocina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , MatrinasRESUMEN
PURPOSE: This study aimed to investigate whether CYP3A4*1G genetic polymorphism influences the metabolism of fentanyl in human liver microsomes in Chinese patients. METHODS: The human liver microsomes were obtained from 88 hepatobiliary surgery patients who accepted liver resection surgery in this study. A normal liver sample (confirmed by the Department of Pathology) was taken from the outer edge of the resected tissue. The metabolism of fentanyl in human liver microsomes was studied. The concentration of fentanyl was measured by high performance liquid chromatography. The CYP3A4*1G variant allele was genotyped using the PCR restriction fragment length polymorphism method. RESULTS: The frequency of the CYP3A4*1G variant allele was 0.188 in the 88 Chinese patients who had received hepatobiliary surgery. The metabolic rate of fentanyl in patients homozygous for the *1G/*1G variant (0.85 ± 0.37) was significantly lower than that in patients bearing the wild-type allele *1/*1 (1.89 ± 0.58) or in patients heterozygous for the *1/*1G variant (1.82 ± 0.65; p < 0.05). There were no gender-related differences in the metabolic rate of fentanyl (p > 0.05) nor was there any correlation between age and metabolic rate of fentanyl (p > 0.05). Results from different hepatobiliary diseases showed no significant difference in the metabolic rate of fentanyl (p > 0.05). The difference of CYP3A4 mRNA among different CYP3A4*1G variant alleles was significant (p < 0.05). There was positive correlation between CYP3A4 mRNA and metabolic rate of fentanyl (p < 0.01). CONCLUSIONS: CYP3A4*1G genetic polymorphism decreases the metabolism of fentanyl. There is a positive correlation between CYP3A4 mRNA level and metabolism of fentanyl.
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Pueblo Asiatico/genética , Citocromo P-450 CYP3A/genética , Fentanilo/metabolismo , Microsomas Hepáticos/metabolismo , Polimorfismo Genético/genética , Alelos , China , Femenino , Fentanilo/farmacocinética , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Hyperammonaemia is a serious metabolic disorder commonly observed in patients with hepatic failure. However, it is unknown whether hyperammonaemia has a direct adverse effect on the hepatocytes and thereby serves as both a cause and effect of hepatic failure. AIMS: The purposes were to determine whether hepatic injury can be caused by hyperammonaemia, and if so, screen the key genes involved in hyperammonaemia. METHODS: Hyperammonaemic rats were established via intragastric administration of the ammonium chloride solution. The liver tissues were assessed via biochemistry, histology, immunohistochemistry and microarray analysis. Selected genes were confirmed by quantitative RT-PCR. RESULTS: Administration of the ammonium chloride caused the hyperammonaemia, accompanied with the changes of plasma markers indicating hepatic injury. A pathological assessment demonstrated increased apoptosis and higher level of cyclin D1 and cyclin A in hyperammonaemic rat liver. Microarray was performed on the liver samples and 198 differentially expressed genes were identified in hyperammonaemic rats and validated by quantitative RT-PCR. These genes were associated with many vital functional classes and belonged to different signal transduction pathways. CONCLUSIONS: This study demonstrates that hyperammonaemia can directly induce hepatic injury via the hepatocyte apoptosis. Gene expression profile may provide the possible explanations and mechanisms for the hepatic injury induced by hyperammonaemia.
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Hiperamonemia/patología , Hígado/patología , Cloruro de Amonio , Animales , Apoptosis , Ciclina A/metabolismo , Ciclina D1/metabolismo , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Hiperamonemia/inducido químicamente , Hiperamonemia/metabolismo , Hígado/metabolismo , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Ratas Sprague-DawleyRESUMEN
Immunological dysfunction is a primary characteristic of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been shown to ameliorate the clinical signs of EAE by suppressing the production of proinflammatory cytokines IFN-γ, TNF-α and IL-17, as well as adhesive molecules. However, whether MAT is simply an immunosuppressive or an immunomodulatory reagent has not been studied. In the present study we focused on possible immunomodulatory mechanisms underlying the effects of MAT in EAE. Our results showed that administration of MAT significantly increased serum production of Th2 cytokines IL-4 and IL-5, and regulatory T cell (Treg) related cytokines IL-10, TGF-ß1, as well as expression of Foxp3, a Treg transcription factor, in the spinal cord. In addition, MAT treatment significantly upregulated CNS expression of Nrf2 and HO-1, which play important roles in inhibiting oxidative stress and CNS inflammation. Together, our findings identify MAT as, not only an immunosuppressive, but also a potent immunomodulatory natural product for the treatment of EAE and which has potential as a novel therapeutic option for MS.
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Alcaloides/farmacología , Encefalomielitis Autoinmune Experimental/inmunología , Inmunomodulación/efectos de los fármacos , Quinolizinas/farmacología , Animales , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Cobayas , Inmunohistoquímica , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Regulación hacia Arriba , MatrinasRESUMEN
INTRODUCTION: Vitamin D deficiency is common in critically ill patients, and was reported to be associated with adverse outcomes. However, the effect of vitamin D deficiency on mortality in critically ill patients remains unclear. METHODS: We searched PubMed and EMBASE from the inception to July 2014 for cohort studies to assess the effect of vitamin D deficiency on the incidence of mortality in critically ill patients. Mortality-specific odds ratio (OR) with 95% confidence interval (CI) were pooled with a random- or fixed-effect models when appropriate. RESULTS: Seven cohort studies with a total of 4,204 participants including 1,679 cases of vitamin D deficiency were included in this meta-analysis. Vitamin D deficiency was significantly associated with an increased hospital mortality (OR 1.76; 95% CI, 1.38 to 2.24; P < 0.001), with very low heterogeneity (I (2) = 2.3%; P = 0.402). The finding of increased hospital mortality in critically ill adult patients was consistently found in every stratum of our subgroup analyses. CONCLUSIONS: This meta-analysis suggests that vitamin D deficiency is associated with increased incidence of hospital mortality in critically ill adult patients.
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Enfermedad Crítica/mortalidad , Mortalidad Hospitalaria/tendencias , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/mortalidad , Estudios de Cohortes , Humanos , Vitamina D/sangre , Deficiencia de Vitamina D/diagnósticoRESUMEN
INTRODUCTION: Observational data have suggested that statin therapy may reduce mortality in patients with infection and sepsis; however, results from randomized studies are contradictory and do not support the use of statins in this context. Here, we performed a meta-analysis to investigate the effects of statin therapy on mortality from infection and sepsis. METHODS: We searched electronic databases (PubMed and Embase) for articles published before November 2013. Randomized or observational studies reporting the effects of statin therapy on mortality in patients with infection or sepsis were eligible. Randomized and observational studies were separately pooled with relative risks (RRs) and random-effects models. RESULTS: We examined 5 randomized controlled trials with 867 patients and 27 observational studies with 337,648 patients. Among the randomized controlled trials, statins did not significantly decrease in-hospital mortality (RR, 0.98; 95% confidence interval (CI), 0.73 to 1.33) or 28-day mortality (RR, 0.93; 95% CI, 0.46 to 1.89). However, observational studies indicated that statins were associated with a significant decrease in mortality with adjusted data (RR, 0.65; 95% CI, 0.57 to 0.75) or unadjusted data (RR, 0.74; 95% CI, 0.59 to 0.94). CONCLUSIONS: Limited evidence suggests that statins may not be associated with a significant reduction in mortality from infection and sepsis. Although meta-analysis from observational studies showed that the use of statins was associated with a survival advantage, these outcomes were limited by high heterogeneity and possible bias in the data. Therefore, we should be cautious about the use of statins in infection and sepsis.
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Mortalidad Hospitalaria/tendencias , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Humanos , Infecciones/tratamiento farmacológico , Infecciones/mortalidad , Estudios Observacionales como Asunto/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto/mortalidad , Resultado del TratamientoRESUMEN
PURPOSE: The purpose of this study was to investigate the associated between serum total bilirubin (STB) levels and long-term outcomes in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: A total of 1,273 consecutive patients were enrolled. Patients were grouped according to their baseline STB levels: Group 1 (STB < 3.4 µmol/L), Group 2 (3.4 µmol/L ≤ STB ≤ 10.3 µmol/L), Group 3 (10.3 µmol/L < STB ≤ 17.1 µmol/L), and Group 4 (STB < 17.1 µmol/L) and the rate of major adverse cardiovascular events (MACE) was determined RESULTS: A total of 1,152 patients were successfully followed up (90.5%) for a mean period of 30 ± 5 months, including 187 patients experiencing a major adverse cardiovascular event (MACE: death from any cause, myocardial infarction, repeat revascularization or readmission). The MACE rate in Groups 3 and 4 was lower than in Groups 1 and 2 (P < 0.01). After adjusted the confounding factors with Cox regression analysis, the MACE rates in Groups 2-4 were still lower than in Group 1 (Group 2, RR=0.293, 95% CI 0.167-0.517, P < 0.01; Group 3, RR=0.142, 95% CI 0.065-0.312, P < 0.01; Group 4, RR=0.134, 95% CI 0.071-0.252, P < 0.01). The cumulative survival rates of Groups 3 and 4 were higher than that of Groups 1and 2 (P < 0.01). CONCLUSIONS: High STB concentration is associated with lower MACE in patients with ACS after PCI.
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Bilirrubina/sangre , Intervención Coronaria Percutánea , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The effects of over-expression of testis-specific expressed gene 1 (TSEG-1) on the viability and apoptosis of cultured spermatogonial GC-1spg cells were investigated, and the immortal spermatogonial cell line GC-1spg (CRL-2053™) was obtained as the cell model in order to explore the function of TSEG-1. We transfected the eukaryotic vector of TSEG-1, named as pEGFP-TSEG-1 into cultured spermatogonial GC-1spg cells. Over-expression of TSEG-1 inhibited the proliferation of GC-1spg cells, and arrested cell cycle slightly at G0/G1 phase. Transfection of TSEG-1 attenuated the transcript levels of Ki-67, PCNA and cyclin D1. In addition, over-expression of TSEG-1 induced early and late apoptosis, and reduced the mitochondrial membrane potential of GC-1spg cells. Moreover, transfection of TSEG-1 significantly enhanced the ratio of Bax/Bcl-2 and transcript levels of caspase 9, and decreased the expression of Fas and caspase 8 in GC-1spg cells. These results indicated over-expression of TSEG-1 suppresses the proliferation and induces the apoptosis of GC-1spg cells, which establishes a basis for further study on the function of TSEG-1.
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Fase G1/fisiología , Histonas/metabolismo , Fase de Descanso del Ciclo Celular/fisiología , Espermatogonias/metabolismo , Animales , Caspasa 8/biosíntesis , Caspasa 8/genética , Línea Celular , Ciclina D1/biosíntesis , Ciclina D1/genética , Histonas/genética , Antígeno Ki-67/biosíntesis , Antígeno Ki-67/genética , Masculino , Ratones , Antígeno Nuclear de Célula en Proliferación/biosíntesis , Antígeno Nuclear de Célula en Proliferación/genética , Espermatogonias/citología , Proteína X Asociada a bcl-2/biosíntesis , Proteína X Asociada a bcl-2/genéticaRESUMEN
Dysfunction of the blood-brain barrier (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, whether this effect of MAT is through protecting the integrity and function of the BBB is not known. In the present study, we show that MAT treatment had a therapeutic effect comparable to dexamethasone (DEX) in EAE rats, with reduced Evans Blue extravasation, increased expression of collagen IV, the major component of the basement membrane, and the structure of tight junction (TJ) adaptor protein Zonula occludens-1 (ZO-1). Furthermore, MAT treatment attenuated expression of matrix metalloproteinase-9 and -2 (MMP-9/-2), while it increased the expression of tissue inhibitors of metalloproteinase-1 and -2 (TIMP-1/-2). Our findings demonstrate that MAT reduces BBB leakage by strengthening basement membrane, inhibiting activities of MMP-2 and -9, and upregulating their inhibitors. Taken together, our results identify a novel mechanism underlying the effect of MAT, a natural compound that could be a novel therapy for MS.