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1.
Med Sci Monit ; 26: e922710, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32450567

RESUMO

BACKGROUND Keratitis is a complex condition in humans and is the second most common cause of legal blindness worldwide. MATERIAL AND METHODS To reveal the genomic loci underlying keratitis, we performed functional annotations of SNP-based and gene-based genome-wide association studies of keratitis in the UK Biobank (UKB) cohort with 337 199 subjects of European ancestry. RESULTS The publicly available SNP-based association results showed a total of 34 SNPs, from 14 distinct loci, associated with keratitis in the UKB. Gene-based association analysis identified 2 significant genes: IQCF3 (p=2.0×10⁻6) and SOD3 (p=2.0×10⁻6). Thirty-two candidate genes were then prioritized using information from multiple sources. The overlap of IQCF3 in these 2 analyses resulted in a total of 33 hub genes. Functional annotation of hub genes was performed and transcriptional factors of IQCF3 and SOD3 were predicted. CONCLUSIONS A total of 34 SNPs from 14 distinct loci were identified as being associated with keratitis, and 32 candidate genes were then prioritized. In addition, IQCF3 and SOD3 were identified by their p values through gene-based tests on the basis of individual SNP-based tests. The functional relationship between these suspect genes and keratitis suggest that IQCF3 and SOD3 are candidate genes underlying keratitis.

2.
Hum Genet ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32239398

RESUMO

Aiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFMadj) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants. Bivariate GWAS meta-analysis identified two novel pleiotropic loci 12q15 (lead SNP rs73134637, p = 3.45 × 10-7) and 10p14 (lead SNP rs2892347, p = 2.63 × 10-7) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosis p = 0.06 and 0.02, BMI p = 0.03 and 4.61 × 10-3, N up to 499,520). Cis-eQTL analysis demonstrated that allele C at rs73134637 was positively associated with IFNG expression in whole blood (N = 369, p = 0.04), and allele A at rs11254759 (10p14, p = 9.49 × 10-7) was negatively associated with PRKCQ expression in visceral adipose tissue (N = 313, p = 0.04) and in lymphocytes (N = 117, p = 0.03). As a proof-of-principle experiment, the function of rs11254759, which is 235 kb 5'-upstream from PRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carrying rs11254759 regulated PRKCQ expression by upregulating PRKCQ promoter activity (p = 4.60 × 10-7) in an allelic specific manner. Mouse model analysis showed that heterozygous PRKCQ deficient mice presented decreased fat mass compared to wild-type control mice (p = 3.30 × 10-3). Mendelian randomization analysis demonstrated that both FNK-BMD and TFMadj were causally associated with fracture risk (p = 1.26 × 10-23 and 1.18 × 10-11). Our findings may provide useful insights into the genetic association between osteoporosis and abdominal obesity.

4.
Skelet Muscle ; 9(1): 28, 2019 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-31757224

RESUMO

BACKGROUND: Low lean body mass is the most important predictor of sarcopenia with strong genetic background. The aim of this study was to uncover genetic factors underlying lean mass development. MATERIALS AND METHODS: We performed a genome-wide association study (GWAS) of fat-adjusted leg lean mass in the Framingham Heart Study (FHS, N = 6587), and replicated in the Women's Health Initiative-African American sub-sample (WHI-AA, N = 847) and the Kansas City Osteoporosis Study (KCOS, N = 2219). We also cross-validated significant variants in the publicly available body mass index (BMI) summary results (N ~ 700,000). We then performed a series of functional investigations on the identified variants. RESULTS: Four correlated SNPs at 6p21.1 were identified at the genome-wide significance (GWS, α = 5.0 × 10-8) level in the discovery FHS sample (rs551145, rs524533, rs571770, and rs545970, p = 3.40-9.77 × 10-9), and were successfully replicated in both the WHI-AA and the KCOS samples (one-sided p = 1.61 × 10-3-0.04). They were further cross-validated by the large-scale BMI summary results (p = 7.0-9.8 × 10-3). Cis-eQTL analyses associated these SNPs with the NFKBIE gene expression. Electrophoresis mobility shift assay (EMSA) in mouse C2C12 myoblast cells implied that rs524533 and rs571770 were bound to an unknown transcription factor in an allelic specific manner, while rs551145 and rs545970 did not. Dual-luciferase reporter assay revealed that both rs524533 and rs571770 downregulated luciferase expression by repressing promoter activity. Moreover, the regulation pattern was allelic specific, strengthening the evidence towards their differential regulatory effects. CONCLUSIONS: Through a large-scale GWAS followed by a series of functional investigations, we identified 2 correlated functional variants at 6p21.1 associated with leg lean mass. Our findings not only enhanced our understanding of molecular basis of lean mass development but also provided useful candidate genes for further functional studies.


Assuntos
Cromossomos Humanos Par 6/genética , Polimorfismo de Nucleotídeo Único , Sarcopenia/genética , Magreza/genética , Idoso , Animais , Índice de Massa Corporal , Linhagem Celular , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Proteínas I-kappa B/genética , Desequilíbrio de Ligação , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Locos de Características Quantitativas , Sarcopenia/patologia , Magreza/patologia
5.
Front Genet ; 10: 947, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681408

RESUMO

As an important trait at birth, infant head circumference (HC) is associated with a variety of intelligence- and mental-related conditions. Despite being dominated by genetics, the mechanism underlying the variation of HC is poorly understood. Aiming to uncover the genetic basis of HC, we performed a genome-wide joint association analysis by integrating the genome-wide association summary statistics of HC with that of its two related traits, birth length and birth weight, using a recently developed integrative method, multitrait analysis of genome-wide association (MTAG), and performed in silico replication in an independent sample of intracranial volume (N = 26,577). We then conducted a series of bioinformatic investigations on the identified loci. Combining the evidence from both the MTAG analysis and the in silico replication, we identified three novel loci at the genome-wide significance level (α = 5.0 × 10-8): 3q23 [lead single nucleotide polymorphism (SNP) rs9846396, p MTAG = 3.35 × 10-8, p replication = 0.01], 7p15.3 (rs12534093, p MTAG = 2.00 × 10-8, p replication = 0.004), and 9q33.3 (rs7048271 p MTAG = 9.23 × 10-10, p replication = 1.14 × 10-4). Each of the three lead SNPs was associated with at least one of eight brain-related traits including intelligence and educational attainment. Credible risk variants, defined as those SNPs located within 500 kb of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in DNase I hypersensitive site region in brain. Nine candidate genes were prioritized at the three novel loci using multiple sources of information. Gene set enrichment analysis identified one associated pathway GO:0048009, which participates in the development of nervous system. Our findings provide useful insights into the genetic basis of HC and the relationship between brain growth and mental health.

6.
Clin Ther ; 41(11): 2263-2272, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31561881

RESUMO

PURPOSE: The aim of the study is to compare the free hexafluoro-isopropanol (HFIP) concentration in adults' blood and the incidence of emergence agitation (EA) after inhaled different concentrations of sevoflurane. METHODS: Sixty adult patients planning to undergo laparoscopic gastrointestinal surgery were randomly assigned to 3 groups. Each group received sevoflurane as the volatile anesthetic at different concentrations: 0.5 minimum alveolar concentration (MAC), 1.0 MAC, and 1.5 MAC. The use of sevoflurane was continued until the end of surgery. Venous blood samples were obtained at 30, 60, 120, and 180 minutes after starting the use of sevoflurane and subsequently at 60, 180, and 300 minutes after discontinuation of volatile anesthetic administration. Blood concentrations of sevoflurane and free HFIP were determined using gas chromatography. The recovery time and the incidence of EA at different time points were evaluated among the 3 groups. FINDINGS: Changes in the blood concentrations of sevoflurane and free HFIP during and after the use of sevoflurane were similar in all 3 groups. The peak blood concentration of free HFIP occurred 60 minutes after onset of sevoflurane anesthesia in all 3 groups (P < 0.05). The lowest level of free HFIP and the longest recovery time were found in the 1.5-MAC group (P < 0.05). No significant difference was found in the incidence of EA or moderate pain among the 3 groups during recovery. IMPLICATIONS: The generation of HFIP would be inhibited when the inhaled sevoflurane concentration increased to 1.5 MAC. However, the incidence of EA during recovery had nothing to do with the inhaled different sevoflurane concentrations (within 1.5 MAC) in adults. ChicCTR.org identifier: ChiCTR-IPD-17011558.

7.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(9): 868-875, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31506144

RESUMO

OBJECTIVE: To study the significance of plasma neutrophil extracellular trap (NET) and its markers in the diagnosis of community-acquired pneumonia (CAP) in children. METHODS: A total of 160 children with CAP were enrolled as the CAP group, and 50 healthy children were enrolled the control group. According to disease severity, the CAP group was further divided into a mild CAP subgroup with 137 children and a severe CAP subgroup with 23 children. According to the pathogen, the CAP group was further divided into a bacterial pneumonia subgroup with 78 children, a Mycoplasma pneumonia subgroup with 35 children, and a viral pneumonia subgroup with 47 children. The levels of plasma NET and its markers [antibacterial peptide (LL-37), extracellular free DNA (cfDNA), and deoxyribonuclease I (DNase I)] were measured. Receiver operating characteristic (ROC) curve was used to analyze the value of each index in diagnosing CAP and assessing its severity. RESULTS: Compared with the control group, the CAP group had significant increases in the levels of NET, LL-37, and cfDNA and a significant reduction in the activity of DNase I (P<0.05). Compared with the mild CAP subgroup, the severe CAP subgroup had significantly higher levels of NET, LL-37 and cfDNA and a significantly lower activity of DNase I (P<0.05). There were no significant differences in the levels of NET, LL-37, and cfDNA and the activity of DNase I among the bacterial pneumonia, Mycoplasma pneumonia, and viral pneumonia subgroups (P>0.05). In the CAP group, plasma NET levels were positively correlated with white blood cell count (WBC), percentage of neutrophils, and serum levels of C-reactive protein (CRP), procalcitonin and tumor necrosis factor-α (r=0.166, 0.168, 0.275, 0.181 and 0.173 respectively, P<0.05); LL-37 and cfDNA levels were positively correlated with WBC (r=0.186 and 0.338 respectively, P<0.05) and CRP levels (r=0.309 and 0.274 respectively, P<0.05); the activity of DNase I was negatively correlated with CRP levels (r=-0.482, P<0.05). The ROC curve analysis showed that NET, LL-37, cfDNA, and DNase I had an area under the ROC curve (AUC) of 0.844, 0.648, 0.727, and 0.913 respectively in the diagnosis of CAP, with optimal cut-off values of 182.89, 46.26 ng/mL, 233.13 ng/mL, and 0.39 U/mL respectively, sensitivities of 88.12%, 35.63%, 54.37%, and 91.25% respectively, and specificities of 74.00%, 92.00%, 86.00%, and 76.00% respectively. In the assessment of the severity of CAP, NET, LL-37, cfDNA, and DNase I had an AUC of 0.873, 0.924, 0.820, and 0.778 respectively, with optimal cut-off values of 257.7, 49.11 ng/mL, 252.54 ng/mL, and 0.29 U/mL respectively, sensitivities of 83.21%, 86.96%, 78.26%, and 95.65% respectively, and specificities of 78.26%, 83.94%, 76.64%, and 56.93% respectively. CONCLUSIONS: Plasma NET and its related markers have a certain value in diagnosing CAP and assessing its severity in children.


Assuntos
Infecções Comunitárias Adquiridas , Armadilhas Extracelulares , Pneumonia , Biomarcadores , Proteína C-Reativa , Criança , Infecções Comunitárias Adquiridas/diagnóstico , Diagnóstico Precoce , Humanos , Curva ROC
8.
Bone ; 127: 37-43, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31158506

RESUMO

The level of serum lipids is associated with bone mineral density (BMD), an important skeletal trait. Yet the causality has not been determined. Here we performed a Mendelian randomization (MR) analysis to test potential causal links between BMD and lipid profile, i.e., low-density lipoprotein cholesterol (LDC-c), total cholesterol (TC), triglyceride (TG) and high-density lipoprotein cholesterol (HDL-c). We observed causal effect of LDL-c, TC and TG to BMD, and reversely the effect of BMD to HDL-c. We further explored the effect of body mass index (BMI) in these causalities and found that the effect of LDL-c, TC and TG to BMD is independent of BMI. Our findings provided useful information in the clinical relevance of blood lipids on BMD variation and osteoporosis risk.

9.
Int J Obes (Lond) ; 43(12): 2480-2490, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30944420

RESUMO

OBJECTIVES: Aiming to uncover the genetic basis of abdominal obesity, we performed a genome-wide association study (GWAS) meta-analysis of trunk fat mass adjusted by trunk lean mass (TFMadj) and followed by a series of functional investigations. SUBJECTS: A total of 11,569 subjects from six samples were included into the GWAS meta-analysis. METHODS: Meta-analysis was performed by a weighted fixed-effects model. In silico replication analysis was performed in the UK-Biobank (UKB) sample (N = 331,093) and in the GIANT study (N up to 110,204). Cis-expression QTL (cis-eQTL) analysis, dual-luciferase reporter assay and electrophoresis mobility shift assay (EMSA) were conducted to examine the functional relevance of the identified SNPs. At last, differential gene expression analysis (DGEA) was performed. RESULTS: We identified an independent SNP rs12409479 at 1p21 (MAF = 0.07, p = 7.26 × 10-10), whose association was replicated by the analysis of TFM in the UKB sample (one-sided p = 3.39 × 10-3), and was cross-validated by the analyses of BMI (one-sided p = 0.03) and WHRadj (one-sided p = 0.04) in the GIANT study. Cis-eQTL analysis demonstrated that allele A at rs12409479 was positively associated with PTBP2 expression level in subcutaneous adipose tissue (N = 385, p = 4.15 × 10-3). Dual-luciferase reporter assay showed that the region repressed PTBP2 gene expression by downregulating PTBP2 promoter activity (p < 0.001), and allele A at rs12409479 induced higher luciferase activity than allele G did (p = 4.15 × 10-3). EMSA experiment implied that allele A was more capable of binding to unknown transcription factors than allele G. Lastly, DGEA showed that the level of PTBP2 expression was higher in individuals with obesity than in individuals without obesity (N = 20 and 11, p = 0.04 and 9.22 × 10-3), suggesting a regulatory role in obesity development. CONCLUSIONS: Taken together, we hypothesize a regulating path from rs12409479 to trunk fat mass development through its allelic specific regulation of PTBP2 gene expression, thus providing some novel insight into the genetic basis of abdominal obesity.

10.
J Bone Miner Res ; 34(6): 1086-1094, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30690781

RESUMO

Bone mineral density (BMD) at various skeletal sites have shared genetic determinants. In the present study, aiming to identify shared loci associated with BMD, we conducted a joint association study of a genomewide association study (GWAS) and a meta-analysis of BMD at different skeletal sites: (i) a single GWAS of heel BMD in 142,487 individuals from the UK Biobank, and (ii) a meta-analysis of 30 GWASs of total body (TB) BMD in 66,628 individuals from the Genetic Factors for Osteoporosis (GEFOS) Consortium. The genetic correlation coefficient of the two traits was estimated to be 0.57. We performed joint association analysis with a recently developed statistical method multi-trait analysis of GWAS (MTAG) to account for trait heterogeneity and sample overlap. The joint association analysis combining samples of up to 209,115 individuals identified 18 novel loci associated with BMD at the genomewide significance level (α = 5.0 × 10-8 ), explaining an additional 0.43% and 0.60% of heel-BMD and TB-BMD heritability, respectively. The vast majority of the identified lead SNPs or their proxies exerted local expression quantitative trait loci (cis-eQTL) activity. Credible risk variants, defined as those SNPs located within 500 kilobases (kb) of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in transcription factor binding sites (p = 3.58 × 10-4 ) and coding regions (p = 5.71 × 10-4 ). Fifty-six candidate genes were prioritized at these novel loci using multiple sources of information, including several genes being previously reported to play a role in bone biology but not reported in previous GWASs (PPARG, FBN2, DEF6, TNFRSF19, and NFE2L1). One newly identified gene, SCMH1, was shown to upregulate the expression of several bone biomarkers, including alkaline phosphatase (ALP), collagen type 1 (COL-I), osteocalcin (OCN), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2), in mouse osteoblastic MC3T3-E1 cells, highlighting its regulatory role in bone formation. Our results may provide useful candidate genes for future functional investigations. © 2019 American Society for Bone and Mineral Research.

11.
Drug Des Devel Ther ; 12: 2897-2903, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30254419

RESUMO

Background: Geraniol is a monoterpene alcohol that has anti-fungal, anti-cancer and anti-nociceptive properties, but its anti-allergic rhinitis (AR) property is unclear. Methods: In this study, the anti-inflammatory role and its possible mechanisms of geraniol in human mast cell line (HMC-1) cells stimulated by inflammatory trigger phorbol 12-myristate 13-acetate plus A23187 (PMACI), as well as in ovalbumin (OVA)-induced AR mice models were investigated. Results: PMACI results in a significant increase in the production of proinflammatory cytokines, such as TNF-α, IL-1ß, MCP-1, IL-6 and as well as histamine. Geraniol was found to inhibit both TNF-α, IL-1ß and IL-6 protein and mRNA expressions at concentrations of 40, 80, 160 µM. In OVA-induced AR models, geraniol treatment was able to suppress AR biomarkers (OVA-specific IgE and IL-1ß as well as histamine) and nasal rub scores. Interestingly, p38, a member of the mitogen-activated protein kinase (MAPK) signaling family, was found to be increasingly hypophosphorylated as geraniol dose was increased. Similar decreases in the nuclear level of p65, a member of the nuclear factor kappa B (NF-κB) signaling pathway, were also observed. Conclusion: Our data highlights that the anti-inflammatory properties of geraniol on AR-related markers in activated HCM-1 cells and OVA-induced AR models may be mediated through the regulation of the MAPK/NF-κB signaling pathway.


Assuntos
Antialérgicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Calcimicina/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Rinite Alérgica/tratamento farmacológico , Terpenos/farmacologia , Acetato de Tetradecanoilforbol/análogos & derivados , Monoterpenos Acíclicos , Animais , Antialérgicos/química , Anti-Inflamatórios não Esteroides/química , Linhagem Celular , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Histamina/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ovalbumina , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/imunologia , Rinite Alérgica/patologia , Relação Estrutura-Atividade , Terpenos/química , Acetato de Tetradecanoilforbol/farmacologia
12.
Bone ; 110: 378-385, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29499414

RESUMO

In the present study, aiming to identify loci associated with osteoporosis, we conducted a joint association study of 2 independent genome-wide association meta-analyses of femoral neck and lumbar spine bone mineral densities (BMDs): 1) an in-house study of 6 samples involving 7484 subjects, and 2) the GEFOS-seq study of 7 samples involving 32,965 subjects. The in-house samples were imputed by the 1000 genomes project phase 3 reference panel. SNP-based association test was applied to 7,998,108 autosomal SNPs in each meta-analysis, and for each SNP the 2 association signals were then combined for joint analysis and for mutual replication. Combining the evidence from both studies, we identified 2 novel loci associated with BMDs at the genome-wide significance level (α=5.0×10-8): 20p12.1 (rs73100693 p=2.65×10-8, closest gene MACROD2) and 20q13.33 (rs2380128 p=3.44×10-8, OSBPL2). We also replicated 7 loci that were reported by two recent studies on heel and total body BMD. Our findings provide useful insights that enhance our understanding of bone development, osteoporosis and fracture pathogenesis.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 13/genética , Estudo de Associação Genômica Ampla/métodos , Osteoporose/genética , Densidade Óssea/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
13.
Brain Behav Immun ; 67: 65-76, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28867282

RESUMO

Increasing evidence indicates that inflammatory processes play a crucial role in the etiopathology of epilepsy and seizure disorders. The Toll/IL-1R domain-containing adapter-inducing IFN-ß (TRIF) activated several transcriptions leading to the production of pro-inflammatory cytokines in the central nervous system, which suggests a potential role for TRIF in the epileptogenesis of epilepsy. In this study, we investigated the roles of TRIF in human and mice epileptogenic tissues. Western blot and immunohistochemistry assays showed that the expression of TRIF was significantly upregulated in neurons and glial cells in both human epileptic tissues and mouse models, and positively correlated with seizure frequency. TRIF expression positively correlated with high-mobility group box 1 (HMGB1) expression. In TRIF-deficient mice, electroencephalograms displayed a significant decrease in seizure frequency and duration time, while KA induced seizures compared with wild-type (WT) mice. The number and duration time of spontaneous seizures were also decreased in the chronic KA-induced TRIF-deficient mouse models. In TLR4-deficient hippocampal neurons and mouse models, TRIF expression was lower compared with WT mice during HMGB1 and KA stimulation. Meanwhile, in KA-induced TRIF-deficient mouse models, microglia activation was significantly suppressed; pro-inflammatory factors including IL-1ß, TNF-α, iNOS, HMGB1 and IFN-ß were reduced; and the survival of the neurons in the hippocampus increased compared with WT mice. Our findings suggested that TRIF may be involved in the epileptogenesis of temporal lobe epilepsy, which would make it a potential therapeutic target for the treatment of epilepsy.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Adolescente , Adulto , Animais , Criança , Encefalite/metabolismo , Feminino , Proteína HMGB1/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Pessoa de Meia-Idade , Células Piramidais/metabolismo , Lobo Temporal/metabolismo , Receptor 4 Toll-Like/genética , Adulto Jovem
14.
Front Plant Sci ; 8: 980, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28642779

RESUMO

In the North China Plain, groundwater tables have been dropping at unsustainable rates of 1 m per year due to irrigation of a double cropping system of winter wheat and summer maize. To reverse the trend, we examined whether alternative crop rotations could save water. Moisture contents were measured weekly at 20 cm intervals in the top 180 cm of soil as part of a 12-year field experiment with four crop rotations: sweet potato→ cotton→ sweet potato→ winter wheat-summer maize (SpCSpWS, 4-year cycle); peanuts → winter wheat-summer maize (PWS, 2-year cycle); ryegrass-cotton→ peanuts→ winter wheat-summer maize (RCPWS, 3-year cycle); and winter wheat-summer maize (WS, each year). We found that, compared to WS, the SpCSpWS annual evapotranspiration was 28% lower, PWS was 19% lower and RCPWS was 14% lower. The yield per unit of water evaporated improved for wheat within any alternative rotation compared to WS, increasing up to 19%. Average soil moisture contents at the sowing date of wheat in the SpCSpWS, PWS, and RCPWS rotations were 7, 4, and 10% higher than WS, respectively. The advantage of alternative rotations was that a deep rooted crop of winter wheat reaching down to 180 cm followed shallow rooted crops (sweet potato and peanut drawing soil moisture from 0 to 120 cm). They benefited from the sequencing and vertical complementarity of soil moisture extraction. Thus, replacing the traditional crop rotation with cropping system that involves rotating with annual shallow rooted crops is promising for reducing groundwater depletion in the North China Plain.

15.
BMC Anesthesiol ; 17(1): 37, 2017 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-28259141

RESUMO

BACKGROUND: This study aimed to compare myocardial protective effects of anaesthesia with intravenous infusion of propofol versus inhalation of sevoflurane in patients undergoing heart valve replacement surgery with cardiopulmonary bypass. METHODS: Seventy-six patients undergoing valve replacement with cardiopulmonary bypass were randomly assigned to propofol or sevoflurane anesthesia during the surgery, respectively. For assessing myocardial injury, cardiac troponin I (cTnI) and creatine kinase isozyme (CK-MB) were determined before induction (T0), 0.5 h (T1) and 3 h (T2) after aortic unclamping, and 24 h (T3) and 48 h (T4) after surgery. The concentrations of interleukin (IL)-6 and IL-10 as the systemic inflammatory and anti-inflammatory markers were also measured at above time points. RESULTS: In the sevoflurane group, the plasma concentrations of cTnI and CK-MB from Tl to T4 and the levels of IL-6 and IL-10 from T1 to T2 were lower than those in the propofol group. Moreover, a higher ratio of automatic heart beat recovery and a shorter length of intensive care unit or hospital stay were found in the sevoflurane group comparing with the propofol group. CONCLUSION: Sevoflurane anaesthesia produced more prominent myocardial protection and attenuated inflammatory response than propofol anaesthesia in patients with valve replacement surgery under cardiopulmonary bypass, resulting in shorter ICU and in-hospital stay. RETROSPECTIVE CLINICAL TRIAL REGISTRATION: Identified as ChiCTR-IOR-16009979 at http://www.chictr.org.cn/ .


Assuntos
Ponte Cardiopulmonar/métodos , Implante de Prótese de Valva Cardíaca/métodos , Éteres Metílicos/farmacologia , Propofol/farmacologia , Substâncias Protetoras/farmacologia , Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Biomarcadores/sangue , Creatina Quinase Forma MB/sangue , Feminino , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Estudos Retrospectivos , Sevoflurano , Fatores de Tempo , Troponina I/sangue
16.
AAPS PharmSciTech ; 18(6): 2149-2156, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28035611

RESUMO

Currently available antiulcer drugs suffered from serious side effects which limited their uses and prompted the need for a safe and efficient new antiulcer agent. The objective of this project work was to retain the drug in the stomach for better antiulcer activity and less side effects. Hence, the aim of our present work was to prepare a gastric floating tablet of Berberine hydrochloride (Ber) with suitable in vitro/vivo properties. In this study, different Ber gastric floating tablets were prepared by simple direct compression using various amounts of HPMCK15M and Carbopol 971PNF combined with other tablet excipients. The properties of the tablets including hardness, buoyancy, swelling ability, in vitro drug release, and in vivo pharmacokinetic study were evaluated. The obtained results disclosed that hardness, floating, swelling, and in vitro drug release of the Ber tablets depended mainly on the ratio of polymer combinations. Moreover, among six formulations, F3 exhibited desirable floating, swelling, and extended drug release. In addition, in vivo pharmacokinetic study suggested that prepared gastric floating tablets had significantly sustained-releasing effects compared with market tablets. Therefore, the developed gastric floating tablets of Ber could be an alternative dosage form for treatment of gastrointestinal disease.


Assuntos
Resinas Acrílicas/farmacologia , Berberina , Sistemas de Liberação de Medicamentos/métodos , Administração Oral , Antiulcerosos/administração & dosagem , Antiulcerosos/farmacocinética , Berberina/administração & dosagem , Berberina/farmacocinética , Disponibilidade Biológica , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Formas de Dosagem , Portadores de Fármacos/farmacologia , Composição de Medicamentos , Excipientes/farmacologia , Humanos , Inibidores de Proteases/farmacologia , Estômago/efeitos dos fármacos , Comprimidos
17.
CNS Neurosci Ther ; 23(1): 57-68, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27534449

RESUMO

AIM: Infantile spasms (IS) are an age-specific epileptic syndrome with specific clinical symptom and electroencephalogram (EEG) features, lacking treatment options, and a poor prognosis. Excessive endogenous corticotropin-releasing hormone (CRH) in infant brain might result in IS. However, the data from human IS are limited. In our study, we investigated the expressions of CRH and its receptor type 1 (CRHR1) in surgical tissues from patients with IS and autopsy controls. METHODS: Specimens surgically removed from 17 patients with IS, and six autopsy controls were included in the study. Real-time PCR, Western blotting, and immunostaining were used to detect the expressions of mRNA, protein expression, and distribution. The correlation between variates was analyzed by Spearman rank correlation. RESULTS: The expressions of CRH and CRHR1 were significantly upregulated in the epileptogenic tissues of IS patients compared with the control group. CRH was distributed mainly in neurons, while CRHR1 was distributed in neurons, astrocytes, and microglia. The expression levels of CRH and CRHR1 were positively correlated with the frequency of epileptic spasms. Moreover, the expression of protein kinase C (PKC), which was an important downstream factor of CRHR1, was significantly upregulated in the epileptogenic tissues of patients with IS and was positively correlated with the CRHR1 expression levels and the frequency of epileptic spasms. CONCLUSION: These results suggest that the CRH signal transduction pathway might participate in the epileptogenesis of IS, supporting the hypothesis that CRH is related to the pathogenesis of IS.


Assuntos
Córtex Cerebral/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Espasmos Infantis/patologia , Regulação para Cima/fisiologia , Adolescente , Adulto , Autopsia , Córtex Cerebral/patologia , Criança , Hormônio Liberador da Corticotropina/genética , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/metabolismo , Proteína Quinase C/metabolismo , RNA Mensageiro/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Transdução de Sinais/fisiologia , Espasmos Infantis/diagnóstico por imagem , Estatísticas não Paramétricas , Adulto Jovem
18.
Cancer Sci ; 107(10): 1506-1519, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27501331

RESUMO

Advanced lung cancer has poor prognosis owing to its low sensitivity to current chemotherapy agents. Therefore, discovery of new therapeutic agents is urgently needed. In this study, we investigated the antitumor effects of peperomin E, a secolignan isolated from Peperomia dindygulensis, a frequently used Chinese folk medicine for lung cancer treatment. The results indicate that peperomin E has antiproliferative effects, promoting apoptosis and cell cycle arrest in non-small-cell lung cancer (NSCLC) cell lines in a dose-dependent manner, while showing lower toxicity against normal human lung epidermal cells. Peperomin E inhibited tumor growth in A549 xenograft BALB/c nude mice without significant secondary adverse effects, indicating that it may be safely used to treat NSCLC. Furthermore, the mechanisms underlying the anticancer effects of peperomin E have been investigated. Using an in silico target fishing method, we observed that peperomin E directly interacts with the active domain of DNA methyltransferase 1 (DNMT1), potentially affecting its genome methylation activity. Subsequent experiments verified that peperomin E decreased DNMT1 activity and expression, thereby decreasing global methylation and reactivating the epigenetically silenced tumor suppressor genes including RASSF1A, APC, RUNX3, and p16INK4, which in turn activates their mediated pro-apoptotic and cell cycle regulatory signaling pathways in lung cancer cells. The observations herein report for the first time that peperomin E is a potential chemotherapeutic agent for NSCLC. The anticancer effects of peperomin E may be partly attributable to its ability to demethylate and reactivate methylation-silenced tumor suppressor genes through direct inhibition of the activity and expression of DNMT1.


Assuntos
Benzodioxóis/farmacologia , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Inativação Gênica , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Ativação Transcricional/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzodioxóis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/química , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Relação Estrutura-Atividade
19.
J Sep Sci ; 39(19): 3661-3668, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27471121

RESUMO

Quality control has been one of the key scientific issues in the modernization of traditional Chinese medicine. This study explored a novel method for quality evaluation of herbal medicines. High-performance liquid chromatography fingerprints and the osteoblast proliferation activity of 18 batches of Achyranthes bidentata, which were prepared with salt, were determined to establish a chromatographic database and an activity database. Correlation analyses of these databases were performed using partial least squares to obtain regression coefficients (positive and negative correlation coefficients). Then, the sums of the products of the positive and negative correlation peak areas and the corresponding coefficients, respectively, were calculated for each sample. The absolute value of the ratios of the sums of the positive and negative products were calculated, our studies showed that this ratio was significantly correlated with the proliferation activity, particularly when the activity was in the best and worst ranges. Therefore, we developed a parameter that was used to evaluate the quality of samples osteoblast proliferation activity. The quality of another ten batches of samples was assessed to verify this method. The results indicated that this method can be used for quality evaluation of herbal medicines according to the dynamic changes in the chemical compounds and activity.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos de Ervas Chinesas/análise , Plantas Medicinais/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicina Herbária , Humanos , Controle de Qualidade
20.
Phytomedicine ; 23(8): 818-27, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27288917

RESUMO

BACKGROUND: Peperomin E (PepE) is a type of secolignan that is a major component of the plant Peperomia dindygulensis. It has been shown to exert anticancer effects in various cancer cell lines; however, the effects of PepE on human gastric cancer remain unexplored. PURPOSE: The aim of this study was to investigate the effectiveness of PepE as a treatment of gastric cancer and to identify the underlying mechanisms of its anticancer activity. STUDY DESIGN: The efficacy of PepE was examined using human gastric carcinoma SGC-7901, BGC-823, MKN-45 cell lines and normal gastric epithelial GES-1 cell line as an in vitro model and SGC-7901 xenograft mice as an in vivo model. METHODS: Cell viability assays were used to examine the anticancer effect of 0-204.8µM concentrations of PepE in vitro. Additionally, flow cytometry and western blotting were used to elucidate the mechanism with a particular focus on apoptosis. SGC-7901 cells were injected into BALB/c mice, which were then treated with 5 or 15mg/kg/day dose of PepE. The in vivo activity of PepE was investigated by measuring tumors and conducting immunohistochemistry experiments. The safety of PepE was investigated by measuring blood biochemical parameters and conducting histopathological analysis. Taxol was used throughout as a positive control. RESULTS: The results showed that PepE exhibited antiproliferative effects against gastric cancer cells and induced their apoptosis in a dose dependent manner with lower toxicity against normal gastric epithelial cells. Mechanistic evaluations indicated that PepE induced apoptosis by reducing the mitochondrial membrane potential (MTP), inducing cytochrome C release from mitochondria, reducing the ratio of Bcl-2/Bax and Bcl-xl/Bad, increasing activation of caspase-3, and decreasing the levels of PI3K and pAkt. The apoptotic effect of PepE on SGC-7901 cells was partially blocked by an Akt activator SC79. PepE potently inhibited in vivo tumor growth with no obvious toxicity following subcutaneous inoculation of SGC-7901 cells in nude mice. CONCLUSIONS: These findings indicate that PepE can inhibit cell proliferation and induce apoptosis of gastric cancer cells through mitochondrial and PI3K/Akt signaling pathways with relative safety and may be a novel effective chemotherapeutic agent against gastric cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Benzodioxóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Proteína Oncogênica v-akt/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Paclitaxel/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia
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