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1.
ACS Nano ; 14(1): 877-890, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31891481

RESUMO

The liver is the primary organ to sequester nanodrugs, representing a substantial hurdle for drug delivery and raising toxicity concerns. However, the mechanistic details underlying the liver sequestration and effects on the liver are still elusive. The difficulty in studying the liver lies in its complexity, which is structured with stringently organized anatomical units called lobules. Graphene oxide (GO) has attracted attention for its applications in biomedicine, especially as a nanocarrier; however, its sequestration and effects in the liver, the major enrichment and metabolic organ, are less understood. Herein, we unveiled the differential distribution of GO in lobules in the liver, with a higher amount surrounding portal triad zones than the central vein zones. Strikingly, liver zonation patterns also changed, as reflected by changes in vital zonated genes involved in hepatocyte integrity and metabolism, leading to compromised hepatic functions. RNA-Seq and DNA methylation sequencing analyses unraveled that GO-induced changes in liver functional zonation could be ascribed to dysregulation of key signaling pathways governing liver zonation at not only mRNA transcriptions but also DNA methylation imprinting patterns, partially through TET-dependent signaling. Together, this study reveals the differential GO distribution pattern in liver lobules and pinpoints the genetic and epigenetic mechanisms in GO-induced liver zonation alterations.

2.
J Nat Prod ; 82(10): 2925-2930, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31490677

RESUMO

A pyridone alkaloid, asperpyridone A (1), which possesses an unusual pyrano[3,2-c]pyridine scaffold, was isolated from solid cultures of the endophytic fungus Aspergillus sp. TJ23. Its structure, including its absolute configuration, was determined using a combination of nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, quantum chemical calculations (electronic circular dichroism), and X-ray crystallography. In vitro bioassays demonstrated that asperpyridone A (1) could function as a potential hypoglycemic agent, which exhibited pronounced glucose uptake effect in liver HepG2 cells, under both normal and insulin-resistant conditions, with higher efficacy than metformin. The underlying mechanism of asperpyridone A was elucidated by analyzing the genes expressed, the Gene Ontology (GO) function enrichment, the protein interaction network, and real-time quantitative reverse transcription polymerase chain reaction, which suggested that asperpyridone A exhibits hypoglycemic activity by activating the insulin signaling pathway. Moreover, on the basis of the hypoglycemic potency, fibroblast growth factor 21 (FGF21) was determined to be a potential target for asperpyridone A.

3.
BMC Infect Dis ; 19(1): 495, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164085

RESUMO

BACKGROUND: There is currently no research on the diagnostic value of metagenomic next-generation sequencing (mNGS) for a single pathogens in CSF. The aim of this study was to analyse the value of mNGS for identifying Streptococcus pneumoniae (S. pneumoniae) in paediatric bacterial meningitis. METHODS: Bacterial meningitis (BM) cases from October 23, 2014, to December 31, 2016, and December 1, 2017, to July 31, 2018 at Beijing Children's Hospital were reviewed. Clinical features and pathogens were analysed. RESULTS: We diagnosed 135 patients with BM in this study. A total of 43 S. pneumoniae were identified by combination methods. 26/135 (19.3%) patients had positive results in S. pneumoniae by blood and/or cerebrospinal fluid (CSF) culture. Alere BinaxNow®Streptococcus pneumoniae Antigen test was positive in 35/135(25.9%) cases. 32/135 (23.7%) S. pneumoniae were identified by mNGS. Six CSF samples were identified as S. pneumoniae only by mNGS technology. Taking culture as the gold standard, the sensitivity and specificity of mNGS for diagnosing S. pneumoniae meningitis were 73.1 and 88.1%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of diagnosing S. pneumoniae meningitis by mNGS were 59.4 and 93.2%, respectively. When comparison between mNGS and combined tests (culture and Alere BinaxNow®Streptococcus pneumoniae Antigen test), the sensitivity and specificity of mNGS for S. pneumoniae identification were 70.3 and 93.9%, the PPV and NPV in the identification of S. pneumoniae by mNGS were 81.4 and 89.3%, respectively. The difference in number of unique reads of S. pneumoniaein from CSF sample (< 14 days onset) and CSF sample (> 14 days from onset) was statistically significant (170.5 VS. 13, P = 0.019). The difference in the collected time of CSF for culture and mNGS was statistically significant (4 days VS. 14 days, P < 0.001). CONCLUSIONS: mNGS has high sensitivity and specificity for S. pneumoniae identification. The pathogen load (number of unique reads) of S. pneumonia is related to the CSF collection time. mNGS was less affected than culture by the use of antibiotics before CSF collection.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Meningites Bacterianas/diagnóstico , Metagenômica/métodos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/isolamento & purificação , Adolescente , Fatores Etários , Antígenos de Bactérias/análise , Antígenos de Bactérias/sangue , Antígenos de Bactérias/líquido cefalorraquidiano , Antígenos de Bactérias/genética , Criança , Pré-Escolar , Testes Diagnósticos de Rotina , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Meningites Bacterianas/sangue , Meningites Bacterianas/líquido cefalorraquidiano , Meningites Bacterianas/microbiologia , Pediatria/métodos , Reação em Cadeia da Polimerase/métodos , Valor Preditivo dos Testes , Sensibilidade e Especificidade
4.
Phytochemistry ; 164: 184-191, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31158603

RESUMO

Eleven highly oxygenated meroterpenoids, named terreustoxins A-K, along with five known analogues, were isolated from the Antarctic fungus Aspergillus terreus. The structures and absolute configurations of these undescribed compounds were characterized by NMR spectroscopy, single-crystal X-ray crystallography, and ECD experiments. Terreustoxins A-D are the first examples of meroterpenoids with two ortho-hydroxy groups at C-6 and C-7 in the terretonins family. Terreustoxin C and terretonin inhibited the proliferation of Con A-induced murine T cells at the concentration of 10 µM.


Assuntos
Aspergillus/química , Oxigênio/farmacologia , Terpenos/farmacologia , Animais , Aspergillus/metabolismo , Proliferação de Células/efeitos dos fármacos , Concanavalina A , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Camundongos , Modelos Moleculares , Conformação Molecular , Oxigênio/química , Oxigênio/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Terpenos/química , Terpenos/metabolismo
5.
J Infect ; 78(4): 323-337, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30659857

RESUMO

In this study, we applied metagenomic next-generation sequencing (mNGS) to detect the causative pathogens in brain abscess samples from 4 pediatric patients. NGS could offer unbiased sequencing and rapid diagnosis of causative pathogens, moreover, it could detect multiple pathogenic microorganisms from abscess samples. In our study, Fusobacterium nucleatum, and Streptococcus intermedius or combinations of them were found in 3/4 of polymicrobial brain abscesses. Internal organ abscesses are illustrative of the shortcomings of bacterial culture. NGS has the ability to identify both common and rare pathogens without any prior suspicious needed, and is able to offer a new platform for quantification of all detected microorganisms. Our study displayed the possible potential that NGS is about to provide the diagnostic tools that can characterize even the most complex microbial communities during brain abscesses and is less affected by prior antibiotic exposure.

6.
Talanta ; 194: 430-436, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609554

RESUMO

Utilizing block copolymers as coatings, a protocol of chiral ligand exchange capillary electrochromatography (CLE-CEC) protocol was designed and developed with dual ligands for D,L-amino acids enantioseparation. Four block copolymers including poly maleic anhydride-co-styrene-co-N-methacryloyl-L-histidine methyl ester [P(MAn-St-MAH)], poly maleic anhydride-co-styrene-co-N-methacryloyl-L-lysine methyl ester [P(MAn-St-MAL)], poly maleic anhydride-co-styrene-co-N-methacryloyl-L-phenylalanine methyl ester [P(MAn-St-MAP)] and poly maleic anhydride-co-styrene-co-N-methacryloyl-L-threonine methyl ester [P(MAn-St-MAT)] were synthesized by reversible addition fragmentation chain transfer polymerization reaction. Key factors affecting the enantioresolution were optimized, including the concentration of Zn (II) central ion, pH value of buffer solution and monomers of the block copolymers. The enantioresolution of the proposed CLE-CEC system could be enhanced dramatically by employing P(MAn-St-MAH) as the immobilized chiral ligand and by coordinating the synergistic effect of free ligand in buffer solution. The principle of improved enantioresolution of the CLE-CEC system with dual ligands was discussed. Well enantioseparation was successfully realized with 7 pairs of D,L-amino acids enantiomers baseline separation and 5 pairs part separation. For quantitative analysis of D,L-alanine, a good linearity was established in the range of 9.4 µM to 1.5 mM (r2 = 0.997) with the limits of detection (LODs) 3.7 µM of D-alanine, 2.0 µM for L-alanine, and limits of quantification (LOQs) 9.0 µM for D-alanine and 6.0 µM for L-alanine. The peak area and migration time reproducibility (n = 6) were 4.1% and 3.5% for D-alanine, 3.7% and 3.1% for L-alanine. Further, the enzyme kinetics study of alanine aminotransferase was investigated with the constructed CLE-CEC system.


Assuntos
Aminoácidos/química , Aminoácidos/isolamento & purificação , Eletrocromatografia Capilar/métodos , Alanina Transaminase/química , Alanina Transaminase/metabolismo , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Concentração de Íons de Hidrogênio , Ligantes , Nanopartículas de Magnetita/química , Polimerização , Polímeros/química , Estereoisomerismo
8.
J Ethnopharmacol ; 230: 9-19, 2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30359762

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Involucrum castaneae(IC)is used in Chinese folk medicine to treat various lung diseases, as well as for its reducing phlegm and anti-inflammatory properties. AIM OF THE STUDY: The purpose of this experiment is to verify the effect of IC on airway inflammation, responsiveness in ovalbumin (OVA)-induced asthmatic guinea pigs. The main chemical components of IC were also analyzed. MATERIALS AND METHODS: The potential of the ethanol extract of Involucrum castaneae (EEIC) to protect against OVA-induced allergic airway response in guinea pigs was investigated. The latency of asthma in guinea pigs were recorded after the allergic asthma induced. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of immunoglobulin E (IgE), interleukin-5 (IL-5), nerve growth factor (NGF) and interferon-γ (IFN-γ) in asthma allergy. Reverse transcription-PCR (RT-PCR) was used to detect the expression of IL-5 mRNA in asthmatic guinea pig lungs. Paraffin sections of lung tissue were used to analyze pathological changes. The total flavonoid content was determined and the chemical components were analyzed by LC-MS/MS. RESULTS: It was found that EEIC was able to reduce the number of eosinophil (EOS) in bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) in the guinea pig model of OVA -induced asthma. Meanwhile, it also significantly reduced the levels of inflammation-related factors IgE and IL-5, decreased the expression of IL-5 mRNA in lung tissue, and increased the level of IFN-γ. Pathological examination of paraffin section of lung tissue showed that EEIC can reduce the thickening of bronchial smooth muscle and reduce the infiltration damage of tissues by various inflammatory cells. The presence of flavonoids, terpenoids and phenolic compounds in EEIC might be responsible for these activities. CONCLUSION: IC alleviated airway inflammation and smooth muscle thickening in guinea pigs with OVA-sensitized allergic asthma. The paper explains the traditional efficacy and material basis of IC and lays a foundation for further development.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Fagaceae , Extratos Vegetais/uso terapêutico , Remodelação das Vias Aéreas/efeitos dos fármacos , Alérgenos , Animais , Antiasmáticos/farmacologia , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Etanol/química , Cobaias , Imunoglobulina E/imunologia , Interferon gama/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Ovalbumina , Extratos Vegetais/farmacologia , Solventes/química
10.
Chem Biodivers ; 15(12): e1800395, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30294975

RESUMO

Eight secondary metabolites, including a new polyketide, named asperetide (1) and a new prenylxanthone derivative, called asperanthone (4), and six known compounds, (S)-3-butyl-7-methoxyphthalide (2), ruguloxanthone C (3), tajixanthone hydrate (5), tajixanthone methanoate (6), salimyxin B (7), and ergosterol (8), were isolated and identified from the medicinal plant-derived fungus, Aspergillus sp. TJ23. The new structures and their absolute configurations were elucidated via multiple methods, including 1D- and 2D-NMR, HR-ESI-MS, UV, IR, and the electronic circular dichroism (ECD) calculations. All of the isolates were characterized from the strain for the first time. The in vitro bioassay showed that compounds 3-5 and 8 exerted inhibitory activities against five cancer cell lines (B16, MDA-MB-231, 4T1, HepG2, and LLC) with IC50 values ranging from 5.13 to 36.8 µm.


Assuntos
Aspergillus/química , Policetídeos/química , Xantonas/química , Aspergillus/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Policetídeos/isolamento & purificação , Policetídeos/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Xantonas/isolamento & purificação , Xantonas/farmacologia
11.
Int J Infect Dis ; 74: 47-53, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30100536

RESUMO

OBJECTIVE: To explore the clinical characteristics and etiology of bacterial meningitis (BM) in Chinese children. METHOD: BM cases in children 28days to 18 years old were collected from January 2014-December 2016 and screened according to World Health Organization standards. Clinical features, pathogens, and resistance patterns were analyzed. RESULTS: Overall, 837 cases were classified into five age groups: 28 days-2 months (17.0%), 3-11 months (27.8%), 12-35 months (24.0%), 3-6 years (13.9%), and >6years (17.3%). Major pathogens were Streptococcus pneumoniae (S. pneumoniae, n=136, 46.9%), group B Streptococcus (GBS, n=29, 10.0%), and Escherichia coli (E. coli, n=23, 7.9%). In infants <3 months old, GBS (46.5%) and E. coli (23.3%) were most common; in children >3 months old, S. pneumoniae (54.7%), which had a penicillin non-susceptibility rate of 55.4% (36/65), was most frequent. The resistance rates of S. pneumoniae and E. coli to cefotaxime and ceftriaxone were 14.0%/40.0% and 11.3%/68.4%, respectively. All GBS isolates were sensitive to penicillin. CONCLUSIONS: The occurrence of BM peaked in the first year of life, while S. pneumoniae was the predominant pathogen in children >3months of old. The antibiotic resistance of S. pneumoniae was a concern.


Assuntos
Escherichia coli/isolamento & purificação , Meningites Bacterianas/microbiologia , Streptococcus agalactiae/isolamento & purificação , Streptococcus pneumoniae/isolamento & purificação , Adolescente , Antibacterianos/farmacologia , Cefotaxima/farmacologia , Ceftriaxona/farmacologia , Criança , Pré-Escolar , China/epidemiologia , Farmacorresistência Bacteriana , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/fisiologia , Feminino , Humanos , Lactente , Masculino , Meningites Bacterianas/tratamento farmacológico , Meningites Bacterianas/epidemiologia , Testes de Sensibilidade Microbiana , Penicilina G/farmacologia , Estudos Retrospectivos , Streptococcus agalactiae/efeitos dos fármacos , Streptococcus agalactiae/genética , Streptococcus agalactiae/fisiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/fisiologia
12.
Sci Rep ; 8(1): 5454, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615766

RESUMO

Rising drug resistance limits the treatment options infected by methicillin-resistant Staphylococcus aureus (MRSA). A promising solution for overcoming the resistance of MRSA is to inhibit the penicillin-binding protein 2a (PBP2a). A novel terpene-polyketide hybrid meroterpenoid, aspermerodione (1), characterized by an unusual 2,6-dioxabicyclo[2.2.1]heptane core skeleton, and a new heptacyclic analogue, andiconin C (2), were isolated and identified from the liquid cultures of endophytic fungus Aspergillus sp. TJ23. The structures and their absolute configurations of all chiral centers were elucidated via extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations and determined via single-crystal X-ray diffraction analysis. Aspemerodione (1) was found to be a potential inhibitor of PBP2a, and work synergistically with the ß-lactam antibiotics oxacillin and piperacillin against MRSA.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Aspergillus/metabolismo , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Policetídeos/química , Policetídeos/farmacologia , Terpenos/química , Terpenos/farmacologia , Antibacterianos/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Policetídeos/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Terpenos/metabolismo
13.
Talanta ; 182: 600-605, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29501199

RESUMO

Alanine aminotransferase (ALT) plays significant role in biological and clinical research. In this study, a unique ALT enzyme reactor based on multifunctional polymer@magnetic nanoparticles has been constructed for the first time and the enzymolysis efficiency has been evaluated by chiral ligand exchange capillary electrophoresis technique. Poly(N-acryloxysuccinimide) has been synthesized by reversible addition-fragmentation chain transfer polymerization method and immobilized on the magnetic nanoparticles via the succinimide group in the polymer. Interestingly, the enzyme also could easily react with the succinimide group, which enables of ALT covalent bonding onto the polymer. The enzyme amount immobilized and the immobilization time have been investigated. Comparing with free ALT in solution (Vmax of free enzyme = 0.6 mM min-1), the resultant enzyme reactor has exhibited good reusability and stability, and displayed about five times enhanced enzymolysis efficiency with L-alanine as the substrate (Vmax of enzyme reactor = 3.4 mM min-1). Furthermore, the prepared enzyme reactor has been applied in ALT inhibitors screening. The enzyme reactors based on the multifunctional polymer@magnetic nanoparticles have depicted great potential in anti-liver drugs development, liver diseases study and ALT related biological process inspect.


Assuntos
Alanina Transaminase/química , Alanina/química , Reatores Biológicos , Enzimas Imobilizadas/química , Nanopartículas de Magnetita/química , Acrilatos/química , Alanina Transaminase/antagonistas & inibidores , Biocatálise , Eletroforese Capilar/métodos , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Enzimas Imobilizadas/antagonistas & inibidores , Reutilização de Equipamento , Ensaios de Triagem em Larga Escala , Humanos , Cinética , Nanopartículas de Magnetita/ultraestrutura , Polimerização , Succinimidas/química
14.
Zhonghua Er Ke Za Zhi ; 53(9): 701-6, 2015 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-26757972

RESUMO

OBJECTIVE: To summarize the clinical characteristics and long-term prognosis of herpes simplex virus encephalitis (HSE) in childhood and to analyze genotype of UNC93B1 and TLR3. METHOD: Data of a total of 30 HSE patients admitted to Beijing Children's Hospital from January 2008 to September 2013 were retrospectively analyzed, the data included clinical manifestations, physical sign, auxiliary examination, therapy and long-term clinical prognosis. The family history obtained during follow-up visit was also analyzed for genetic predisposition. With parents' agreement, the blood specimens of patients were collected in EDTA anticoagulant tubes, the first 2 genetic etiologies UNC93B1 and TLR3 were sequenced, and the genetic susceptibility to HSE in childhood was summarized. RESULT: (1) All the 30 patients (100%) had fever, 28 (93%) had seizure, 25 (83%) had altered state of consciousness, only 11 (37%) had personality changes, and in 8 (73%) appeared at or after 2 weeks of onset . (2) During the long-term follow up, 2 (7%) patients died after discharge, 23 patients (82%) had neurological sequelae, 13 patients (57%) had moderate, severe disability and vegetative state. (3) After sequencing of UNC93B1, and TLR3, one patient was found homozygous for a single-nucleotide substitution at position C.414C>G in exon 4 of UNC93B1 which affected the expression of UNC93B1, and may block or decrease the production of interferon. (4) Six single nucleotide polymorphisms (SNPs) were found in this study, their genotype frequency and gene frequency of Chinese were respectively searched in Genomes Project in NCBI and defined 1 000 genomes group. The genotype frequency of UNC93B1 rs7149 between 1 000 genomes group and HSE group was significantly different (χ² = 55.37, P<0.05). The frequency of CC type and C type was higher in HSE group, both of them had significant difference (χ² = 93.90, P<0.05, OR=61.563; χ² = 134.40, P<0.05, OR=12.491). CONCLUSION: HSE lacks specific clinical manifestations, the long-term prognosis is poor. One HSE patient carrying a heterozygous mutation in UNC93B1 which may lead to the susceptibility to HSE and had harmful effect on long-term prognosis. The SNP UNC93B1 rs7149 may also have relationship with susceptibility to HSE and the children carrying CC genotype or C gene in this gene site maybe more susceptible to HSE.


Assuntos
Encefalite por Herpes Simples/genética , Predisposição Genética para Doença , Criança , Encefalite por Herpes Simples/diagnóstico , Frequência do Gene , Genótipo , Humanos , Proteínas de Membrana Transportadoras/genética , Mutação , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Retrospectivos , Receptor 3 Toll-Like/genética
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