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1.
Bioorg Chem ; 101: 103965, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32485471

RESUMO

New Delhi Metallo-ß-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all ß-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06-0.94 µM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time-kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 µg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.

2.
Spectrochim Acta A Mol Biomol Spectrosc ; 228: 117780, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31753651

RESUMO

A sensitive, efficient and quencher-free fluorescence aptasensor to detect Ochratoxin A (OTA) based on aptamer, 2-aminopurine (2AP) labeled Oligonucleotide sequence, as well as exonuclease I (Exo I) activity was developed. In which the aptamer specific to OTA was modified into a hairpin structure, and 8 bases at the 3' ends are exposed (H); also, 2AP is embedded in the oligonucleotide complementary to the 8 bases (2AP-probe).The detection principle based on 2AP-probe could be bonded to its complementary sequence and quenches the fluorescence of 2AP; The aptamer has a stronger affinity for the target than its complementary sequence; Exo I can dissociate single-stranded DNA and has little effect on double-stranded DNA as well as folded DNA. In the absence of OTA, the fluorescence of 2AP is quenched due to the complementary pairing of H and 2AP-probe; in the presence of OTA, H selective binding target is detached from 2AP-probe, and the fluorescence of 2AP is slightly restored. Moreover, when the Exo I is added to the detection system, 2AP-probe is dissociated by the Exo I to release the free 2AP, and the fluorescence of the system is further enhanced thereby realizing the detection of OTA. The detection limit of the aptasensor was low as 0.03 nM with a linear range of 0.5-100 nM. Moreover, the aptasensor has good selectivity and practicability and also has good potential in realizing the detection of toxic and harmful substances in food complex matrices.

3.
Org Lett ; 22(1): 98-101, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31829608

RESUMO

The recently discovered antibiotic burnettramic acid A (1) and three new congeners, burnettramic acids C-E (2-4), were identified from the co-cultures of two marine Aspergillus strains. The structure of burnettramic acid A was revised on the basis of reinterpretation of the nuclear magnetic resonance (NMR) data and chemical derivatization. The full absolute configurations of burnettramic acids were established using the Mosher ester method and Marfey's analysis, combined with density functional theory calculation of NMR and electric circular dichroism data.

4.
Microbiologyopen ; 8(12): e940, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31588663

RESUMO

OBJECTIVE: To find antagonistic strains in the respiratory tract having bacteriostatic properties against common pathogens. METHODS: The oropharyngeal microbiota of five healthy children aged 4-6 years were collected and α-hemolytic bacteria screened on 15% sheep blood agar. Bacteriostatic effects of the isolated α-hemolytic bacteria on Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pyogenes were evaluated by the Oxford cup method. Antagonistic strains were identified by mass spectrometry, and the16S rDNAs were sequenced, and their best bacteriostatic concentrations and antagonistic spectra for Klebsiella pneumoniae, Proteus vulgaris, Enterobacter cloacae, Acinetobacter Baumanii, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pyogenes were evaluated. RESULTS: Of 300 isolated α-hemolytic bacterial clones, four exhibited bacteriostatic activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pyogenes. Mass spectrometric analyses revealed that two of them were Streptococcus mitis and two others were Streptococcus parasanguinis strains. Further tests showed that all 4 antagonistic strains also had bacteriostatic effects on Klebsiella pneumoniae, Proteus vulgaris, Enterobacter cloacae, and Acinetobacter Baumanii, and the mode of action was not mediated by lactic acid production. CONCLUSION: Four antagonistic Streptococcus strains derived from oropharyngeal microbiotas showed bacteriostatic effects on pathogens and may be involved in pharyngeal microbiome homeostasis.

5.
Exp Ther Med ; 18(5): 3484-3492, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31602224

RESUMO

Atmospheric particulate matter with a diameter <2.5 µm (PM2.5) and pollution are worldwide environmental problems and may have negative effects on cardiovascular disease through the lung and gut. The dynamics of intestinal microflora in response to particulate pollutants is unclear. The present study investigated changes in the gut microbiota related to pollutant exposure using spontaneously hypertensive rats (SHR). DNA was extracted from fecal samples. Amplicon Generation and the quality control of PCR products were performed. PCR products was sequenced on an Illumina HiSeq 2500 platform. Data analysis included: operational taxonomic unit (OTU) clustering and species annotation, alpha diversity, beta diversity, principal coordinates analysis (PCoA), and the use of PICRUSt bioinformatics software. The microbial diversity of the SHR rats was inversely associated with exposure to pollutants. In terms of relative abundance, 24 bacterial genera and 2 genera in particular (Actinobacillus and Fusobacterium) significantly declined, and one genus (Treponema) increased. Moreover, pollutant exposure was associated with the accumulation of genes from the gut microbiota that are implicated in cardiovascular diseases. From the long-term exposure experiment, rats appeared to respond to pollutant injury. In conclusion, these results suggest that the effects of atmospheric pollutants on organisms are not limited to the respiratory tract, but also include the gastrointestinal tract. Pollutants are likely to influence the intestinal microbiota and promote the progression of cardiovascular disease.

6.
Molecules ; 24(15)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31382398

RESUMO

A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3ß-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 µM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1-16 µg/mL.


Assuntos
Antivirais/farmacologia , Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Penicillium/química , Antivirais/química , Produtos Biológicos/química , Linhagem Celular , HIV/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
7.
Environ Sci Pollut Res Int ; 26(21): 22040-22050, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31144181

RESUMO

Exposure to fine particulate matter (PM2.5) could induce lung impairment aggravation. Moreover, endogenous substances are known to play a significant role in lung impairment. Therefore, the research objectives was to investigate the influence of PM2.5-induced lung impairment on the levels of the eight endogenous substances, γ-aminobutyric acid (GABA), acetylcholine (ACh), glutamate (Glu), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA), noradrenaline (NE), dopamine (DA), and 3, 4-dihydroxyphenylacetic acid (DOPAC). A sensitive UPLC-MS/MS method for the simultaneous determination of these endogenous substances in rat plasma and lung tissues was developed. The validated method was successfully applied for comparing profiles of analytes in rat plasma and lung tissues. The results indicated that five endogenous substances, namely, GABA, Ach, Glu, DA, and DOPAC, had a significant change in the rats with PM2.5-induced lung impairment.


Assuntos
Pulmão/metabolismo , Material Particulado/toxicidade , Animais , Cromatografia Líquida , Dopamina , Ácido Glutâmico , Masculino , Neurotransmissores , Ratos , Serotonina , Espectrometria de Massas em Tandem/métodos , Ácido gama-Aminobutírico
8.
Environ Pollut ; 246: 972-979, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31126003

RESUMO

In order to investigate the relationship between air pollution and the respiratory tract microbiota, 114 healthy volunteers aged 18-21 years were selected during the winter heating period in Northeast China; 35 from a lightly polluted region (group A), 40 from a moderately polluted region (group B) and 39 from a heavily polluted region (group C). Microbial genome DNA was extracted from throat swab samples to study the oral flora composition of the volunteers by amplifying and sequencing the V3 regions of prokaryotic 16S rRNA. Lung function tests were also performed. The relative abundance of Bacteroidetes and Fusobacteria were significantly lower and Firmicutes Proteonacteria and Actinobacteria higher in participants from polluted regions. Within bacteria classes, Bacterioida abundance was lower and Clostridia abundance higher in polluted areas, which was also reflected in the order of abundance. In samples from region C, the abundance of Prevotellaceae, Veillonellaceae, Porphyromonadaceae, Fusobacteriaceae Paraprevollaceae and Flavobacteriaceae were lowest among the 3 regions studied, whereas the abundance of Lachnospiraceae and Ruminococcaceae were the highest. From group A to group C, the relative class abundances of Prevotella, Veillonella, Fusobacterium, Camphylobacter and Capnocytophaga Porphyromonas, Peptostreptococcus and Moraxella became lower in polluted areas. Pulmonary function correlated with air pollution and the oropharyngeal microbiota differed within regions of high, medium and low air pollution. Thus, during the winter heating period in Northeast China, the imbalance of the oropharyngeal microbiota might be caused by air pollution and is likely associated with impairment of lung function in young people.


Assuntos
Poluição do Ar/análise , Bactérias/classificação , Microbiota , Sistema Respiratório/microbiologia , Adolescente , Bactérias/isolamento & purificação , Bacteroidetes/isolamento & purificação , China , Feminino , Calefação , Humanos , Masculino , RNA Ribossômico 16S/química , Estações do Ano , Análise de Sequência de DNA , Adulto Jovem
9.
Exp Ther Med ; 17(6): 4371-4378, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31086573

RESUMO

Fine particulate matter (PM2.5) pollution has become a serious problem in China. This study aims to elucidate the toxicity mechanism of PM2.5. Protein levels were detected by western blotting and RT-qPCR, and cell cycle was detected by flow cytometry. The results showed that exposure to PM2.5 induces cell cycle arrest and downregulation of the expression of cyclin D1 protein. Moreover, the protein expression of thymidylate synthase (TS) enzyme was found to be downregulated and the mRNA expression of TS was upregulated after PM2.5 exposure. Knockout of TS gene promoted cell cycle arrest and downregulation of the expression of cyclin D1 protein after PM2.5 exposure. Our data further revealed that PM2.5 exposure downregulates the expression of TS and cyclin D1 partially through the downregulation of the mammalian target of rapamycin (mTOR)/P70S6K1 signaling pathway. Thus, these findings indicate that PM2.5-induced cell cycle arrest might be due to the downregulation of mTOR/P70S6K1 signaling pathway, and thus inhibits the expression of TS protein.

10.
J Nat Prod ; 82(5): 1391-1395, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31013089

RESUMO

Raistrickindole A (1), a new indole diketopiperazine alkaloid containing an unusual pyrazino[1',2':2,3][1,2]oxazino[6,5- b]indole tetraheterocyclic ring system, a new benzodiazepine derivative, raistrickin (2), and the known haenamindole (3) and sclerotigenin (4) were isolated from the marine-derived fungus Penicillium raistrickii IMB17-034. Their structures were elucidated by extensive spectroscopic analyses and TDDFT calculations of the NMR and ECD data. Compounds 1 and 2 showed inhibitory activities against the hepatitis C virus.

11.
Environ Sci Pollut Res Int ; 26(9): 8623-8632, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30707384

RESUMO

Fine particulate matter is a global challenge to human health. We investigated the effects and potential mechanisms of fine particulate matter on respiratory tract microecology in a lung injury mouse model. BALB/c mice were randomized into exposed and control groups. We found that the levels of soluble tumor necrosis factor receptor I was increased following the PM2.5 exposure. 16S rRNA sequencing of respiratory tract lavage fluid confirmed that the composition of the respiratory tract microecology was altered by the exposure. Lactobacillus was the most abundant of bacterial species present. Collectively, these results establish a link between exposure to fine particulate matter and alterations to the respiratory tract microecology. Elucidation of the underlying mechanisms may lead to treatment strategies in lung injury.


Assuntos
Material Particulado/toxicidade , Sistema Respiratório/microbiologia , Animais , Modelos Animais de Doenças , Humanos , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos BALB C , RNA Ribossômico 16S , Sistema Respiratório/efeitos dos fármacos
12.
Eur J Med Chem ; 167: 367-376, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776696

RESUMO

Metallo-ß-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) pose an emerging threat to public health worldwide. An effective inhibitor of MBLs is therefore urgently needed for clinical use. In this study, two acyclic pyridine-containing ligands, H2dedpa and compound 8, were discovered with excellent activities when combined with meropenem (MEM) against MBL (blaNDM and blaIMP)-producing clinical isolates, including Escherichia coli, Citrobacter freundii, Proteus mirabilis, Enterobacter cloacae and Klebsiella pneumoniae. In particular, these two compounds improved the activity of MEM against E. coli harboring the blaNDM-4 gene by nearly 40,960 times. H2dedpa (IC50 = 0.17 ±â€¯0.04 µM) and compound 8 (IC50 = 0.04 ±â€¯0.02 µM) showed higher inhibitory activity against blaNDM-1 enzyme than the positive control ethylenediaminetetraacetic acid (EDTA, IC50 = 28.84 ±â€¯0.70 µM). A sterilization kinetics experiment showed that H2dedpain combined with MEM could kill 99.9% of bacteria within 24 h H2dedpa and compound 8 are therefore promising MBL inhibitors.


Assuntos
Enterobacter/efeitos dos fármacos , Etilaminas/farmacologia , Meropeném/farmacologia , Piridinas/farmacologia , Farmacorresistência Bacteriana/genética , Sinergismo Farmacológico , Quimioterapia Combinada , Enterobacter/enzimologia , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/genética , Ligantes , Piridinas/química , beta-Lactamases/efeitos dos fármacos , beta-Lactamases/genética , beta-Lactamases/isolamento & purificação
13.
Transl Psychiatry ; 8(1): 258, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30498208

RESUMO

Antipsychotic pharmacotherapy is strongly obesogenic and is associated with increased oxidative stress in patients with schizophrenia. However, whether these changes reflect psychopathology, antipsychotic efficacy, or some other factor is not known. Our study aims to investigate the degree of oxidative stress in different BMI categories and to identify clinical symptomatology that may be paired with increased oxidative stress in a schizophrenia population. To this end, we performed a cross-sectional study and recruited 89 long-term inpatients with schizophrenia and collected the following variables: plasma malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), routine biochemical analysis, and psychopathology through the Positive and Negative Syndrome Scale (PANSS). The results indicate that the levels of the lipid peroxidation product, MDA, were significantly higher in the high BMI group than the low (normal) BMI group. As expected, high BMI was associated with an atherogenic lipid profile; however, it was also associated with fewer psychopathological symptoms. Multiple regression analysis found that MDA levels, the PANSS general psychopathology subscore, and triglyceride levels (all p < 0.05) were independent contributors to the BMI in patients. These results suggested that oxidative stress may play an important role in antipsychotic-induced weight gain. Further investigations using the longitudinal design in first-episode schizophrenia patients are needed to explore the beneficial effect of antioxidants on the abnormal lipid metabolism mediated by antipsychotic treatment.


Assuntos
Antipsicóticos/efeitos adversos , Obesidade/induzido quimicamente , Obesidade/metabolismo , Estresse Oxidativo , Esquizofrenia/metabolismo , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico
14.
Environ Sci Pollut Res Int ; 25(36): 36136-36146, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30357727

RESUMO

Particulate matter smaller than 2.5 µm (PM2.5) is a continuing challenge to pulmonary health. Here, we investigated the mechanisms involved in PM2.5 exposure-induced acute lung injury in rats. We analyzed biochemical and morphological changes following a 2-week "real-world" exposure. And then we found that PM2.5 exposure increased the concentrations of total protein, malondialdehyde, hydrogen peroxide, nitric oxide, and soluble elastin in bronchoalveolar lavage fluid, levels of cytokines in blood, and expression of MMP-9 in airways. Further, alveolar macrophage and neutrophil counts increased following PM2.5 exposure, and edema and lung lesions were observed. Our results suggest that PM2.5 exposure can induce oxidative stress and acute inflammatory responses, which can damage the micro-environment and decrease the repair ability of the lung, resulting in tissue damage.


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Ambiental/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Material Particulado/toxicidade , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/sangue , Elastina/metabolismo , Peróxido de Hidrogênio/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Malondialdeído/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
15.
Iran J Public Health ; 47(9): 1261-1271, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30320000

RESUMO

Background: We aimed to evaluate the risk factors of the daily mortality associated with air pollution causing acute lower respiratory tract infections. Methods: We applied a short time series analysis to the air pollution record, meteorological data and 133 non-accidental death data in Shengyang, China, in 2013-2015. After controlling the seasonality, day of week and weather conditions, the group employed an over-dispersed Possion generalized addictive model to discuss the associations among different variables, then performed the stratified analysis according to age, gender, and season. Results: Mean concentrations of particulate matter with aerodynamic diameters of < 10 µm (PM10) and < 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) were 122.4, 74.8, 79.4, 47.7, and 86.2 µg/m3, respectively. An increase of 10 µg/m3 in the 8-day moving average concentrations of PM10, PM2.5, SO2, NO2, and O3 corresponded to 0.18% (95% confidence interval [CI]: 0.10%, 0.26%), 0.21% (95% CI: 0.11%, 0.31%), 0.16% (95% CI: 0.04%, 0.30%), 0.43% (95% CI: 0.07%, 0.90%), and 0.10% (95% CI: -0.08%, 0.31%) increase in the daily mortality. The effects of air pollution lasted 9 days (lag 0-8), and they were more statistically significant in the elderly than in other age groups. Conclusion: These findings clarified the burden of air pollution on the morbidity of acute lower respiratory tract infections and emphasized the urgency of the control and prevention of air pollution and respiratory diseases in China.

16.
Oncol Lett ; 16(4): 4507-4511, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30214586

RESUMO

The aim of the study was to find out the association between air pollution and meteorological conditions with the death of residents living in Shenyang due to malignant tumors. Tumor related death data of residents of five urban districts in Shenyang were obtained from Shenyang Center for Disease Control and Prevention. Daily temperature, pressure, wind speed and humidity data of Shenyang from 2010 to 2015 were obtained from Shenyang Meteorological Bureau. Urban air pollution data were obtained from the Shenyang Environmental Monitoring Center Station, Shenyang Environmental Protection Bureau of China. All data were analyzed by the Poisson regression model. During the period from 2010 to 2015, the number of deaths among malignancies in Shenyang was 215,141,000, and the death rate of malignancies in Shenyang was increasing year by year from 2010 to 2015. Mortality rate is higher in men than in women, and mortality rate increased with aging and the highest mortality rate was observed in the 75-80 years age group. Average concentration of aerodynamic diameter of <10 µm particles, the aerodynamic diameter of <2.5 µm particles, sulfur dioxide (SO2) and nitrogen dioxide (NO2) was 122.37, 74.75, 79.36, and 47.65 µg/m3, respectively. After control of confounding factors, it was observed that every 10 µg/m3 increase of PM2.5 is followed by the 0.024% (95% confidence interval: 0.005% and 0.043%) increase of malignant tumor mortality rate. The results show that the increase of air pollution is related to the number of malignant tumors-related deaths in Shenyang, China, and season, sex and age are also influencing factors.

17.
Mar Drugs ; 16(10)2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30241346

RESUMO

Six new tetracenomycin congeners, saccharothrixones E⁻I (1⁻5) and 13-de-O-methyltetracenomycin X (6), were isolated from the rare marine-derived actinomycete Saccharothrix sp. 10-10. Their structures were elucidated by spectroscopic analysis and time-dependent density functional theory (TDDFT)-electronic circular dichroism (ECD) calculations. Saccharothrixones G (3) and H (4) are the first examples of tetracenomycins featuring a novel ring-A-cleaved chromophore. Saccharothrixone I (5) was determined to be a seco-tetracenomycin derivative with ring-B cleavage. The new structural characteristics, highlighted by different oxidations at C-5 and cleavages in rings A and B, enrich the structural diversity of tetracenomycins and provide evidence for tetracenomycin biosynthesis. Analysis of the structure⁻activity relationship of these compounds confirmed the importance of the planarity of the naphthacenequinone chromophore and the methylation of the polar carboxy groups for tetracenomycin cytotoxicity.


Assuntos
Actinomycetales/química , Antineoplásicos/farmacologia , Organismos Aquáticos/química , Naftacenos/farmacologia , Policetídeos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Dicroísmo Circular , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftacenos/química , Naftacenos/isolamento & purificação , Policetídeos/química , Quinonas/química , Relação Estrutura-Atividade
18.
Tuberculosis (Edinb) ; 112: 37-44, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30205967

RESUMO

One lead 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole was identified as an inhibitor of shikimate dehydrogenase with antitubercular activity. Following up this compound, we optimized the lead through systematic modification of the 3 and 6 positions. The antitubercular activities in vitro, shikimate dehydrogenase inhibitory activities and cytotoxicity of derivatives were determined. We found IMB-SD62 with lower cytotoxicity and better activity. Thus, we studied the in vivo efficacy of IMB-SD62 against Mycobacterium tuberculosis and pharmacokinetics of IMB-SD62. In vivo acute M. tuberculosis H37Rv infection assay, IMB-SD62 showed antitubercular activity with the mean lung CFU counts decreasing 1.7 lg. The plasma pharmacokinetics study in rats showed that the oral bioavailability of IMB-SD62 was 14% and the half time was 1.05 h. The results of tissue distribution indicated that IMB-SD62 was mainly absorbed by liver and lung. In vitro metabolism study suggested that the metabolic ways of IMB-SD62 were dealkylated, oxidized and demethylated. CYP enzyme inhibition of IMB-SD62 in human liver microsomes was also evaluated. IMB-SD62 showed barely inhibition on CYP3A4 and CYP2D6. The excretion study manifested that IMB-SD62 was mainly eliminated by fecal excretion in rats. We concluded that based on these pharmaceutical properties, IMB-SD62 has the potential to be developed into new TB drug.


Assuntos
Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiadiazóis/farmacologia , Tuberculose Pulmonar/tratamento farmacológico , Administração Oral , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/metabolismo , Animais , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Disponibilidade Biológica , Biotransformação , Modelos Animais de Doenças , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Fezes/química , Haplorrinos , Humanos , Eliminação Intestinal , Masculino , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Mycobacterium tuberculosis/enzimologia , Ratos Sprague-Dawley , Tiadiazóis/administração & dosagem , Tiadiazóis/farmacocinética , Distribuição Tecidual , Tuberculose Pulmonar/microbiologia
19.
Environ Toxicol Pharmacol ; 60: 169-175, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29730225

RESUMO

Here we investigate the effects and potential mechanisms of PM2.5 on tumor development in a lung cancer mouse model. Tumor-bearing mice (n = 32) were established and randomized into two groups: the PM2.5 or NS exposure group. Compared with the NS exposure group, mice in the PM2.5 exposure group showed an increased number of tumor nodules, increased BAL fluid protein levels, and elevated expressions of MMP1, IL1ß and VEGF. Measurement of angiogenesis from blood serum using an angiogenesis antibody array revealed increased levels of 12 angiogenesis factors in mice after PM2.5 exposure. We also isolated bacteria from the upper respiratory tract of the mice and found that the microecosystem of the upper respiratory tract of tumor-bearing mice was perturbed by PM2.5 exposure. Our findings further establish a key link between PM2.5 and lung cancer and further elucidation of these mechanisms may reveal potential treatment strategies for lung cancer.


Assuntos
Poluentes Atmosféricos/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Material Particulado/toxicidade , Células A549 , Animais , Líquido da Lavagem Broncoalveolar/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Camundongos SCID , Transplante de Neoplasias , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
AMB Express ; 8(1): 13, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29392444

RESUMO

The generation of conditional mutants has been an effective approach to studying bacteria and validating drug targets, and mutants of Mycobacteria are no exception. However unlike other bacteria, there is still a paucity of available tools for Mycobacteria. We constructed a new plasmid containing tetracycline-repressive expression system (TetRr1.7) and Xer Site-Specific recombinase system to generate label-free controllable expression strains. The plasmid was subsequently used to construct a strain of M. tuberculosis expressing the only copy of D-alanine:D-alanine ligase under the control of the tetracycline-repressive promoter. The results showed that the mutant strain lost the ability of colony formation, became more sensitive to D-cycloserine and the cell wall of the mutant strain was disrupted when anhydrotetracycline was added to the medium. Taken together these observations, confirmed that the expression of D-alanine:D-alanine ligase was tightly controlled by the promoter. In conclusion, the new plasmid is a convenient tool for constructing stable conditional mutant strains in Mycobacteria and can be used for future target identification.

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