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2.
BMC Genomics ; 23(1): 20, 2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-34996351

RESUMO

BACKGROUND: Carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) causes serious infections with significant morbidity and mortality. However, the epidemiology and transmission mechanisms of CR-hvKP and the corresponding carbapenem-resistant plasmids require further investigation. Herein, we have characterized an ST11 K. pneumoniae strain EBSI041 from the blood sample encoding both hypervirulence and carbapenem resistance phenotypes from a patient in Egypt. RESULTS: K. pneumoniae strain EBSI041 showed multidrug-resistance phenotypes, where it was highly resistant to almost all tested antibiotics including carbapenems. And hypervirulence phenotypes of EBSI041 was confirmed by the model of Galleria mellonella infection. Whole-genome sequencing analysis showed that the hybrid plasmid pEBSI041-1 carried a set of virulence factors rmpA, rmpA2, iucABCD and iutA, and six resistance genes aph(3')-VI, armA, msr(E), mph(E), qnrS, and sul2. Besides, blaOXA-48 and blaSHV-12 were harboured in a novel conjugative IncL-type plasmid pEBSI041-2. The blaKPC-2-carrying plasmid pEBSI041-3, a non-conjugative plasmid lacking the conjugative transfer genes, could be transferred with the help of pEBSI041-2, and the two plasmids could fuse into a new plasmid during co-transfer. Moreover, the emergence of the p16HN-263_KPC-like plasmids is likely due to the integration of pEBSI041-3 and pEBSI041-4 via IS26-mediated rearrangement. CONCLUSION: To the best of our knowledge, this is the first report on the complete genome sequence of KPC-2- and OXA-48-coproducing hypervirulent K. pneumoniae from Egypt. These results give new insights into the adaptation and evolution of K. pneumoniae during nosocomial infections.


Assuntos
Infecções por Klebsiella , Klebsiella pneumoniae , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Carbapenêmicos/farmacologia , Egito , Humanos , Infecções por Klebsiella/epidemiologia , Klebsiella pneumoniae/genética , Plasmídeos/genética , beta-Lactamases/genética
3.
Infect Drug Resist ; 12: 2729-2737, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564923

RESUMO

Purpose: The main objectives of the present study were to detect the antimicrobial susceptibility and molecular characteristics of Klebsiella pneumoniae isolated from different hosts and to investigate the possibility of K. pneumoniae transmission between animals and humans. Materials and methods: A total of 189 nonduplicate K. pneumoniae isolates were collected from hospitals and four species of animals in Henan Province, China. The disk diffusion method was used for antimicrobial susceptibility testing, and resistance and virulence genes were screened by polymerase chain reaction (PCR). The molecular types were identified through multilocus sequence typing (MLST), and the hypermucoviscous (HMV) phenotype was identified using the "string-forming test". Pearson's parameters were used to determine the potential link among the molecular types and resistance and virulence genes of all K. pneumoniae strains. Results: The resistance rates of the 189 K. pneumoniae isolates against 15 antibiotics ranged from 11.6% to 77.8%. The highest multidrug resistance rate was detected in the pig strains (93.6%), followed by the human strains (90.4%), chicken strains (88.9%), cow strains (52.0%) and sheep strains (50.0%). Forty-eight (25.4%) K. pneumoniae strains presented the HMV phenotype. entB, fimH-1 and mrkD were the most prevalent of the detected virulence genes, and magA and rmpA were the least prevalent genes in all the isolates. The MLST analysis revealed 24 unique sequence types (STs) among from the 189 isolates. ST11, ST235 and ST258 were common STs among the five isolates of host origin. ST258 exhibited significantly positive correlations with blaNDM, magA and the HMV phenotype and a negative correlation with qnrB. Conclusion: K. pneumoniae strains from different hosts, including humans and animals, have common molecular types and similar phenotypes, and these strains can potentially be transmitted between humans and animals.

4.
Mol Med Rep ; 18(3): 2850-2856, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30015961

RESUMO

Sterol regulatory element binding protein­1c (SREBP­1c), which serves an essential role in the process of fat synthesis, is a key adjustment factor that regulates the dynamic balance of lipid metabolism. SREBP­1c activates the transcription of multiple genes encoding for enzymes involved in the synthesis of triglycerides (TG) and fatty acids (FA) and accelerates lipid synthesis. Previous analysis indicated that long non­coding RNA HCV regulated 1 (lncHR1) participates in lipid metabolism in vivo and regulates the level of SREBP­1c protein. However, the mechanism of lncHR1 in regulating SREBP­1c levels has not been revealed. In the present study, a fatty degeneration cell model was used to study how lncHR1 regulates the SREBP­1c protein at the cellular level. Furthermore TG accumulation was assessed according to morphological analysis. Reverse transcription­quantitative polymerase chain reaction and western blotting were used to detected the expression of SREBP­1c. An activator and an inhibitor of phosphoinositide 3­kinase/AKT phosphorylation (IGF­1 and LY294002, respectively) were used to study the effect of lncHR1 on this pathway. It was verified that lncHR1 regulated SREBP­1c levels and the phosphorylation of AKT in the steatosis cell model. Detailed molecular mechanisms mediated by lncHR1 were associated with the phosphorylation AKT/FoxO1 in Huh7 cell lines. Simultaneously, lncHR1 affected the location of FoxO1 inside and outside of the nucleus. Furthermore, the phosphorylation of PDK1 upstream of AKT was regulated through overexpression or knockdown lncHR1, as determined by western blotting. Taken together, these data show that lncHR1 inhibits SREBP­1c levels through the phosphorylation of the PDK1/AKT/FoxO1 axis.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Proteína Forkhead Box O1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/antagonistas & inibidores , Linhagem Celular Tumoral , Cromonas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Modelos Biológicos , Morfolinas/farmacologia , Ácido Oleico/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo
5.
Oncotarget ; 8(16): 27286-27299, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28460483

RESUMO

Epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) both overexpressed on non-small cell lung cancer (NSCLC) and are known cooperatively to promote tumor progression and drug resistance. This study was to construct a novel bispecific fusion protein EGF-IGF-LDP-AE consisting of EGFR and IGF-IR specific ligands (EGF and IGF-1) and lidamycin, an enediyne antibiotic with potent antitumor activity, and investigate its antitumor efficacy against NSCLC. Binding and internalization assays showed that EGF-IGF-LDP protein could bind to NSCLC cells with high affinity and then internalized into cells with higher efficiency than that of monospecific proteins. In vitro, the enediyne-energized analogue of bispecific fusion protein (EGF-IGF-LDP-AE) displayed extremely potent cytotoxicity to NSCLC cell lines with IC50<10-11 mol/L. Moreover, the bispecific protein EGF-IGF-LDP-AE was more cytotoxic than monospecific proteins (EGF-LDP-AE and LDP-IGF-AE) and lidamycin. In vivo, EGF-IGF-LDP-AE markedly inhibited the growth of A549 xenografts, and the efficacy was more potent than that of lidamycin and monospecific counterparts. EGF-IGF-LDP-AE caused significant cell cycle arrest and it also induced cell apoptosis in a dosage-dependent manner. Pretreatment with EGF-IGF-LDP-AE inhibited EGF-, IGF-stimulated EGFR and IGF-1R phosphorylation, and blocked two main downstream signaling molecules AKT and ERK activation. These data suggested that EGF-LDP-IGF-AE protein would be a promising targeted agent for NSCLC patients with EGFR and/or IGF-1R overexpression.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Enedi-Inos , Receptores ErbB/antagonistas & inibidores , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Neoplasias Pulmonares/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Enedi-Inos/química , Receptores ErbB/metabolismo , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Ligação Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Oncotarget ; 7(51): 85318-85331, 2016 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-27863401

RESUMO

Imbalances in intestinal bacteria correlate with colitis-associated colorectal cancer (CAC). Traditional Chinese medicines have been used to adjust the gut microbiota, and isoliquiritigenin (ISL), a flavonoid extracted from licorice, has shown antitumor efficacy. In this study, the effects of ISL on CAC development and the gut microbiota were evaluated using an azoxymethane and dextran sulphate sodium (AOM/DSS)-induced mouse model of CAC (CACM). Histopathological analysis suggested that ISL reduced tumor incidence in vivo. Moreover, high-throughput sequencing and terminal restriction fragment length polymorphism (T-RFLP) studies of the bacterial 16S rRNA gene revealed that the structure of the gut microbial community shifted significantly following AOM/DSS treatment, and that effect was alleviated by treatment with high-dose ISL (150 mg/kg). Compared to the microbiota in the control mice (CK), the levels of Bacteroidetes decreased and the levels of Firmicutes increased during CAC development. ISL reversed the imbalance at the phylum level and altered the familial constituents of the gut microbiota. Specifically, the abundance of Helicobacteraceae increased after treatment with high-dose ISL, while the abundance of Lachnospiraceae and Rikenellaceae decreased. At the genus level, ISL reduced the abundance of opportunistic pathogens (Escherichia and Enterococcus), and increased the levels of probiotics, particularly butyrate-producing bacteria (Butyricicoccus, Clostridium, and Ruminococcus). Thus, ISL protects mice from AOM/DSS-induced CAC, and ISL and the gut microbiota may have synergistic anti-cancer effects.


Assuntos
Bacteroidetes/efeitos dos fármacos , Chalconas/uso terapêutico , Colite/tratamento farmacológico , Neoplasias Colorretais/prevenção & controle , Firmicutes/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Helicobacteraceae/efeitos dos fármacos , Animais , Bacteroidetes/genética , Colite/complicações , Colite/microbiologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/microbiologia , Modelos Animais de Doenças , Firmicutes/genética , Glycyrrhiza , Helicobacteraceae/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos BALB C , Probióticos , RNA Ribossômico 16S/análise
7.
Asian Pac J Cancer Prev ; 14(10): 6069-75, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24289627

RESUMO

BACKGROUND: At present, the diagnosis of colorectal cancer (CRC) requires a colorectal biopsy which is an invasive procedure. We undertook this pilot study to develop an alternative method and potential new biomarkers for diagnosis, and validated a set of well-integrated tools called ClinProt to investigate the serum peptidome in CRC patients. METHODS: Fasting blood samples from 67 patients diagnosed with CRC by histological diagnosis, 55 patients diagnosed with colorectal adenoma by biopsy, and 65 healthy volunteers were collected. Division was into a model construction group and an external validation group randomly. The present work focused on serum proteomic analysis of model construction group by ClinProt Kit combined with mass spectrometry. This approach allowed construction of a peptide pattern able to differentiate the studied populations. An external validation group was used to verify the diagnostic capability of the peptidome pattern blindly. An immunoassay method was used to determine serum CEA of CRC and controls. RESULTS: The results showed 59 differential peptide peaks in CRC, colorectal adenoma and health volunteers. A genetic algorithm was used to set up the classification models. Four of the identified peaks at m/z 797, 810, 4078 and 5343 were used to construct peptidome patterns, achieving an accuracy of 100% (> CEA, P < 0. 05). Furthermore, the peptidome patterns could differentiate the validation group with high accuracy close to 100%. CONCLUSIONS: Our results showed that proteomic analysis of serum with MALDI-TOF MS is a fast and reproducible approach, which may provide a novel approach to screening for CRC.


Assuntos
Adenoma/sangue , Biomarcadores Tumorais/sangue , Proteínas Sanguíneas/análise , Neoplasias Colorretais/sangue , Separação Imunomagnética/métodos , Proteômica , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adenoma/patologia , Estudos de Casos e Controles , Colo/metabolismo , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fragmentos de Peptídeos/análise , Mapeamento de Peptídeos , Prognóstico , Reto/metabolismo
8.
Oncol Rep ; 27(5): 1639-45, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22293713

RESUMO

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) amplification occurs in over 30% of esophageal carcinomas. Combination therapies with EGFR and HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for esophageal cancer. We evaluated the antitumor effects of lapatinib, a dual tyrosine kinase inhibitor which simultaneously inhibits EGFR and HER2, 5-fluorouracil (5-Fu) alone and in combination on esophageal cancer cells. The antiproliferative activity of lapatinib, 5-Fu and lapatinib plus 5-Fu was measured by MTT assay and the combination index (CI) values were calculated. Additionally, cell cycle distribution of lapatinib alone and the combination with 5-Fu were detected by flow cytometry analysis. Annexin V-FITC and propidium iodide stain were used for analyzing the apoptotic cells after cells were treated with either agent alone or in combination. The EGFR and HER2 activated signaling pathways were monitored by western blotting. The combination of lapatinib and 5-Fu synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect on esophageal cancer cells. The potentiation effect of combined treatment was associated with downregulation of EGFR and HER2 signaling pathways because data from western blot analysis showed that lapatinib in combination with 5-Fu markedly reduced the phosphorylation of EGFR and HER2, and inhibited the activation of downstream signaling molecules, such as AKT and ERK. A significant G1 arrest was also observed in cell cycle analysis after exposing cells to lapatinib, however, combination with 5-Fu did not enhance G1 arrest. These results indicate that the combination of the lapatinib and 5-Fu is a promising treatment option for esophageal carcinoma with HER2 amplification.


Assuntos
Receptores ErbB/antagonistas & inibidores , Neoplasias Esofágicas/metabolismo , Fluoruracila/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Amplificação de Genes , Humanos , Lapatinib , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
9.
Wei Sheng Yan Jiu ; 33(2): 183-5, 2004 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-15209000

RESUMO

OBJECTIVE: To explore the effects of taurine on the heart defects in chick embryos induced by homocysteine (HCY). METHODS: Through the teratogenicity test of Chick Embryos, the taurine and HCY were given to yolk sac of 3 day's chick embryos. Histopathological examination after another 2 days culture. RESULTS: The occurrence of heart defects on HCY group were significantly increased. The growth of vitelline vessels was decreased. The prevention of tautine on the heart defects in chick embryos induced by HCY was very significantly effective. CONCLUSION: Taurine can prevent the developmental disturbance of hearts induced by HCY in this experiment.


Assuntos
Cardiopatias Congênitas/prevenção & controle , Homocisteína , Taurina/farmacologia , Animais , Embrião de Galinha , Cardiopatias Congênitas/induzido quimicamente
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