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1.
Acta Pharmacol Sin ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34795411

RESUMO

Hydrogen sulfide (H2S) is widely recognized as the third endogenous gas signaling molecule and may play a key role in cancer biological processes. ADT-OH (5-(4-hydroxyphenyl)-3H-1,2-dithiocyclopentene-3-thione) is one of the most widely used organic donors for the slow release of H2S and considered to be a potential anticancer compound. In this study, we investigated the antimetastatic effects of ADT-OH in highly metastatic melanoma cells. A tail-vein-metastasis model was established by injecting B16F10 and A375 cells into the tail veins of mice, whereas a mouse footpad-injection model was established by injecting B16F10 cells into mouse footpads. We showed that administration of ADT-OH significantly inhibited the migration and invasion of melanoma cells in the three different animal models. We further showed that ADT-OH dose-dependently inhibited the migration and invasion of B16F10, B16F1 and A375 melanoma cells as evaluated by wound healing and Transwell assays in vitro. LC-MS/MS and bioinformatics analyses revealed that ADT-OH treatment inhibited the EMT process in B16F10 and A375 cells by reducing the expression of FAK and the downstream response protein Paxillin. Overexpression of FAK reversed the inhibitory effects of ADT-OH on melanoma cell migration. Moreover, after ADT-OH treatment, melanoma cells showed abnormal expression of the H2S-producing enzymes CSE/CBS and the AKT signaling pathways. In addition, ADT-OH significantly suppressed the proliferation of melanoma cells. Collectively, these results demonstrate that ADT-OH inhibits the EMT process in melanoma cells by suppressing the CSE/CBS and FAK signaling pathways, thereby exerting its antimetastatic activity. ADT-OH may be used as an antimetastatic agent in the future.

2.
J Med Genet ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544842

RESUMO

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(4): 598-604, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34323037

RESUMO

Objective: To investigate the in vitro eradicative effect of self-assembled azithromycin/rhamnolipid nanoparticles (AZI-RHL NPs) on P seudomonas aeruginosa ( P. aeruginosa) biofilm. Methods: AZI-RHL NPs were prepared and characterized. The minimum inhibitory concentration (MIC) of AZI-RHL NPs on planktonic P. aeruginosa was measured by the broth microdilution method. The eradicative effect of AZI-RHL NPs on P. aeruginosa biofilm was evaluated via crystal violet staining and SYTO 9/PI live/dead staining. Fluorescence labeling was used to measure the eradicative effect of NPs on extracellular polymeric substances (EPS). In addition, crystal violet staining was performed to evaluate the inhibitory effect of AZI-RHL NPs on the adhesion of P. aeruginosa on human bronchial epithelial BEAS-2B cells. To investigate the ability of AZI-RHL NPs to penetrate mucus, the interaction between NPs and mucin was measured via particle size changes after co-incubation with mucin solution. Results: The AZI-RHL NPs had a particle size of about 121 nm and were negatively charged on the surface, displaying a high encapsulation efficiency and a high drug loading capacity of 96.72% and 45.08% for AZI, respectively and 99.38% and 53.07% for RHL, respectively. The MIC of AZI-RHL NPs on planktonic P. aeruginosa was half of that of using AZI alone. AZI-RHL NPs displayed the capacity to effectively destroy the biofilm structure and remove the proteins and polysaccharides in EPS, eradicating biofilms in addition to reducing the survival rate of bacteria in the biofilm. AZI-RHL NPs were shown to have inhibited P. aeruginosa adhesion on BEAS-2B cells and prevented the residual bacteria from forming a new biofilm. There was no significant change in the particle size of NPs after co-incubation with mucin solution, indicating a weak interaction between NPs and mucin, and suggesting that NPs could penetrate the mucus and reach the P. aeruginosa infection sites. Conclusion: AZI-RHL NPs were able to effectively enhance the removal of P. aeruginosa biofilm through a four-step strategy of biofilm eradication, including penetrating the mucus, disintegrating the biofilm structure, killing the bacteria dispersed from biofilm, and preventing the adhesion of residual bacteria. We hope that this study will provide a replicable common strategy for the treatment of refractory infections caused by P. aeruginosa and other types of biofilms.


Assuntos
Nanopartículas , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Azitromicina/farmacologia , Biofilmes , Glicolipídeos , Humanos , Testes de Sensibilidade Microbiana
4.
Tuberculosis (Edinb) ; 112: 120-125, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30205964

RESUMO

OBJECTIVE: To perform a prospective evaluation on the diagnostic performance of an in-house developed, duplex nested IS6110 real-time Polymerase-Chain-Reaction (PCR) assay (IS6110-qPCR assay) for rapid pulmonary TB diagnosis. METHODS: A total of 503 sputum specimens were prospectively collected from July 2016 to November 2016. Diagnostic accuracy and optimal cut-off Cycle-threshold (Ct) value for IS6110-qPCR assay was determined by Receiver Operating Characteristic (ROC) curve. Using the optimal cut-off Ct, diagnostic performance of IS6110-qPCR assay was assessed with reference to both bacteriological and clinical information. Meanwhile, limit of detection (LOD) was calculated using Mycobacterium tuberculosis H37Rv as reference strain. RESULT: ROC curve analysis of IS6110-qPCR assay showed a high Area Under the Curve (AUC) value (0.948) with optimal Ct value at 24.140. Prospective analysis of IS6110-qPCR assay with cut-off Ct = 24.140 showed a high overall sensitivity and specificity of 97.2% and 99.7%, respectively. No cross reactivity was observed among all non-tuberculous mycobacteria specimens in this study. LOD analysis on MTB-spiked sputum showed an average detection limit of 5.0 CFU/mL at Ct = 23.18 (±SD, 0.57). CONCLUSION: IS6110-qPCR assay is a highly accurate and cost-effective assay developed for primary screening of suspected TB cases, which is particularly suitable for regions with limited resources but high TB burden.


Assuntos
Técnicas Bacteriológicas , DNA Bacteriano/genética , Mycobacterium tuberculosis/genética , Reação em Cadeia da Polimerase em Tempo Real , Tuberculose Pulmonar/diagnóstico , Técnicas Bacteriológicas/normas , Calibragem , Marcadores Genéticos , Hong Kong , Humanos , Valor Preditivo dos Testes , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real/normas , Padrões de Referência , Reprodutibilidade dos Testes , Escarro/microbiologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologia , Fluxo de Trabalho
5.
Oncol Rep ; 28(6): 2156-62, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23007606

RESUMO

Copy number variation (CNV) is crucial for gene regulation in humans. A number of studies have revealed that CNV contributes to the initiation and progression of cancer. In this study, we analysed four breast cancer cell lines and six fresh frozen tissues from patients to evaluate the CNV present in the genome using microarray-based comparative genomic hybridization (aCGH). Six genes located at 16q22.1 were analysed by real-time PCR. The real-time PCR analysis revealed that the loss of CDH1/E2F4 may be associated with worse clinical and pathological findings. Interestingly, covariation of CDH1, CDH3, CTCF and E2F4 was found to be associated with triple negative breast cancer and HER-2 receptor status. In conclusion, our study supports the idea that CNV at 16q22.1 in breast cancer is a frequent event; furthermore, it reveals the covariation of CDH1, CDH3, CTCF and E2F4. The role of the covariation is more complex than a simple additive effect of these four separate genes, which may provide a novel target for breast cancer.


Assuntos
Neoplasias da Mama/genética , Caderinas/genética , Carcinoma Ductal de Mama/genética , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA , Fator de Transcrição E2F4/genética , Antígenos CD , Fator de Ligação a CCCTC , Caderinas/deficiência , Linhagem Celular Tumoral , Aberrações Cromossômicas , Fator de Transcrição E2F4/deficiência , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Repressoras/genética
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