Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 65
Filtrar
1.
Pharmacogenomics ; 22(13): 821-831, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34505535

RESUMO

Aim: The relationship between hyperuricemia and polymorphisms of transporter genes in coronary artery disease (CAD) patients in China remains unclear. Materials & methods: A total of 258 hyperuricemia patients with CAD and 242 control patients with CAD were recruited in this case-control study. Twenty-four SNPs in genes of ABCG2, PDZK1, URAT1, OAT4, GLUT9, ABCC4, NPT1 and NPT4 were genotyped using direct sequencing in all subjects. Results: The mutation of ABCG2 rs2231142 locus increases the risk of hyperuricemia, and there is a gene dose effect in the influence of mutant heterozygotes and homozygotes. rs3825017 in URAT1 and rs62293298 in GLUT9 were also confirmed to be associated with hyperuricemia. Conclusion: Age, weight, creatinine clearance rate, diuretics and SNPs on ABCG2, URAT1 and GLUT9 were all risk factors of hyperuricemia.

2.
BMC Infect Dis ; 21(1): 913, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488670

RESUMO

BACKGROUND: While miliary tuberculosis (TB) in pregnancy is rare after in vitro fertilization and embryo transfer (IVF-ET), it poses a serious threat to the health of pregnant women and their fetuses. The present study aimed to describe the clinical features of miliary TB and pregnancy outcomes of patients after IVF-ET. METHODS: Data of infertile patients who received IVF-ET at Peking University Third Hospital between January 2012 and December 2017 were retrospectively analyzed. Patients who developed miliary TB during pregnancy were identified, and clinical characteristics of miliary TB were described. RESULTS: Out of 62,755 infertile women enrolled, 7137 (11.4 %) showed signs of prior pulmonary TB on chest X-ray (CXR). Among the 15,136 women (mean age: 33.2 ± 5.0 years) who successfully achieved clinical pregnancy, seven patients aged 28-35 years had miliary TB during pregnancy, with two patients having a complication of TB meningitis. All these patients presented with fever. Notably, old TB lesions were detected on CXR in six patients before IVF-ET; nevertheless, no anti-TB therapy was administered. Furthermore, salpingography revealed oviduct obstruction in all patients (7/7). Patients received anti-TB therapy following a diagnosis of miliary TB and were clinically cured. However, pregnancy was terminated due to spontaneous (4/7) and induced (3/7) abortion. CONCLUSIONS: TB reactivation, mostly as miliary TB and TB meningitis, is severe in pregnant women after IVF-ET and deleterious to pregnancy outcomes. Signs of prior TB on CXR may be risk factors for TB reactivation during pregnancy.


Assuntos
Infertilidade Feminina , Tuberculose Miliar , Adulto , Transferência Embrionária , Feminino , Fertilização In Vitro , Humanos , Infertilidade Feminina/terapia , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Tuberculose Miliar/diagnóstico
3.
World J Surg Oncol ; 19(1): 232, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362378

RESUMO

BACKGROUND: The aim of this study is to unravel the role of Cyanidin-3-glucoside (C3G) and its potential mechanisms in lung adenocarcinoma (LUAD). METHODS: The cell clones, proliferation, apoptosis, migration, and invasion in H1299 and A549 cells were determined by colony formation assay, 5-ethynyl-20 deoxyuridine (EdU) assay, flow cytometry, and transwell assay, respectively. The expression of p53-induced gene 3 (TP53I3) was assessed and the prognostic values of TP53I3 in LUAD via the dataset from the Cancer Genome Atlas (TCGA). In addition, the mRNA and protein expressions were detected by quantitative real-time PCR (qRT-PCR) and western blot. RESULTS: C3G inhibited the proliferation, migration, and invasion of, and also promoted the apoptosis in H1299 and A549 cells. The database of TCGA showed TP53I3 was highly expressed in LUAD tissues and correlated with the poor prognosis of LUAD patients. Moreover, we also found that C3G inhibited the proliferation, migration and invasion, and promoted apoptosis in H1299 and A549 cells by downregulating TP53I3. Additionally, C3G could inhibit the activation of phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in H1299 and A549 cells by downregulating TP53I3. CONCLUSION: This study demonstrated that C3G could inhibit the proliferation, migration and invasion, and also facilitate the apoptosis through downregulating TP53I3 and inhibiting PI3K/AKT/mTOR pathway in LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Antocianinas , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
4.
Environ Pollut ; 290: 118027, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34428706

RESUMO

With the fast growth of the production and application of engineered nanomaterials (ENMs), nanoparticles (NPs) that escape into the environment have drawn increasing attention due to their ecotoxicological impacts. Motile microalgae are a type of primary producer in most ecosystems; however, the impacts of NPs on the motility of microalgae have not been studied yet. So the toxic impacts of three common metal oxide NPs (nTiO2, nZnO, and nFe2O3) on swimming speed and locomotion mode of a marine microalgae, Platymonas subcordiformis, were investigated in this study. Our results demonstrated that both the velocity and linearity (LIN) of swimming were significantly decreased after the exposure of P. subcordiformis to the tested NPs. In addition, the obtained data indicate that NPs may suppress the motility of P. subcordiformis by constraining the energy available for swimming, as indicated by the significantly lower amounts of intracellular ATP and photosynthetic pigments and the lower activities of enzymes catalyzing glycolysis. Incubation of P. subcordiformis with the tested NPs generally resulted in the overproduction of reactive oxygen species (ROS), aggravation of lipid peroxidation, and induction of antioxidant enzyme activities, suggesting that imposing oxidative stress, which may impair the structural basis for swimming (i.e. the membrane of flagella), could be another reason for the observed motility suppression. Moreover, NP exposure led to significant reductions in the cell viability of P. subcordiformis, which may be due to the disruption of the energy supply (i.e., photosynthesis) and ROS-induced cellular damage. Our results indicate that waterborne NPs may pose a great threat to motile microalgae and subsequently to the health and stability of the marine ecosystem.

5.
J Clin Pharmacol ; 61(10): 1376-1385, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33974709

RESUMO

Most patients experience severe hematological toxicity during treatment with gemcitabine; thus, preventing such toxicity would improve the treatment effects and patient quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets, and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single-locus analysis showed that the single-nucleotide polymorphisms (SNPs) RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia, hENT1 rs760370 and hCNT3 rs7867504 and rs4877831 were associated with severe leukopenia, CDA rs2072671, DCTD rs7663494, and WEE1 rs3910384 were associated with severe anemia, and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P < .0038). The gene-gene interaction analysis identified the overall best models, including a 2-way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leukopenia (P = .0022) and a 3-locus model (CDA rs207671, DCTD rs7663494, and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P = .0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, in which the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC, and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggest that the gene-gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine-induced hematological toxicity. Moreover, we propose a promising data-mining analysis approach (generalized multifactor dimensionality reduction) to detect and characterize gene-gene interactions.

6.
Sci Total Environ ; 783: 147003, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-33865135

RESUMO

Microplastics (MPs) and polycyclic aromatic hydrocarbons (PAHs) are universally detected in the marine ecosystem and may exert adverse impacts on marine species. Although under realistic pollution scenarios, PAH pollution usually occurs as a mixture of different PAH compounds, the toxic impacts of PAH mixtures on marine organisms remain largely unknown to date, including their interactions with other emergent pollutants such as MPs. In this study, the single and combined toxic impacts of polystyrene MPs and a mixture of PAHs (standard mix of 16 representative PAHs) on haematic parameters were evaluated in the blood clam Tegillarca granosa. Our data demonstrated that blood clams treated with the pollutants examined led to decreased total haemocyte count (THC), changed haematic composition, and inhibited phagocytosis of haemocytes. Further analyses indicated that MPs and a mixture of PAHs may exert toxic impacts on haematic parameters by elevating the intracellular contents of reactive oxygen species (ROS), giving rise to lipid peroxidation (LPO) and DNA damage, reducing the viability of haemocytes, and disrupting important molecular signalling pathways (indicated by significantly altered expressions of key genes). In addition, compared to clams treated with a single type of pollutant, coexposure to MPs and a mixture of PAHs exerted more severe adverse impacts on all the parameters investigated, indicating a significant synergistic effect of MPs and PAHs.


Assuntos
Bivalves , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , Animais , Ecossistema , Microplásticos , Plásticos , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
7.
Intern Emerg Med ; 16(7): 1883-1893, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33728578

RESUMO

Persistent inflammation, immunosuppression and catabolism syndrome (PICS) in critically ill patients are associated with unreliable creatinine (Cr)-based estimated glomerular filtration rate (eGFR) and alteration in vancomycin clearance (CL) due to ongoing muscle wasting and renal dysfunction (RD). Currently, cystatin C (Cys) is of great interest for eGFR due to its muscle independence. Patients receiving intravenous vancomycin with trough concentration monitoring after intensive care unit stay ≥ 14 days were retrospectively enrolled. Those with C-reactive protein > 30.0 mg/L, lymphocytes count < 0.80 × 109, albumin < 30 mg/L and weight loss > 10% were diagnosed with PICS. Impact of PICS on vancomycin trough achievement was analyzed. Plasma Cys and Cr levels with their eGFRs in RD were compared in patients with and without PICS. Furthermore, the performance of eGFRs in predicting vancomycin CL was quantificationally evaluated by population pharmacokinetics (PPK) analysis using the Phoenix NLME software. Of 69 enrolled patients, 32 (46.4%) were PICS. PICS was predictive of Cr-guided vancomycin supratherapeutic trough concentrations (OR = 5.26, P = 0.013). Significant elevation of Cys, not of Cr, was observed in patients with PICS suffering from RD (P = 0.022), causing substantial differences among eGFRs. Fifty-two and 17 patients were enrolled for the modeling group and validation group, respectively. A one-compartment PPK model with first-order elimination adequately described the data of 126 Ctrough. Prediction of vancomycin CL with Cys and Cr-based eGFR (CKD-EPIcys-cr) significantly reduced the interindividual variability of CL (from 75.6 to 28.5%). External validation with 34 Ctrough showed the robustness and accuracy of this model. This study showed the negative impact of PICS on Cr-guided vancomycin trough achievement. PPK model with CKD-EPIcys-cr can be used to optimize vancomycin dosage in patients with PICS.

8.
IEEE Trans Image Process ; 30: 3474-3486, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33661733

RESUMO

Performance of blind image quality assessment (BIQA) models has been significantly boosted by end-to-end optimization of feature engineering and quality regression. Nevertheless, due to the distributional shift between images simulated in the laboratory and captured in the wild, models trained on databases with synthetic distortions remain particularly weak at handling realistic distortions (and vice versa). To confront the cross-distortion-scenario challenge, we develop a unified BIQA model and an approach of training it for both synthetic and realistic distortions. We first sample pairs of images from individual IQA databases, and compute a probability that the first image of each pair is of higher quality. We then employ the fidelity loss to optimize a deep neural network for BIQA over a large number of such image pairs. We also explicitly enforce a hinge constraint to regularize uncertainty estimation during optimization. Extensive experiments on six IQA databases show the promise of the learned method in blindly assessing image quality in the laboratory and wild. In addition, we demonstrate the universality of the proposed training strategy by using it to improve existing BIQA models.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação , Bases de Dados Factuais , Humanos , Laboratórios
9.
Theranostics ; 11(4): 1828-1844, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33408784

RESUMO

This study aimed to screen novel anticancer strategies from FDA-approved non-cancer drugs and identify potential biomarkers and therapeutic targets for colorectal cancer (CRC). Methods: A library consisting of 1056 FDA-approved drugs was screened for anticancer agents. WST-1, colony-formation, flow cytometry, and tumor xenograft assays were used to determine the anticancer effect of azelastine. Quantitative proteomics, confocal imaging, Western blotting and JC-1 assays were performed to examine the effects on mitochondrial pathways. The target protein of azelastine was analyzed and confirmed by DARTS, WST-1, Biacore and tumor xenograft assays. Immunohistochemistry, gain- and loss-of-function experiments, WST-1, colony-formation, immunoprecipitation, and tumor xenograft assays were used to examine the functional and clinical significance of ARF1 in colon tumorigenesis. Results: Azelastine, a current anti-allergic drug, was found to exert a significant inhibitory effect on CRC cell proliferation in vitro and in vivo, but not on ARF1-deficient or ARF1-T48S mutant cells. ARF1 was identified as a direct target of azelastine. High ARF1 expression was associated with advanced stages and poor survival of CRC. ARF1 promoted colon tumorigenesis through its interaction with IQGAP1 and subsequent activation of ERK signaling and mitochondrial fission by enhancing the interaction of IQGAP1 with MEK and ERK. Mechanistically, azelastine bound to Thr-48 in ARF1 and repressed its activity, decreasing Drp1 phosphorylation. This, in turn, inhibited mitochondrial fission and suppressed colon tumorigenesis by blocking IQGAP1-ERK signaling. Conclusions: This study provides the first evidence that azelastine may be novel therapeutics for CRC treatment. ARF1 promotes colon tumorigenesis, representing a promising biomarker and therapeutic target in CRC.


Assuntos
Fator 1 de Ribosilação do ADP/metabolismo , Neoplasias do Colo/tratamento farmacológico , Dinaminas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Ftalazinas/farmacologia , Proteínas Ativadoras de ras GTPase/metabolismo , Fator 1 de Ribosilação do ADP/genética , Animais , Antialérgicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Dinaminas/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Ativadoras de ras GTPase/genética
10.
Mar Pollut Bull ; 164: 111995, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33493858

RESUMO

Living in close proximity to the sediment of coastal areas, bivalves may be exposed to veterinary antibiotic residuals and microplastics (MPs) simultaneously. However, the immunotoxic impacts of veterinary antibiotics remain unknown in bivalves, let alone their interactions with MPs. Therefore, the immune responses of two representative veterinary antibiotics, oxytetracycline and florfenicol, was investigated in a bivalve species, the blood clam (Tegillarca granosa). The effects of the copresence of MPs on the immune responses triggered by these antibiotics were also analyzed. Results showed that exposure to antibiotics investigated led to significant alteration in hematic parameters and reduction in lectin content in serum. In addition to inducing ROS production, aggravating lipid peroxidation and DNA damage, and suppressing the hemocyte viability, antibiotic treatments also downregulated the expression of immune- and detoxification-related genes but upregulated apoptosis-related Caspase-3. Furthermore, the toxic impacts of antibiotics were found to be significantly increased by the copresence of MPs.


Assuntos
Bivalves , Poluentes Químicos da Água , Animais , Antibacterianos/toxicidade , Imunidade , Microplásticos , Plásticos , Poliestirenos , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
11.
Int J Clin Pharm ; 43(1): 174-180, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32815111

RESUMO

Background The misunderstanding of adverse drug reaction labelling information is not conducive to the rational use of drugs. There has been no research on how doctors can effectively transmit information on adverse drug reactions to patients in China. Objective To assess how well patients understand the adverse reactions presented in the labelling of drugs and how much information they want from their doctor regarding the adverse reactions. Setting The study was conducted in secondary medical institutions, tertiary medical institutions and community healthcare centres in Shanghai. Method A cross-sectional self-administered survey was conducted from November 2018 to March 2019. Mixed methods involving paper questionnaires and online surveys (scan a QR code by the WeChat app) were used. Main outcome measure Participants' demand for adverse reaction information. Results A total of 295 people completed the questionnaires, of which 31.8% of people thought that the greater the number of adverse reactions listed on the label of a drug, the more insecure they felt about that drug. At the same time, 30.13% of people thought that if the adverse reactions listed on a label were undefined, then the drug was safe for use (for example, some Chinese patent medicines). Most of the respondents (45.4%) thought that it was better to give a brief description of possible adverse reactions and to answer patients' questions in detail only if necessary. Conclusions Most patients wanted doctors to give them a brief introduction to serious and common adverse reactions when they prescribed drugs, and only a small percentage of people wanted to obtain all the information about adverse reactions. It was found that many people misunderstood the contents of the adverse reactions provided on the labels and equated the number of adverse reactions with drug safety.

12.
J Clin Ultrasound ; 49(3): 250-253, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32954549

RESUMO

Apert syndrome is characterized by craniosynostosis, mid-facial hypoplasia, and symmetric syndactyly. Prenatal diagnosis is challenging until the skull and facial anomalies become more pronounced during the third trimester. We present a case in which typical sonographic signs of Apert syndrome were observed after 23 weeks of gestation. Following termination of the pregnancy, both clinical features such as craniofacial abnormalities and syndactyly and cranial 3D-CT images showed high correlation with the previous sonographic findings. Furthermore, genetic analysis revealed a spontaneous mutation, c.755C≥G (p.S252W), in the FGFR2 gene, with this mutation implicated in the etiology of Apert syndrome.


Assuntos
Acrocefalossindactilia/diagnóstico por imagem , Acrocefalossindactilia/genética , Tomografia Computadorizada por Raios X , Ultrassonografia Pré-Natal , Autopsia , Feminino , Humanos , Mutação , Gravidez , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Crânio/anormalidades
13.
Eur J Clin Pharmacol ; 77(4): 595-605, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33179758

RESUMO

PURPOSE: This study aimed to predict the presence and mechanism of busulfan drug-drug interactions (DDIs) in hematopoietic stem cell transplantation (HSCT) using pharmacokinetic interaction (PKI) network-based molecular structure similarity and network pharmacology. METHODS: Logistic function models were established to predict busulfan DDIs based on the assumption that an approved drug tends to interact with the drug used in HSCT (DH) if structurally similar to the drugs in the PKI network of the DH. The PKI network of the DH represented the association between drugs and the proteins related to the PK of the DH. The most appropriate model was applied to predict busulfan DDIs in HSCT. Candidate targets for busulfan DDIs and their interacting were identified by network pharmacology. RESULTS: Six of the top ten predicted busulfan DDIs were clinically relevant and involved voriconazole, fludarabine, itraconazole, cyclophosphamide, metronidazole, and melphalan. Candidate targets for these DDIs were CYP450s (3A4, 2B6, 2C9, and 2C19), GSTs (GSTA1, GSTP1, GSTT1, and GSTM1), and ABC transporters (ABCB1, ABCC1, ABCC2, and ABCC3), in the targets of drug-induced liver injury (DILI). The networks of interacting proteins and candidate targets indicated the regulatory potential of pregnane X receptor (PXR), as a nuclear receptor. Enrichment analysis showed the metabolism of drugs and xenobiotics, glutathione metabolism, and bile secretion associated with busulfan DDIs and DILI. CONCLUSIONS: This study has successfully predicted busulfan DDIs in HSCT through PKI-based molecular structure similarity. The mechanism of busulfan DDI and DILI was attributed mostly to CYP450s, GSTs, and ABC transporters, and PXR was identified as a potential target.

14.
Adv Sci (Weinh) ; 7(22): 2002306, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33240775

RESUMO

Resistance to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) of cancer cell remains a key obstacle for clinical cancer therapies. To overcome TRAIL resistance, this study identifies curcumol as a novel safe sensitizer from a food-source compound library, which exhibits synergistic lethal effects in combination with TRAIL on non-small cell lung cancer (NSCLC). SILAC-based cellular thermal shift profiling identifies NRH:quinone oxidoreductase 2 (NQO2) as the key target of curcumol. Mechanistically, curcumol directly targets NQO2 to cause reactive oxygen species (ROS) generation, which triggers endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) death receptor (DR5) signaling, sensitizing NSCLC cell to TRAIL-induced apoptosis. Molecular docking analysis and surface plasmon resonance assay demonstrate that Phe178 in NQO2 is a critical site for curcumol binding. Mutation of Phe178 completely abolishes the function of NQO2 and augments the TRAIL sensitization. This study characterizes the functional role of NQO2 in TRAIL resistance and the sensitizing function of curcumol by directly targeting NQO2, highlighting the potential of using curcumol as an NQO2 inhibitor for clinical treatment of TRAIL-resistant cancers.

15.
Signal Transduct Target Ther ; 5(1): 271, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33243974

RESUMO

Metastasis is the main factor of treatment failure in cancer patients, but the underlying mechanism remains to be elucidated and effective new treatment strategies are urgently needed. This study aims to explore novel key metastasis-related microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC). By comparing miRNA profiles of the highly metastatic ESCC cell sublines, we established through serial in vivo selection with the parental cells, we found that the expression level of miR-515-3p was lower in ESCC tumor tissues than adjacent normal tissues, further decreased in metastatic tumors, and moreover, markedly associated with advanced stage, metastasis and patient survival. The in vitro and in vivo assays suggested that miR-515-3p could increase the expression of the epithelial markers as well as decrease the expression of the mesenchymal markers, and more importantly, suppress invasion and metastasis of ESCC cells. Mechanistically, we revealed that miR-515-3p directly regulated vimentin and matrix metalloproteinase-3 (MMP3) expression by binding to the coding sequence and 3'untranslated region, respectively. In addition, the data from whole-genome methylation sequencing and methylation-specific PCR indicated that the CpG island within miR-515-3p promoter was markedly hypermethylated in ESCC cell lines and ESCC tumor tissues, which may lead to deregulation of miR-515-3p expression in ESCC. Furthermore, our preclinical experiment provides solid evidence that systemic delivery of miR-515-3p oligonucleotide obviously suppressed the metastasis of ESCC cells in nude mice. Taken together, this study demonstrates that miR-515-3p suppresses tumor metastasis and thus represents a promising prognostic biomarker and therapeutic strategy in ESCC.

16.
Cancer Lett ; 489: 66-78, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32544514

RESUMO

Lung cancer is the most frequent cancer worldwide with a poor prognosis. Identification of novel cancer targets and useful therapeutic strategies without toxicity are urgently needed. In this study, we screened natural products for anticancer bioactivity in a library consisting of 429 small molecules. We demonstrated for the first time that daurisoline, a constituent of Rhizoma Menispermi, repressed lung cancer cell proliferation by inducing cell cycle arrest at the G1 phase. Furthermore, daurisoline was found not only to suppress the growth of lung tumor xenografts in animals without obvious side effects, but also to inhibit cell migration and invasion. Mechanistically, quantitative proteomics and bioinformatics analyses, Western blotting and qRT-PCR confirmed that daurisoline exerted its anticancer effects by inhibiting the expression levels of ß-catenin and its downstream targets c-myc and cyclin D1. Furthermore, our data from Drug Affinity Responsive Target Stability (DARTS), isothermal titration calorimetry (ITC) and a series of functional assays demonstrated that daurisoline could target HSP90 directly and disrupt its interaction with ß-catenin, therefore increasing the ubiquitin-mediated proteasomal degradation of ß-catenin. This study reveals that daurisoline could be a promising therapeutic strategy for the treatment of lung cancer.


Assuntos
Antineoplásicos/farmacologia , Benzilisoquinolinas/farmacologia , Carcinogênese/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Neoplasias Pulmonares/patologia , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cancers (Basel) ; 12(2)2020 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-32024300

RESUMO

Background: Colorectal cancer (CRC) is a high incidence of malignant tumors that lacks highly effective and targeted drugs and thus it is in urgent need of finding new specific molecular targets. Methods and Results: In this study, by using WST-1 (Highly water-soluble tetrazolium salt-1) and colony formation assays, we found that C20orf27 (chromosome 20 open reading frame 27), a functionally unknown protein, enhanced the growth and proliferation of CRC cells. The nude mouse tumor formation experiments verified that C20orf27 promoted the growth of CRC. Signal pathway analysis identified the TGFßR-TAK1-NFĸB cascade as a mediator in C20orf27-induced CRC progression. Inhibition experiments using NFĸB inhibitors reversed this progression. Co-immunoprecipitation showed that C20orf27 promoted the activation of the TGFßR-TAK1-NFĸB pathway by interacting with PP1c (the catalytic subunit of type 1 phosphatase). Conclusions: Our results firstly characterized the functional role and molecular mechanism of C20orf27 in driving CRC growth and proliferation through the TGFßR-TAK1-NFĸB pathway, suggesting its potential as a novel CRC candidate therapeutic target and tumor marker.

18.
Chemistry ; 26(19): 4193-4203, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31805202

RESUMO

Lithium (Li) metal is considered as the most promising anode material for rechargeable high-energy batteries. Nevertheless, the practical implement of Li anodes is significantly hindered by the growth of Li dendrites, which can cause severe safety issues. To inhibit the formation of Li dendrites, coating an artificial layer on the Li metal anode has been shown to be a facile and effective approach. This review mainly focuses on recent advances in artificial layers for stable Li metal anodes. It summarizes the progress in this area and discusses the different types of artificial layers according to their mechanisms for Li dendrite inhibition, including regulation of uniform deposition of Li metal and suppression of Li dendrite growth. By doing this, it is hoped that this contribution will provide instructional guidance for the future design of new artificial layers.

19.
Cancer Chemother Pharmacol ; 85(2): 293-308, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31834435

RESUMO

PURPOSE: This study aimed to develop a population pharmacokinetic (PPK) model to investigate the impact of GSTA1, GSTP1, and GSTM1 genotypes on busulfan pharmacokinetic (PK) variability in Chinese adult patients. METHODS: Forty-three and 19 adult patients who underwent hematopoietic stem cell transplantation (HSCT) were enrolled for modeling group and validation group, respectively. All patients received twice-daily intravenous busulfan as part of conditioning regimen before HSCT. The PPK model was developed by nonlinear mixed-effect modeling. Covariates investigated were age, sex, actual body weight, body surface area, diagnoses, hepatic function markers, GST genotypes and conditioning regimen. RESULTS: A total of 488 busulfan concentrations from 43 patients were obtained for the PPK model. The PK of intravenous busulfan was described by one-compartment model with first-order elimination with estimated clearance (CL) of 14.2 L/h and volume of distribution of 64.1 L. Inclusion of GSTA1 genotype as a covariate accounted for 1.1% of the inter-individual variability of busulfan CL (from 17.8% in the basic model to 16.7% in the final model). The accuracy and applicability of the final model were externally validated in the independent group. The difference of busulfan PK between Chinese patients and Caucasian patients existed because of the rarity of haplotype *B in Chinese population. CONCLUSIONS: Although the GSTA1 genotype-based PPK model of intravenous busulfan was successfully developed and externally validated, the GSTA1 genotype was not considered to be clinically relevant to busulfan CL. We did not suggest the guidance of GSTA1 genotype on initial busulfan dose in Chinese adult patients.


Assuntos
Bussulfano/farmacocinética , Glutationa Transferase/genética , Imunossupressores/farmacocinética , Administração Intravenosa/métodos , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Bussulfano/administração & dosagem , Feminino , Genótipo , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores/administração & dosagem , Masculino , Polimorfismo Genético/genética , Condicionamento Pré-Transplante/métodos
20.
Small ; 15(42): e1903087, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31448553

RESUMO

Inhomogeneous microcapsules that can encapsulate various cargo for controlled release triggered by osmotic shock are designed and reported. The microcapsules are fabricated using a microfluidic approach and the inhomogeneity of shell thickness in the microcapsules can be controlled by tuning the flow rate ratio of the middle phase to the inner phase. This study demonstrates the swelling of these inhomogeneous microcapsules begins at the thinnest part of shell and eventually leads to rupture at the weak spot with a low osmotic pressure. Systematic studies indicate the rupture fraction of these microcapsules increases with increasing inhomogeneity, while the rupture osmotic pressure decreases linearly with increasing inhomogeneity. The inhomogeneous microcapsules are demonstrated to be impermeable to small probe molecules, which enables long-term storage. Thus, these microcapsules can be used for long-term storage of enzymes, which can be controllably released through osmotic shock without impairing their biological activity. The study provides a new approach to design effective carriers to encapsulate biomolecules and release them on-demand upon applying osmotic shock.


Assuntos
Cápsulas/química , Microtecnologia/métodos , Pressão Osmótica , Soluções Hipotônicas , Microfluídica , Peso Molecular , Imagem Óptica , Peptídeo Hidrolases/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...