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1.
J Hazard Mater ; : 121451, 2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31796364

RESUMO

Polybrominated diphenyl ether-47 (BDE-47) is a congener of polybrominated diphenyl ethers (PBDEs) and relates to different health risks. However, in vivo study of the association between BDE-47 and breast cancer was scarce. In this study, we performed in vivo exposure of BDE-47 to breast cancer nude mice and conducted mass spectrometry-based metabolomics and lipidomics analysis to investigate the metabolic changes in mice. Results showed that the tumor sizes were positively associated with the dosage of BDE-47. Metabolomics and lipidomics profiling analysis indicated that BDE-47 induced significant alterations of metabolic pathways in livers, including glutathione metabolism, ascorbate and aldarate metabolism, and lipids metabolism, etc. The upregulations of phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs) suggested the membrane remodeling, and the downregulations of Lyso-PCs and Lyso-PEs might be associated with the tumor growth. Targeted metabolomics analysis revealed that BDE-47 inhibited fatty acid ß-oxidation (FAO) and induced incomplete FAO. The inhibition of FAO and downregulation of PPARγ would contribute to inflammation, which could promote tumor growth. In addition, BDE-47 elevated the expression of the cytokines TNFRSF12A, TNF-α, IL-1ß and IL-6, and lowered the cytokines SOCS3 and the nuclear receptor PPARα. The changes of cytokines and receptor may contribute to the tumor growth of mice.

2.
Mol Ther Nucleic Acids ; 18: 518-532, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31671345

RESUMO

Long non-coding RNAs (lncRNAs) have been shown to be crucial regulators in numerous human diseases. However, little is known about their effects on early recurrent miscarriage (RM). Here we aimed to investigate the role of lncRNA EPB41L4A-AS1 on placental trophoblast cell metabolic reprogramming, which might be involved in the pathogenesis of RM. After microarray and GEO database analyses, we found that EPB41L4A-AS1 was significantly increased in early RM placental tissue, and this increase may relate to estradiol-mediated upregulation of PGC-1α. EPB41L4A-AS1 overexpression inhibits glycolysis but increases the dependence on fatty acid oxidation in mitochondrion metabolism and suppresses the Warburg effect, which is necessary for rapid growth of the placental villus, leading to miscarriage. Mechanistic analyses demonstrated that EPB41L4A-AS1 functions as a lncRNA in the regulation of VDAC1 and HIF-1α expression through enhancement of H3K4me3 levels in the promoters of VDAC1 and HIF1A-AS1, a natural antisense transcript (NAT) lncRNA of HIF-1α. Taken together, these findings demonstrate that aberrant expression of EPB41L4A-AS1 is involved in the etiology of early RM, and it may be a candidate diagnostic hallmark and a potential therapeutic target for early RM treatment.

3.
Anal Chim Acta ; 1086: 82-89, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31561797

RESUMO

The location of double bond in unsaturated fatty acids (FAs) plays a critical role in their physiological properties. However, structural identification and quantification of unsaturated FAs by mass spectrometry are still challenging. In this work, we reported the coupling of epoxidation reaction of the C=C in unsaturated FAs and liquid chromatography-mass spectrometry (LC-MS) with multiple reaction monitoring (MRM) mode for accurate identification and quantification of C=C isomers of FAs. Epoxidation of the C=C in unsaturated FAs was induced by a dioxide of ketone, tetrahydrothiopyran-4-one 1,1-dioxide, as a catalyst and Oxone as an oxidant in less than 5 min with nearly 100% yield. All the C=C bonds were epoxidized to obtain a single product, simplifying the chromatographic separation of epoxidation products to enable more accurate quantification analysis. The epoxidation products were stable at room temperature and can produce highly abundant diagnostic ions indicative of C=C locations by tandem mass spectrometry using collision-induced association (CID). The application of this approach for the analysis of FAs isomers in human plasma demonstrated the potential of our method for the qualitative and quantitative analysis of unsaturated FAs in complex biological samples, which is valuable in biological and medical analysis.

4.
PLoS Genet ; 15(7): e1008099, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31339880

RESUMO

The length of cilia is controlled by a poorly understood mechanism that involves members of the conserved RCK kinase group, and among them, the LF4/MOK kinases. The multiciliated protist model, Tetrahymena, carries two types of cilia (oral and locomotory) and the length of the locomotory cilia is dependent on their position with the cell. In Tetrahymena, loss of an LF4/MOK ortholog, LF4A, lengthened the locomotory cilia, but also reduced their number. Without LF4A, cilia assembled faster and showed signs of increased intraflagellar transport (IFT). Consistently, overproduced LF4A shortened cilia and downregulated IFT. GFP-tagged LF4A, expressed in the native locus and imaged by total internal reflection microscopy, was enriched at the basal bodies and distributed along the shafts of cilia. Within cilia, most LF4A-GFP particles were immobile and a few either diffused or moved by IFT. We suggest that the distribution of LF4/MOK along the cilium delivers a uniform dose of inhibition to IFT trains that travel from the base to the tip. In a longer cilium, the IFT machinery may experience a higher cumulative dose of inhibition by LF4/MOK. Thus, LF4/MOK activity could be a readout of cilium length that helps to balance the rate of IFT-driven assembly with the rate of disassembly at steady state. We used a forward genetic screen to identify a CDK-related kinase, CDKR1, whose loss-of-function suppressed the shortening of cilia caused by overexpression of LF4A, by reducing its kinase activity. Loss of CDKR1 alone lengthened both the locomotory and oral cilia. CDKR1 resembles other known ciliary CDK-related kinases: LF2 of Chlamydomonas, mammalian CCRK and DYF-18 of C. elegans, in lacking the cyclin-binding motif and acting upstream of RCKs. The new genetic tools we developed here for Tetrahymena have potential for further dissection of the principles of cilia length regulation in multiciliated cells.

5.
Food Chem ; 292: 81-89, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31054696

RESUMO

How to effectively increase or decrease the ability of A. oryzae to produce enzymes was the key to improve the quality of soy sauce. However, multi-core property of A. oryzae resulted in genetic instability of the new strain. Here, A. oryzae 3.042-3 which can stably produce mononuclear spores was constructed based on A. oryzae 3.042. A. oryzae 3.042-3-c obtained by transformation of the fragment of cis-CreA into A. oryzae 3.042-3 exhibited genetic stability. The fragment containing the cis-acting and the promoter CreA from A. oryzae was connected to chromosome VII in A. oryzae 3.042-3-c. Compared with A. oryzae 3.042-3, the cellulase activity of A. oryzae 3.042-3-c was reduced by 50.5% and the pectinase activity was decreased by 10.0%. At the end of the soy sauce fermentation, the salt-free solid content of A. oryzae 3.042-3-c was higher 58.9% than that of A. oryzae 3.042-3. The kinds and contents of the flavor components of the soy sauce from the fermentation by A. oryzae 3.042-3-c were higher than those of the A. oryzae 3.042 and A. oryzae 3.042-3, especially in alcohols and esters. HEMF was only found in the soy sauce from A. oryzae 3.042-3-c. The results indicated that the new strain A. oryzae 3.042-3-c could improve the quality of soy sauce from the low-salt solid fermentation by decreasing enzyme activity of cellulase and pectinase.


Assuntos
Aspergillus oryzae/enzimologia , Proteínas Fúngicas/metabolismo , Alimentos de Soja/análise , Aspergillus oryzae/genética , Celulase/genética , Celulase/metabolismo , Cromossomos Fúngicos , Qualidade dos Alimentos , Proteínas Fúngicas/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Alimentos de Soja/microbiologia
6.
ACS Appl Mater Interfaces ; 11(31): 28246-28253, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31117449

RESUMO

Direct arylation polymerization (DARP) is a novel approach to obtain conjugated polymers (CPs) through the straightforward C-H activation of monomer building blocks. In this work, a convenient DARP method with high efficiency and excellent regioselectivity is developed to synthesize a series of donor-acceptor (D-A)-type CPs composed of electron-acceptor moiety fluorenones (FOs) and various electron-donor moieties. CPs with different band gaps are obtained in good yields and display large Stokes shifts up to 295 nm. Two ionic CPs, PFOP-NEt3(+) and PFOP-COO(-), were prepared in a polar solvent system to improve the water solubility and biocompatibility using the proposed DARP method. Detailed photophysical studies of these two CPs suggest that both solvation and hydrogen bonds play important roles in determining the polymers' spectroscopic properties. Further studies of the cationic polymer PFOP-NEt3(+) in cell imaging demonstrate its potential application in labeling cell membranes and lysosomes given its low cytotoxicity, excellent photostability, and specific subcellular localization.

7.
Molecules ; 24(10)2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108884

RESUMO

A series of benzimidazole carboxamide derivatives have been synthesized and characterized by 1H-NMR, 13C-NMR and HRMS. PARP inhibition assays and cellular proliferation assays have also been carried out. Compounds 5cj and 5cp exhibited potential anticancer activities with IC50 values of about 4 nM against both PARP-1 and PARP-2, similar to the reference drug veliparib. The two compounds also displayed slightly better in vitro cytotoxicities against MDA-MB-436 and CAPAN-1 cell lines than veliparib and olaparib, with values of 17.4 µM and 11.4 µM, 19.8 µM and 15.5 µM, respectively. The structure-activity relationship based on molecular docking was discussed as well.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Neoplasias/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Relação Estrutura-Atividade
8.
Talanta ; 200: 480-486, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31036212

RESUMO

A simpler, more rapid and selective biosensor has been developed for the sensitive detection of circulating miRNAs (c-miRNAs) based on duplex-specific nuclease (DSN)-assisted target recycling coupled with rolling circle amplification (RCA) using SYBR Gold Dye as a signal indicator. This biosensor exhibits a tremendously low detection limit of 0.3 fM of c-miRNAs and shows high selectivity for one-base mismatched c-miRNA. In addition, most importantly, the biosensor could accurately determine the amounts of target c-miRNA in total c-miRNAs isolated from human serums and human cancer cell lines, which confirms that the biosensor could be used to quantify c-miRNAs in complex biological samples and for the clinical early diagnosis of cancers based on c-miRNAs detection.


Assuntos
Técnicas Biossensoriais , MicroRNA Circulante/sangue , Endonucleases/química , Fluorescência , Técnicas de Amplificação de Ácido Nucleico , MicroRNA Circulante/isolamento & purificação , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Células Tumorais Cultivadas
9.
Cell Mol Life Sci ; 76(15): 3005-3018, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31006037

RESUMO

The accumulation of intracellular ß-amyloid peptide (Aß) is important pathological characteristic of Alzheimer's disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aß clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , RNA Longo não Codificante/metabolismo , Acetilcoenzima A/metabolismo , Acetilação/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Animais , Caveolina 2/antagonistas & inibidores , Caveolina 2/genética , Caveolina 2/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Camundongos , Camundongos Transgênicos , Neuroglia/citologia , Neuroglia/metabolismo , Fragmentos de Peptídeos/farmacologia , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
10.
Bioorg Chem ; 87: 200-208, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901675

RESUMO

DNMT and HDAC are closely related to each other and involved in various human diseases especially cancer. These two enzymes have been widely recognized as antitumor targets for drug discovery. Besides, research has indicated that combination therapy consisting of DNMT and HDAC inhibitors exhibited therapeutic advantages. We have reported a DNMT and HDAC dual inhibitor 15a of which the DNMT enzymatic inhibitory potency needs to be improved. Herein we reported the development of a novel dual DNMT and HDAC inhibitor C02S which showed potent enzymatic inhibitory activities against DNMT1, DNMT3A, DNMT3B and HDAC1 with IC50 values of 2.05, 0.93, 1.32, and 4.16 µM, respectively. Further evaluations indicated that C02S could inhibit DNMT and HDAC at cellular levels, thereby inversing mutated methylation and acetylation and increasing expression of tumor suppressor proteins. Moreover, C02S regulated multiple biological processes including inducing apoptosis and G0/G1 cell cycle arrest, inhibiting angiogenesis, blocking migration and invasion, and finally suppressing tumor cells proliferation in vitro and tumor growth in vivo.

11.
Org Biomol Chem ; 17(10): 2635-2639, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30768084

RESUMO

Several donor-acceptor type conjugated polyelectrolytes containing naphthalimide are developed. Different polymer chain configurations of the backbones of polymers lead to different photophysical properties. The para-substituted polymers show extended conformations with quite low quantum yields in high polarity solvents because of twisted intramolecular charge transfer features, while the meta-substituted polymers can form helices and demonstrated significantly improved quantum yields in water and methanol, as well as achieving sensitive, ultrafast and ratiometric detection of trace methylene blue in water.

12.
Chemosphere ; 222: 235-242, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30708157

RESUMO

Highlighted evidence suggests the possible implication of bisphenol A (BPA) exposure on a variety of biological functions, such as DNA damage. Similar to DNA, exposed to BPA may also have potential risks to RNA damage due to its induction of reactive oxygen species. However, there are no related research reports about such health risks of BPA. Therefore, this work tried to investigate the BPA exposure induced oxidative RNA damage by detecting urinary nucleosides, the end-products of RNA metabolism. An ultra-high performance liquid chromatography-Orbitrap mass spectrometry method was applied to selectively and sensitively determine urinary nucleosides. As a result, 66 nucleosides were identified and the effects of BPA exposure on these nucleosides in rat urine samples were evaluated. The nucleosides showed different changing tendency along with different exposure dose of BPA. The strongest effect was observed in high does-exposure rats, indicating dose-response relationship between BPA-treatment and urinary nucleosides. Significant change of some nucleosides, including 8-oxoguanosine, was observed in the high-dose exposure group, suggesting obvious RNA damage to rats. To the best of our knowledge, it is the first study about the RNA damage induced by BPA exposure. The results provided a new perspective on the toxic effects of BPA exposure.


Assuntos
Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , RNA/efeitos dos fármacos , Animais , Cromatografia Líquida de Alta Pressão , Dano ao DNA/efeitos dos fármacos , Humanos , Masculino , Espectrometria de Massas , Nucleosídeos/efeitos dos fármacos , Nucleosídeos/urina , Oxirredução , Estresse Oxidativo , RNA/química , Ratos , Espécies Reativas de Oxigênio/efeitos adversos
13.
EBioMedicine ; 41: 200-213, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30796006

RESUMO

BACKGROUND: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. METHODS: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. FINDINGS: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. INTERPRETATION: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer.


Assuntos
Núcleo Celular/metabolismo , Glicólise , Histona Desacetilase 2/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Neoplasias/metabolismo , RNA Longo não Codificante/genética , Transporte Ativo do Núcleo Celular , Animais , Glutaminase/metabolismo , Células HeLa , Células Hep G2 , Humanos , Camundongos , Camundongos Nus , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , RNA Longo não Codificante/metabolismo
14.
Anal Chem ; 91(3): 1701-1705, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30636414

RESUMO

Acylcarnitines are closely related to many metabolic diseases and likely to be good biomarkers for clinical diagnosis. Studies on acylcarnitines may help deepen the understanding of their functions associated with disease processes. However, the diversity of their structures and lack of commercial standards make them difficult to be fully detected. In this work, a highly efficient isotope labeling strategy was developed to detect acylcarnitines in biological samples using liquid chromatography-mass spectrometry (LC-MS). A pair of reagents with or without deuterium labeling tags containing both a positive charge and a primary amine group were synthesized, which were used to label the carboxyl group of acylcarnitines. The reaction was performed under mild conditions to avoid hydrolysis of acylcarnitines. The reaction products had two positive charges, forming a double charge peak in MS spectra and with mass-to-charge ratio difference (Δ m/ z) of 4.0251 Da between the light- and heavy-labeled products. The feature made it possible to distinguish signals of acylcarnitines from other carboxyl metabolites with Δ m/ z of 8.0502 Da between their light- and heavy-labeled products. On the basis of the characteristics and the tandem mass spectrometry (MS/MS) spectra, a total of 108 acylcarnitines were discovered and identified in urine samples. Our established approach will be very helpful for the studies of diseases associated with acylcarnitines metabolism.

15.
Bioorg Chem ; 86: 44-51, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30685643

RESUMO

Human dihydroorotate dehydrogenase (hDHODH) is a flavin-dependent enzyme essential to pyrimidine de novo biosynthesis, which serves as an attractive therapeutic target for the treatment of autoimmune disorders. A novel series of hDHODH inhibitors was developed based on a lead which was obtained by a medicinal chemistry exploration. Most compounds showed moderate to significant potency against hDHODH, compounds 5d, 5e, and 6a effectively inhibited the activities of hDHODH with IC50 values from 0.9 to 2.8 µM. Further studies showed that compound 5e also effectively suppressed proliferation of the activated PBMCs (IC50 = 20.35 µM). Surprisingly, compound 5e also showed anti-pulmonary fibrotic activity similar to that of pirfenidone in vitro assay. Therefore, compound 5e might have potential to be developed as a novel hDHODH inhibitors for autoimmune diseases therapy.

16.
Genetics ; 211(2): 651-663, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30593491

RESUMO

In a single cell, ciliates maintain a complex pattern of cortical organelles that are arranged along the anteroposterior and circumferential axes. The underlying molecular mechanisms of intracellular pattern formation in ciliates are largely unknown. Ciliates divide by tandem duplication, a process that remodels the parental cell into two daughters aligned head-to-tail. In the elo1-1 mutant of Tetrahymena thermophila, the segmentation boundary/division plane forms too close to the posterior end of the parental cell, producing a large anterior and a small posterior daughter cell, respectively. We show that ELO1 encodes a Lats/NDR kinase that marks the posterior segment of the cell cortex, where the division plane does not form in the wild-type. Elo1 acts independently of CdaI, a Hippo/Mst kinase that marks the anterior half of the parental cell, and whose loss shifts the division plane anteriorly. We propose that, in Tetrahymena, two antagonistic Hippo circuits focus the segmentation boundary/division plane at the equatorial position, by excluding divisional morphogenesis from the cortical areas that are too close to cell ends.


Assuntos
Divisão Celular , Polaridade Celular , Proteínas Serina-Treonina Quinases/genética , Proteínas de Protozoários/genética , Transdução de Sinais , Tetrahymena/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Protozoários/metabolismo , Tetrahymena/citologia , Tetrahymena/metabolismo
17.
Sci Rep ; 8(1): 15753, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30361678

RESUMO

Epidemiological observations have shown that schizophrenia patients after long-term drug treatment exhibited reduced tumor incidences. The potential anticancer effects of antipsychotic drugs are subsequently demonstrated. These drugs are of great interest as agents against untreatable brain metastases because of their ability to traverse the blood-brain barrier (BBB). Most drugs tested thus far are the first-generation antipsychotics (FGAs). But their clinical application may be limited due to high risks of deaths in elderly patients. There is an urgent need to find additional BBB-traversing anticancer agents with lower risks of deaths. In this work, we investigated antitumor activities of eight second-generation-antipsychotic (SGA) drugs, since they exhibit lower mortality rates than FGAs. We discovered that sertindole showed broad antiproliferative activities against seven cancer types including 29 cell-lines and exhibited potent effects toward breast cancer cell-lines, with half maximal concentration to inhibit proliferation by 50% (IC50) as low as 800 nM. We further found that sertindole caused cell death through autophagy-associated apoptosis and its directly-binding inhibition of 5-HT6 involved in this process. In xenotransplant mice, sertindole administration approaching maximal therapeutic dose attenuated breast-tumor growth by 22.7%. Therefore, our study reveals promising anticancer potentials of sertindole against breast cancers, with probable applications for breast-to-brain metastases.

18.
Int J Cancer ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30289981

RESUMO

Triple-negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC-2036 inhibited the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC-2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC-2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC-2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt-NFκB signaling to exert its antitumor effect in TNBC. DCC-2036 also inhibited the growth and metastasis of xenografted MDA-MB-231 cells (AXL/MET-high TNBC cells) but not MDA-MB-468 cells (AXL-low TNBC cells) in NSG mice in vivo. Furthermore, DCC-2036 significantly inhibited tumor growth and invasion of AXL/MET-high TNBC PDX tumors but not AXL/MET-low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC-2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC-2036 even at a high dosage. Therefore, DCC-2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.

19.
Analyst ; 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30298867

RESUMO

Single cell analysis has become of great interest with unprecedented capabilities for the systematic investigation of cell-to-cell variation in large populations. Rapid and multi-parametric analysis of intercellular biomolecules at the single-cell level is imperative for the improvement of early disease diagnosis and personalized medicine. However, the small size of cells and the low concentration levels of target biomolecules are critical challenges for single cell analysis. In recent years, microfluidic platforms capable of handling small-volume fluid have been demonstrated to be powerful tools for single cell analysis. In addition, microfluidic techniques allow for precise control of the localized microenvironment, which yield more accurate outcomes. Many different microfluidic techniques have been greatly improved for highly efficient single-cell manipulation and highly sensitive detection over the past few decades. To date, microfluidics-based single cell analysis has become the hot research topic in this field. In this review, we particularly highlight the advances in this field during the past three years in the following three aspects: (1) microfluidic single cell manipulation based on microwells, micropatterns, droplets, traps and flow cytometric methods; (2) detection methods based on fluorescence, mass spectrometry, electrochemical, and polymerase chain reaction-based analysis; (3) applications in the fields of small molecule detection, protein analysis, multidrug resistance analysis, and single cell sequencing with droplet microfluidics. We also discuss future research opportunities by focusing on key performances of throughput, multiparametric target detection and data processing.

20.
Anal Chim Acta ; 1036: 97-106, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30253842

RESUMO

The ability to rapidly screen drugs and drug delivery systems with a more accurate tumor model to better predict their in vivo performance is of great importance in drug development, because there have been some limitations in currently used tumor models. To address this problem, we developed an in vitro breast tumor model on a chip, composed of a microvessel wall, the extracellular matrix (ECM) and uniformly sized multicellular tumor spheroids (MCTS), for the evaluation of nanoparticle-based drug delivery systems. A carbon dots (CDs)-based drug delivery system was synthesized as a model to evaluate the real-time monitoring ability of the system transport through the endothelium and the penetrability into MCTS with a high spatio-temporal resolution on the established platform. Moreover, a modified 96-well plate was used to hold the microfluidic devices for in situ cytotoxicity assays of the MCTS by a microplate reader. Our findings revealed that the synthesized drug delivery system could be transported across an endothelial monolayer within 3 h and was nontoxic to the cells throughout the experiment. In addition, we demonstrated the capabilities of this model by assessing the delivery and efficacy of the drug delivery system in BT549 and T47D spheroids, two cell lines representative of triple negative breast cancer (TNBC) and non-TNBC, respectively. This microfluidic platform enables evaluation of dynamic transport behavior and in situ cytotoxicity evaluation in one system. The established platform provides a more accurate and low-cost in vitro model for rapid drug screening in pre-clinical studies.

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