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1.
Acta Pharmacol Sin ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34522005

RESUMO

Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1-GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.

2.
Cell Death Discov ; 4: 24, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30109143

RESUMO

To better understand the resistance mechanism of non-small cell lung cancers (NSCLCs) to gefitinib, the metabolic profiles of gefitinib-resistant A549 cells and gefitinib-sensitive PC-9 cells were analyzed with a metabolomics analytical platform. A549 and PC-9 cells exhibited significant differences in the levels of glutamine-related metabolites. After gefitinib treatment, the glutamine level decreased in A549 cells but showed no change in PC-9 cells. The glutamine consumed by A549 cells was used to generate ATP and glutathione (GSH). As glutamine utilization was suppressed in gefitinib-treated PC-9 cells, the resulting ATP shortage and ROS accumulation led to cell death. The difference in glutamine metabolism was caused by differential changes in the levels of glutamine synthetase (GS, encoded by glutamate-ammonia ligase (GLUL)). GLUL expression was upregulated in gefitinib-sensitive cells, but it was either absent from gefitinib-resistant cells or no significant change was observed in the gefitinib-treated cells. GLUL overexpression in A549 cells significant sensitized them to gefitinib and decreased their invasive capacity. Conversely, knockout GS in PC-9 cells reduced gefitinib sensitivity and enhanced metastasis. Furthermore, the continuous exposure of gefitinib-sensitive HCC827 cells to gefitinib created gefitinib-resistant (GR) HCC827 cells, which exhibited a GLUL deletion and resistance to gefitinib. Thus, GLUL plays a vital role in determining the sensitivity of NSCLCs to gefitinib. Elevated GS levels mediate increased glutamine anabolism, and this novel mechanism sensitizes NSCLCs to gefitinib. The inhibition of glutamine utilization may serve as a potential therapeutic strategy to overcome gefitinib resistance in the clinic.

3.
Cell Death Discov ; 4: 24, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29531821

RESUMO

Arresting cell cycle has been one of the most common approaches worldwide in cancer therapy. Specifically, arresting cells in the G2/M phase is a promising therapeutic approach in the battle against lung cancer. In the present study, we demonstrated the anticancer activities and possible mechanism of compound #2714, which can prompt G2/M phase arrest followed by cell apoptosis induction in Lewis lung carcinoma LL/2 cells. In vitro, #2714 significantly inhibited LL/2 cell viability in a concentration- and time-dependent manner while exhibiting few toxicities on non-cancer cells. The mechanism study showed that cell proliferation inhibition due to the treatment with #2714 correlated with G2/M phase arrest and was followed by LL/2 cell apoptosis. The characterized changes were associated with the downregulation of phosphorylated cell division cycle 25C (Cdc25C) and upregulation of p53. Apoptosis-associated activation of cleaved caspase-3 was also detected. Moreover, #2714 strongly attenuated LL/2 cell proliferation by disrupting the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). In vivo, intraperitoneal administration of #2714 (25-100 mg/kg/day) to mice bearing established tumors in xenograft models significantly prevented LL/2 tumor growth (58.1%) without detectable toxicity. Compound #2714 significantly increased apoptosis in LL/2 lung cancer cells in mice models, as observed via terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, and the data from an immunohistochemical analysis showed that #2714 remarkably inhibited the proliferation and angiogenesis of lung cancer in vivo. Taken together, our data suggest that #2714 has a high potential anti-lung cancer efficacy with a pathway-specific mechanism of G2/M phase arrest and subsequent apoptosis induction both in vitro and in vivo; its potential to be an anticancer candidate warrants further investigation.

4.
Oncol Lett ; 15(3): 2839-2846, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29435010

RESUMO

Sunitinib based adjuvant chemotherapy combined with chloroquine (CQ) for the treatment of renal cell carcinoma (RCC) is in clinical trials; however, its anti-RCC effect and the mechanism remain unclear. In the present study, the anti-RCC effect of sunitinib with CQ and the underlying mechanism was investigated. An MTT assay demonstrated that CQ enhanced the proliferation inhibitory effect of sunitinib against the OS-RC-2 RCC cell line. CQ inhibited sunitinib-induced autophagy in OS-RC-2, which was evidenced by the inhibition of autophagic vacuoles, acidic vesicular organelle formation, light chain 3 (LC3)-II recruitment to the autophagosomes and the conversion of LC3-I to LC3-II, as induced by sunitinib. The inhibition of autophagy by CQ enhanced sunitinib-induced apoptosis, which was characterized by the activation of caspase-3, caspase-9, Bcl-2 and p53. Additionally, the exposure of OS-RC-2 cells to CQ and sunitinib resulted in the inhibition of AKT, tuberous sclerosis complex 2, mechanistic target of rapamycin and p70 ribosomal S6 kinase, which are associated with cell proliferation. In in vivo study, a combination of sunitinib with CQ in mice significantly reduced OS-RC-2 cell xenograft growth compared with the sunitinib alone group. In conclusion, the present study demonstrated that CQ may enhance the anti-RCC effect of sunitinib by inhibiting the autophagy induced by sunitinib, and enhance the rate of apoptosis. Inhibiting cell proliferation may also serve a role in the synergistic antitumor effect of sunitinib and CQ. These data suggest that combination therapy of sunitinib with CQ may be a promising strategy for adjuvant chemotherapy in RCC.

5.
Yi Chuan ; 39(8): 763-768, 2017 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-28903903

RESUMO

Caenorhabditis elegans is one of the most important model organisms in the study of biology. It is ideal for laboratory teaching due to its short life cycle and low cost. It enriches the teaching content and can motivate students' interest of learning. In this article, we have shown cased C. elegans for the observation of life cycle and mating, as well as the investigation of single nucleotide polymorphism (SNP) and RNA interfere. In addition, we also discuss the details of the experimental design, basic requirement, preparations and related information. We conclude that C. elegans can be used as the experimental materials for teaching college laboratory courses, such as genetic, cell biology, model biology and developmental biology.


Assuntos
Caenorhabditis elegans/genética , Animais , Genética , Laboratórios , Aprendizagem , Projetos de Pesquisa , Estudantes , Ensino
6.
Bioorg Med Chem Lett ; 27(15): 3591-3594, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28579329

RESUMO

Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity.


Assuntos
Antineoplásicos/química , Antineoplásicos/toxicidade , Cisplatino/análogos & derivados , Cisplatino/toxicidade , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Animais , Biotina/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Rim/citologia , Rim/patologia , Nefropatias/patologia , Células LLC-PK1 , Proteômica , Suínos
7.
Bioorg Med Chem Lett ; 26(18): 4552-4557, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27524309

RESUMO

Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is recognized as an attractive therapeutic target in multiple malignancies. In this study, a series of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides were synthesized and biologically evaluated for their potential LSD1 inhibitory effect. Among them, compounds 5a and 5n showed the most potent LSD1 inhibitory activity with IC50 values of 1.4 and 1.7nM, respectively, which were about 10 times more potent compared with (E)-N-(1-(5-chloro-2-hydroxyphenyl) ethylidene)-3-(morpholinosulf-only) benzohydrazide (J. Med. Chem.2013, 56, 9496-9508; as reference compound). Compounds 5a and 5n also exhibited marked anti-proliferation activities against cancer cell lines that highly expressed LSD1. These results suggest that these optimized compounds might be served as promising LSD1 inhibitors against cancer, which merit further study.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Conformação Molecular , Relação Estrutura-Atividade
9.
BMC Cancer ; 16: 371, 2016 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-27356757

RESUMO

BACKGROUND: Gastric cancer is the fourth most common cancer and the second most deadly cancer worldwide. Study on molecular mechanisms of carcinogenesis will play a significant role in diagnosing and treating gastric cancer. Metabolic profiling may offer the opportunity to understand the molecular mechanism of carcinogenesis and help to identify the potential biomarkers for the early diagnosis of gastric cancer. METHODS: In this study, we reported the metabolic profiling of tissue samples on a large cohort of human gastric cancer subjects (n = 125) and normal controls (n = 54) based on (1)H nuclear magnetic resonance ((1)H NMR) together with multivariate statistical analyses (PCA, PLS-DA, OPLS-DA and ROC curve). RESULTS: The OPLS-DA model showed adequate discrimination between cancer tissues and normal controls, and meanwhile, the model excellently discriminated the stage-related of tissue samples (stage I, 30; stage II, 46; stage III, 37; stage IV, 12) and normal controls. A total of 48 endogenous distinguishing metabolites (VIP > 1 and p < 0.05) were identified, 13 of which were changed with the progression of gastric cancer. These modified metabolites revealed disturbance of glycolysis, glutaminolysis, TCA, amino acids and choline metabolism, which were correlated with the occurrence and development of human gastric cancer. The receiver operating characteristic diagnostic AUC of OPLS-DA model between cancer tissues and normal controls was 0.945. And the ROC curves among different stages cancer subjects and normal controls were gradually improved, the corresponding AUC values were 0.952, 0.994, 0.998 and 0.999, demonstrating the robust diagnostic power of this metabolic profiling approach. CONCLUSION: As far as we know, the present study firstly identified the differential metabolites in various stages of gastric cancer tissues. And the AUC values were relatively high. So these results suggest that the metabolic profiling of gastric cancer tissues has great potential in detecting this disease and helping to understand its underlying metabolic mechanisms.


Assuntos
Biomarcadores Tumorais/metabolismo , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética/métodos , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC , Neoplasias Gástricas/metabolismo
10.
Oncol Rep ; 35(4): 2081-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26847587

RESUMO

Cancer cells activate autophagy in response to anticancer therapies. Autophagy induction is a promising therapeutic approach to treat cancer. In a previous study, YL4073 inhibited the growth of liver cancer and induced liver cancer cell apoptosis. Here, we demonstrated the anticancer activity and specific mechanisms of YL4073 in Lewis lung carcinoma LL/2 cells. Our results show that YL4073-induced autophagy was followed by apoptotic cell death. The anticancer and autophagy stimulating efficacy was confirmed by several factors, including the appearance of autophagic vacuoles, formation of acidic vesicular organelles, recruitment of microtubule-associated protein 1 light chain 3 II (LC3-II) to the autophagosomes, conversion and cleavage of LC3-I to LC3-II, upregulation of Beclin 1 expression, and formation of the Atg12-Atg5 conjugate in LL/2 cells after YL4073 treatment for 24 or 48 h. Furthermore, P53 activation and p-histone H3 phosphorylation occurred after cell exposure to YL4073 for 48 h, suggesting that cell apoptosis had occurred. Pharmacological inhibition of autophagy using 3-methyladenine increased cell apoptosis. Molecular level studies revealed that YL4073 inhibited survival signalling by blocking the activation of Akt and mTOR phosphorylation and reduced the expression of p-mTOR downstream targets for phosphorylation, including p70S6K, p-TSC, p-MAPK, and p-AMPK. This suggests that the Akt/mTOR/p70S6K and TSC/MAPK/AMPK pathways are involved in the effects of YL4073 treatment in LL/2 cells. In addition, YL4073 significantly inhibited LL/2 tumor growth and induced apoptosis in vivo. These data suggest that YL4073 has a significant anticancer effect, with a pathway-specific mechanism of autophagy both in vitro and in vivo.


Assuntos
Antineoplásicos/administração & dosagem , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Carcinoma Pulmonar de Lewis/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Células NIH 3T3 , Fosforilação/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia
11.
J Med Chem ; 58(9): 3957-74, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25835317

RESUMO

A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were designed and synthesized. Structure-activity relationship (SAR) analysis of these compounds led to the discovery of compound 1j, which showed the highest inhibitory potency against the Src kinase and the most potent antiviability activity against the typical TNBC cell line MDA-MB-231 among all the synthesized compounds. Further kinase inhibition assays showed that compound 1j was a multikinase inhibitor and potently inhibited Src (IC50 = 0.0009 µM) and MAPK signaling protein kinases B-RAF and C-RAF. In an MDA-MB-231 xenograft mouse model, a once-daily dose of compound 1j at 30 mg/kg for 18 days completely suppressed the tumor growth with a tumor inhibition rate larger than 100% without obvious toxicity. It also displayed good pharmacokinetic properties in a preliminary pharmacokinetic assay. Western blot and immunohistochemical assays revealed that compound 1j significantly inhibited Src and MAPK signaling and markedly induced apoptosis in tumor tissues.


Assuntos
Acetileno/análogos & derivados , Acetileno/química , Antineoplásicos/química , Benzamidas/química , Pirazóis/química , Pirimidinas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Quinases da Família src/antagonistas & inibidores , Acetileno/farmacocinética , Acetileno/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzamidas/farmacocinética , Benzamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Xenoenxertos , Humanos , Masculino , Camundongos SCID , Transplante de Neoplasias , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia , Quinases da Família src/química
12.
Molecules ; 20(5): 7620-36, 2015 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-25923513

RESUMO

A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC50 value of 1.2 µM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the fact that no quinoline derivative has been reported as an EZH2 inhibitor, this compound could serve as a lead compound for further optimization.


Assuntos
Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Azepinas/farmacologia , Complexo Repressor Polycomb 2/antagonistas & inibidores , Aminoquinolinas/síntese química , Antineoplásicos/síntese química , Azepinas/síntese química , Linhagem Celular Tumoral , Metilação de DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Histonas/genética , Humanos , Neoplasias/patologia , Relação Estrutura-Atividade
13.
Comput Biol Med ; 51: 122-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24907415

RESUMO

Drug-induced ototoxicity, as a toxic side effect, is an important issue needed to be considered in drug discovery. Nevertheless, current experimental methods used to evaluate drug-induced ototoxicity are often time-consuming and expensive, indicating that they are not suitable for a large-scale evaluation of drug-induced ototoxicity in the early stage of drug discovery. We thus, in this investigation, established an effective computational prediction model of drug-induced ototoxicity using an optimal support vector machine (SVM) method, GA-CG-SVM. Three GA-CG-SVM models were developed based on three training sets containing agents bearing different risk levels of drug-induced ototoxicity. For comparison, models based on naïve Bayesian (NB) and recursive partitioning (RP) methods were also used on the same training sets. Among all the prediction models, the GA-CG-SVM model II showed the best performance, which offered prediction accuracies of 85.33% and 83.05% for two independent test sets, respectively. Overall, the good performance of the GA-CG-SVM model II indicates that it could be used for the prediction of drug-induced ototoxicity in the early stage of drug discovery.


Assuntos
Descoberta de Drogas/métodos , Doenças do Labirinto/induzido quimicamente , Modelos Biológicos , Máquina de Vetores de Suporte , Descoberta de Drogas/instrumentação , Humanos , Doenças do Labirinto/metabolismo , Valor Preditivo dos Testes
14.
Int J Mol Sci ; 15(5): 7199-212, 2014 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-24776763

RESUMO

Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (P(eff)) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 µg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10⁻4 mg·min⁻¹·cm⁻². The P(eff) value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.


Assuntos
Absorção Intestinal , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Biofarmácia , Cães , Mucosa Intestinal/metabolismo , Masculino , Neoplasias/tratamento farmacológico , Permeabilidade , Inibidores de Proteínas Quinases/administração & dosagem , Ratos , Ratos Sprague-Dawley , Solubilidade
15.
Bioorg Med Chem Lett ; 24(5): 1426-31, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24491459

RESUMO

A series of novel benzamide derivatives were prepared and evaluated using cell-based measurements. Among these compounds, 10f significantly inhibited Hedgehog signaling and showed equivalent or more potency than GDC-0449 in different tests. Furthermore, compound 10f potently inhibited the proliferation of Daoy, a medulloblastoma cell line that is reported to be resistant to GDC-0449, which indicated a promising prospect in the treatment of Hedgehog signaling pathway related cancer in clinical trial.


Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonas/síntese química , Sulfonas/farmacologia , Animais , Benzamidas/química , Linhagem Celular Tumoral , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened , Relação Estrutura-Atividade , Sulfonas/química , Peixe-Zebra
16.
Mol Cancer ; 12(1): 121, 2013 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-24138801

RESUMO

BACKGROUND: Rectal cancer is one of the most prevalent tumor types. Understanding the metabolic profile of rectal cancer is important for developing therapeutic approaches and molecular diagnosis. METHODS: Here, we report a metabonomics profiling of tissue samples on a large cohort of human rectal cancer subjects (n = 127) and normal controls (n = 43) using 1H nuclear magnetic resonance (1H NMR) based metabonomics assay, which is a highly sensitive and non-destructive method for the biomarker identification in biological systems. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal projection to latent structure with discriminant analysis (OPLS-DA) were applied to analyze the 1H-NMR profiling data to identify the distinguishing metabolites of rectal cancer. RESULTS: Excellent separation was obtained and distinguishing metabolites were observed among the different stages of rectal cancer tissues (stage I = 35; stage II = 37; stage III = 37 and stage IV = 18) and normal controls. A total of 38 differential metabolites were identified, 16 of which were closely correlated with the stage of rectal cancer. The up-regulation of 10 metabolites, including lactate, threonine, acetate, glutathione, uracil, succinate, serine, formate, lysine and tyrosine, were detected in the cancer tissues. On the other hand, 6 metabolites, including myo-inositol, taurine, phosphocreatine, creatine, betaine and dimethylglycine were decreased in cancer tissues. These modified metabolites revealed disturbance of energy, amino acids, ketone body and choline metabolism, which may be correlated with the progression of human rectal cancer. CONCLUSION: Our findings firstly identify the distinguishing metabolites in different stages of rectal cancer tissues, indicating possibility of the attribution of metabolites disturbance to the progression of rectal cancer. The altered metabolites may be as potential biomarkers, which would provide a promising molecular diagnostic approach for clinical diagnosis of human rectal cancer. The role and underlying mechanism of metabolites in rectal cancer progression are worth being further investigated.


Assuntos
Biomarcadores Tumorais/metabolismo , Metaboloma , Neoplasias Retais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Componente Principal , Neoplasias Retais/patologia , Reto/metabolismo , Reto/patologia
17.
Mol Cancer ; 12: 25, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23556477

RESUMO

BACKGROUND: The biomarker identification of human esophageal cancer is critical for its early diagnosis and therapeutic approaches that will significantly improve patient survival. Specially, those that involves in progression of disease would be helpful to mechanism research. METHODS: In the present study, we investigated the distinguishing metabolites in human esophageal cancer tissues (n = 89) and normal esophageal mucosae (n = 26) using a (1)H nuclear magnetic resonance ((1)H-NMR) based assay, which is a highly sensitive and non-destructive method for biomarker identification in biological systems. Principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA) were applied to analyse (1)H-NMR profiling data to identify potential biomarkers. RESULTS: The constructed OPLS-DA model achieved an excellent separation of the esophageal cancer tissues and normal mucosae. Excellent separation was obtained between the different stages of esophageal cancer tissues (stage II = 28; stage III = 45 and stage IV = 16) and normal mucosae. A total of 45 metabolites were identified, and 12 of them were closely correlated with the stage of esophageal cancer. The downregulation of glucose, AMP and NAD, upregulation of formate indicated the large energy requirement due to accelerated cell proliferation in esophageal cancer. The increases in acetate, short-chain fatty acid and GABA in esophageal cancer tissue revealed the activation of fatty acids metabolism, which could satisfy the need for cellular membrane formation. Other modified metabolites were involved in choline metabolic pathway, including creatinine, creatine, DMG, DMA and TMA. These 12 metabolites, which are involved in energy, fatty acids and choline metabolism, may be associated with the progression of human esophageal cancer. CONCLUSION: Our findings firstly identify the distinguishing metabolites in different stages of esophageal cancer tissues, indicating the attribution of metabolites disturbance to the progression of esophageal cancer. The potential biomarkers provide a promising molecular diagnostic approach for clinical diagnosis of human esophageal cancer and a new direction for the mechanism study.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Esôfago/metabolismo , Esôfago/patologia , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Redes e Vias Metabólicas , Metaboloma , Metabolômica , Pessoa de Meia-Idade , Membrana Mucosa/metabolismo
18.
Mol Biosyst ; 8(12): 3185-96, 2012 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-23014807

RESUMO

Combination therapies are urgently needed for optimal clinical benefit, but an efficient strategy for rational discovery of drug combinations, especially combinations of experimental drugs, is still lacking. Consequently, we proposed here a network-based computational method to identify novel synergistic drug combinations. A large-scale drug combination network (DCN), which provides an alternative way to study the underlying mechanisms of drug combinations, was constructed by integrating 345 drug combination relationships, 1293 drug-target interactions and 15134 target-protein interactions. It was illustrated that synergistic drugs seldom have identical or directly connected targets, while most targets in DCN can be reached from every other by 2 to 4 edges (interactions). Accordingly, the concept 'neighbor community' was introduced to characterize the relationships between synergistic drugs by specifying the interactions between drug targets and their neighbor proteins in the context of DCN. A subsequent study revealed that the integrated topological and functional properties of neighbor communities can be employed to successfully predict drug combinations. It was shown that this method can achieve 88% prediction accuracy and 0.95 AUC (Area Under ROC Curve), demonstrating its good performance in specificity and sensitivity. Moreover, ten predicted synergistic drug combinations unknown to the method were confirmed by recent literature, and three predicted new combinations of experimental drug BI-2536 were validated by in vitro assays. The results suggested that this method provides a means to explore promising drug combinations at an earlier stage of the drug development process.


Assuntos
Biologia Computacional/métodos , Combinação de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Linhagem Celular Tumoral , Descoberta de Drogas , Interações Medicamentosas , Humanos
19.
Curr Drug Metab ; 13(4): 354-63, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22443532

RESUMO

Nanomaterials have unique physicochemical properties compared with those bulk materials of the same composition. Possible undesirable results of these capabilities are harmful interactions with biological systems and the environment, with the potential to generate toxicity. A number of studies on the effects of Nanomaterials in vitro and in vivo systems have been published. However, while the number of nanomaterials types and applications continues to increase, studies to characterize their effects after exposure and to address their potential toxicity are few in comparison, there is still a need for further studies that conclusively establish their safety/toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials in the marketplace is urgently required and achievable. The major goal of this review is to summarize 1) analytical techniques applied for characterization of nanomaterials, 2) current analytical methods to assess nanomaterials toxicity in vitro and in vivo; 3) research progress of polymeric nanomaterials toxicity; 4) outlook.


Assuntos
Nanoestruturas/toxicidade , Animais , Humanos , Nanoestruturas/análise , Polímeros/toxicidade , Medição de Risco/métodos
20.
J Clin Immunol ; 32(4): 820-36, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22392045

RESUMO

Core 1 beta 1,3-galactosyltransferase also known as T-antigen-synthase or T-synthase is a key enzyme for the synthesis of the common core 1 O-glycan structure (T-antigen). Although T-synthase is known to be important in human immune-related diseases, the effects of T-synthase and T-antigen on host immune responses remain poorly defined. In this study, a T-synthase-specific short hairpin RNA (shRNA) was transfected into murine colon carcinoma CT26 cells or mouse muscle tissues via intramuscular electroporation to assess the effects of T-synthase on T cells and cytokines. T-synthase knockdown significantly induced galectin-1 secretion both in vivo and in vitro and strongly enhanced Th2 cytokine (IL-10 and IL-4) production in vivo. Further, the increased production of galectin-1 induced by T-synthase knockdown promoted CD8(+) T-cell apoptosis, which, when combined with the increased production of CD4(+) T cell-derived Th2 cytokines prolonged the survival of skin allografts in mice. Our data suggest core 1 beta 1,3-galactosyltransferase-shRNA could serve not only as a useful tool in organ transplantation but also as a powerful tool for investigating O-glycans and glycoprotein synthesis and function.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Galectina 1/metabolismo , Sobrevivência de Enxerto , Interferência de RNA , Transplante de Pele/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Interleucina-10/biossíntese , Interleucina-4/biossíntese , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno , Pele/imunologia , Transplante Homólogo
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