RESUMO
A series of novel substituted uracil-1'(N)-acetic acid esters (5-9) and 4-pyridone-1'(N)-acetic acid esters (10-11) of 20(S)-camptothecins (CPTs) have been synthesized by the acylation method. All of these new esters were assayed for in vitro cytotoxicity against five human cancer cell lines A549, Bel7402, BGC-823, HCT-8 and A2780. The in vitro bioassay results showed that all the synthesized compounds 5-11 had cytotoxities that were higher than TPT and comparable to CPT on these five tumor cell lines, some of them even showed comparable or superior cytotoxic activity to CPT. The in vitro data exhibited the cytotoxicity of the ester depended on that of its parent compound. The ester 5, 6, 8, 10, 11 even possessed the cytotoxity activity comparable to or even a little better than CPT on A549, HCT-8 and A2780. The compound 11 had the same level of cytoxity on Bel7402 as that of CPT. Here the synthesis and the in vitro antitumor evaluation of a series of novel 20-O-linked substituted uracil-1'(N)-acetic acid and 4-pyridone-1'(N)-acetic acid esters derivatives of CPTs are reported.
Assuntos
Antineoplásicos , Neoplasias Ovarianas , Piridonas , Humanos , Feminino , Ácido Acético , Linhagem Celular Tumoral , Uracila/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Camptotecina/farmacologia , Antineoplásicos/farmacologia , Ésteres/farmacologia , Relação Estrutura-AtividadeRESUMO
Ozone (O3) is a major component of air pollution, which has been associated with airway inflammation characterized by the influx of neutrophils in asthmatic subjects. Canonical transient receptor potential 6 (TRPC6) channel is recently identified as a target of oxidative stress which is involved in airway inflammation. However, the regulatory role of TRPC6 in airway epithelial cells and neutrophils has not yet been illuminated in detail. In this study, we investigated the role of TRPC6 in neutrophil adhesion to airway epithelial cells exposed to O3 in vivo and in vitro approaches. Using transgenic mice, the results showed that TRPC6-deficiency attenuated O3-induced neutrophil recruitment to airway epithelial cells and intercellular adhesion molecule-1 (ICAM-1) expression. In vitro, O3 induced ICAM-1 expression and neutrophil adhesion to 16HBE cells (human airway epithelial cell line) and which were reduced by both TRPC6 silencing short hairpin RNA (shRNA) and TRPC6 inhibitor Larixyl Acetate (LA). We also confirmed that TRPC6-dependent Ca2+ entry and NF-κB activation in 16HBE cells were required for ICAM-1-mediated neutrophil adhesion exposed to O3. In conclusion, this study demonstrated the contribution of TRPC6 to O3-induced neutrophil adhesion to airway epithelial cells via NF-κB activation and ICAM-1 expression, which may provide new potential concepts for preventing and treating air pollutant-related inflammatory lung diseases.
Assuntos
Adesão Celular , Células Epiteliais/fisiologia , Inflamação/prevenção & controle , Molécula 1 de Adesão Intercelular/metabolismo , NF-kappa B/metabolismo , Neutrófilos/fisiologia , Ozônio/toxicidade , Canal de Cátion TRPC6/fisiologia , Animais , Células Epiteliais/efeitos dos fármacos , Feminino , Inflamação/induzido quimicamente , Inflamação/patologia , Molécula 1 de Adesão Intercelular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , Neutrófilos/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Transdução de SinaisRESUMO
receptor potential canonical (TRPC) channels are presently an emerging target for airway disorders. Recent evidence has indicated that TRPC6 as a member of the TRPC family plays an important role in airway inflammation, but its precise function in bronchial epithelial cells remains unclear. The aim of this study was to investigate the role of TRPC6 in Toll-like receptor 4 (TLR4)-mediated inflammation in human bronchial epithelial cells stimulated by endotoxin [lipopolysaccharide (LPS)]. Hyp9 is a simplified phloroglucinol derivative of hyperforin that highly selectively activates TRPC6 channels. The results show that the activation of TRPC6 by Hyp9 induced the production of interleukin (IL)-8 and IL-6. LPS was also able to induce the release of IL-8 and IL-6, which was significantly aggravated by Hyp9 and reduced by knockdown of TRPC6. Treatment with LPS not only chronically induced the expression of TRPC6 mRNA and protein in a TLR4-dependent manner but also acutely increased Ca2+ influx through TRPC6 channels. In addition, LPS-induced overexpression of TRPC6 and Ca2+ influx were associated with the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt. Importantly, TRPC6 was required for the activation of ERK1/2, p38, and NF-κB. In conclusion, these data reveal that LPS induced the overexpression of TRPC6 and TRPC6-dependent Ca2+ influx via the TLR4/PI3K/Akt pathway resulting in Ca2+ mobilization, which subsequently promoted the activation of ERK1/2, p38, and NF-κB and the inflammatory response in bronchial epithelial cells.
Assuntos
Brônquios/diagnóstico por imagem , Células Epiteliais/efeitos dos fármacos , Inflamação/induzido quimicamente , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Canal de Cátion TRPC6/agonistas , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Brônquios/enzimologia , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Células Epiteliais/enzimologia , Humanos , Inflamação/enzimologia , Inflamação/genética , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Canal de Cátion TRPC6/genética , Canal de Cátion TRPC6/metabolismo , Terpenos/farmacologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/metabolismoRESUMO
In this study, we investigated the protective effect of the antioxidant N-acetyl-L-cysteine (NAC) on the lung inflammation caused by ozone (O3) exposure in mice. Thirty-two C57BL/6 mice were randomly divided into control group, O3 group, O3+NAC group and NAC group. Mice were exposed to O3 (1.0 ppm) or fresh air for 3 h on the day 1, day 3 and day 5, respectively. NAC (100 mg/kg) was intraperitoneally applied to the mice 1 h before each exposure. At 24 h after the 3-time exposure, the alveolar wall structure was severely damaged and the infiltrated inflammatory cells were apparent perivascularly and peribronchiolarly. Significant increases in the total white blood cell count, macrophage, lymphocyte and neutrophil counts, as well as total protein concentration were observed in the bronchoalveolar lavage fluid (BALF) (P < 0.05). The IL-6, IL-8 (P < 0.01) and MDA levels (P < 0.05) in the lung homogenates were elevated coherently. Administration of NAC could attenuate the alveolar wall structure damage induced by O3 exposure and reduce the amount of infiltrated inflammatory cells, total and differential leukocyte counts (P < 0.05), as well as the IL-6, IL-8 (P < 0.01) and MDA release (P < 0.05). Western blotting results showed that the O3 exposure up-regulated the p38 MAPK and NF-κB p65 protein expression in the lung tissue of mice (P < 0.05), which could be alleviated by NAC (P < 0.05). These results indicated that NAC could protect against O3-induced pulmonary inflammation in mice. The beneficial effect of NAC might be related with the p38 MAPK and NF-κB p65 signal pathway.
Assuntos
Pneumonia , Acetilcisteína , Animais , Antioxidantes , Líquido da Lavagem Broncoalveolar , Interleucina-6 , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B , Neutrófilos , OzônioRESUMO
Herein, a novel fluorescent/colorimetric/photothermal biosensor is proposed for aflatoxin B1 (AFB1) detection in food based on Prussian blue nanoparticles (PBNPs) (â¼50 nm), gold nanoclusters (AuNCs), and an aptamer (Apt) within three hours. Briefly, a multifunctional compound, namely PBNPs-PEI@AuNCs, was synthesized from PBNPs as the loading carrier, polyethyleneimine (PEI) as the cross-linking agent, and AuNCs directly combined on the surface of PBNPs. The AFB1 Apt was then modified on the PBNPs-PEI@AuNCs to form a PBNPs-PEI@AuNCs-Apt probe, whereby when AFB1 is present, AFB1 is specifically captured by the probe. Meanwhile, the MNPs@antibody was also introduced to capture AFB1, thereby forming a "sandwich" structure compound. After magnetic separation, high temperature was applied to this "sandwich" structure compound to induce the denaturation of the Apt. Then the fluorescent/colorimetric/photothermal signals were collected from the PBNPs-PEI@AuNCs@Apt to give information on its related condition. The detection limits of the biosensor were 0.64 × 10-14, 0.96 × 10-14, and 0.55 × 10-12 g mL-1 for the three signals, which were outputted independently and could be verified with each other to ensure the accuracy of the results. Moreover, the colorimetric and photothermal strategies with this probe do not require large-scale instruments, providing a promising choice for achieving the rapid field detection of AFB1.
Assuntos
Aflatoxina B1 , Técnicas Biossensoriais , Ferrocianetos , Ouro , Nanopartículas Metálicas , Aflatoxina B1/análise , Aflatoxina B1/química , Ouro/química , Técnicas Biossensoriais/métodos , Ferrocianetos/química , Nanopartículas Metálicas/química , Aptâmeros de Nucleotídeos/química , Limite de Detecção , Colorimetria/métodos , Contaminação de Alimentos/análise , Polietilenoimina/químicaRESUMO
Whole-body molecular imaging is able to directly map spatial distribution of molecules and monitor its biotransformation in intact biological tissue sections. Imaging mass spectrometry (IMS), a label-free molecular imaging method, can be used to image multiple molecules in a single measurement with high specificity. Herein, a novel easy-to-implement, whole-body IMS method was developed with air flow-assisted ionization in a desorption electrospray ionization mode. The developed IMS method can effectively image molecules in a large whole-body section in open air without sample pretreatment, such as chemical labeling, section division, or matrix deposition. Moreover, the signal levels were improved, and the spatial assignment errors were eliminated; thus, high-quality whole-body images were obtained. With this novel IMS method, in situ mapping analysis of molecules was performed in adult rat sections with picomolar sensitivity under ambient conditions, and the dynamic information of molecule distribution and its biotransformation was provided to uncover molecular events at the whole-animal level. A global view of the differential distribution of an anticancer agent and its metabolites was simultaneously acquired in whole-body rat and model mouse bearing neuroglioma along the administration time. The obtained drug distribution provided rich information for identifying the targeted organs and predicting possible tumor spectrum, pharmacological activity, and potential toxicity of drug candidates.
Assuntos
Ar , Espectrometria de Massas , Imagem Molecular/métodos , Imagem Corporal Total/métodos , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Glioma/metabolismo , Glioma/patologia , Indolizinas/farmacocinética , Indolizinas/farmacologia , Masculino , Camundongos , Fenantrenos , Fenantrolinas/farmacocinética , Fenantrolinas/farmacologia , Ratos , Ratos WistarRESUMO
Ethylene-responsive element-binding factor (ERF) genes constitute one of the largest transcription factor gene families in plants. In Arabidopsis and rice, only a few ERF genes have been characterized so far. Flower senescence is associated with increased ethylene production in many flowers. However, the characterization of ERF genes in flower senescence has not been reported. In this study, 13 ERF cDNAs were cloned from petunia. Based on the sequence characterization, these PhERFs could be classified into four of the 12 known ERF families. Their predicted amino acid sequences exhibited similarities to ERFs from other plant species. Expression analyses of PhERF mRNAs were performed in corollas and gynoecia of petunia flower. The 13 PhERF genes displayed differential expression patterns and levels during natural flower senescence. Exogenous ethylene accelerates the transcription of the various PhERF genes, and silver thiosulphate (STS) decreased the transcription of several PhERF genes in corollas and gynoecia. PhERF genes of group VII showed a strong association with the rise in ethylene production in both petals and gynoecia, and might be associated particularly with flower senescence in petunia. The effect of sugar, methyl jasmonate, and the plant hormones abscisic acid, salicylic acid, and 6-benzyladenine in regulating the different PhERF transcripts was investigated. Functional nuclear localization signal analyses of two PhERF proteins (PhERF2 and PhERF3) were carried out using fluorescence microscopy. These results supported a role for petunia PhERF genes in transcriptional regulation of petunia flower senescence processes.
Assuntos
Proteínas de Ligação a DNA/genética , Flores/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Petunia/efeitos dos fármacos , Reguladores de Crescimento de Plantas/farmacologia , Proteínas de Plantas/genética , Sequência de Aminoácidos , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Etilenos/farmacologia , Flores/efeitos dos fármacos , Flores/genética , Flores/metabolismo , Dados de Sequência Molecular , Petunia/genética , Petunia/crescimento & desenvolvimento , Petunia/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Estrutura Terciária de Proteína , Alinhamento de SequênciaRESUMO
⢠Smart usage of single molecule photobleaching technology and dual-color fluorescence colocalization is of critical importance for exploiting the sensing platform. Here, we provide the detailed protocols related to the article "A split aptamer sensing platform for highly sensitive detection of theophylline based on dual-color fluorescence colocalization and single molecule photobleaching" (published online by Biosensors and Bioelectronics) (Liu et al., 2020). The protocols contain: (1) how to clean the slides; (2) how to prepare the probe and detection sample; (3) Single molecule imaging; 4) Data processing by using the Image J. Finally, we used a simple model to confirm the feasibility of the method for integrating dual-color fluorescence colocalization and single molecule photobleaching technology on the theophylline sensing platform. ⢠A simple, ultrasensitive method for the detection of theophylline. ⢠The method is easily comprehensible. ⢠Both strategy formulation and data processing are simple, learnability, and highly reproducible.
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Ozone (O3) plays an extremely important role in airway inflammation by generating reactive oxygen species (ROS) including hydrogen peroxide, then promoting redox actions and causing oxidative stress. Evidences indicate that TRPC6 (canonical transient receptor potential channel 6) is a redox-regulated Ca2+ permeable nonselective cation channel, but its role in the setting of oxidative stress-related airway inflammation remains unknown. Here, we found that both TRPC6-/- mice and mice pretreated with SAR7334, a potent TRPC6 inhibitor, were protected from O3-induced airway inflammatory responses. In vitro, both knockdown of TRPC6 expression with shRNA and TRPC6 blockage markedly attenuated the release of cytokines IL-6 and IL-8 induced by O3 or H2O2 in 16HBE cells (human bronchial epithelial cell line). Treatment with O3 or H2O2 enhanced TRPC6 protein expression in vivo and vitro. We also observed that TRPC6-dependent increase of intracellular Ca2+ concentration ([Ca2+]i) was triggered by H2O2, which consisted of the release from intracellular calcium store and the influx of extracellular Ca2+ and could be further strengthened by 6-h O3 exposure in both 16HBE cells and HBEpiCs (primary human bronchial epithelial cells). Moreover, we confirmed that the activation of MAPK signals (ERK1/2, p38, JNK) was required for the inflammatory response induced by O3 or H2O2 while only the phosphorylation of ERK pathway was diminished in the TRPC6-knockdown situation. These results demonstrate that oxidative stress regulates TRPC6-mediated Ca2+ cascade, which leads to the activation of ERK pathway and inflammation and could become a potential target to treat oxidative stress-associated airway inflammatory diseases.
Assuntos
Células Epiteliais/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases , Estresse Oxidativo/efeitos dos fármacos , Canal de Cátion TRPC6/genética , Animais , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Células Epiteliais/metabolismo , Humanos , Inflamação/induzido quimicamente , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Canal de Cátion TRPC6/efeitos dos fármacosRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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As a new class of promising fluorescent carbon nanomaterials, carbon dots (CDs) have been well developed in recent years for their excellent fluorescent properties, simple synthetic approaches, good biocompatibility and various detection applications, which can be expected to replace the tradition semi-quantum dots. This review aims presents the current progress in the development of CDs with an emphasis on fluorescent properties, synthetic approaches and applications in food safety. First, the fluorescent properties of CDs are briefly introduced. To seek more reasonable synthetic approaches, the characteristics of the diverse methods of CD synthesis are summarized. And then, applications of CDs as fluorescent probes in food safety are discussed, with emphasis on the determination of metal ions/anions, pesticides, veterinary drugs, bacteria, functional components and banned additives. Finally, the challenges, such as how to explain the diversity of fluorescent properties, and how to form a uniform synthesis procedure to improve the quantum yield (QY), for CDs are presented. Although CDs have found many applications in food safety, it is still a challenge to detect a specific target in complex samples. Therefore, combination with other biochemistry technology to exploit novel ligands against the specific target with high binding affinity and selectivity is vitally important for developing sensitive and specific sensing probes in the future.
Assuntos
Carbono/química , Inocuidade dos Alimentos/métodos , Pontos Quânticos/química , Corantes Fluorescentes/químicaRESUMO
A series of novel substituted uracil-1'(N)-acetic acid esters (6-20) of camptothecins (CPTs) were synthesized by the acylation method. These new compounds were evaluated for in vitro antitumor activity against tumor cell lines, A549, Bel7402, BGC-823, HCT-8 and A2780. In vitro results showed that most of the derivatives exhibited comparable or superior cytotoxicity compare to CPT (1) and topotecan (TPT, 2), with 12 and 13 possessing the best efficacy. Four compounds, 9, 12, 13 and 16, were selected to be evaluated for in vivo antitumor activity against H22, BGC-823 and Bel-7402 in mice. In vivo testing results indicated that 12 and 13 had antitumor activity against mouse liver carcinoma H22 close to Paclitaxel and cyclophosphamide. 12 had similar antitumor activity against human gastric carcinoma BGC-823 in nude mice compared to irinotecan (3) and possessed better antitumor activity against human hepatocarcinoma Bel-7402 in nude mice than 2. It is also discovered that 12 showed a similar mechanism but better inhibitory activity on topoisomerase I (Topo I) compared to 2. These findings indicate that 20(S)-O-fluorouracil-1'(N)-acetic acid ester derivative of CPTs, 12, could be developed as an antitumor drug candidate for clinical trial.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias/tratamento farmacológico , Uracila/análogos & derivados , Uracila/uso terapêutico , Acetatos/síntese química , Acetatos/química , Acetatos/farmacologia , Acetatos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Camptotecina/síntese química , Camptotecina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Humanos , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Uracila/síntese química , Uracila/farmacologiaRESUMO
The aim of the present study was to develop a lipid emulsion loaded with a paclitaxel-cholesterol complex (PTX-CH Emul) in order to improve the safety and efficacy of paclitaxel (PTX) and evaluate its antitumor activity against commercially available formulation Taxol®. PTX-CH Emul resembling a low density lipoprotein lipid structure, exhibited an ideal particle size, high drug loading capability, high drug encapsulation efficiency and excellent stability. PTX-CH Emul showed superior in vitro anticancer efficacy against triple-negative MDA-MB-231 breast cancer cells when compared with a paclitaxel emulsion (PTX Emul) and Taxol. The IC70 value of PTX-CH Emul was almost 1.5- and 2.4-fold lower than that of PTX Emul and Taxol, respectively. Compared with PTX Emul and Taxol, PTX-CH Emul exhibited stronger and more rapid inhibitory effects on 3D tumor spheroids of MDA-MB-231 cells. Additionally, in vivo tumor-targeting study showed that PTX-CH Emul had higher specificity and efficiency in intratumoral accumulation as compared to PTX Emul. Finally, the maximum tolerated dose (MTD) of PTX-CH Emul was 2.25fold higher than that of Taxol, suggesting that PTX-CH Emul exhibited better safety profiles in vivo than Taxol. At the MTDs, PTX-CH Emul exhibited superior antitumor efficacy in nude mice bearing MDA-MB-231 xenografts in comparison to Taxol. Therefore, PTX-CH Emul as reported here showed high potential as a drug carrier for PTX in clinical applications involving the targeting of triple-negative breast cancer.
Assuntos
Colesterol/administração & dosagem , Colesterol/química , Emulsões/química , Lipídeos/química , Paclitaxel/administração & dosagem , Paclitaxel/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Feminino , Humanos , Lipídeos/administração & dosagem , Neoplasias Mamárias Animais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da PartículaRESUMO
AIM: To improve the biological activity of A-ring modified analogues of camptothecin. METHODS: A-ring modified camptothecins were synthesized from 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin (SN-38) in three or four steps. Their cytotoxicity was evaluated using MTY assay, and their in vivo antitumnor activity against mouse liver cancer H22 was tested. Results Five hexacyclic camptothecins (6a, 6b, 6c, 7a and 7b) are target compounds, and ten camptothecin derivatives are new compounds. CONCLUSION: The modification of a 1,4-oxazine-2-one ring fused with positions 9 and 10 of A-ring will reduce the antitumor activity of camptothecins.
Assuntos
Antineoplásicos/síntese química , Camptotecina/análogos & derivados , Camptotecina/síntese química , Compostos Policíclicos/síntese química , Animais , Antineoplásicos/farmacologia , Camptotecina/química , Camptotecina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , Feminino , Humanos , Irinotecano , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Transplante de Neoplasias , Compostos Policíclicos/farmacologiaRESUMO
OBJECTIVE: To detect the expression of transient receptor potential canonical 1 (TRPC1) in a mouse model of ozone-induced lung inflammation and explore its role in lung inflammation. METHODS: In a mouse model of lung inflammation established by ozone exposure, the expression of TRPC1 in the inflammatory lung tissues was detected by RT-PCR, Wstern blotting and immunohistochemistry. RESULTS: Compared to the control mice, the mice exposed to ozone showed significantly increased expression level of TRPC1 mRNA and protein in the inflammatory lung tissues (P<0.05). Immunohistochemistry showed increased TRPC1 protein expressions in the alveolar epithelial cells, bronchial epithelial cells, and inflammatory cells in the inflammatory lung tissues (P<0.05). The mRNA and protein expression levels of TRPC1 were positively correlated with the counts of white blood cells, macrophages, neutrophils and lymphocytes in the bronchoalveolar lavage fluid of the exposed mice (P<0.01). CONCLUSION: TRPC1 may play a role in ozone-induced lung inflammation in mice.
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Inflamação/patologia , Pulmão/patologia , Ozônio/efeitos adversos , Canais de Cátion TRPC/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Expressão Gênica , Pulmão/metabolismo , Camundongos , Pneumonia/metabolismo , Pneumonia/patologia , RNA MensageiroRESUMO
OBJECTIVE: The chemopreventive activity and mechanism of dehydroepiandrosterone (DHEA) were studied. METHODS: Model of 7, 12-dimethylbenz (alpha) anthracene (DMBA) induced breast carcinoma in Sprague-Dawley rats, uitra-violet (UV)-induced DNA damage and Salmonella mutation assay were used. RESULTS: In DMBA-induced rat mammary tumor model, the rats were orally given daily DHEA for 2 weeks before DMBA and continued for 10 weeks after DMBA administration. The results showed significant inhibition of tumor development by DHEA. The incidence of mammary carcinoma also decreased significantly on daily dose of oral 25 mg/kg DHEA with the mean tumor volume per rat also remarkably reduced by 92%. Moreover, 25 mg/kg DHEA treatment could significantly increase the carcinoma latency for about 3.5 weeks as compared with the control. Using polymerase chain reaction (PCR) assay, in vitro 10(-9) mol/L DHEA showed significant inhibitory effect on UV-induced DNA damage by 90%. In Ames test, DHEA was found to decrease DMBA and benzo (alpha) pyrene-induced TA98 and TA100 His(+) revertants markedly and the number of Salmonella clones were significantly reduced by 53.2% and 73.0% on dose of 5 microgram DHEA/plate. It was also shown that in vitro 10(-7) mol/L DHEA could also effectively inhibit the G-6-PDH activity, which might play an important role in its chemoprophylaxis activities. CONCLUSION: The results strongly prove that DHEA is a potent cancer chemoprophylaxis agent, which exhibits inhibitory potential on mutation and chemical carcinogen in vivo and in vitro.
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Antimutagênicos/farmacologia , Desidroepiandrosterona/farmacologia , Neoplasias Mamárias Experimentais/prevenção & controle , 9,10-Dimetil-1,2-benzantraceno/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Animais , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glucosefosfato Desidrogenase/antagonistas & inibidores , Glucosefosfato Desidrogenase/metabolismo , Neoplasias Mamárias Experimentais/induzido quimicamente , Testes de Mutagenicidade , Ratos , Ratos Sprague-Dawley , Salmonella/efeitos dos fármacos , Salmonella/genética , Fatores de Tempo , Células Tumorais CultivadasRESUMO
OBJECTIVE: To investigate the inducing effect of Brucea javanica on the apoptpsis of HL-60 cells. METHOD: HL-60 cells were treated with Brucea javanica 1:100, 1:40, 1:20 (v/v) respectively for 6 h and DNA agarose gel electrophoresis, flow cytometry, fluorescence microscope, electron microscope were used to observe the apoptosis inducing effect of Brucea javanica. RESULT: DNA ladder was seen in the 1:40 group. The apoptosis cell percentages of 1:40 and 1:20 group were 86.8% and 97% respectively. Cells of 1:40 group showed obvious apoptosis character under fluorescence microscope. Cells were induced apoptosis in 1:20 and 1:40 Brucea javanica under electron microscope. CONCLUSION: 1:20 and 1:40 Brucea Javanica showed obvious apoptosis inducing effect of HL-60.
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Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Brucea , Óleos de Plantas/farmacologia , Plantas Medicinais , Brucea/química , Células HL-60 , Humanos , Óleos de Plantas/isolamento & purificação , Plantas Medicinais/químicaRESUMO
BACKGROUND & OBJECTIVE: SHEN QI JIN KANG (SQJK) capsule is a complex preparation, consisting of effective components extracted from radix astragali, ginseng, curcuma, etc. It has been demonstrated to be able to decrease tumor volume, increase life quality and prolong survival time in clinic application. The study was to investigate the antitumor effects of SQJK capsule in vivo and in vitro, and further explore the possible mechanisms. METHODS: The proliferation of cancer cells treated with SQJK was measured by MTT assay in twelve cell lines; cell apoptosis was observed under an electric microscopic and detected by flow cytometry in MCF-7 and MA891 cells; altered telomerase activity in A549 cells was examined by a telomerase activity detection kit. Furthermore, the inhibitory effect of SQJK on tumors was also surveyed in vivo by using mice and nude mice models bearing transplanted tumors. RESULTS: Inhibitory concentration 50% (IC(50)) of SQJK on A549, U251, MCF-7, Ketr-3, EJ, and A2780 cells was 30.954 microg/ml, 31.746 microg/ml, 37.220 microg/ml, 40.366 microg/ml, 41.398 microg/ml, and 45.083 microg/ml, respectively. Typical sub-G1 peaks, indicating the occurrence of apoptosis, were revealed in MA891and MCF-7 cells treated with SQJK. Morphological changes including cell shrinkage and condensation of chromosomes were observed. The telomerase activity of A549 was inhibited after 48 h of SQJK treatment. SQJK 1.8 g/kg inhibited the weights of transplanted tumors (MA891, H22, S180 in mice and PC-3 (M), MCF-7 and Ketr-3 in nude mice) by 50.84%, 48.91%, 40.88%, 62.50%, 47.83% and 30.06%, while SQJK 3.6 g/kg inhibited the weights by 56.49%, 59.62%, 55.70%, 70.76%, 58.66% and 50.18%, respectively. CONCLUSION: SQJK has demonstrated antitumor bioactivity both in vitro and in vivo, which may be related to its effects of inducing apoptosis and decreasing telomerase activity.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Telomerase/metabolismo , Carga Tumoral/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/isolamento & purificação , Feminino , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Plantas Medicinais/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Resveratrol (3,4',5-trihydroxy-trans-stilbene), a naturally occurring phytoalexin found in grapes and wine, possesses cancer-preventive activity. Angiogenesis is a crucial step in the growth and metastasis of cancers. We have investigated the effect of resveratrol on angiogenesis in vitro and ex vivo, and found that resveratrol directly inhibited human umbilical vein endothelial cell growth and decreased the gelatinolytic activities of matrix metalloproteinase-2. Tube formation was inhibited by treatment with resveratrol after plating endothelial cells on Matrigel. Resveratrol treatment also inhibited endothelial cell attachment to basement membrane components fibronectin and laminin, and displays similar behavior on cell chemotaxis. In addition, resveratrol has been found to be an angiogenesis inhibitor in the rat aorta matrix culture model. Therefore, inhibition of angiogenesis associated with cancer may be a novel mechanism for the anticancer activity of resveratrol.
Assuntos
Inibidores da Angiogênese/farmacologia , Plantas Medicinais/química , Estilbenos/farmacologia , Animais , Adesão Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Masculino , Inibidores de Metaloproteinases de Matriz , Ratos , Ratos Wistar , ResveratrolRESUMO
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring phytoalexin found in grapes and wine, and has been reported to exert a variety of important pharmacological effects. We have investigated the activity of resveratrol on proliferation and differentiation of the acute promyelocytic leukemia cell line NB4. The growth inhibitory properties of resveratrol appear to be due to its induction of apoptotic cell death, as determined by morphological changes, DNA fragmentation, increased proportion of the subdiploid cell population and decreased mitochondrial transmembrane potential (Deltapsi(m)). Colorimetric assay for activity of caspase-3 showed an obvious increase in caspase-3 activity in cells after treatment with resveratrol. However, the expression levels of protein Bcl-2 and Bax show no significant change in response to resveratrol treatment. These results suggest that apoptosis of NB4 cells induced by resveratrol requires caspase-3 activation and is related to the mitochondrial transmembrane potential. The combination of resveratrol and all-tran-retinoic acid (ATRA) induced 100% of the NB4 cells to become NBT-positive, whereas only a small part of cells became positive for NBT after a similar exposure to either resveratrol or ATRA alone. Thus, resveratrol may be useful in treating acute promyelocytic leukemia.