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1.
Nat Prod Res ; : 1-6, 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31303068

RESUMO

This study seeks to discover flavonoids from a traditional Chinese herb, Artemisia rupestris L., with synergistic antibacterial effects against multidrug-resistant Staphylococcus aureus. Five flavonoids, artemetin (1), chrysosplenetin (2), pachypodol (3), penduletin (4) and chrysoeriol (5) were obtained by various column chromatographic methods. Their chemical structures were determined on the basis of comprehensive spectroscopic analysis and comparison with literature data. Three of the compounds (2, 4 and 5) exhibited synergistic activity when combined with norfloxacin against SA1199B, an effluxing fluoroquinolone-resistant strain. The fractional inhibitory concentration indices (FICIs) of 2, 4 and 5 in combination with norfloxacin were 0.375, 0.079 and 0.266 respectively, suggesting synergy. Compound 5 also showed synergistic effects against EMRSA-15 and EMRSA-16 when combined with ciprofloxacin and oxacillin exhibiting FICIs of 0.024 and 0.375 respectively. Real time ethidium bromide (EtBr) efflux assay, qRT-PCR and molecular docking were employed to explore the mechanisms of the synergistic effects.

2.
Artigo em Inglês | MEDLINE | ID: mdl-30176356

RESUMO

Antimicrobial resistance is the greatest threat to the treatment of bacterial infectious diseases. The development of resistance-modifying agents represents a promising strategy to mitigate the spread of bacterial antibiotic resistance. A natural product, isovalerylshikonin (IVS), was isolated from traditional Chinese medicine Arnebia euchroma in this study, which exhibited marginal antibacterial activity against drug-resistant Staphylococcus aureus RN4220, with an MIC of 16 mg/L. In addition, a synergistic effect between IVS and streptomycin was detected by the microdilution antimicrobial checkerboard assay, with a reduction in the MIC of IVS by up to 32-fold against RN4220. A bacterial EtBr efflux assay and RT-PCR were performed to investigate the mechanism of the synergy. IVS significantly inhibited the bacterial efflux and expression of msrA mRNA in the in vitro experiment. A peritonitis/sepsis model was employed to test the in vivo synergistic activity of IVS and STM. IVS synergistically decreased the bacteria count with STM in peritoneal, spleen and liver, and increased mouse survival with STM in 7 days. The acute toxicity of IVS was tested, and the LD50 of IVS with a single exposure was 2.584 g/kg in mice. Overall, isovalerylshikonin, a low toxicity resistance-modifying agent, exhibited synergistic antibacterial activities in vitro and in vivo against drug-resistant S. aureus. The effects were mediated by suppression of msrA mRNA expression and bacterial efflux. In addition, these data support that IVS is a potential resistance-modifying agent against microbial resistance caused by msrA efflux pump.

3.
Phytochem Anal ; 28(6): 496-504, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28589595

RESUMO

INTRODUCTION: High-speed counter-current chromatography (HSCCC) is an efficient and non-absorption separation technique, but limitations still exist in simultaneous isolation of complex structures of natural products. Moreover, particular methods are various for different kinds of natural products. OBJECTIVE: A novel HSCCC strategy combined with an online storage recycling elution (OSR-CCC) technique was developed for the quick separation of naturally occurring dihydroflavonoids from the extract of the herb Sophora alopecuroides L. METHODOLOGY: In the separation procedure, a storage loop and two six-port valves were connected to a HSCCC system. Effluent A was subjected to an online storage loop and then to recycling separation three times after effluent B was collected in head-to-tail mode. After completion of the recycling separation of effluent A, the elution was switched to tail-to-head mode to collect effluent C. A biphasic solvent system of n-hexane/ethyl acetate/methanol/water (9:6:6:8, v/v/v/v) was used as the separation solvent during the whole elution. RESULTS: Six constituents were isolated simultaneously from the extract (200 mg) of S. alopecuroides by running HSCCC non-stop, and their purities were higher than 95.0%. Their structures were determined as the pterocarpan glycoside sophoratonkin (1) (10.0 mg) and five dihydroflavonoids, alopecurone F (2) (5.4 mg), lehmannin (3) (11.0 mg), alopecurone A (4) (35.0 mg), sophoraflavanone G (5) (21.0 mg), alopecurone B (6) (31.0 mg). CONCLUSION: This recycling HSCCC method combined with an online storage technique could be a rapid, effective and simple approach to isolate stilbene-dihydroflavonoids from herbs of the Sophora genus simultaneously. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Distribuição Contracorrente/métodos , Flavonoides/química , Sophora/química , Fracionamento Químico , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais
4.
Nat Prod Commun ; 11(6): 739-40, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27534105

RESUMO

Panax ginseng has been used in traditional oriental medicine for thousands of years. Ginsenosides, the major chemical components of the roots, are considered to be responsible for the medicinal properties of ginseng. Ginsenosides increase with the age of ginseng root in general knowledge, and in this study the content of ginsenosides in ginseng of different ages was quantified. Separation and determination of eight main ginsenosides, Rg1, Re, Rb1, Rc, Rg2, Rb2, Rb3 and Rd, was performed by high performance liquid chromatography with UV detection at 203 nm. The content of Rg1, Re, Rb1, Rc, Rg2 and Rd increased from 5 to 16-year-old ginseng and then decreased, while Rb2 and Rb3 increased in the range of 5-12 years, but then slowly decreased. However, the total eight ginsenosides in 16 year old ginseng had a higher content than that in any other from 5-18 years old. As a result, the content of ginsenosides and total ginsenosides was not positively related to age from 5-18 years, which is not in full agreement with the general knowledge of ginseng. Thus, this study suggests that the older wild ginseng may not result in better medicinal ginseng for herbal medicines.


Assuntos
Ginsenosídeos/química , Panax/química , Panax/crescimento & desenvolvimento , Extratos Vegetais/química , Estrutura Molecular , Raízes de Plantas/química , Raízes de Plantas/crescimento & desenvolvimento , Fatores de Tempo
5.
J Chromatogr A ; 1464: 79-86, 2016 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-27554028

RESUMO

Counter-current Chromatography (CCC) has gradually become a popular method for preparative separation, especially in natural product isolation. As an effective separation method, one-dimensional (1D) CCC often results in insufficiently resolved peaks, due to limitations in the separation efficiency and peak capacity in an equipment. Therefore, two dimensional (2D)/multi-dimensional (multi-D) CCC strategies with recycling elution mode were developed to achieve successful separation of target compounds. However, the reported 2D or multi-D CCC approaches lead to experimental costs, complicated procedures, higher requirements for equipment, and increased time consumption. In this study, an online-storage recycling (OSR) CCC strategy was designed to achieve sequential recycling elution for multi-fractions of effluent in non-stop separation with single instrument using three 6-port valves and two storage loops, which would be realized by introducing 2D or multi-D CCC method before. In this non-stop separation system, the fraction C of effluent was subjected to recycling separation while the other fractions (A and B) were storing online, following which these two fractions were subjected to subsequent recycling separations in order, after the completion of the previous recycling elution. Then, six natural occurring naphthaquinone analogues, namely, shikonin (1), propionylshikonin (2), deoxyshikonin (3), isobutyrylshikonin (4), ß, ß-dimethylacrylshikonin (5) and isovalerylshikonin (6), were isolated from the crude extract of Arnebia euchroma in single run. The purities of all compounds were > 95.0% as determined by HPLC, and their structures were determined by means of UV, MS, (1)H NMR, (13)C NMR, and optical rotatory dispersion (ORD).


Assuntos
Boraginaceae/química , Distribuição Contracorrente/métodos , Extratos Vegetais/isolamento & purificação , Quinonas/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/análise , Quinonas/análise
6.
Oncotarget ; 7(27): 41540-41558, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27172794

RESUMO

Because colorectal cancer (CRC) stem-like cells (CCS-like cells) contribute to poor patient prognosis, these cells are a potential target for CRC therapy. However, the mechanism underlying the maintenance of CCS-like cell properties remains unclear. Here, we found that patients with advanced stage CRC expressed high levels of polycomb group protein enhancer of zeste homologue 2 (EZH2). High expression of EZH2 in tumor tissues correlated with poor patient prognosis. Conversely, silencing EZH2 reduced CRC cell proliferation. Surprisingly, EZH2 was more highly expressed in the CCS-like cell subpopulation than in the non-CCS-like cell subpopulation. EZH2 knockdown significantly reduced the CD133+/CD44+ subpopulation, suppressed mammosphere formation, and decreased the expression of self-renewal-related genes and strongly impaired tumor-initiating capacity in a re-implantation mouse model. Gene expression data from 433 human CRC specimens from TCGA database and in vitro results revealed that EZH2 helped maintain CCS-like cell properties by activating the Wnt/ß-catenin pathway. We further revealed that p21cip1-mediated arrest of the cell cycle at G1/S phase is required for EZH2 activation of the Wnt/ß-catenin pathway. Moreover, the specific EZH2 inhibitor EPZ-6438, a clinical trial drug, prevented CRC progression. Collectively, these findings revealed EZH2 maintaining CCS-like cell characteristics by arresting the cell cycle at the G1/S phase. These results indicate a new approach to CRC therapy.


Assuntos
Proliferação de Células/genética , Neoplasias Colorretais/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Células-Tronco Neoplásicas/patologia , Via de Sinalização Wnt , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Via de Sinalização Wnt/genética , Adulto Jovem , beta Catenina/genética , beta Catenina/metabolismo
8.
J Ethnopharmacol ; 175: 668-83, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26387740

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Plants of the genus Mahonia Nuttall (Berberidaceae) have a long history of medical use in Traditional Chinese Medicine (TCM) for the treatment of a wide range of health disorders, such as tuberculosis, periodontitis, dysentery, pharyngolaryngitis, eczema, and wounds. In the theory of TCM, most Mahonia species exert the effects of relieving internal heat, eliminating dampness, removing toxins, suppressing pain, promoting blood circulation, inhibiting cough and alleviating inflammation. The aim of the review is to provide comprehensive summary on ethnopharmacology, phytochemistry, pharmacology, toxicology and clinical trials of Mahonia species used in TCM based on scientific literature. Available scientific evidence supporting the therapeutic effects of Mahonia species in TCM is demonstrated and opportunities for future research are discussed to highlight the scientific gaps in our knowledge that deserves further investigation. METHODS: The available information on the ethnopharmacological uses in Chinese medicine, phytochemistry, pharmacology and clinical practice of the genus Mahonia was collected from Chinese Herbal Classics, published books, un-published resources, dissertations and various worldwide-accepted scientific databases: CNKI, PubMed, ScienceDirect, SpringerLink, Google Scholar, Wiley, TPL (www.theplantlist.org), SciFinder, and Embase. RESULTS: A variety of ethnomedical usages of Mahonia have been recorded in ancient Chinese books and references. The phytochemical research of this genus has resulted in the identification of more than 150 chemical constituents, among which alkaloids are predominant. The isolated compounds and crude extracts have been shown to exhibit a wide spectrum of in vitro and in vivo pharmacological effects, including antimicrobial, anti-inflammatory, hepatoprotective, antioxidant, antimutagenic and analgesic properties. Preparations containing Mahonia species have been demonstrated to exert good efficacy for the clinical treatment of dysentery, internal and external hemorrhage, acne vulgaris and chronic pharyngitis, among other diseases. CONCLUSIONS: The available scientific references demonstrate that the traditional medical uses of some important Mahonia species in TCM have been evaluated in modern pharmacological studies. Isoquinoline alkaloids may contribute to some of the activities shown by the plants of this genus. However, further studies employing scientific technologies and methods are warranted to reveal the phytochemistry of this genus, particularly to detail the active compounds and the underlying mechanisms.


Assuntos
Mahonia , Medicina Tradicional Chinesa , Etnofarmacologia , Humanos , Mahonia/química , Mahonia/toxicidade , Compostos Fitoquímicos/análise , Fitoterapia , Preparações de Plantas/química , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêutico , Preparações de Plantas/toxicidade
9.
Int Immunopharmacol ; 24(2): 182-190, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25523460

RESUMO

Rubi Fructus, a traditional Chinese medicine, was considered as an anti-inflammatory agent in folk medicine. In the present study, we investigated the signalling pathways involved in the anti-inflammatory effects of goshonoside-F5 (GF5), isolated from Rubi Fructus, in peritoneal macrophages and examined its therapeutic effect in a mouse endotoxic shock model. GF5 decreased NO and PGE2 production in LPS-stimulated macrophages (IC50=3.84 and 3.16µM). This effect involved the suppression of NOS-2 and COX-2 gene expression at the transcriptional level. Examination of the effects of GF5 on NF-κB signalling demonstrated that it inhibits the phosphorylation of IκB-α and IκB-ß, blocking their degradation and the nuclear translocation of the NF-κB p65 subunit. Moreover, inhibition of MAPK signalling was also observed, and phosphorylation of p38 and JNK was suppressed in the presence of GF5. Inflammatory cytokines, including IL-6 and TNF-α, were down-regulated by this compound after activation with LPS (IC50=17.04 and 4.09µM). Additionally, GF5 (30 and 90mg/kg, i.p.) significantly reduced the circulating cytokine levels (IL-6 and TNF-α) and increased survival in a mouse model of endotoxemia. These results show that GF5 significantly inhibits the pro-inflammatory response induced by LPS, both in vitro and in vivo. Our results provide a strong pharmacological basis for further understanding the potential therapeutic role of GF5 in inflammatory disease and shed new light on the bioactivity of ent-labdane diterpene glucoside.


Assuntos
Anti-Inflamatórios/administração & dosagem , Flavonoides/administração & dosagem , Macrófagos Peritoneais/efeitos dos fármacos , Medicina Tradicional Chinesa/métodos , Choque Séptico/tratamento farmacológico , Animais , Células Cultivadas , Imunossupressão , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Fosforilação/efeitos dos fármacos , Rubus/imunologia , Choque Séptico/imunologia , Choque Séptico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
10.
CNS Neurol Disord Drug Targets ; 13(5): 874-84, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24040794

RESUMO

Total bakkenolides is the major component of the rhizome of Petasites trichinous Franch.. In this study, we investigated its neuroprotective effects in a rat transient focal cerebral ischemia-reperfusion model, and in an in vitro cerebral ischemia model, oxygen-glucose deprivation of cultured nerve cells. Oral administration of total bakkenolides immediately after reperfusion at doses of 5, 10 and 20 mg/kg markedly reduced brain infarct volume and neurological deficits. Total bakkenolides significantly attenuated cell death and apoptosis in primarily cultured neurons subject to 1-h hypoxia followed by 24-h reoxygenation. Morphologic observations directly confirmed its protective effect on neurons. We also demonstrated that total bakkenolides could inhibit nuclear factor-κB (NF-κB) activation by blocking the classic activation pathway through suppression of phosphorylation of IκB-kinase complex, NF-κB/p65 and inhibitor protein IκB, inducing nuclear translocation of NF-κB/p65 and degradation of IκB. Further, total bakkenolides inhibited the activation of Akt and the extracellular signal-regulated kinase 1/2, two important upstream activators of NF-κB. In conclusion, our results provide a strong pharmacological basis for further understanding the potential therapeutic role of total bakkenolides in cerebral ischemic disease and shed new light on its neuroprotective mechanism.


Assuntos
Ataque Isquêmico Transitório/prevenção & controle , NF-kappa B/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Sesquiterpenos/uso terapêutico , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Infarto Encefálico/etiologia , Infarto Encefálico/prevenção & controle , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/citologia , Marcação In Situ das Extremidades Cortadas , Ataque Isquêmico Transitório/complicações , Masculino , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/química , Sesquiterpenos/farmacologia
11.
Neurosci Lett ; 541: 77-82, 2013 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-23523648

RESUMO

Research in mesenchymal stem cells (MSCs) is mainly focused on applications for treatments of brain and spinal cord injury as well as mechanisms underlying effects of MSCs. However, due to numerous limitations, there is little information on selection of appropriate sources of MSCs for transplantation in clinical applications. Therefore, in this study we compared various properties of human umbilical cord-derived MSCs (HUCMSCs) with human placenta-derived MSCs (HPDMSCs), including cell proliferation, apoptosis, cellular morphology, ultrastructure, and their ability to secrete various growth factors (i.e. vascular endothelial growth factor, insulin-like growth factors-1, and hepatocyte growth factor), which will allow us to select appropriate MSC sources for cellular therapy. Cell culture, flow cytometry, transmission electron microscope (TEM) and atomic force microscope (AFM) were used for assessment of HUCMSCs and HPDMSCs. Results showed that the two types of cells appeared slightly different when they were observed under AFM. HUCMSCs appeared more fibroblast-like, whereas HPDMSCs appeared as large flat cells. HUCMSCs had higher proliferative rate and lower rate of apoptosis than HPDMSCs (p<0.05). However, HPDMSCs secreted more of the three growth factors than HUCMSCs (p<0.05). Results of TEM revealed that the two types of MSCs underwent active metabolism and had low degree of differentiation, especially HUCMSCs. Results of AFM showed that HUCMSCs had stronger ability of mass transport and cell migration than HPDMSCs. However, HPDMSCs displayed stronger adhesive properties than HUCMSCs. Our findings indicate that different sources of MSCs have different properties, and that care should be taken when choosing the appropriate sources of MSCs for stem cell transplantation.


Assuntos
Apoptose , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/citologia , Células-Tronco Mesenquimais/citologia , Placenta/citologia , Adulto , Feminino , Células Endoteliais da Veia Umbilical Humana/ultraestrutura , Humanos , Células-Tronco Mesenquimais/ultraestrutura , Gravidez , Cultura Primária de Células
12.
Rejuvenation Res ; 16(2): 124-33, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23374025

RESUMO

The aim of this study was to assess the ability of a traditional Chinese medicinal ginger root extract (GRE) to prevent behavioral dysfunction in the Alzheimer disease (AD) rat model. Rat AD models were established by an operation (OP) in which rats were treated with a one-time intra-cerebroventricuIar injection of amyloid ß-protein (Aß) and continuous gavage of aluminum chloride every day for 4 weeks. GRE was administered intra-gastrically to rats. After 35 days, learning and memory were assessed in all of the rats. Brain sections were processed for immunohistochemistry and Hematoxylin & Eosin (H&E) and Nissl staining. The latency to show significant memory deficits was shorter in the group that received OP with a high dose of GRE (HG)(OP+HG) than in the groups that received OP with a low or moderate dose of GRE (LG, MG)(OP+LG, OP+MG) (p<0.05). The expression of superoxide dismutase (SOD) and catalase (CAT) in the OP+MG and OP+LG groups was up-regulated compared to the OP+HG groups (p<0.05). The rats in the OP+HG groups had lower levels of nuclear factor-κB (NF-κB), interleukin-1ß (IL-1ß), and malondialdehyde (MDA) expression than the rats in the OP+MG and OP+LG groups (p<0.05). This experiment demonstrates that the administration of GRE reverses behavioral dysfunction and prevents AD-like symptoms in our rat model.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Comportamento Animal , Gengibre , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Catalase/metabolismo , Feminino , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Coloração e Rotulagem , Superóxido Dismutase/metabolismo
13.
Zhongguo Zhong Yao Za Zhi ; 38(24): 4351-6, 2013 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-24791544

RESUMO

High-performance liquid chromatographic coupled with variable wavelength detection (HPLC-VWD) has been developed for simultaneous determination of 5 analytes including ellagic acid, quercetin, kaempferol-3-O-beta-D-rutinoside, tiliroside and kaempferol, and high-performance liquid chromatographic with an evaporative light scattering detector (HPLC-ELSD) has been established to determine goshonoside-F5 in extract of Rubi Fructus. Chromatographic separations were carried out on an Agilent ZORBAX SB-C18 column (4.6 mm x 250 mm, 5.0 microm). All calibration curves of reference standards revealed good linearity (R2 > 0.999 5) within the concentration ranges tested. The method limits of detection ranged 0.297-90.144 ng and the method limits ofquantitation ranged 0.990-300.480 ng, respectively. Recoveries of 6 analytes were from 97.11% to 101.7%, with RSD less than 2.1%. The result shows that amounts of the 6 analytes in the samples from 16 localities were found to be different. The higher latitude of growing environment, the more ellagic acid in herb. The content of total flavonoids in sample from east localities were higher than that in middle and west localities, and the content of goshonoside-F5 in Bozhou, Anhui province was higher than others. This method was found to be simple, accurate, sensitive with good repeatability. Those results might serve as a sound foundation for further study, quality control and application of Rubi Fructus.


Assuntos
Ácido Elágico/análise , Flavonoides/análise , Rosaceae/química , Cromatografia Líquida de Alta Pressão , Geografia
14.
Cancer Sci ; 100(9): 1708-13, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19500106

RESUMO

Chemotherapy resistance in solid tumors is broad and encompasses diverse unrelated drugs. Three-dimensional multicellular spheroids (MCSs) are a good model for studying in vitro drug resistance. In the current study, we investigated the role of focal adhesion kinase (FAK) in 5-fluorouracil (5-FU) chemoresistance in colon carcinoma MCS culture cells. The expression of FAK was inhibited significantly by specific small hairpin RNA targeting FAK. The suppression of FAK expression did not affect the growth of spheroid cells. However, silencing of FAK combined with 5-FU treatment significantly decreased the 50% inhibitory concentration (IC(50)) of 5-FU and markedly increased the population of apoptosis cells, which was associated with the reduction of the levels of Akt and nuclear factor-kappa B (NF-kappaB). Moreover, knockdown of FAK could inhibit tumor growth and increase the sensitivity of the tumor to 5-FU in the nude mouse xenograft. These results indicate that while not affecting cellular proliferation in the absence of 5-FU, RNA interference targeting FAK potentiated 5-FU-induced cytotoxicity in vitro and in vivo, and partially reversed multicellular resistance, which may contribute to its chemosensitizing effect through efficiently suppressing Akt/NF-kappaB activity.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/enzimologia , Resistencia a Medicamentos Antineoplásicos , Quinase 1 de Adesão Focal/fisiologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Western Blotting , Proliferação de Células , Fluoruracila/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/genética , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Lett ; 284(2): 182-8, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19435649

RESUMO

Since multicellular resistance (MCR) has been shown to be as adhesion-dependent, the role of alphav integrin in MCR of HT29 was investigated in this paper. Down-regulation of alphav integrin reduced MCR to oxaliplatin, but did not detectably change the drug sensitivity of monolayers. Down-regulation of alphav integrin decreased phosphorylated NF-kappaB p65 and increased phosphorylated JNK2 in multicellular spheroids. Cell-cell adhesion and cell-cell junctions in multicellular spheroids resembled the in vivo situation. Since force, including adhesion, can activate alphav integrin, cell-cell contact may contribute to activation of alphav integrin, through which increasing phosphorylated p65 and decreasing phosphorylated JNK2 takes part in MCR.


Assuntos
Adenocarcinoma/patologia , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Terapia Genética , Vetores Genéticos/farmacologia , Integrina alfaV/genética , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Retroviridae/genética , Adenocarcinoma/terapia , Animais , Antineoplásicos Alquilantes/farmacologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/transplante , Neoplasias do Colo/terapia , Regulação para Baixo/efeitos dos fármacos , Vetores Genéticos/uso terapêutico , Integrina alfaV/biossíntese , MAP Quinase Quinase 7/metabolismo , Camundongos , Proteínas de Neoplasias/metabolismo , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/genética , Esferoides Celulares/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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