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1.
Biol Trace Elem Res ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31691189

RESUMO

Patients with radiotherapy are at significant risks of bone loss and fracture. On the other hand, osteoporosis often occurs in disorders characterized by iron overload. Either ionizing radiation (IR) or iron overload alone has detrimental effects on bone metabolism, but their combined effects are not well defined. In this study, we evaluated the effects of IR on bone loss in an iron-overload mouse model induced by intraperitoneal injection of ferric ammonium citrate (FAC). In the present study, we found that IR additively aggravated iron overload induced by FAC injections. Iron overload stimulated hepcidin synthesis, while IR had an inhibitory effect and even inhibited the stimulatory effects of iron overload. Micro-CT analysis demonstrated that the loss of bone mineral density and bone volume, and the deterioration of bone microarchitecture were greatest in combined treatment group. Iron altered the responses of bone cells to IR. Iron enhanced the responses of osteoclasts to IR with elevated osteoclast differentiation, but did not affect osteoblast differentiation. Our study indicates that IR and iron in combination lead to a more severe impact on the bone homeostasis when compared with their respective effects. IR aggravated iron overload induced bone loss by heightened bone resorption relative to formation. The addictive effects may be associated with the exacerbated iron accumulation and osteoclast differentiation.

2.
Sensors (Basel) ; 19(20)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618874

RESUMO

Deformation monitoring of engineering structures using the advanced Global Navigation Satellite System (GNSS) has attracted research interest due to its high-precision, constant availability and global coverage. However, GNSS application requires precise coordinates of points of interest through quick and reliable resolution of integer ambiguities in carrier phase measurements. Conventional integer ambiguity resolution algorithms have been extensively researched indeed in the past few decades, although the application of GNSS to structural health monitoring is still limited. In particular, known a priori information related to the structure of a body of interest is not normally considered. This study proposes a composite strategy that incorporates modified least-squares ambiguity decorrelation adjustment (MLAMBDA) method with priori information of the structural deformation. Data from the observation sites of Baishazhou Bridge are used to test method performance. Compared to MLAMBDA methods that do not consider priori information, the ambiguity success rate (ASR) improves by 20% for global navigation satellite system (GLONASS) and 10% for Multi-GNSS, while running time is reduced by 60 s for a single system and 180 s for Multi-GNSS system. Experimental results of Teaching Experiment Building indicate that our constrained MLAMBDA method improves positioning accuracy and meets the requirements of structural health monitoring, suggesting that the proposed strategy presents an improved integer ambiguity resolution algorithm.

3.
Toxicol Lett ; 313: 50-59, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31238089

RESUMO

Iron overload causes osteoporosis by enhancing osteoclastic bone resorption. During differentiation, osteoclasts demand high energy and contain abundant mitochondria. In mitochondria, iron is used for the synthesis of Fe-S clusters to support mitochondria biogenesis and electron transport chain. Moreover, mitochondrial reactive oxygen species (ROS) play an important role in osteoclastogenesis. Activation of MAPKs (ERK1/2, JNK, and p38) by ROS is essential and contribute to osteoclast differentiation. How iron chelation impairs electron transport chain and ROS dependent MAPKs activation during osteoclast differentiation is unknown. This study aimed to determine the direct effects of iron chelation on osteoclast differentiation, electron transport chain and MAPKs activation. In the present study, we found that when iron chelator, deferoxamine (DFO), was added, a dose-dependent inhibition of osteoclast differentiation and bone resorption was observed. Supplementation of transferrin-bound iron recovered osteoclastogenesis. Iron chelation resulted in a marked decrease in ferritin level, and increased expression of transferrin receptor 1 and ferroportin. As an iron chelator, DFO negatively affected mitochondrial function through decreasing activities of all the complexes. Expressions of mitochondrial subunits encoded both by mitochondrial and nuclear DNA were decreased. DFO augmented production of mitochondrial ROS, but inhibited the phosphorylation of ERK1/2, JNK, and p38, even in the presence of hydrogen peroxide. These results suggest that iron chelation directly inhibits iron-uptake stimulated osteoclast differentiation and suppresses electron transport chain. Iron chelation negatively regulates MAPKs activation, and this negative regulation is independent on ROS stimulation.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Osteoclastos/efeitos dos fármacos , Animais , Reabsorção Óssea , Proteínas de Transporte de Cátions/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Ferritinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Osteoclastos/enzimologia , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Receptores da Transferrina/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Artigo em Inglês | MEDLINE | ID: mdl-31011890

RESUMO

Gut microbiome lives in the intestinal tract of animals and plays an important role in almost all life processes. Gut microbiome balance is beneficial to health, and imbalance leads to many diseases, one of which is obesity epidemic. However, gut microbiome is also influenced by host hormone, and different gut microbiome composition is observed between the sexes. Here, we studied whether castrated male Guizhou minipigs with obesity own the same gut microbiome composition and microbial function predictions with those in obese females. We sequenced the hypervariable regions V3 to V4 of bacterial 16s rRNA of fecal samples collected from our study subjects. We observed that the operational taxonomic units were small, which suggested that the abundance of gut microbiome may be influenced by low genetic diversity of host. Our results also suggested that the castrated male has different gut microbial composition compared to the obese female. An increasing Firmicutes/Bacteroidetes ratio was observed in both castrated male and obese female groups, which suggested that the main adipogenic gut microorganism in obese Guizhou minipigs in our studies is the same with that in other obese mammals. However, we also observed that there were function prediction differences of obese Guizhou minipigs between female and castrated male, which suggested that the influence of gut microbiome on obesity between them is different.

5.
Brain Res ; 1676: 9-18, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28823954

RESUMO

Vascular endothelial growth factor (VEGF) stimulation and bone marrow mesenchymal stem cell (BMSC) transplantation have been implicated in the treatment of acute cerebral infarction for their pivotal roles in behavioral recovery, neuroprotection, neurogenesis, and angiogenesis. However, the effects of BMSC transplants are likely limited because of low transplant survival after acute cerebral infarction, and delivery of VEGF alone also has limited effects on recovery because the protein is cleared quickly. This study attempted to explore whether VEGF could be transferred into BMSC via an adenovirus and whether transplanting VEGF-transfected BMSC into the rat brain provides sufficient neuroprotection after transient middle cerebral artery occlusion. The adenovirus carried VEGF into BMSC (Ad-VEGF-BMSC), and purified adenovirus was transferred into BMSC (Ad-BMSC). Western blots were used to detect the expression of VEGF protein after transfection. Rats exposed to 90-min middle cerebral artery occlusion (MCAO) were treated with Ad-VEGF-BMSC, Ad-BMSC, BMSC and Dulbecco's Modified Eagle's Medium (DMEM) after ischemia reperfusion for 24h. The Sham group only received surgery. After transplantation of Ad-VEGF-BMSC into the perifocal area of the ischemic rat brain, we found increased expression and secretion of VEGF and BDNF as well as a higher level of MAP2, increased microvascular density, improved behavioral function and enhanced BMSC survival. Our results indicated that transplantation of Ad-VEGF-BMSC improved ischemic neurological deficiency after MCAO in rats. This finding provides a potential valuable therapeutic intervention for cerebral ischemic diseases.


Assuntos
Infarto Cerebral/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adenoviridae/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sobrevivência Celular , Infarto Cerebral/metabolismo , Infarto Cerebral/patologia , Modelos Animais de Doenças , Vetores Genéticos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Proteínas Associadas aos Microtúbulos/metabolismo , Microvasos/metabolismo , Microvasos/patologia , Neuroproteção , Distribuição Aleatória , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/genética
6.
Mol Biol Rep ; 41(12): 7775-82, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25096513

RESUMO

The highly polymorphic swine leucocyte antigen (SLA) genes play an important role in swine immune responses to infectious diseases, vaccines and production performance. The pig resource with well defined SLA genes is useful for xenotransplantation and immunological studies. In this study, we have characterized three SLA class I genes (SLA-1, SLA-3, SLA-2) of 22 founder Guizhou minipigs using sequence-based typing method. Thirteen alleles were detected in this population, compared with the SLA allele sequences in GenBank, 11 of 13 SLA class I alleles were novel in Guizhou minipigs. There are four SLA I haplotypes, none of them previously reported in other pigs. Based on these alleles sequences information, we developed a simple method implemented to SLA-typing for unknown offsprings of Guizhou minipigs, relying on designed 13 sequence specific primers that could discriminate each one among which located in each locus using PCR in a SLA typing assay. According the combination methods of sequence-based typing and PCR-SSP, we were able to rapidly conduct SLA typing for Guizhou breeding stock and identify four SLA haplotypes present in the herd. This resource population of SLA-defined Guizhou minipigs will be useful as animal models for xenotransplantation and further immunological research.


Assuntos
Antígenos de Histocompatibilidade Classe I/genética , Reação em Cadeia da Polimerase/métodos , Análise de Sequência de DNA/métodos , Porco Miniatura/genética , Animais , Haplótipos , Filogenia , Suínos
7.
Mol Inform ; 33(8): 536-43, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27486039

RESUMO

In this paper, a specific design strategy targeting c-met kinase was reported based on docking modeling and topomer comparative molecular field analysis (Topomer CoMFA). A novel U-shape conformation which is distinct from the literature was demonstrated by molecular docking among 68 U-shape c-met inhibitors. According to the docking results, two Topomer CoMFA models with high predictive ability were established based on the two fragment rule. The results from both docking and topomer CoMFA showed that the π-π stacking interaction with Tyr1230 and the hydrogen bond with hinge region play an important role in inhibitory activity. Furthermore, the flexible linker and the adjacent solvent group would be favorable to stabilize the conformation and to enhance the two interactions mentioned above. Based on our patent, 14 new compounds were designed by our design strategy. The binding mode exhibited as expected and their activities were predicted by topomer CoMFA model. The preliminary biological tests showed most of them have potent activity to c-met kinase. Our study would provide guidelines to design some new U-shaped c-met inhibitors with new scaffolds and optimize the current molecules.

8.
PLoS One ; 8(11): e80005, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24244593

RESUMO

The display of full-length antibody on the cell surface was achieved by fusing a transmembrane domain of the platelet-derived growth factor receptor (PDGFR) to the C-terminus of the heavy chain constant region. We also incorporated a furin cleavage site between the constant region and PDGFR transmembrane domain to obtain secreted antibodies. As a result, antibodies can be expressed simultaneously on the cell surface in a membrane-anchored version for screening and selecting through fluorescence-activated cell sorting (FACS) analysis, as well as in conditioned medium in a secreted version for function analysis.


Assuntos
Anticorpos/genética , Vetores Genéticos/química , Cadeias Pesadas de Imunoglobulinas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Animais , Anticorpos/química , Anticorpos/metabolismo , Células CHO , Membrana Celular/metabolismo , Cricetulus , Enzimas de Restrição do DNA/genética , Enzimas de Restrição do DNA/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Furina/metabolismo , Expressão Gênica , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Cadeias Pesadas de Imunoglobulinas/química , Cadeias Pesadas de Imunoglobulinas/metabolismo , Engenharia de Proteínas , Proteólise , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo
9.
Eur J Med Chem ; 65: 112-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23702473

RESUMO

Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of indazoles were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibition on c-Met and compound 4d showed highest activity against c-Met with IC50 value of 0.17 µM in TR-FRET-based assay and IC50 value of 5.45 µM in cell-based assay as compared to other tested compounds. Molecular docking experiments verified the results and explained the molecular mechanism of pretty activities to c-Met.


Assuntos
Desenho de Drogas , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Indazóis/síntese química , Indazóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-Atividade
10.
Eur J Pharmacol ; 710(1-3): 39-48, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23588118

RESUMO

Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Cumarínicos/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Contagem de Células , Cumarínicos/farmacologia , Ácido Clorídrico , Interleucina-6/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Peroxidase/imunologia , Fator de Necrose Tumoral alfa/imunologia
11.
Biol Pharm Bull ; 36(3): 399-406, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23318249

RESUMO

Mollugin, a kind of naphthohydroquinone, is a major constituent isolated from Rubia cordifolia L. and demonstrated to possess anti-inflammatory activity in recent reports. However, the effects and mechanism of action of mollugin in inflammation have not been fully defined. The present study was therefore designed to investigate whether mollugin suppresses the inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Mollugin attenuated the LPS-induced expression of nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß and IL-6 but augmented the expression of tumor necrosis factor (TNF)-α. Mollugin did not inhibit the degradation of inhibitory kappa B (IκB)-α or the nuclear translocation of p65 nuclear factor-kappa B (NF-κB) but rather enhanced the phosphorylation of p65 subunits evoked by LPS. Mollugin did not inhibit the phosphorylation of extracellular-signal-related kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK) 1/2 either. Mollugin significantly reduced the LPS-mediated phosphorylation of Janus kinase (JAK) 2, signal transducers and activators of transcription (STAT) 1 and STAT3. Molecular docking analysis showed that mollugin binds to JAK2 in a manner similar to that of AG490, a specific JAK2 inhibitor. We conclude that mollugin may be a JAK2 inhibitor and inhibits LPS-induced inflammatory responses by blocking the activation of the JAK-STAT pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Janus Quinase 2/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Piranos/farmacologia , Fator de Transcrição STAT1/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Células Cultivadas , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Janus Quinase 2/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo
12.
Cancer Lett ; 329(2): 189-96, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23142285

RESUMO

Cisplatin is a chemotherapeutic drug widely used for the treatment of gastric cancer. The benefit of including COX-2-selective inhibitors in cisplatin-based regimens on anti-cancer effect remains uncertain. In the present study, celecoxib and SC-236 antagonized cisplatin-induced cytotoxicity and apoptosis, whereas indomethancin and nimesulide exerted no effect, implying a COX-2-independent mechanism. Celecoxib decreased whole-cell cisplatin accumulation and DNA platination, resulting from reduced influx. In addition, combined treatment did not elicit greater antitumor activity than cisplatin or celecoxib monotherapy in vivo in a gastric xenograft model. Therefore, treatment strategies with celecoxib in combination with cisplatin should act cautiously.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Celecoxib , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/metabolismo , Ciclo-Oxigenase 2/metabolismo , Adutos de DNA/metabolismo , Dinoprostona/metabolismo , Interações de Medicamentos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Líquido Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
ACS Med Chem Lett ; 4(8): 806-10, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900750

RESUMO

A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4'-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (compound 5b or SMU-B) was identified as a potent, highly selective, well-tolerated, and orally efficacious c-Met/ALK dual inhibitor, which showed pharmacodynamics effect by inhibiting c-Met phosphorylation in vivo and significant tumor growth inhibitions (>50%) in GTL-16 human gastric carcinoma xenograft models.

14.
Eur J Med Chem ; 54: 813-22, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22809558

RESUMO

A series of novel isoindoline-1,3-diones containing 1,2,4-triazole moiety were synthesized via a one-pot reaction. Bioassay indicated that compounds 33, 35, 37 and 39 exhibited much higher activities against Botryodiplodia theobromae than commercial fungicide triadimefon at the dosage of 150 mg/L. Most interestingly, compounds 36, 37 and 45 displayed much stronger antitumor activities against four human cell lines than positive control Fluorouracil. Particularly, compound 37 had four-fold improvement compared to Fluorouracil in inhibiting A549 and HepG2 cell proliferation with IC(50) values of 6.76 and 9.44 µM, respectively. Further flow-activated cell sorting analysis revealed that compound 37 displayed apoptosis-inducing effect on HepG2 cells in a dose-dependent manner. These encouraging results could be helpful for the development of new antitumor compounds.


Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Isoindóis/síntese química , Isoindóis/farmacologia , Triazóis/química , Antifúngicos/química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Fungos/efeitos dos fármacos , Humanos , Isoindóis/química
15.
Bioorg Med Chem Lett ; 22(13): 4471-4, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22647723

RESUMO

A series of 3,4-disubstituted-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazoles and some novel 5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles bearing 3,4,5-trimethoxyphenyl moiety were synthesized and screened for their anticancer activity. The preliminary bioassay results indicated that compounds 14 and 16 showed much stronger cytotoxicity than Doxorubicin against HepG2 cell lines with IC(50) values of 0.58 and 3.17 µM, respectively. Meanwhile compound 16 also exhibited a broad spectrum of antitumor activity against MCF-7 and MKN45 with IC(50) values of 10.92 and 13.79 µM, respectively.


Assuntos
Antineoplásicos/síntese química , Tiadiazóis/química , Triazóis/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Conformação Molecular , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/toxicidade , Triazóis/síntese química , Triazóis/toxicidade
16.
Eur J Med Chem ; 50: 370-5, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22381355

RESUMO

Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of spiro[indoline-3, 4'-piperidine]-2-ones were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibitory effect on c-Met with IC(50) values of 0.0147-17 µM in TR-FRET-based assay and IC(50) values of 1.56-1400 µM in cell-based assay. Furthermore, our docking experiments verified the results and explained the molecular mechanism of eminent activities to c-Met.


Assuntos
Desenho de Drogas , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Sítios de Ligação , Western Blotting , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Neoplasias Gástricas/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
17.
Int J Mol Sci ; 13(2): 2387-404, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22408460

RESUMO

Kinase insert domain receptor (KDR) inhibitors have been proved to be very effective anticancer agents. Molecular docking, 3D-QSAR methods, CoMFA and CoMSIA were performed on pyrrolo[3,2-d]pyrimidine derivatives as non-ATP competitive KDR inhibitors (type II). The bioactive conformation was explored by docking one potent compound 20 into the active site of KDR in its DFG-out inactive conformation. The constructed CoMFA and CoMSIA models produced statistically significant results with the cross-validated correlation coefficients q(2) of 0.542 and 0.552, non-cross-validated correlation coefficients r(2) of 0.912 and 0.955, and predicted correction coefficients r(2) (pred) of 0.913 and 0.897, respectively. These results ensure the CoMFA and CoMSIA models as a tool to guide the design of a series of new potent KDR inhibitors.


Assuntos
Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirróis/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sítios de Ligação , Simulação por Computador , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Relação Quantitativa Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
Phytother Res ; 26(9): 1320-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22294521

RESUMO

Myrislignan is a new kind of lignan isolated from Myristica fragrans Houtt. Its antiinflammatory effects have not yet been reported. In the present study, the antiinflammatory effects and the underlying mechanisms of myrislignan in lipopolysaccharide (LPS)-induced inflammation in murine RAW 264.7 macrophage cells were investigated. Myrislignan significantly inhibited LPS-induced production of nitric oxide (NO) in a dose-dependent manner. It inhibited mRNA expression and release of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). This compound significantly inhibited mRNA and protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) dose-dependently in LPS-stimulated macrophage cells. Further study showed that myrislignan decreased the cytoplasmic loss of inhibitor κB-α (IκB-α) protein and the translocation of NF-κB from cytoplasm to the nucleus. Our results suggest that myrislignan may exert its antiinflammatory effects in LPS-stimulated macrophages cells by inhibiting the NF-κB signalling pathway activation.


Assuntos
Anti-Inflamatórios/farmacologia , Lignanas/farmacologia , Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Proteínas I-kappa B/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , Inibidor de NF-kappaB alfa , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Inflammation ; 35(3): 967-77, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22083490

RESUMO

Praeruptorin C, D, and E (PC, PD, and PE) are three pyranocoumarins isolated from the dried root of Peucedanum praeruptorum Dunn of Umbelliferae. In the present study, we investigated the anti-inflammatory effect of these compounds in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Pyranocoumarins significantly inhibited LPS-induced production of nitric oxide, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The mRNA and protein expressions of inducible nitric oxide synthase, IL-6, and TNF-α were also suppressed by these compounds. Both PD and PE exhibited greater anti-inflammatory activities than PC. Further study showed that pyranocoumarins suppressed the cytoplasmic loss of inhibitor κB-α protein and inhibited the translocation of NF-κB from cytoplasm to nucleus. In addition, pyranocoumarins suppressed LPS-induced STAT3 tyrosine phosphorylation. Taken together, the results suggest that pyranocoumarins may exert anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages through the inhibition of NF-κB and STAT3 activation.


Assuntos
Inflamação/tratamento farmacológico , Macrófagos/imunologia , NF-kappa B/metabolismo , Piranocumarinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Apiaceae , Linhagem Celular , Cumarínicos/farmacologia , Quinase I-kappa B/metabolismo , Mediadores da Inflamação , Interleucina-6/biossíntese , Interleucina-6/genética , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
J Mol Model ; 18(3): 1207-18, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21695506

RESUMO

Vascular endothselial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR) have been identified as new promising targets for the design of novel anticancer agents. It is reported that 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives exhibit potent inhibitory activities toward KDR. To investigate how their chemical structures relate to the inhibitory activities and to identify the key structural elements that are required in the rational design of potential drug candidates of this class, molecular docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods were performed on 78 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives as KDR inhibitors. Surflex-dock was used to determine the probable binding conformations of all the compounds at the active site of KDR. As a result, multiple hydrophobic and hydrogen-bonding interactions were found to be two predominant factors that may be used to modulate the inhibitory activities. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were developed based on the docking conformations. The CoMFA model produced statistically significant results with the cross-validated correlation coefficient q(2) of 0.504 and the non-cross-validated correlation coefficient r(2) of 0.913. The best CoMSIA model was obtained from the combination of steric, electrostatic and hydrophobic fields. Its q(2) and r(2) being 0.595 and 0.947, respectively, indicated that it had higher predictive ability than the CoMFA model. The predictive abilities of the two models were further validated by 14 test compounds, giving the predicted correction coefficients r (pred) (2) of 0.727 for CoMFA and 0.624 for CoMSIA, respectively. In addition, the CoMFA and CoMSIA models were used to guide the design of a series of new inhibitors of this class with predicted excellent activities. Thus, these models may be used as an efficient tool to predict the inhibitory activities and to guide the future rational design of 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives-based novel KDR inhibitors with potent activities.


Assuntos
Simulação por Computador , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Ureia/análogos & derivados , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Aminas , Humanos , Ligação Proteica , Piridinas , Ureia/química , Ureia/farmacologia
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