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1.
J Med Chem ; 64(9): 5535-5550, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-33902285

RESUMO

Diabetic retinopathy is the leading cause of blindness which is associated with excessive angiogenesis. Using the structure of wondonin marine natural products, we previously created a scaffold to develop a novel type of antiangiogenesis agent that possesses minimized cytotoxicity. To overcome its poor pharmaceutical properties, we further modified the structure. A new scaffold was derived in which the stereogenic carbon was changed to nitrogen and the 1,2,3-triazole ring was replaced by an alkyl chain. By comparing the bioactivity versus cytotoxicity, compound 31 was selected, which has improved aqueous solubility and an enhanced selectivity index. Mechanistically, 31 suppressed angiopoietin-2 (ANGPT2) expression induced by high glucose in retinal cells and exhibited in vivo antiangiogenic activity in choroidal neovascularization and oxygen-induced retinopathy mouse models. These results suggest the potential of 31 as a lead to develop antiangiogenic small-molecule drugs to treat diabetic retinopathy and as a chemical tool to elucidate new mechanisms of angiogenesis.

2.
Biomed Pharmacother ; 133: 111041, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378949

RESUMO

Poly (ADP-ribose) polymerase 1 (PARP1)-dependent cell death in the retinal pigment epithelium (RPE) is implicated in dry age-related macular degeneration (AMD). Although PARP1 inhibitors are available for treating dry AMD, their delivery route is not ideal for patients. The aim of this study was to test the efficacy of a novel PARP1-inhibitory compound (PIC) in vitro and in vivo. This study presents PIC, a novel small molecule, with superior efficacy to PARP1 inhibitors in the market. PIC demonstrated a distinctive inhibitory profile against PARP isotypes than the FDA-approved PARP1 inhibitors. PIC inhibited PARP1 activation at an IC50 of 0.41 ± 0.15 nM in an enzyme-based assay in vitro and at IC50 and EC50 in ARPE-19 cells of 0.11 ± 0.02 nM and 0.22 ± 0.02 nM, respectively, upon H2O2 insult. PIC also moderated mitochondrial fission and depolarization and maintained cellular energy levels under oxidative stress in ARPE-19 cells. Furthermore, PIC demonstrated good corneal penetration in a rat model, presenting PIC as a promising candidate for eye drop therapeutics for dry AMD. When PIC was administered as an eye drop formulation, RPE morphology was preserved, maintaining the thickness of the outer nuclear layers under sodium iodate (SI) treatment in rats. In SI-treated rabbits, eye drop administration of PIC also retained the structural and functional integrity when analyzed using funduscopy and electroretinogram. Collectively, our data portray PIC as an attractive treatment measure for dry AMD.


Assuntos
Degeneração Macular/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Administração Oftálmica , Animais , Antioxidantes/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Humanos , Iodatos , Degeneração Macular/induzido quimicamente , Degeneração Macular/enzimologia , Degeneração Macular/patologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Absorção Ocular , Soluções Oftálmicas , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Coelhos , Ratos Sprague-Dawley , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/patologia
3.
PLoS One ; 15(12): e0242413, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33270672

RESUMO

The maintenance of buildings has become an important issue with the construction of many high-rise buildings in recent years. However, the cleaning of the outer walls of buildings is performed in highly hazardous environments over long periods, and many accidents occur each year. Various robots are being studied and developed to reduce these incidents and to relieve workers from hazardous tasks. Herein, we propose a method of spraying high-pressure water using a pump and nozzle, which differs from conventional methods. The cleaning performance parameters, such as water pressure, spray angle, and spray distance, were optimized using the Taguchi method. Cleaning experiments were performed on window specimens that were contaminated artificially. The cleaning performance of the proposed method was evaluated using the image-evaluation method. The optimum condition was determined based on the results of a sensitive analysis performed on the image data. In addition, the reaction force due to high pressure and impact force on the specimens were investigated. These forces were not sufficient to affect the propeller thrust or cause damage to the building's surface. We expect to perform field tests in the near future based on the output of this research.

4.
Prostaglandins Other Lipid Mediat ; 144: 106347, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31229523

RESUMO

We previously reported the strong inhibitory potency of N-phenyl-N'-(4- benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH) on lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production in macrophages. Herein, we characterized PBCH as a microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor and evaluated its anti-inflammatory effects using in vivo experimental models. PBCH inhibited PGE2 production in various activated cells in addition to inhibiting the mPGES-1 activity. In the ear edema and paw edema rat models, PBCH significantly reduced ear thickness and paw swelling, respectively. Besides, in adjuvant-induced arthritis (AIA) rat model, PBCH decreased paw swelling, plasma rheumatoid factor (RF), and receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. Furthermore, while PBCH reduced the plasma prostaglandin E metabolite (PGEM) levels, it did not affect the plasma levels of prostacyclin (PGI2) and thromboxane A2 (TXA2). Our data suggest that PBCH downregulates PGE2 production by interfering with the mPGES-1 activity, thus reducing edema and arthritis in rat models.


Assuntos
Anti-Inflamatórios/farmacologia , Dinoprostona/metabolismo , Regulação para Baixo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Tiazóis/farmacologia , Células A549 , Animais , Anti-Inflamatórios/uso terapêutico , Dinoprostona/biossíntese , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidrazinas/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Tiazóis/uso terapêutico
5.
J Ginseng Res ; 42(3): 370-378, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29989018

RESUMO

Background: Ginseng has been the subject of many experimental and clinical studies to uncover the diverse biological activities of its constituent compounds. It is a traditional medicine that has been used for its immunostimulatory, antithrombotic, antioxidative, anti-inflammatory, and anticancer effects. Ginseng may interact with concomitant medications and alter metabolism and/or drug transport, which may alter the known efficacy and safety of a drug; thus, the role of ginseng may be controversial when taken with other medications. Methods: We extensively assessed the effects of Korean Red Ginseng (KRG) in rats on the expression of enzymes responsible for drug metabolism [cytochrome p450 (CYP)] and transporters [multiple drug resistance (MDR) and organic anion transporter (OAT)] in vitro and on the pharmacokinetics of two probe drugs, midazolam and fexofenadine, after a 2-wk repeated administration of KRG at different doses. Results: The results showed that 30 mg/kg KRG significantly increased the expression level of CYP3A11 protein in the liver and 100 mg/kg KRG increased both the mRNA and protein expression of OAT1 in the kidney. Additionally, KRG significantly increased the mRNA and protein expression of OAT1, OAT3, and MDR1 in the liver. Although there were no significant changes in the metabolism of midazolam to its major metabolite, 1'-hydroxymidazolam, KRG significantly decreased the systemic exposure of fexofenadine in a dose-dependent manner. Conclusion: Because KRG is used as a health supplement, there is a risk of KRG overdose; thus, a clinical trial of high doses would be useful. The use of KRG in combination with P-glycoprotein substrate drugs should also be carefully monitored.

6.
Circ Res ; 123(5): e5-e19, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-30030219

RESUMO

RATIONALE: Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]-related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation. OBJECTIVE: To investigate the physiological/pathophysiological role of CTRP1 in BP regulation. METHODS AND RESULTS: CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ΔCAG). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)-signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice. CONCLUSIONS: For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.


Assuntos
Adipocinas/metabolismo , Pressão Sanguínea , Desidratação/metabolismo , Hipotensão/metabolismo , Adipocinas/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Linhagem Celular , Células Cultivadas , Desidratação/complicações , Desidratação/fisiopatologia , Feminino , Glucocorticoides/metabolismo , Humanos , Hipotensão/tratamento farmacológico , Hipotensão/etiologia , Hipotensão/fisiopatologia , Losartan/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Vasoconstrição , Quinases Associadas a rho/metabolismo
7.
J Pharm Biomed Anal ; 150: 39-42, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29216583

RESUMO

Mesupron, the first-in-class inhibitor of urokinase-type plasminogen activator (uPA) is known to regulate cell proliferation and migration, and is under investigation for the treatment of metastatic breast cancer. In this study, a quantification method was developed for the determination of mesupron in rat plasma using liquid chromatography with a tandem mass spectrometry (LC-MS/MS). After protein precipitation with acetonitrile including itraconazole (internal standard, IS), the analytes were chromatographed on a reversed phased column with a mobile phase of acetonitrile and water (7:3, v/v, including 0.1% formic acid). The ion transitions of the precursor to the product ion were principally protonated ion [M+H]+ at m/z 630.4→398.3 for mesupron and 705.2→392.1 for the IS. The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods This method was successfully applied to a pharmacokinetic study of mesupron after intravenous administration in rats.


Assuntos
Antineoplásicos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Piperazinas/farmacocinética , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Intravenosa , Animais , Antineoplásicos/administração & dosagem , Piperazinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sulfonamidas/administração & dosagem
8.
Respir Med ; 108(3): 524-30, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24462477

RESUMO

Although combined pulmonary fibrosis and emphysema (CPFE) might be relevant to lung cancer, no comparison studies have been done. We evaluated the risk of lung cancer among CPFE patients compared to IPF and emphysema patients. We retrospectively reviewed the medical records of patients who were diagnosed as CPFE, IPF and emphysema using chest CT scans at Seoul National University Hospital from Jan 2000 to Dec 2011. Patients with CPFE were enrolled and matched (1:1:2) with IPF and emphysema patients based on the radiological criteria. The main outcome was time to diagnosis of lung cancer and evaluated with Cox-proportional hazard regression. Forty-eight CPFE, 48 IPF, and 96 emphysema patients were included in this study. Twenty-five cases of lung cancer occurred. The CPFE group had a higher risk of lung cancer (adjusted HR 4.62, 95% CI 1.58-13.55) than that of the emphysema group. Also, IPF group had a higher risk of lung cancer (adjusted HR 4.15, 95% CI 1.03-16.78) than that of emphysema group. However, there was no statistically significant difference in lung cancer risk between the CPFE and IPF group. Additionally, the CPFE group had a higher risk of lung cancer or death (adjusted HR 4.62, 95% CI 2.25-9.47) than that of the emphysema group. In conclusion, patients with CPFE and IPF had a higher risk of lung cancer than those with emphysema, although lung cancer risk was similar between CPFE and IPF.


Assuntos
Neoplasias Pulmonares/epidemiologia , Enfisema Pulmonar/epidemiologia , Fibrose Pulmonar/epidemiologia , Idoso , Volume Expiratório Forçado , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/diagnóstico por imagem , Radiografia , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Fumar/epidemiologia , Fatores de Tempo , Capacidade Vital
9.
Clin Orthop Surg ; 5(4): 327-33, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24340154

RESUMO

For comminuted shaft fracture of clavicle, the operative goal, aside from sound bone healing without complications of direct reduction, is maintenance of the original length in order to maintain the normal biomechanics of adjacent joint. Our bridge plating technique utilizing distraction through a lumbar spreader was expected to be effective for restoring clavicular length with soft tissue preservation. However, there are two disadvantages. First, there is more exposure to radiation compared to conventional plating; and second, it is difficult to control the rotational alignment. Despite these disadvantages, our technique has important benefits, in particular, the ability to preserve clavicular length without soft tissue injury around the fracture site.


Assuntos
Clavícula/cirurgia , Fixação Interna de Fraturas/instrumentação , Fixação Interna de Fraturas/métodos , Fraturas Cominutivas/cirurgia , Adulto , Idoso , Clavícula/diagnóstico por imagem , Clavícula/lesões , Feminino , Seguimentos , Fraturas Cominutivas/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Radiografia , Amplitude de Movimento Articular , Adulto Jovem
10.
Clin Orthop Surg ; 4(3): 227-33, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22949955

RESUMO

BACKGROUND: To characterize the recently issued femur shaft insufficiency fracture in terms of a patient's own epidemiological status. METHODS: Fourteen patients were treated for insufficiency fracture from July 2002 to June 2008, excluding cases including the risk factors of insufficiency fracture. All patients were female, and their mean age was 75.6 years (range, 65 to 89 years). The mean follow-up period was 50.6 months (range, 14 to 86 months). RESULTS: The mean body weight of the Koreans in the same age group was 58.1 ± 9.7 kg, and the mean height was 155.5 ± 8.8 cm. The mean body weight of our insufficiency fracture patients was 45.7 kg and it was statistically significantly lower than that of the Koreans in the same age group (p < 0.001). The mean height was 147.3 cm and it was significantly shorter than the mean height of the Koreans in the same age group (p = 0.002). In regard to menopausal time, the mean menopausal time of the Koreans was 48.0 ± 4.2 years, it was 44 years in our study, as menopause occurred statistically significantly earlier (p = 0.017). The patients with insufficiency fracture showed statistically lower weight, shorter stature and an earlier menopausal period than that of the general population. CONCLUSIONS: In early menopausal, underweight, and short patients prescribed osteoporosis medication for an extended period of time, if predromal symptom is present, it is necessary to suspect insufficiency fracture of the femur.


Assuntos
Fraturas do Fêmur/patologia , Fraturas de Estresse/patologia , Idoso , Idoso de 80 Anos ou mais , Estatura , Feminino , Fraturas do Fêmur/epidemiologia , Fraturas do Fêmur/cirurgia , Fêmur , Fraturas de Estresse/epidemiologia , Fraturas de Estresse/cirurgia , Humanos , Menopausa , República da Coreia/epidemiologia , Fatores de Risco
11.
J Shoulder Elbow Surg ; 21(12): 1753-63, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22541867

RESUMO

BACKGROUND: We evaluated the integrity and functional outcomes of rotator cuff tear after performing the double-pulley suture bridge (DPSB) repair technique according to the tear size by using serial ultrasonographic examinations. MATERIALS AND METHODS: The study included 41 consecutive arthroscopic rotator repairs using the DPSB technique. The average follow-up was 28 months. We completed the serial ultrasonographic examinations and compared the results with the functional outcome using the American Shoulder and Elbow Surgeons (ASES) score, the Constant score, the Korean Shoulder Scoring (KSS) system, and the University of California, Los Angeles (UCLA) score. RESULTS: The overall retear rate was 19.5% (8 of 41), comprising 50% (2 of 4) for massive tears, 18% (2 of 11) for large tears, 17% (4 of 23) for medium tears, and no failures for small tears (0 of 3). The retear rate was 17.6% (6 of 34) after complete repair and 28.6% (2 of 7) after repair with gap formation. Seventy-five percent (6 of 8) of retears were identified within 6 months after operation and 25% (2 of 8) were identified more than 1 year after repair. The functional outcomes of the intact group and the retear group according to the ASES score, the Constant score, the KSS, and the UCLA score were 96, 93, 94, and 33, and 90, 82, 87, and 31, respectively (P > .05). CONCLUSION: The overall retear rate after DPSB repair was 19.5% with 2 time periods of retear. The outcome improved independent of the tear size and the cuff integrity.


Assuntos
Artroscopia/métodos , Amplitude de Movimento Articular , Recuperação de Função Fisiológica/fisiologia , Manguito Rotador/cirurgia , Articulação do Ombro/cirurgia , Técnicas de Sutura , Traumatismos dos Tendões/cirurgia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Manguito Rotador/diagnóstico por imagem , Lesões do Manguito Rotador , Ruptura , Articulação do Ombro/lesões , Articulação do Ombro/fisiopatologia , Suturas , Traumatismos dos Tendões/diagnóstico por imagem , Traumatismos dos Tendões/fisiopatologia , Resultado do Tratamento , Ultrassonografia
12.
Bioorg Med Chem Lett ; 22(7): 2522-6, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22374216

RESUMO

Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinonas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Estabilidade de Medicamentos , HIV-1/fisiologia , Humanos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Nevirapina/farmacologia , Pirimidinonas/farmacologia , Ratos , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Tiazóis/química
13.
Bioorg Med Chem Lett ; 22(5): 2119-24, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22305583

RESUMO

3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) were selected and derivatized through a HIV-1 replication assay based on GFP reporter cells. Compounds 14, 25, 31, and 36 exhibited significant inhibition of HIV-1 replication with a good safety profile. Chiral separation of each enantiomer by fractional crystallization showed that only the S enantiomer retained anti-HIV activity. Compound (S)-40, a novel and potent DHPM analog, could serve as an advanced lead for further development and the determination of the mechanism of action.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirimidinonas/química , Pirimidinonas/farmacologia , Replicação Viral/efeitos dos fármacos , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Estereoisomerismo , Relação Estrutura-Atividade
14.
ACS Med Chem Lett ; 3(8): 678-82, 2012 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900529

RESUMO

We identified a novel class of aryl-substituted triazine compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) during a high-throughput screening campaign that evaluated more than 200000 compounds for antihuman immunodeficiency virus (HIV) activity using a cell-based full replication assay. Herein, we disclose the optimization of the antiviral activity in a cell-based assay system leading to the discovery of compound 27, which possessed excellent potency against wild-type HIV-1 (EC50 = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene. The X-ray crystal structure of compound 27 complexed with wild-type reverse transcriptase confirmed the mode of action of this novel class of NNRTIs. Introduction of a chloro functional group in the pyrazole moiety dramatically improved hERG and CYP inhibition profiles, yielding highly promising leads for further development.

15.
Yonsei Med J ; 53(1): 106-10, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22187239

RESUMO

PURPOSE: Accurate indications and the extent of surgery for branch duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas are still debatable. In particular, small tumor is located at the head portion of pancreas presents a dilemma. The purpose of this study is to compare the efficacy of enucleation (EN) with that of pancreaticoduodenectomy (PD) in patients with small (2 cm

Assuntos
Adenocarcinoma Mucinoso/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Papilar/cirurgia , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Adenocarcinoma Mucinoso/patologia , Idoso , Carcinoma Ductal Pancreático/patologia , Carcinoma Papilar/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Resultado do Tratamento
16.
J Nanosci Nanotechnol ; 7(11): 4150-3, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18047139

RESUMO

We report the fabrication and characterization of poly-Si nanowire transistors on flexible substrates. The nanowire transistors are fabricated on a SiO2/Si substrate using conventional CMOS processes, and then they are transferred onto polyimide substrates. The transfer process is performed by spin-coating of polyimide, curing (annealing) of the polyimide layer, and removal of the SiO2 sacrificial layer. The optimized curing condition results in the maximum bending of 150 degrees with full recovery. The nanowire transistors exhibit transistor characteristics as a function of the backgate bias. Our new process can be applied to the fabrication of Si-nanowire transistors with larger mobilities.


Assuntos
Cristalização/métodos , Imidas/química , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Nanotecnologia/instrumentação , Silício/química , Transistores Eletrônicos , Desenho de Equipamento , Análise de Falha de Equipamento , Teste de Materiais , Nanotecnologia/métodos , Tamanho da Partícula , Plásticos/química
17.
Cancer Res ; 66(17): 8511-9, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16951163

RESUMO

Glioblastoma is a severe type of primary brain tumor, and its highly invasive character is considered to be a major therapeutic obstacle. Several recent studies have reported that ionizing radiation (IR) enhances the invasion of tumor cells, but the mechanisms for this effect are not well understood. In this study, we investigated the possible signaling mechanisms involved in IR-induced invasion of glioma cells. IR increased the matrix metalloproteinase (MMP)-2 promoter activity, mRNA transcription, and protein secretion along with the invasiveness of glioma cells lacking functional PTEN (U87, U251, U373, and C6) but not those harboring wild-type (WT)-PTEN (LN18 and LN428). IR activated phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin, and blockade of these kinases by specific inhibitors (LY294002, Akt inhibitor IV, and rapamycin, respectively) and transfection of dominant-negative (DN) mutants (DN-p85 and DN-Akt) or WT-PTEN suppressed the IR-induced MMP-2 secretion in U251 and U373 cells. In addition, inhibitors of epidermal growth factor receptor (EGFR; AG490 and AG1478), Src (PP2), and p38 (SB203580), EGFR neutralizing antibody, and transfection of DN-Src and DN-p38 significantly blocked IR-induced Akt phosphorylation and MMP-2 secretion. IR-induced activation of EGFR was suppressed by PP2, whereas LY294002 and SB203580 did not affect the activations of p38 and PI3K, respectively. Finally, these kinase inhibitors significantly reduced the IR-induced invasiveness of these cells on Matrigel. Taken together, our findings suggest that IR induces Src-dependent EGFR activation, which triggers the p38/Akt and PI3K/Akt signaling pathways, leading to increased MMP-2 expression and heightened invasiveness of PTEN mutant glioma cells.


Assuntos
Receptores ErbB/fisiologia , Glioma/patologia , Metaloproteinase 2 da Matriz/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular Tumoral , Primers do DNA , Receptores ErbB/efeitos da radiação , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Glioblastoma/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/efeitos da radiação , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/efeitos da radiação , Fosforilação , Proteínas Proto-Oncogênicas c-akt/efeitos da radiação , Radiação Ionizante , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos da radiação , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos da radiação
18.
Mol Cancer Res ; 4(3): 209-20, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16547158

RESUMO

The net balance of matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) system has been known to be a key factor in tumor cell invasion. In the present study, we investigated the molecular mechanisms of anti-invasive and antimigrative activity of transforming growth factor (TGF)-beta1 on HT1080 human fibrosarcoma cells. In in vitro Matrigel invasion and Transwell migration assays, TGF-beta1 dose-dependently inhibited the invasion and migration of HT1080 cells, respectively. Gelatin zymography, Western blot, and real-time PCR analysis showed that TGF-beta1 enhanced the expression and secretion of MMP-2, TIMP-1, and, to a lesser degree, MMP-9 but not membrane type 1-MMP and TIMP-2. The addition of recombinant TIMP-1 protein reduced the Matrigel invasion and Transwell migration of HT1080 cells, similar to TGF-beta1. Because augmentation of TIMP-1 might be the major factor for the anti-invasive and antimigrative activity of TGF-beta1, we investigated possible molecular mechanisms responsible for the expression of TIMP-1 induced by TGF-beta1. Treatment of HT1080 cells with TGF-beta1 rapidly phosphorylated three mitogen-activated protein kinases [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase] and Akt. Among these kinases, the inhibition of only ERK1/2 pathway by PD98059, a specific inhibitor of MAPK/ERK kinase(MEK)-1, and transfection of dominant-negative MEK 1 effectively blocked the TIMP-1 induction by TGF-beta1. Mithramycin, a specific inhibitor of Sp1 transcription factor, but not curcumin, an inhibitor of activator protein-1, and transfection of Sp1 small interfering RNA significantly inhibited the TGF-beta1-induced expression of TIMP-1. In addition, electrophoretic mobility shift assay showed that TGF-beta1 up-regulated Sp1 DNA-binding activity, and PD98059 and mithramycin effectively inhibited these events. Finally, pretreatment of HT1080 cells with PD98059 and mithramycin, but not curcumin, restored the invasive activity of these cells. Taken together, these data suggest that TGF-beta1 modulates the net balance of the MMPs/TIMPs the systems in HT1080 cells for anti-invasion and antimigration by augmenting TIMP-1 through ERK1/2 pathway and Sp1 transcription factor.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrossarcoma/metabolismo , Fibrossarcoma/patologia , Fator de Transcrição Sp1/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Movimento Celular/efeitos dos fármacos , Ativação Enzimática , Flavonoides/farmacologia , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Invasividade Neoplásica , Fosforilação , Inibidor Tecidual de Metaloproteinase-1/genética , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta1
19.
Int J Cancer ; 118(11): 2711-20, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16388516

RESUMO

Emodin (1,3,8-trihydroxy-6-methylanthraquinone), an active component in the root and rhizome of Rheum palmatum, is a tyrosine kinase inhibitor with a number of biological activities, including antitumor effects. Here, we examine the effects of emodin on vascular endothelial growth factor (VEGF)-A-induced angiogenesis, both in vitro and in vivo. In vitro, emodin dose-dependently inhibits proliferation, migration into the denuded area, invasion through a layer of Matrigel and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated with VEGF-A. Emodin also inhibits basic fibroblast growth factor-induced proliferation and migration of HUVECs and VEGF-A-induced tube formation of human dermal microvascular endothelial cells. Specifically, emodin induces the cell cycle arrest of HUVECs in the G0/G1 phase by suppressing cyclin D1 and E expression and retinoblastoma protein phosphorylation, and suppresses Matrigel invasion by inhibiting the basal secretion of matrix metalloproteinase-2 and VEGF-A-stimulated urokinase plasminogen activator receptor expression. Additionally, emodin effectively inhibits phosphorylation of VEGF-A receptor-2 (KDR/Flk-1) and downstream effector molecules, including focal adhesion kinase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, Akt and endothelial nitric oxide synthase. In vivo, emodin strongly suppresses neovessel formation in the chorioallantoic membrane of chick and VEGF-A-induced angiogenesis of the Matrigel plug in mice. Our data collectively demonstrate that emodin effectively inhibits VEGF-A-induced angiogenesis in vitro and in vivo. Moreover, inhibition of phosphorylation of KDR/Flk-1 and downstream effector molecules is a possible underlying mechanism of the anti-angiogenic activity of emodin. Based on these data, we propose that an interaction of emodin with KDR/Flk-1 may be involved in the inhibitory function of emodin toward VEGF-A-induced angiogenesis in vitro and responsible for its potent anti-angiogenic in vivo.


Assuntos
Emodina/farmacologia , Neovascularização Patológica/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Materiais Biocompatíveis , Ciclo Celular , Movimento Celular , Proliferação de Células , Colágeno , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Células Endoteliais , Humanos , Laminina , Camundongos , Invasividade Neoplásica/fisiopatologia , Fosforilação , Proteoglicanas , Cordão Umbilical/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos
20.
Int J Oncol ; 28(1): 119-25, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16327987

RESUMO

Cisplatin is a DNA-damaging chemotherapeutic drug that may have a role in the adjuvant chemotherapy of several solid tumors, such as malignant glioblastoma, and the status of p53 tumor suppressor protein is a critical determinant of cisplatin chemosensitivity. In the present study, we showed the relationship of p53 status and chemosensitivity of cisplatin between two human malignant glioblastoma cell lines, A172 and T98G, harboring wild-type and mutant-type p53, respectively. Cisplatin was found to be more cytotoxic to A172 than T98G cells in a time- and concentration-dependent manner. Cisplatin-induced cytotoxicity manifested as apoptosis, characterized by genomic DNA fragmentation, nuclear condensation and an increase in sub-G1 population. Cisplatin induced the accumulation of p53 and p21 proteins in A172 cells, but not in T98G cells. The introduction of the adenovirus-mediated wild-type p53 gene into T98G cells resulted in the decrease of viability as well as the increase in sub-G1 population with p53 accumulation, activation of caspase-3 protease and release of cytochrome c from the mitochondria. These data strongly suggest that the expression of p53 is essential for the cytotoxic effect of cisplatin in human malignant glioblastoma cells, A172 and T98G, and the introduction of apoptotic signal molecules, such as p53, will be beneficial to achieve chemosensitivity in malignant glioma.


Assuntos
Neoplasias Encefálicas/patologia , Cisplatino/farmacologia , Glioblastoma/patologia , Proteína Supressora de Tumor p53/biossíntese , Apoptose , Caspase 3 , Caspase 9 , Caspases/metabolismo , Citocromos c/metabolismo , Dano ao DNA , Ativação Enzimática , Genes p53 , Humanos , Transdução Genética , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/fisiologia
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