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1.
Anticancer Res ; 40(1): 109-119, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892559

RESUMO

BACKGROUND/AIM: Although molecular targeting therapy is an attractive treatment for cancer, resistance eventually develops in most cases. Here, we evaluated chemotherapeutic efficacy on non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor inhibitors mechanistically. MATERIALS AND METHODS: Antitumor effects of taxotere were evaluated using multiple models, including xenograft, and patient-derived models developed from adenocarcinoma cancer patients. Protein expressions were analyzed after drug treatment. RESULTS: Taxotere inhibited tumor growth of NSCLC cells harboring drug resistance, and reduced the expression of phosphorylated MET proto-oncogene, receptor tyrosine kinase (MET). A tumor-inhibitory effect of taxotere was also demonstrated in vivo in xenografts in mice, patient-derived primary lung tumor cells and patient-derived xenograft with concomitant repression of phosphorylated MET expression. Chemotherapeutic and MET-targeting drug exhibited a synergistic cell growth-inhibitory effect. CONCLUSION: These results suggest that the anticancer drug taxane may be an adjuvant for lung tumors exhibiting enhanced signaling of MET networks.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Phytomedicine ; 36: 183-193, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29157814

RESUMO

BACKGROUND: Mistletoe extract of Visucm album extract (VAE) contains many biologically active components and has been reported to be not only a complementary and alternative medicine, but also a potent therapeutic agent for many types of cancer. PURPOSE: In this study, we examined the effect of VAE on expression and activation of Axl and scrutinized the involvement of Axl in the anti-cancer activity of VAE in parental and chemo-resistant non-small cell lung cancer (NSCLC) cells. METHODS: The levels of Axl protein and mRNA were determined by Western blot analysis and RT-PCR, respectively. Phosphorylation of Axl upon Gas6 stimulation was observed by Western blot analysis. For ectopic expression or gene silencing of Axl, the recombinant plasmid, pcDNA3-Axl, or specific siRNA targeting Axl were transfected into A549 and H460 cells using Lipofectamine 2000, respectively. The anti-cancer activity of mistletoe extract was examined against the parental cells and each of their cisplatin- or erlotinib-resistant cells using trypan blue exclusion assays and colony formation assay. RESULTS: The levels of Axl mRNA were also reduced by VAE treatment, implying the transcriptional downregulation of Axl expression by VAE. In addition, the phosphorylation of Axl protein upon its ligand, Gas6, stimulation was found to be abrogated by VAE. We next found cytotoxic effect of VAE on both the parental NSCLC cells and their variants which are resistant to cisplatin (A549/CisR and H460/CisR) or erlotinib (H460/ER and H1975/ER). Treatment of these cells with VAE caused a dose-dependent decrease of cell viability and clonogenicity. This anti-proliferative effect of VAE was attenuated in Axl-overexpressing cells, while it was augmented in cells transfected Axl specific siRNA. Next, we also found that in cisplatin-resistant cells and erlotinib-resistant cells, VAE treatment decreased Axl protein level, colonogenicity. The levels of several cell cycle regulator, p21 and apoptosis related protein, X-linked inhibitor of apoptosis, was found to be induced and reduced by VAE treatment, respectively. CONCLUSION: Taken together, our data provide that VAE targets Axl to suppress cell proliferation and to circumvent cisplatin- and erlotinib-resistance in NSCLC cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Viscum album/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética
3.
Proc Inst Mech Eng H ; 231(9): 821-830, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28478734

RESUMO

Finite element models of an isolated vertebral body cannot accurately predict compressive strength of the spinal column because, in life, compressive load is variably distributed across the vertebral body and neural arch. The purpose of this study was to develop and validate a patient-specific finite element model of a functional spinal unit, and then use the model to predict vertebral strength from medical images. A total of 16 cadaveric functional spinal units were scanned and then tested mechanically in bending and compression to generate a vertebral wedge fracture. Before testing, an image processing and finite element analysis framework (SpineVox-Pro), developed previously in MATLAB using ANSYS APDL, was used to generate a subject-specific finite element model with eight-node hexahedral elements. Transversely isotropic linear-elastic material properties were assigned to vertebrae, and simple homogeneous linear-elastic properties were assigned to the intervertebral disc. Forward bending loading conditions were applied to simulate manual handling. Results showed that vertebral strengths measured by experiment were positively correlated with strengths predicted by the functional spinal unit finite element model with von Mises or Drucker-Prager failure criteria ( R2 = 0.80-0.87), with areal bone mineral density measured by dual-energy X-ray absorptiometry ( R2 = 0.54) and with volumetric bone mineral density from quantitative computed tomography ( R2 = 0.79). Large-displacement non-linear analyses on all specimens did not improve predictions. We conclude that subject-specific finite element models of a functional spinal unit have potential to estimate the vertebral strength better than bone mineral density alone.


Assuntos
Análise de Elementos Finitos , Disco Intervertebral/fisiologia , Modelagem Computacional Específica para o Paciente , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Cadáver , Feminino , Humanos , Disco Intervertebral/diagnóstico por imagem , Masculino , Teste de Materiais , Tomografia Computadorizada por Raios X
4.
Oncotarget ; 7(50): 83308-83318, 2016 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-27829217

RESUMO

Breast cancer is the most common malignant disease occurring in women and represents a substantial proportion of the global cancer burden. In these patients, metastasis but not the primary tumor is the main cause of breast cancer-related deaths. Here, we report the novel finding that DN10764 (AZD7762, a selective inhibitor of checkpoint kinases 1 and 2) can suppress breast cancer metastasis. In breast cancer cells, DN10764 inhibited cell proliferation and GAS6-mediated AXL signaling, consequently resulting in suppressed migration and invasion. In addition, DN10764 induced caspase 3/7-mediated apoptosis in breast cancer cells and inhibited tube formation of human umbilical vein endothelial cells. Finally, DN10764 significantly suppressed the tumor growth and metastasis of breast cancer cells in in vivo metastasis models. Taken together, these data suggest that therapeutic strategies targeting AXL in combination with systemic therapies could improve responses to anti-cancer therapies and reduce breast cancer recurrence and metastases.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Neoplasias Pulmonares/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Tiofenos/farmacologia , Ureia/análogos & derivados , Células A549 , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Oncotarget ; 7(47): 77664-77682, 2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27765910

RESUMO

Mutation of p53 occasionally results in a gain of function, which promotes tumor growth. We asked whether destabilizing the gain-of-function protein would kill tumor cells. Downregulation of the gene reduced cell proliferation in p53-mutant cells, but not in p53-null cells, indicating that the former depended on the mutant protein for survival. Moreover, phenformin and 2-deoxyglucose suppressed cell growth and simultaneously destabilized mutant p53. The AMPK pathway, MAPK pathway, chaperone proteins and ubiquitination all contributed to this process. Interestingly, phenformin and 2-deoxyglucose also reduced tumor growth in syngeneic mice harboring the p53 mutation. Thus, destabilizing mutant p53 protein in order to kill cells exhibiting "oncogene addiction" could be a promising strategy for combatting p53 mutant tumors.


Assuntos
Desoxiglucose/administração & dosagem , Mutação , Neoplasias/patologia , Fenformin/administração & dosagem , Proteína Supressora de Tumor p53/genética , Células A549 , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxiglucose/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Introdução de Genes , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Metástase Neoplásica , Fenformin/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Biol Chem ; 287(48): 40722-31, 2012 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-23043106

RESUMO

BACKGROUND: Laminar flow protects from atherosclerosis in endothelium. RESULTS: Laminar flow induces Nrf2 activation dependent on ERK5 activation, leading to up-regulation of downstream genes of Nrf2. CONCLUSION: ERK5 requires Nrf2 activation to exert cytoprotective effect on HUVEC. ERK5 inhibitor BIX02189 regulates Nrf2 activation in vivo. SIGNIFICANCE: Identifying ERK5 as a molecular target for regulating flow-mediating Nrf2-dependent gene expression may have significant therapeutic potential for treating atherosclerosis. Atherosclerosis is often observed in areas where disturbed flow is formed, whereas atheroprotective region is found in areas where steady laminar flow is developed. It has been reported that some genes activated by blood flow play important roles in vascular function and pathogenesis of atherosclerosis. Extracellular signal-regulated kinase 5 (ERK5) has been reported to regulate endothelial integrity and protect from vascular dysfunction and disease under laminar flow. Krüppel-like factor 2 (KLF2) and NF-E2-related factor 2 (Nrf2) are major transcriptional factors that contribute to anti-atherogenic responses under laminar flow. Implication of ERK5 in laminar flow-mediated regulation of KLF2-dependent gene has been established, whereas the role of ERK5 in laminar flow-mediated activation of Nrf2 pathway has not been addressed yet. In this study, we found that the blockage of ERK5 either by genetic depletion with siRNA or by biochemical inactivation with a specific chemical compound inhibited laminar flow-induced up-regulation of Nrf2-dependent gene expressions, whereas activation of ERK5 increased transcriptional activity and nuclear translocation of Nrf2, which suggests that ERK5 mediates laminar flow-induced up-regulation of Nrf2-dependent gene expression. Further functional studies showed that ERK5 provides protection against oxidative stress-induced cytotoxicity dependent on Nrf2. Molecular interaction between ERK5 and Nrf2 was further induced by laminar flow. Finally, flow-dependent nuclear localization of Nrf2 was inhibited by BIX02189, a specific inhibitor of MEK5, in aorta of mice in vivo. Collectively, these data demonstrate that laminar flow-induced activation of ERK5-Nrf2 signal pathway plays a critical role for anti-inflammatory and anti-apoptotic mechanism in endothelial cells.


Assuntos
Aterosclerose/prevenção & controle , Aterosclerose/fisiopatologia , Endotélio Vascular/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fluxo Sanguíneo Regional , Ativação Transcricional , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Endotélio Vascular/citologia , Endotélio Vascular/enzimologia , Células Endoteliais da Veia Umbilical Humana/enzimologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 7 Ativada por Mitógeno/genética , Fator 2 Relacionado a NF-E2/metabolismo , Regulação para Cima
7.
Exp Mol Med ; 42(10): 712-20, 2010 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-20739833

RESUMO

Synthetic oligodeoxynucleotides (ODN) with a CpG-motif are recognized by Toll-like receptor 9 (TLR9) and pleiotropic immune responses are elicited. Stimulation of macrophages with TLR9 agonist prevented apoptosis induced by serum deprivation through increased expression of FLICE-like inhibitory protein (FLIP). CpG ODN-mediated anti-apoptosis depended on the TLR9-Akt-FoxO3a signaling pathway. Inhibition of TLR9 by small interfering (si) RNA or an inhibitor suppressed CpG ODN-mediated anti-apoptosis. Analysis of signaling pathways revealed that the anti-apoptotic effect of CpG ODN required phosphorylation of FoxO3a and its translocation from the nucleus to the cytosol. Overexpression of FoxO3a increased apoptosis induced by serum deprivation and CpG ODN blocked these effects through FLIP expression. In contrast, siRNA knock-down of FoxO3a decreased apoptosis by serum deprivation. In addition, Akt activation was involved in CpG ODN-induced phosphorylation of FoxO3a, expression of FLIP, and anti-apoptosis. Taken together, these results demonstrate the involvement of Akt-FoxO3a in TLR9-mediated anti-apoptosis and indicate that FoxO3a is a distinct regulator for FLIP expression.


Assuntos
Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Fatores de Transcrição Forkhead/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Células Cultivadas , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/metabolismo , Proteína Oncogênica v-akt/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Receptor Toll-Like 9/genética
8.
FEBS J ; 277(13): 2830-7, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20528914

RESUMO

Macrophage activation contributes to the pathogenesis of atherosclerosis. In the vascular system, the major source of reactive oxygen species is the NADPH oxidase (Nox) family. Nox1 is induced by lipopolysaccharide (LPS) in macrophages, but the expression mechanism is not fully understood. We found that LPS causes beta-catenin accumulation by glycogen synthase kinase 3beta (GSK3beta) inactivation, and that beta-catenin accumulation increases Nox1 expression. LPS induced Nox1 mRNA expression and reactive oxygen species generation in Raw264.7 cells. Using bone marrow-derived macrophages from toll-like receptor 4 mutant mice, we also tested whether LPS-induced Nox1 expression is toll-like receptor 4 dependent. LPS caused GSK3beta phosphorylation, induced beta-catenin accumulation and increased nuclear translocation. The GSK3beta inhibitor LiCl potentiated LPS-induced Nox1 expression in accordance with beta-catenin accumulation and nuclear translocation. Conversely, ectopic expression of a constitutively active GSK3beta mutant severely attenuated Nox1 expression. These findings identify a novel regulatory pathway controlling Nox1 expression by LPS-stimulated macrophages.


Assuntos
Quinase 3 da Glicogênio Sintase/metabolismo , Macrófagos/metabolismo , NADH NADPH Oxirredutases/biossíntese , Receptor 4 Toll-Like/metabolismo , beta Catenina/metabolismo , Animais , Células Cultivadas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Lipopolissacarídeos/farmacologia , Cloreto de Lítio/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , NADH NADPH Oxirredutases/genética , NADPH Oxidase 1 , Relação Estrutura-Atividade
9.
J Immunol ; 183(11): 7497-504, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19917703

RESUMO

Foam cell formation is the most important process in atherosclerosis, and low density lipoprotein oxidation by reactive oxygen species (ROS) is the key step in the conversion of macrophages to foam cells. This study reveals the control mechanism of the gene for NADPH oxidase 1 (Nox1), which produces ROS in the formation of foam cells by stimulating TLR4. Treatment of macrophages by the TLR4 agonist LPS stimulated ROS production and ROS-mediated macrophage to foam cell conversion. This LPS-induced ROS production and foam cell formation could be abrogated by pretreatment of macrophages with N-acetyl cysteine or apocynin. LPS increased Nox1 promoter activity, and resultant expression of mRNA and protein. Small interfering RNA mediated inhibition of Nox1 expression decreased LPS-induced ROS production and foam cell formation. LPS-mediated Nox1 expression and the responses occurred in a calcium-independent phospholipase A(2) (iPLA(2))-dependent manner. The iPLA(2)beta-specific inhibitor S-BEL or iPLA(2)beta small interfering RNA attenuated LPS-induced Nox1 expression, ROS production, and foam cell formation. In addition, activation of iPLA(2)beta by LPS caused Akt phosphorylation and was followed by increased Nox1 expression. These results suggest that the binding of LPS and TLR4 increases Nox1 expression through the iPLA(2)beta-Akt signaling pathway, and control ROS production and foam cell formation.


Assuntos
Células Espumosas/imunologia , Regulação da Expressão Gênica/imunologia , Fosfolipases A2 do Grupo IV/imunologia , NADH NADPH Oxirredutases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais/imunologia , Animais , Aterosclerose/imunologia , Aterosclerose/metabolismo , Western Blotting , Sinalização do Cálcio/imunologia , Linhagem Celular , Citometria de Fluxo , Células Espumosas/metabolismo , Expressão Gênica , Fosfolipases A2 do Grupo IV/metabolismo , Lipopolissacarídeos/imunologia , Camundongos , Microscopia Confocal , NADH NADPH Oxirredutases/metabolismo , NADPH Oxidase 1 , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo
10.
J Gerontol A Biol Sci Med Sci ; 64(3): 351-62, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19264704

RESUMO

Secretory phospholipase A(2) (sPLA(2)) is involved in various cellular physiological and pathological responses, especially in inflammatory responses. Accumulating evidence suggests that inflammation is an underlying basis for the molecular alterations that link aging and age-related pathological processes. However, the involvement of sPLA(2) in cellular senescence is not clear. In this study, we found that sPLA(2) treatment induces cellular senescence in human dermal fibroblasts (HDFs), as confirmed by increases in senescence-associated beta-galactosidase activity, changes in cell morphology, and upregulation of p53/p21 protein levels. sPLA(2)-induced senescence was observed in p16-knockdown HDFs and p16-null mouse fibroblasts, but not in p53-knockdown HDFs and p53-null mouse fibroblasts. Treatment with sPLA(2) increases reactive oxygen species (ROS) production, and an antioxidant, N-acetylcysteine, inhibits sPLA(2)-induced cellular senescence. These results suggest that sPLA(2) has a role in cellular senescence in HDFs during inflammatory response by promoting ROS-dependent p53 activation and might therefore contribute to inflammatory disorders associated with aging.


Assuntos
Senescência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fosfolipases A2/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Envelhecimento/fisiologia , Western Blotting , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Senescência Celular/fisiologia , Feminino , Fibroblastos/metabolismo , Citometria de Fluxo , Humanos , Masculino , Probabilidade , Sensibilidade e Especificidade , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
11.
Neurosci Lett ; 442(3): 174-9, 2008 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-18644424

RESUMO

We investigated the effect of electromyography (EMG)-triggered neuromuscular electrical stimulation (NMES; EMG-stim) on functional recovery of the hemiparetic hand and the related cortical activation pattern in chronic stroke patients. We enrolled 14 stroke patients, who were randomly assigned to the EMG-stim (n=7) or the control groups (n=7). The EMG-stim was applied to the wrist extensor of the EMG-stim group for two sessions (30 min/session) a day, five times per week for 10 weeks. Four functional tests (box and block, strength, the accuracy index, and the on/offset time of muscle contraction) and functional MRI (fMRI) were performed before and after treatment. fMRI was measured at 1.5 T in parallel with timed finger flexion-extension movements at a fixed rate. Following treatment, the EMG-stim group showed a significant improvement in all functional tests. The main cortical activation change with such functional improvement was shifted from the ipsilateral sensorimotor cortex (SMC) to the contralateral SMC. We demonstrated that 10-week EMG-stim can induce functional recovery and change of cortical activation pattern in the hemiparetic hand of chronic stroke patients.


Assuntos
Encéfalo/fisiopatologia , Terapia por Estimulação Elétrica , Recuperação de Função Fisiológica/fisiologia , Reabilitação do Acidente Vascular Cerebral , Eletromiografia , Feminino , Lateralidade Funcional , Mãos/fisiologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/fisiopatologia
12.
NeuroRehabilitation ; 23(3): 239-44, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18560140

RESUMO

OBJECTIVES: Constraint-induced movement therapy (CIMT) has been demonstrated to be effective in improving hemiparetic upper extremity function in stroke patients, but few studies have been performed to assess orthosis modification. We investigated the effect of the newly designed small orthosis named modified opposition restriction orthosis (MORO) in chronic hemiparetic patients with stroke. DESIGN: Twenty-one stroke patients were randomly assigned to the CIMT group or control group. Thirteen patients in the CIMT group wore MORO confining the thumb and index finger for at least 5 hours of each day, 7 days a week for 8 weeks. The affected upper extremity function was evaluated using the manual function test (MFT), Purdue Pegboard (PP) score, and motor activity log (MAL) at pre and post-CIMT. RESULTS: Four of the 13 patients in the CIMT group dropped out due to motivational problems, and 9 patients remained in the CIMT group at the end of the study. The patients in the CIMT group showed a mean improvement of 195.8% on MAL AOU (Amount of Use), 24.6% on PP score, and 5.5% on MFT. CONCLUSION: This new MORO would be effective for use in a CIMT program in chronic hemiparetic patients with stroke.


Assuntos
Braquetes , Terapia por Exercício/instrumentação , Hemiplegia/reabilitação , Destreza Motora/fisiologia , Reabilitação do Acidente Vascular Cerebral , Adulto , Idoso , Braço/fisiopatologia , Feminino , Dedos/fisiopatologia , Seguimentos , Hemiplegia/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Músculo Esquelético/fisiopatologia , Amplitude de Movimento Articular/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Polegar/fisiopatologia
13.
NeuroRehabilitation ; 23(3): 283-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18560146

RESUMO

The aim of this study was to compare the areas of brain activation between complex and simple exercises in a unimanual hand and to assess the possibility of an exercise task for paretic hands following stroke. The subjects included 11 healthy right-handed volunteers. The complex exercise was a wooden ball rotation task with the unimanual hand and the simple exercise was a hand grasp task performed during a functional MRI scan. Stronger activation of the left primary sensorimotor cortex, the left premotor area, and the ipsilateral cerebellum emerged when the complex movement was performed. Ipsilateral activity was located in the primary sensory cortex and premotor area, and contralateral activity was shown in the left cerebellum. These results suggest that a unimanual ball rotation task may be appropriate for rehabilitation of a movable paretic hand in an early stage of stroke recovery, which should provide motor and sensory input using external stimuli, while the simple motor task may appropriate in a compensatory stage, and should inhibit the ipsilateral activity due to maladaptive plasticity.


Assuntos
Encéfalo/fisiologia , Terapia por Exercício/métodos , Força da Mão/fisiologia , Processamento de Imagem Assistida por Computador , Imagem Tridimensional , Imagem por Ressonância Magnética , Destreza Motora/fisiologia , Adulto , Mapeamento Encefálico , Cerebelo/fisiologia , Dominância Cerebral/fisiologia , Feminino , Lobo Frontal/fisiologia , Humanos , Masculino , Córtex Motor/fisiologia , Vias Neurais/fisiologia , Córtex Somatossensorial/fisiologia
14.
Neurosci Lett ; 435(1): 56-9, 2008 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-18325666

RESUMO

Transcranial direct current stimulation (tDCS) can modulate motor cortex excitability in the human brain. We attempted to demonstrate the cortical stimulation effect of tDCS on the primary motor cortex (M1) using functional MRI (fMRI). An fMRI study was performed for 11 right-handed healthy subjects at 1.5 T. Anodal tDCS was applied to the scalp over the central knob of the M1 in the left hemisphere. A constant current with an intensity of 1.0 mA was applied. The total fMRI paradigm consisted of three sessions with a 5-min resting period between each session. Each session consisted of five successive phases (resting-tDCS-tDCS-tDCS-tDCS), and each of the phases was performed for 21s. Our findings revealed that no cortical activation was detected in any of the stimulation phases except the fourth tDCS phase. In the result of group analysis for the fourth tDCS phase, the average map indicated that the central knob of the left primary motor cortex was activated. In addition, there were activations on the left supplementary motor cortex and the right posterior parietal cortex. We demonstrated that tDCS has a direct stimulation effect on the underlying cortex. It seems that tDCS is a useful modality for stimulating a target cortical region.


Assuntos
Mapeamento Encefálico/métodos , Terapia por Estimulação Elétrica/métodos , Imagem por Ressonância Magnética/métodos , Córtex Motor/fisiologia , Movimento/fisiologia , Adulto , Circulação Cerebrovascular/fisiologia , Eletricidade , Eletrônica Médica/instrumentação , Eletrônica Médica/métodos , Potencial Evocado Motor/fisiologia , Feminino , Lateralidade Funcional/fisiologia , Humanos , Masculino , Córtex Motor/anatomia & histologia , Córtex Motor/irrigação sanguínea , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Tratos Piramidais/fisiologia , Resultado do Tratamento
15.
Neurosci Lett ; 426(2): 123-7, 2007 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-17897782

RESUMO

Diffusion tensor tractography (DTT) is useful for exploring the state of the corticospinal tract (CST). An accurate estimation of the integrity of the CST in the early stage of a cerebral infarct would enable a determination of motor recovery. DTT was performed to classify CST integrity following a corona radiata infarct to evaluate if the procedure could characterize the motor outcome of the affected hand. Fifty-five patients with completely paralyzed hands due to a corona radiata infarct were recruited for the study, and DTT images were obtained within 7-30 days after a stroke. The DTI findings for the patients were classified into four groups. In type A, the CST was preserved around the infarct; in type B, the CST originated from a cortex other than the primary motor cortex; in type C, the CST was interrupted at the infarct; in type D, the CST failed to reach the infarct due to degeneration. Six months after a stroke, the motor function of the affected hand was evaluated with the motricity index (MI) for the hand, the Medical Research Council score (MRC) for finger extensors and the modified Brunnstrom classification (MBC). These indices were significantly influenced by the DTT type (p<0.05). The highest MI, MRC and MBC were seen in the DTT type A patients; the lowest MI, MRC and MBC were seen in the DTT type D patients (p<0.05). The integrity of the corticospinal tract determined by DTT obtained during the early stage of a corona radiata infarct seems to be helpful in predicting the motor outcome of the affected hand.


Assuntos
Mapeamento Encefálico , Infarto Cerebral/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Atividade Motora/fisiologia , Tratos Piramidais/patologia , Infarto Cerebral/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade
16.
NeuroRehabilitation ; 22(2): 77-84, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17656831

RESUMO

OBJECTIVES: We tried to examine whether visual biofeedback tracking training (VBTT) can improve both the gait performance and cortical activation pattern in chronic stroke patients. DESIGN: We enrolled 10 chronic hemiparetic patients with stroke(mean age 46.3 +/- 5.19 years). The patients were randomly assigned to the training group (5 patients) or the control group (5 patients). VBTT was to follow the PC-generated sine waves with the knee joint electrogoniometer, and the two sine waves should appear as close to overlapping as possible on the PC monitor. The training was performed for 39 minutes/day, 5 days/week, for 4 weeks. Pre-training and post-training accuracy of tracking, functional status of gait, and functional MRI (fMRI) were measured. fMRI was performed at 1.5 T in parallel with timed knee flexion-extension movements at a fixed rate. RESULTS: The accuracy of the tracking performance, walking speed, and motor scale for gait improved in the training group. Primary sensorimotor cortex (SM1) cortical activation shifted significantly from the unaffected to the affected hemisphere in the training group. CONCLUSIONS: We demonstrated that cortical activation changes occurred with gait function improvement in chronic stroke patients throughout the 4-week VBTT program. It seems that the cortical reorganization was induced by VBTT.


Assuntos
Biorretroalimentação Psicológica , Marcha/fisiologia , Córtex Motor/fisiopatologia , Paresia/reabilitação , Desempenho Psicomotor , Reabilitação do Acidente Vascular Cerebral , Adulto , Feminino , Humanos , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Paresia/etiologia , Paresia/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia
17.
NeuroRehabilitation ; 22(2): 105-8, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17656835

RESUMO

OBJECTIVES: Diffusion tensor image tracography (DTT) could be useful for exploration of the state of the corticospinal tract at the subcortical white matter level. We investigated the neural pathway associated with motor recovery in the patients with corona radiata infarct (CR) using DTT. DESIGN: Three hemiparetic patients who showed severe weakness of the affected upper extremity at stroke onset, were recruited. DTT was performed twice (subacute and chronic stage) using 1.5-T system. Three-dimensional reconstructions of the fiber tracts were obtained with FA <0.2, angle >45 degrees as termination criteria. RESULTS: In all patients, the motor function of the affected upper extremity has recovered to be functional state at second DTT scanning. The motor tracts of the affected hemisphere were observed to pass along the posterior portion of the CR infarct on both the first and second DTT. CONCLUSIONS: It seems that the motor function of the affected upper extremity of the patients recovered via the posterior portion of infarct. This finding may reflect functional reorganization of the motor pathway following damage to the corticospinal tract.


Assuntos
Infarto Encefálico/fisiopatologia , Cápsula Interna , Atividade Motora/fisiologia , Paresia/fisiopatologia , Tratos Piramidais/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Idoso , Braço/fisiopatologia , Infarto Encefálico/complicações , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paresia/etiologia , Fatores de Tempo
18.
Neurosci Lett ; 421(2): 142-6, 2007 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-17566651

RESUMO

We tried to investigate the motor outcome according to diffusion tensor tractography (DTT) findings for the corticospinal tract (CST) in the early stage for hemiparetic patients with intracerebral hemorrhage (ICH). Forty patients with severe paralysis of the affected side were enrolled. DTT was obtained in the early stage of the stroke (7-30 days) and was classified into four groups: type A, the CST originating from primary motor cortex was preserved around the hematoma; type B, the CST was similar to type A except the fiber originated from the adjacent areas to the primary motor cortex; type C, the CST was interrupted at or around the hematoma; and type D, the CST did not reach the hematoma due to degeneration (Fig. 1). Six months after onset, motor function was measured and the statistical influence of the DTT type was tested. Initially, none of the motor function scales of the affected side differed among the four DTT types. Six months after the onset of ICH, motor functions of the same side were significantly different according to DTT type (p<0.05). All motor scales were highest in the DTT type A group, and were lowest in the DTT type D group (p<0.0003). The early DTT findings for CST may be used to predict the motor outcome of the affected extremities in hemiparetic patients with ICH.


Assuntos
Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Atividade Motora/fisiologia , Tratos Piramidais/patologia , Adulto , Mapeamento Encefálico , Distribuição de Qui-Quadrado , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor , Recuperação de Função Fisiológica
19.
Exp Mol Med ; 39(2): 239-45, 2007 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-17464186

RESUMO

Unmethylated CpG oligodeoxynucleotides (CpG ODNs) activate immune cells to produce immune mediators. This study demonstrates that in murine macrophage RAW 264.7 cells, CpG ODN-mediated matrix metalloproteinase-9 (MMP-9) expression is regulated at transcriptional level and requires de novo protein synthesis. Inhibition of ERK and p38 MAPK, but not JNK, results in significant decrease of CpG ODN-induced MMP-9 expression. We found that endosomal maturation inhibitors, chloroquine and bafilomycin A, block CpG ODN-induced ERK and p38 MAPK activation and the subsequent MMP-9 expression. We also observed that CpG ODN induces NF-kappaB activation and NF-kappaB is a downstream target of p38 MAPK. Taken together, our data demonstrate that CpG ODN triggers MMP-9 expression via TLR-9 dependent ERK and p38 MAPK activation followed by NF-kappaB activation.


Assuntos
Metaloproteinase 9 da Matriz/biossíntese , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Receptor Toll-Like 9/metabolismo , Animais , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Camundongos , 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 , Transdução de Sinais/efeitos dos fármacos , Receptor Toll-Like 9/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
FEBS Lett ; 580(18): 4533-8, 2006 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-16870179

RESUMO

CpG oligodeoxunucleotide (ODN) plays an important role in immune cell function. The present study examined whether temporal control of toll-like receptor (TLR)-9 by CpG ODN can regulate the expression of matrix metalloproteinase-9 (MMP-9). CpG ODN induced the release of tumor necrosis factor (TNF)-alpha and the expression of TNF receptor (TNFR)-II, but not of TNFR-I, in a time-dependent manner and stimulated significant, though delayed, MMP-9 expression. The endosomal acidification inhibitors, chloroquine or bafilomycin A, inhibited CpG ODN-induced TNF-alpha, TNFR-II, and MMP-9 expression. CpG ODN induced the phosphorylation of Akt, and the inhibition of Akt by LY294002 suppressed CpG ODN-induced TNF-alpha, TNFR-II, and MMP-9 expressions. Moreover, neutralizing TNF-alpha antibody significantly suppressed CpG ODN-induced MMP-9 expression, suggesting the involvement of TNF-alpha. These observations suggest that CpG ODN may play important roles in macrophage activation by regulating the expression of MMP-9 via a TLR-9/Akt/TNF-alpha-dependent signaling pathway.


Assuntos
Metaloproteinase 9 da Matriz/biossíntese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Toll-Like 9/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Adjuvantes Imunológicos/farmacologia , Animais , Linhagem Celular , Indução Enzimática , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/imunologia , Metaloproteinase 9 da Matriz/genética , Camundongos , Oligodesoxirribonucleotídeos/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais
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