Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
ACS Chem Neurosci ; 10(5): 2385-2396, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30785256

RESUMO

Painful diabetic neuropathy (PDN) is among the common complications in diabetes mellitus (DM), with its underlying mechanisms largely unknown. Synapsin II is primarily expressed in the spinal dorsal horn, and its upregulation mediates a superfluous release of glutamate and a deficiency of GABAergic interneuron synaptic transmission, which is directly implicated in the facilitation of pain signals in the hyperalgesic nociceptive response. Recently, synapsin II has been revealed to be associated with the modulation of neurite outgrowth, whereas the process of this neuronal structural neuroplasticity following neuronal hyperexcitability still remains unclear. In this study, we found that under conditions of elevated glucose, TNF-α induced the activation of mTOR, mediating the upregulation of synapsin II and neurite outgrowth in dorsal horn neurons. In vivo, we demonstrated that mTOR and synapsin II were upregulated and coexpressed in the spinal dorsal horn neurons in rats with streptozotocin (STZ)-induced diabetes. Furthermore, the intrathecal administration of the mTOR inhibitor rapamycin or synapsin II shRNA significantly diminished the expression of synapsin II, effectively mitigating hyperalgesia in PDN rats. We are the first to discover that in STZ-induced diabetic rats the activation of mTOR mediates the upregulation of synapsin II and neurite outgrowth, both contributing to hyperalgesia. These findings may benefit the clinical therapy of PDN by provision of a novel target.

3.
Biochem Biophys Res Commun ; 503(4): 2517-2523, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30208520

RESUMO

Acute kidney injury induced by renal ischemia-reperfusion (IR) is a prominent risk factor in the development towards renal fibrosis. Ras-related C3 botulinum toxin substrate 1(Rac1) has been involved in the pathophysiology of fibrotic disorders. But the role of Rac1 in the pathogenesis of IR-induced renal fibrosis is still unknown. Here, we examined the effects of NSC23766, an inhibitor of Rac1, on the progression of renal fibrosis after IR injury. In mice, IR induced Rac1 activation in kidneys. Rac1 inhibition alleviated renal damage and dysfunction. Mice treated with NSC23766 displayed diminished collagen area in the kidneys compared with IR controls, which was associated with reduction of extracellular matrix (ECM) proteins and α-SMA. Furthermore, Rac1 inhibition reduced profibrotic molecules levels in the kidneys of mice with IR. Finally, Rac1 inhibition impaired the accumulation of bone marrow-derived M2 macrophages and the transition of M2 macrophages to myofibroblasts. In cultured mouse monocytes, IL-4 treatment activated Rac1, which was abrogated by NSC23766. Moreover, application with IL-4 induced polarization of monocytes to M2 phenotype and increased the levels of ECM proteins and α-SMA, which was abolished by NSC23766. In summary, Rac1 plays a crucial role in the pathogenesis of renal fibrosis after IR via regulation of expressions of profibrotic molecules, bone-marrow derived M2 macrophages recruitment, and M2 macrophages-myofibroblasts transition.

4.
Artif Cells Nanomed Biotechnol ; 46(8): 1617-1624, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28974111

RESUMO

Neurotoxicity of local anaesthetics has been alerted by more and more peoples. Cav3.1 and Cav3.2 T-type calcium channels were closely related with local anaesthetics toxicity. However, the role of Cav3.3, another subtype of the T-type calcium channel, on the neurotoxicity induced by local anaesthetics remains unclear. CaMKIIγ is a kind of multifunctional kinase and associated with a variety of physiological and pathological process. T-type calcium channel is closely related with CaMKIIγ. Up-regulation CaMKIIγ can increase T-type currents at the dorsal root ganglia (DRG). On the contrary, down-regulation results in the T-type currents decrease. Is the relation between Cav3.3 T-type channel calcium and CaMKIIγ involved with the ropivacaine hydrochloride neurotoxicity? In this study, we generated pAd-Cav3.3 and pAd-shRNA adenovirus vector to up-regulate and down-regulate Cav3.3 mRNA expression of the DRG. The cells treated or untreated with ropivacaine hydrochloride (3 mM) for 4 h were used to evaluate the neurotoxicity. Cell viability, cell death rate and apoptosis rate, Cav3.3 and CaMKIIγ expression were detected with MTT method, Hoechst-PI, flow cytometry, qRT-PCR and western blotting. Results showed that the cell viability of the DRG treated with ropivacaine hydrochloride markedly decreased, death rate and apoptosis rate, Cav3.3 and CaMKIIγ mRNA and protein expression significantly increased. Cav3.3 overexpression aggravated DRG injury induced by ropivacaine hydrochloride and inhibition of Cav3.3 expression improved the cell damages. Cav3.3 can regulate CaMKIIγ mRNA and protein expression. In conclusion, Cav3.3 regulated CaMKIIγ in DRG, which was involved with the cell injury induced by ropivacaine hydrochloride.

5.
Sci Rep ; 7(1): 5262, 2017 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-28701796

RESUMO

T-type calcium channels are intimately involved in the local anesthetics neurotoxicity. Does CaMKIIγ regulate T-type calcium currents in local anesthetics neurotoxicity? This study generated pAd-CaMKIIγ and pAd-shRNA adenovirus vectors to up- and down-regulate CaMKIIγ mRNA expression in dorsal root ganglion neurons (DRG). Normal DRG (Normal group), empty vector DRG (Empty vector group), pAd-CaMKIIγ DRG (pAd-CaMKIIγ group) and pAd-shRNA DRG (pAd-shRNA group) were treated or untreated with 3 mM ropivacaine hydrochloride for 4 h. Cell viability, apoptosis rate, CaMKIIγ, pCaMKIIγ, Cav3.2, and Cav3.3 expression were detected. Ultrastructural changes in DRG were observed under a transmission electron microscope. The results demonstrated that the cell viability of DRG treated with ropivacaine hydrochloride decreased markedly, the apoptosis rate, CaMKIIγ, pCaMKIIγ, Cav3.2, Cav3.3 expression increased significantly. CaMKIIγ up-regulation aggravated ropivacaine hydrochloride-induced cell damage and increased Cav3.2 and Cav3.3 expression. In conclusion, CaMKIIγ regulated Cav3.2 and Cav3.3 expression in DRG, which was involved with ropivacaine hydrochloride-induced cell injury.

6.
Eur J Pharmacol ; 812: 18-27, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28668506

RESUMO

Acute kidney injury caused by ischemia-reperfusion injury (IRI) is a major risk factor for chronic kidney disease, which is characterized by renal interstitial fibrosis. However, the molecular mechanisms underlying renal fibrosis induced by IRI are not fully understood. Our results showed that interleukin (IL)-33 was induced markedly after IRI insult, and the kidneys of mice following IRI plus IL-33 treatment presented more severe renal fibrosis compared with mice treated with IRI alone. Therefore, we investigated whether inhibition of IL-33 protects against IRI-induced renal fibrosis. Mice were administrated with soluble ST2 (sST2), a decoy receptor that neutralizes IL-33 activity, or vehicle by intraperitoneal injection for 14 days after IRI challenge. We revealed that mice treated with sST2 exhibited less severe renal dysfunction and fibrosis in response to IRI compared with vehicle-treated mice. Inhibition of IL-33 suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidneys after IRI stress, which was associated with less expression of extracellular matrix proteins. Furthermore, inhibition of IL-33 also showed a significant reduction of F4/80+ macrophages and CD3+ T cells in the kidneys of mice after IRI treatment. Finally, Treatment with IL-33 inhibitor reduced proinflammatory cytokine and chemokine levels in the kidneys of mice following IRI insult. Taken together, our findings indicate that IL-33 signaling plays a critical role in the pathogenesis of IRI-induced renal fibrosis through regulating myeloid fibroblast accumulation, inflammation cell infiltration, and the expression of proinflammatory cytokines and chemokines.


Assuntos
Interleucina-33/metabolismo , Rim/patologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Animais , Fibrose , Rim/metabolismo , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
7.
Drug Dev Ind Pharm ; 43(9): 1460-1471, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28402143

RESUMO

In this study, furbiprofen/hydroxypropyl-ß-cyclodextrin (HPßCD) inclusion complexes were prepared to improve the drug dissolution and facilitate its application in hydrophilic gels. Inclusion complexes were prepared using a supercritical fluid processing and a conventional optimized co-lypholization method was employed as a reference. The entrapment efficacy and drug loading of both methods were investigated. Evaluation of drug dissolution enhancement was conducted in deionized water as well as buffer solutions of different pH. Carbopol 940 gels of both flurbiprofen and flurbiprofen/HPßCD inclusion complexes, with or without penetration enhancers, were prepared and percutaneous permeation studies were performed using rat abdominal skin samples. Formation of flurbiprofen/HPßCD inclusion complexes was confirmed by Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. The results obtained showed that SCF processing produced a higher EE (81.91 ± 1.54%) and DL (6.96 ± 0.17%) compared with OCL with values of 69.11 ± 2.23% and 4.00 ± 1.01%, respectively. A marked instantaneous release of flurbiprofen/HPßCD inclusion complexes prepared by SCF processing (103.04 ± 2.66% cumulative release within 5 min, a 10-fold increase in comparison with flurbiprofen alone) was observed. In addition, this improvement in dissolution was shown to be pH-independent (the percentage cumulative release at pH 1.2, 4.5, 6.8 and 7.4 at 5 min was 95.19 ± 1.71, 101.75 ± 1.44, 105.37 ± 4.58 and 96.84 ± 0.56, respectively). Percutaneous permeability of flurbiprofen-in-HPßCD-in-gels could be significantly accelerated by turpentine oil and was related to the water content in the system. An in vivo pharmacokinetic study showed a 2-fold increase in Cmax and a shortened Tmax as well as a comparable relative bioavailability when compared with the commercial flurbiprofen Cataplasms (Zepolas®). With their superior dissolution, these flurbiprofen/HPßCD inclusion complexes prepared by SCF processing could provide improved applications for flurbiprofen.


Assuntos
Flurbiprofeno/química , Flurbiprofeno/farmacocinética , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Química Farmacêutica , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Varredura , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
8.
Acta Pharm ; 67(1): 85-97, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28231046

RESUMO

Advantages of the supercritical fluid (SCF) process compared to the conventional solution stirring method (CSSM) in the preparation of daidzein-hydroxypropyl-ß-cyclodextrin (HPßCD) complexes were investigated. Formation of daidzein/ HPßCD inclusion complexes was confirmed by Fourier transformed-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM). Particle size, inclusion yield, drug solubility and dissolution of daidzein/HPßCD complexes were evaluated. Compared to CSSM, the SCF process resulted in higher inclusion yield and higher solubility. Also, extended dissolution of daidzein from the SCF processed HPßCD inclusion complexes was observed, with only 22.94 % released in 45 min, compared to its rapid release from those prepared by CSSM, with 98.25 % drug release in 15 min. This extended release of daidzein from SCF prepared inclusion complexes was necessary to avoid drug precipitation and improve drug solubilisation in the gastrointestinal tract. The results showed that the SCF process is a superior preparation method for daidzein-hydroxypropyl-ß-cyclodextrin complexes.


Assuntos
Cromatografia com Fluido Supercrítico , Excipientes/química , Isoflavonas/química , Fitoestrógenos/química , Tecnologia Farmacêutica/métodos , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Preparações de Ação Retardada , Composição de Medicamentos , Estudos de Viabilidade , Cinética , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Difração de Pó , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria
9.
Neurosci Lett ; 619: 21-8, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-26946108

RESUMO

The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation and protein synthesis, and it is specifically inhibited by rapamycin. In chronic pain conditions, mTOR-mediated local protein synthesis is crucial for neuronal hyperexcitability and synaptic plasticity. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 plays a major role in action potential initiation and propagation and cellular excitability in DRG (dorsal root ganglion) neurons. In this study, we investigated if mTOR modulates the phosphorylation of Nav1.8 that is associated with neuronal hyperexcitability and behavioral hypersensitivity in STZ-induced diabetic rats. Painful diabetic neuropathy (PDN) was induced in Sprague-Dawley rats by intraperitoneal injection with streptozotocin (STZ) at 60mg/kg. After the onset of PDN, the rats received daily intrathecal administrations of rapamycin (1µg, 3µg, or 10µg/day) for 7 days; other diabetic rats received the same volumes of dimethyl sulfoxide (DMSO). Herein, we demonstrate a marked increase in protein expression of total mTOR and phospho-mTOR (p-mTOR) together with the up-regulation of phosphor-Nav1.8 (p-Nav1.8) prior to the mechanical withdrawal threshold reaching a significant reduction in dorsal root ganglions (DRGs). Furthermore, the intrathecal administration of rapamycin, inhibiting the activity of mTOR, suppressed the phosphorylation of DRG Nav1.8, reduced the TTX-R current density, heightened the voltage threshold for activation and lowered the voltage threshold for inactivation and relieved mechanical hypersensitivity in diabetic rats. An intrathecal injection (i.t.) of rapamycin inhibited the phosphorylation and enhanced the functional availability of DRG Nav1.8 attenuated STZ-induced hyperalgesia. These results suggest that rapamycin is a potential therapeutic intervention for clinical PDN.


Assuntos
Nefropatias Diabéticas/fisiopatologia , Gânglios Espinais/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Sirolimo/farmacologia , Estreptozocina , Animais , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/metabolismo , Hiperalgesia/fisiopatologia , Injeções Espinhais , Masculino , Neurônios/fisiologia , Fosforilação , Estimulação Física , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Tato
10.
J Anesth ; 29(6): 821-30, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26002230

RESUMO

PURPOSE: Hypoxia promotes the progression of lung cancer cells. Unfortunately, anesthetic technique might aggravate hypoxia of lung cancer cells. Sevoflurane is a commonly used anesthetic. Its effect on hypoxia-induced aggressiveness of lung cancer cells remains unknown. The aim of the study is to investigate the effects of sevoflurane on hypoxia-induced growth and metastasis of lung cancer cells. As hypoxia-inducible factor-1α (HIF-1α) plays a pivotal role in mediating the adaptation and tolerance of cancer cells under hypoxic microenvironment, the role of HIF-1α in the effect of sevoflurane on hypoxia-induced growth and metastasis has also been elucidated. METHODS: A549 cells were treated with normoxia, hypoxia, co-treatment of sevoflurane and hypoxia, and dimethyloxaloylglycine (DMOG, a HIF-1α agonist) for 4 h, respectively. MTT assay and colony formation assay were used to evaluate cell growth. Transwell assay was performed to detect invasion and migration ability. The protein level of HIF-1α, X-linked inhibitor of apoptosis protein (XIAP), survivin, fascin, heparanase (HPA), and p38 MAPK were determined by Western blotting. RESULTS: Hypoxia enhanced proliferation and metastatic potential of cells. Sevoflurane could suppress hypoxia-induced growth and metastasis ability of cells. Furthermore, HIF-1α, XIAP, survivin, fascin and HPA were down-regulated significantly by the co-treatment of sevoflurane and hypoxia as compared to hypoxia treatment. DMOG abolished the inhibiting effects of sevoflurane on hypoxia-induced growth and metastasis ability of cells. In addition, sevoflurane partly reversed the increase of p38 MAPK activity that was induced by hypoxia. CONCLUSIONS: Sevoflurane could suppress hypoxia-induced growth and metastasis of lung cancer cells, which might be associated with modulating HIF-1α and its down-stream genes. Moreover, p38 MAPK signaling pathway was involved in the regulation of HIF-1α by sevoflurane.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Éteres Metílicos/farmacologia , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Sevoflurano , Transdução de Sinais/efeitos dos fármacos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética
11.
J Neuropathol Exp Neurol ; 73(6): 548-58, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24806305

RESUMO

Angiogenic gene therapy in patients with cerebral infarcts may have clinical benefit, but its potential is diminished by the difficulty of introducing genes into the brain. We evaluated the safety and efficacy of ultrasound-targeted microbubble destruction (UTMD) for delivery of genes to the brains of normal mice and after transient middle cerebral artery occlusion. In normal mice, disruption of the blood-brain barrier detected with trypan blue staining was reversible within 24 hours of a single UTMD administration. Expression of reporter genes in the brain after UTMD demonstrated successful targeted gene delivery and transfection. Decreased neurologic function after transient middle cerebral artery occlusion was attenuated versus controls at 7 days after UTMD delivery of vascular endothelial growth factor. Ultrasound-targeted microbubble destruction delivery of the VEGF gene resulted in decreased infarct areas, increased vessel density, and reduced apoptosis versus controls. There was no evidence of permanent brain injury throughout the study. Thus, UTMD was a safe, minimally invasive, effective technique for gene delivery to the brain. Vascular endothelial growth factor transfection of brain cells conferred beneficial effects on histopathologic parameters and neurologic function, and stimulated angiogenesis in a mouse stroke model.


Assuntos
Infarto Encefálico/etiologia , Infarto Encefálico/terapia , Técnicas de Transferência de Genes , Infarto da Artéria Cerebral Média/complicações , Microbolhas/uso terapêutico , Ultrassom , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Animais , Apoptose/genética , Vasos Sanguíneos/patologia , Barreira Hematoencefálica/patologia , Modelos Animais de Doenças , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Infarto da Artéria Cerebral Média/patologia , Camundongos , Neovascularização Fisiológica , Exame Neurológico , Fosfopiruvato Hidratase/metabolismo , Azul Tripano , Fator A de Crescimento do Endotélio Vascular/genética
12.
Neurosci Lett ; 560: 81-5, 2014 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-24370596

RESUMO

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are the main enzymes that produce oxidative stress, which plays an important role in painful diabetic neuropathy. Curcumin has been reported to exert an antinociceptive effect in a rat model of diabetic neuropathy by suppressing oxidative stress in the spinal cord. However, it remains unknown whether the mechanism by which curcumin ameliorates diabetic neuropathy can be attributed to spinal NADPH oxidases. This study was designed to determine the effect of curcumin on diabetic neuropathy and to investigate its precise mechanism in relation to NADPH oxidase-mediating oxidative stress in the spinal cord. Diabetic neuropathy was induced in Sprague-Dawley rats by intraperitoneal injection with 1% streptozotocin (STZ; 60 mg/kg). After the onset of diabetic neuropathy, a subset of the diabetic rats received daily intragastric administrations of curcumin (200mg/kg) or intraperitoneal injections of apocynin (2.5mg/kg) for 14 consecutive days, whereas other diabetic rats received equivalent volumes of normal saline (NS). STZ resulted in diabetic neuropathy with hyperglycemia and a lower paw withdrawal threshold (PWT), accompanied by elevations in the expression of the NADPH oxidase subunits p47(phox) and gp91(phox) and in the levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA) and a reduction in superoxide dismutase (SOD) activity (P<0.05) in the spinal cord. Both curcumin and apocynin ameliorated diabetic neuropathy. In conclusion, curcumin attenuated neuropathic pain in diabetic rats, at least partly by inhibiting NADPH oxidase-mediating oxidative stress in the spinal cord.


Assuntos
Antioxidantes/farmacologia , Curcumina/farmacologia , Neuropatias Diabéticas/tratamento farmacológico , NADPH Oxidases/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Acetofenonas/farmacologia , Animais , Antioxidantes/uso terapêutico , Peso Corporal/efeitos dos fármacos , Curcumina/uso terapêutico , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/fisiopatologia , Peróxido de Hidrogênio/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Malondialdeído/metabolismo , NADPH Oxidases/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Estreptozocina , Superóxido Dismutase/metabolismo
13.
CNS Neurosci Ther ; 19(12): 926-36, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24165291

RESUMO

AIMS: To study the role of curcumin on glioma cells via the SHH/GLI1 pathway in vitro and vivo. METHODS: The effects of curcumin on proliferation, migration, apoptosis, SHH/GLI1 signaling, and GLI1 target genes expression were evaluated in multiple glioma cell lines in vitro. A U87-implanted nude mice model was used to study the role of curcumin on tumor volume and the suppression efficacy of GLI1. RESULTS: Curcumin showed cytotoxic effects on glioma cell lines in vitro. Both mRNA and protein levels of SHH/GLI1 signaling (Shh, Smo, GLI1) were downregulated in a dose- and time-dependent manner. Several GLI1-dependent target genes (CyclinD1, Bcl-2, Foxm1) were also downregulated. Curcumin treatment prevented GLI1 translocating into the cell nucleus and reduced the concentration of its reporter. Curcumin suppressed cell proliferation, colony formation, migration, and induced apoptosis which was mediated partly through the mitochondrial pathway after an increase in the ratio of Bax to Bcl2. Intraperitoneal injection of curcumin in vivo reduced tumor volume, GLI1 expression, the number of positively stained cells, and prolonged the survival period compared with the control group. CONCLUSION: This study shows that curcumin holds a great promise for SHH/GLI1 targeted therapy against gliomas.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Curcumina/uso terapêutico , Glioma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Neoplasias Encefálicas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Modelos Animais de Doenças , Glioma/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Estimativa de Kaplan-Meier , Camundongos , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de Zinco
14.
Biomed Pharmacother ; 67(6): 503-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23639227

RESUMO

Sevoflurane, an inhalational anesthetic, and cisplatin (DDP)-based chemotherapy have been widely used during lung cancer surgery. However, the effect of sevoflurane on the sensitivity of lung cancer cells to DDP chemotherapy remains unclear. In this study, the effects of combined treatment with sevoflurane and cisplatin on the growth and invasion of human lung adenocarcinoma A549 cell line have been investigated. The underlying mechanism has also been explored. In our experiment, A549 cells were treated with 2.5% sevoflurane, 10µmol/L DDP, or the co-treatment of sevoflurane and DDP for 4h, respectively. Cell proliferation was evaluated by the MTT assay and colony formation assay. Apoptosis was assessed by flow cytometry. Cell invasion was detected by Transwell assay. The expressions of X-linked inhibitor of apoptosis protein (XIAP), Survivin, matrix metalloproteinase (MMP)-2 and MMP-9 were determined by western blotting. Our results showed that sevoflurane combined with DDP resulted in a more pronounced inhibition of tumor cells growth and invasion as compared with either drug alone. Besides, XIAP, Survivin, MMP-2, and MMP-9 were downregulated more significantly by the co-treatment of the two drugs as compared to sevoflurane treatment or DDP treatment alone. Taken together, the growth-inhibitory and invasion-inhibitory synergy between sevoflurane and DDP in human adenocarcinoma A549 cell line was found in this study. Furthermore, we showed that the growth-inhibitory synergy between sevoflurane and DDP might be associated with the downregulation of XIAP and Survivin, and the invasion-inhibitory synergy between sevoflurane and DDP might be involved in the downregulation of MMP-2 and MMP-9.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Regulação para Baixo/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Éteres Metílicos/administração & dosagem , Invasividade Neoplásica , Sevoflurano , Survivina , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
15.
CNS Neurosci Ther ; 19(7): 477-83, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23551751

RESUMO

AIMS: Mcl-1, an antiapoptotic member of the Bcl-2 family, is overexpressed in human glioblastoma, conferring a survival advantage to tumor cells. The mechanisms underlying its dysregulation have not been clarified. In this study, we explored the involvement of micro-RNAs that acted as endogenous sequence-specific suppressors of gene expression. METHODS AND RESULTS: Using computational and TCGA analysis, we identified miR-139 as being downregulated in glioblastoma in comparison with human brain tissue, as well as possessing a putative target site in Mcl-1 mRNA. Overexpression of miR-139 led to a clear decrease in Mcl-1 expression in gliomas. Reporter assays revealed direct post-transcriptional regulation involving miR-139 and the 3'-untranslated region of Mcl-1. Human glioma tissues with low expression of miR-139 displayed higher expression of Mcl-1 protein than those with high expression, suggesting that low miR-139 contributes to Mcl-1 overexpression. In addition, upregulation of miR-139 suppressed the proliferation and enhanced temozolomide (TMZ)-induced apoptosis. Finally, we observed that Mcl-1 knockdown resulted in similar effects compared with miR-139 transfection. CONCLUSION: Our results suggested that miR-139 negatively regulated Mcl-1 and induced apoptosis in cooperation with an anticancer drug TMZ in glioma.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Dacarbazina/análogos & derivados , Glioma/patologia , MicroRNAs/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese , Regiões 3' não Traduzidas , Animais , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dacarbazina/farmacologia , Humanos , Imuno-Histoquímica , Luciferases/genética , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Transplante de Neoplasias , Oligonucleotídeos/genética , Inclusão em Parafina , Plasmídeos/genética , Reação em Cadeia da Polimerase em Tempo Real , Temozolomida
16.
Biomed Pharmacother ; 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23582789

RESUMO

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

17.
Neuroreport ; 24(3): 131-6, 2013 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-23370493

RESUMO

TRESK gene recombinant adenovirus (10 IU/ml), which has been constructed successfully in our previous study, was implemented through an intrathecal injection. The fact that the method can effectively upregulate the expression of TRESK mRNA in the dorsal root ganglia of spared nerve injury in rats was verified. We also investigated the role of TRESK gene recombinant adenovirus in attenuating tactile allodynia and thermal hyperalgesia in spared nerve injury rats. Spared nerve injury to the sciatic nerve induced persistent tactile allodynia, but had no effect on thermal hyperalgesia. Intrathecal injection of TRESK gene recombinant adenovirus (25 µl) into the region of lumbar enlargement in advance reduced tactile allodynia. Moreover, intrathecal injection of TRESK gene recombinant adenovirus (25 µl) significantly alleviated the activation of astrocytes in spinal cord induced by spared nerve injury. The current study shows that an intrathecal injection of the TRESK gene recombinant adenovirus attenuated the activity of astrocytes in spinal cord, which contributed to relieving neuropathic pain in spared nerve injury rats. According to the result reported in our previous study, attenuating the expression of TRESK in dorsal root ganglia was involved in the development of neuropathic pain. On the basis of these results, we theorized that the therapeutic utility of upregulation of TRESK in dorsal root ganglia was effective in relieving neuropathic pain syndromes induced by peripheral nerve injury.


Assuntos
Adenoviridae/genética , Canais de Potássio/uso terapêutico , Ciática/tratamento farmacológico , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Vetores Genéticos , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/tratamento farmacológico , Injeções Espinhais , Masculino , Medição da Dor , Canais de Potássio/biossíntese , Canais de Potássio/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Ciática/patologia , Medula Espinal/metabolismo
18.
Mol Med Rep ; 5(4): 1049-52, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22307830

RESUMO

The present study was conducted to determine whether the activation of TRESK in the dorsal root ganglion (DRG) by the TRESK gene recombinant adenovirus vector inhibits the capsaicin-evoked substance P (SP) release using a radioimmunoassay. TRESK is an outwardly rectifying K+ current channel that contributes to the resting potential and is the most important background potassium channel in DRG. Previous studies have shown that neuropathic pain (NP) is closely related to the regulation of certain potassium channels in DRG neurons, while DRG-released SP is important in the peripheral mechanism of NP. In the present study, the TRESK gene adenovirus vector significantly enhanced the TRESK mRNA and protein of the cultured rat DRG neurons. Radioimmunoassay analysis revealed that the capsaicin­mediated SP release was significantly inhibited by the TRESK gene recombinant adenovirus vector in rat DRG neurons. These findings suggest that TRESK plays a role in adjusting the release of SP in DRG, which is related to NP.


Assuntos
Adenoviridae/genética , Antipruriginosos/farmacologia , Capsaicina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Vetores Genéticos , Canais de Potássio/metabolismo , Substância P/metabolismo , Animais , Células Cultivadas , Gânglios Espinais/citologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Canais de Potássio/genética , Ratos , Ratos Sprague-Dawley
19.
Acta Biomater ; 7(3): 1104-13, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20974299

RESUMO

Axillary dissection during breast cancer surgery produces extensive lymphatic vessel damage that often leads to lifelong secondary lymphedema of the arm. We have developed a biodegradable material conduit for lymphatic vessel reconstruction where fibers electrospun along the conduit lumen promote endothelial cell alignment and migration in vitro. The diameter and density of the electrospun fibers were optimized for cell migration and direction on two-dimensional substrates by seeding human lymphatic endothelial cells (LECs) onto aligned fibers of varying diameters and densities, randomly oriented fibers, and film substrates with no fibers. We found that LECs became aligned in the fiber direction, with cells seeded on the randomly oriented fibers becoming oriented in random directions, whereas cells seeded on the highly aligned fibers became highly aligned. Cell migration was dependent upon fiber alignment and density, with optimal migration found on 1300 nm diameter aligned fibers of low density. Blood endothelial cells seeded on the fibers exhibited similar behavior as the LECs. Fiber alignment was preserved upon rolling the two-dimensional substrate into the tubular geometry of a lymphatic vessel. The data suggest that aligned electrospun fibers may promote endothelial migration across the conduit in a manner that is independent of lymphatic growth factors.


Assuntos
Materiais Biocompatíveis , Movimento Celular , Endotélio/citologia , Vasos Linfáticos/citologia , Humanos , Vasos Linfáticos/ultraestrutura , Microscopia Eletrônica de Varredura
20.
Asian Pac J Cancer Prev ; 12(12): 3415-20, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22471490

RESUMO

PURPOSE: Sevoflurane, an inhalational anesthetic, is used extensively during lung cancer surgery. However, the effect of sevoflurane on growth of lung carcinoma cells remains unclear. The purpose of this study is to investigate effects on proliferation, apoptosis, and cell cycling in the A549 human lung adenocarcinoma cell line. METHODS: A549 cells were treated with 1.7%, 3.4%, and 5.1 % sevoflurane for 2, 4, and 6 hours. Cell proliferation was evaluated by the MTT assay and colony formation assay. Apoptosis and cell cycle was analyzed by flow cytometry. Expression of X-linked inhibitor of apoptosis protein (XIAP), survivin, Bcl-2, Bax, caspase-3, cyclin A, cyclin B1, and cdc2 was measured by Western blotting. RESULTS: Significant inhibition of cell proliferation and induction of apoptosis were found in A549 cells after sevoflurane treatment. Simultaneously, expression of XIAP and survivin was supressed, while that of caspase-3 increased significantly, but Bcl-2 and Bax were not altered. Sevoflurane caused cell cycle arrest at the G2/M phase. At the same time, data revealed that cyclin A, cyclin B1, and cdc2 expression was down-regulated after sevoflurane treatment. CONCLUSION: This study demonstrated that sevoflurane inhibited proliferation, and induced apoptosis in human lung adenocarcinoma A549 cells, associated with down-regulated expression of XIAP and suvivin, and activating caspase-3.


Assuntos
Adenocarcinoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Éteres Metílicos/farmacologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Western Blotting , Ensaio de Unidades Formadoras de Colônias , Citometria de Fluxo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Inibidores da Agregação de Plaquetas/farmacologia , Sevoflurano , Células Tumorais Cultivadas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA