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1.
Chembiochem ; 23(18): e202200259, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-35838006

RESUMO

The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''-trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on reactive oxygen species (ROS) production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Complexos de Coordenação , Neoplasias Pulmonares , Neoplasias Ovarianas , Rutênio , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Ligantes , Compostos Organofosforados , Fosfinas , Espécies Reativas de Oxigênio , Rutênio/farmacologia , Água
2.
Biomacromolecules ; 23(7): 3031-3040, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35748772

RESUMO

Biomaterials capable of precisely controlling the delivery of agrochemicals/biologics/drugs/fragrances have significant markets in the agriscience/healthcare industries. Here, we report the development of degradable electroactive polymers and their application for the controlled delivery of a clinically relevant drug (the anti-inflammatory dexamethasone phosphate, DMP). Electroactive copolymers composed of blocks of polycaprolactone (PCL) and naturally occurring electroactive pyrrole oligomers (e.g., bilirubin, biliverdin, and hemin) were prepared and solution-processed to produce films (optionally doped with DMP). A combination of in silico/in vitro/in vivo studies demonstrated the cytocompatibility of the polymers. The release of DMP in response to the application of an electrical stimulus was observed to be enhanced by ca. 10-30% relative to the passive release from nonstimulated samples in vitro. Such stimuli-responsive biomaterials have the potential for integration devices capable of delivering a variety of molecules for technical/medical applications.


Assuntos
Materiais Biocompatíveis , Polímeros , Eletricidade , Pirróis
3.
Dig Dis Sci ; 67(5): 1773-1782, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-33939145

RESUMO

INTRODUCTION: Epithelial barrier function (EBF) disruption is a key mechanism underlying gastroesophageal reflux disease (GERD). Our aim was to assess whether two novel technologies, probe-based confocal laser endomicroscopy (pCLE) and mucosal integrity testing (MIT), could assess EBF. METHODS: We prospectively enrolled patients undergoing upper endoscopy for refractory GERD or non-GERD conditions. Patients underwent esophagogastroduodenoscopy, pCLE, MIT, esophageal biopsy at 2 cm and 6 cm above the esophagogastric junction, and wireless pH testing. To assess EBF in vitro, biopsies were mounted in a mini-Ussing chamber, 1 ml of fluorescein was instilled on the mucosal side, and concentration of fluorescein on the serosal side was measured at 3 h. RESULTS: We enrolled 54 subjects (28 GERD, 26 non-GERD based on Lyon consensus criteria). In vivo permeability assessed by pCLE did not differ significantly between GERD vs. non-GERD patients and did not correlate with in vitro permeability. Mean MIT at 2 cm was lower in GERD compared to non-GERD (1914 vs. 3727 ohms). MIT correlated inversely with in vitro permeability at 2 cm and at 6 cm. Using a predictive model that used slope and intercept of MIT at 2 cm and 6 cm, sensitivity and specificity of MIT at identifying GERD was 76% and 72%, respectively. CONCLUSION: pCLE did not differentiate GERD vs non-GERD and did not correlate with EBF measured in vitro. MIT, on the other hand, may be more promising as it differentiated GERD vs non-GERD and correlated with EBF measured in vitro.


Assuntos
Refluxo Gastroesofágico , Impedância Elétrica , Esofagoscopia , Fluoresceínas , Humanos , Lasers , Estudos Prospectivos
4.
Environ Sci Technol ; 53(12): 6718-6728, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31083927

RESUMO

The buffering of phosphorus concentrations in soil solution by the soil-solid phase is an important process for providing plant root access to nutrients. Accordingly, the size of labile solid phase-bound phosphorus pool and the rate at which it can resupply phosphorous into the dissolved phase can be important variables in determining when the plant availability of the nutrient may be limited. The phosphorus labile pool (Plabile) and its desorption kinetics were simultaneously evaluated in 10 agricultural UK soils using the diffusive gradients in thin-films (DGT) technique. The DGT-induced fluxes in the soil and sediments model (DIFS) was fitted to the time series of DGT deployments (1-240 h), which allowed the estimation of Plabile, and the system response time ( Tc). The Plabile concentration was then compared to that obtained by several soil P extracts including Olsen P, FeO-P, and water extractable P, in order to assess if the data from these analytical procedures can be used to represent the labile P across different soils. The Olsen P concentration, commonly used as a representation of the soil labile P pool, overestimated the desorbable P concentration by 6-fold. The use of this approach for the quantification of soil P desorption kinetic parameters found a wide range of equally valid solutions for Tc. Additionally, the performance of different DIFS model versions working in different dimensions (1D, 2D, and 3D) was compared. Although all models could provide a good fit to the experimental DGT time series data, the fitted parameters showed a poor agreement between different model versions. The limitations of the DIFS model family are associated with the assumptions taken in the modeling approach and the three-dimensional (3D) version is here considered to be the most precise among them.


Assuntos
Poluentes do Solo , Solo , Difusão , Cinética , Fósforo
5.
Physiol Plant ; 2018 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-29498417

RESUMO

Citrate and phytase root exudates contribute to improved phosphorus (P) acquisition efficiency in Nicotiana tabacum (tobacco) when both exudates are produced in a P deficient soil. To test the importance of root intermingling in the interaction of citrate and phytase exudates, Nicotiana tabacum plant-lines with constitutive expression of heterologous citrate (Cit) or fungal phytase (Phy) exudation traits were grown under two root treatments (roots separated or intermingled) and in two soils with contrasting soil P availability. Complementarity of plant mixtures varying in citrate efflux rate and mobility of the expressed phytase in soil was determined based on plant biomass and P accumulation. Soil P composition was evaluated using solution 31 P NMR spectroscopy. In the soil with limited available P, positive complementarity occurred in Cit+Phy mixtures with roots intermingled. Root separation eliminated positive interactions in mixtures expressing the less mobile phytase (Aspergillus niger PhyA) whereas positive complementarity persisted in mixtures that expressed the more mobile phytase (Peniophora lycii PhyA). Soils from Cit+Phy mixtures contained less inorganic P and more organic P compared to monocultures. Exudate-specific strategies for the acquisition of soil P were most effective in P-limited soil and depended on citrate efflux rate and the relative mobility of the expressed phytase in soil. Plant growth and soil P utilization in plant systems with complementary exudation strategies are expected to be greatest where exudates persist in soil and are expressed synchronously in space and time.

6.
Environ Sci Technol ; 50(21): 11521-11531, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27700099

RESUMO

We have used an integrated approach to study the mobility of inorganic phosphorus (P) from soil solid phase as well as the microbial biomass P and respiration at increasing doses of citric and oxalic acid in two different soils with contrasting agronomic P status. Citric or oxalic acids significantly increased soil solution P concentrations for doses over 2 mmol kg-1. However, low organic acid doses (<2 mmol kg-1) were associated with a steep increase in microbial biomass P, which was not seen for higher doses. In both soils, treatment with the tribasic citric acid led to a greater increase in soil solution P than the dibasic oxalic acid, likely due to the rapid degrading of oxalic acids in soils. After equilibration of soils with citric or oxalic acids, the adsorbed-to-solution distribution coefficient (Kd) and desorption rate constants (k-1) decreased whereas an increase in the response time of solution P equilibration (Tc) was observed. The extent of this effect was shown to be both soil and organic acid specific. Our results illustrate the critical thresholds of organic acid concentration necessary to mobilize sorbed and precipitated P, bringing new insight on how the exudation of organic acids regulate chemical-microbial soil phosphorus transformations.


Assuntos
Fósforo , Solo , Ácidos , Compostos Orgânicos , Poluentes do Solo
7.
Environ Sci Technol ; 50(7): 3371-81, 2016 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-26911395

RESUMO

The mobility and resupply of inorganic phosphorus (P) from the solid phase were studied in 32 soils from the UK. The combined use of diffusive gradients in thin films (DGT), diffusive equilibration in thin films (DET) and the "DGT-induced fluxes in sediments" model (DIFS) were adapted to explore the basic principles of solid-to-solution P desorption kinetics in previously unattainable detail. On average across soil types, the response time (Tc) was 3.6 h, the desorption rate constant (k-1) was 0.0046 h(-1), and the desorption rate was 4.71 nmol l(-1) s(-1). While the relative DGT-induced inorganic P flux responses in the first hour is mainly a function of soil water retention and % Corg, at longer times it is a function of the P resupply from the soil solid phase. Desorption rates and resupply from solid phase were fundamentally influenced by P status as reflected by their high correlation with P concentration in FeO strips, Olsen, NaOH-EDTA and water extracts. Soil pH and particle size distribution showed no significant correlation with the evaluated mobility and resupply parameters. The DGT and DET techniques, along with the DIFS model, were considered accurate and practical tools for studying parameters related to soil P desorption kinetics.


Assuntos
Modelos Teóricos , Fósforo/química , Solo/química , Disponibilidade Biológica , Difusão , Ácido Edético/química , Monitoramento Ambiental/métodos , Cinética , Fósforo/análise , Fósforo/farmacocinética , Poluentes do Solo/análise , Poluentes do Solo/química , Reino Unido
8.
Mol Pharm ; 11(4): 1294-300, 2014 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-24641451

RESUMO

Development of therapeutic strategies for tumor-selective delivery of therapeutics through exploitation of the proteolytic tumor phenotype has significant scope for improvement of cancer treatment. ICT2588 is a peptide-conjugated prodrug of the vascular disrupting agent (VDA) azademethylcolchicine developed to be selectively hydrolyzed by matrix metalloproteinase-14 (MMP-14) within the tumor. In this report, we extend our previous proof-of-concept studies and demonstrate the therapeutic potential of this agent against models of human colorectal, lung, breast, and prostate cancer. In all tumor types, ICT2588 was superior to azademethylcolchicine and was greater or comparable to standard clinically used agents for the respective tumor type. Prodrug activation in clinical human lung tumor homogenates relative to stability in human plasma and liver was observed, supporting clinical translation potential. A major limiting factor to the clinical value of VDAs is their inherent cardiovascular toxicity. No increase in plasma von Willebrand factor (vWF) levels, an indicator of systemic vascular dysfunction and acute cardiovascular toxicity, was detected with ICT2588, thereby supporting the tumor-selective activation and reduced potential of ICT2588 to cause cardiovascular toxicity. Our findings reinforce the improved therapeutic index and tumor-selective approach offered by ICT2588 and this nanotherapeutic approach.


Assuntos
Antineoplásicos/uso terapêutico , Sistema Cardiovascular/efeitos dos fármacos , Colchicina/análogos & derivados , Neoplasias/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Pró-Fármacos/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Colchicina/efeitos adversos , Colchicina/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/efeitos adversos , Fator de von Willebrand/análise
9.
J Neurooncol ; 106(3): 461-71, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21858729

RESUMO

Herein we continue the study of matrix metalloproteinase-1 (MMP-1) with respect to glioblastoma multiforme (GBM) cell tumorigenicity and angiogenesis. A model of tumorigenicity with cells stably altered to over-express or knock-down MMP-1 revealed that it significantly increases tumor incidence and size. Organized endothelial growth in human umbilical vein endothelial cell (HUVEC)-GBM co-cultures was significantly increased in the presence of MMP-1. CD31 analysis of model tumors elucidated a substantial recruitment of endothelium in MMP-1 enhanced samples. Antibody arrays indicated an inverse expression of certain anti-angiogenic factors with respect to MMP-1, the most notable of which was a significant increase in tissue inhibitor of metalloproteinases-4 (TIMP-4) in the absence of MMP-1, as validated by immunoblot.


Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Metaloproteinase 1 da Matriz/genética , Inibidores Teciduais de Metaloproteinases/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Células Endoteliais/patologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Camundongos Nus , Mutação/genética , Neovascularização Patológica/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteômica , Inibidores Teciduais de Metaloproteinases/genética , Veias Umbilicais/citologia , Inibidor Tecidual 4 de Metaloproteinase
10.
J Pharmacol Exp Ther ; 339(3): 799-806, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21917561

RESUMO

The orally active microtubule-disrupting agent (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2-yl)phenyl)urea (CYT997), reported previously by us (Bioorg Med Chem Lett 19:4639-4642, 2009; Mol Cancer Ther 8:3036-3045, 2009), is potently cytotoxic to a variety of cancer cell lines in vitro and shows antitumor activity in vivo. In addition to its cytotoxic activity, CYT997 possesses antivascular effects on tumor vasculature. To further characterize the vascular disrupting activity of CYT997 in terms of dose and temporal effects, we studied the activity of the compound on endothelial cells in vitro and on tumor blood flow in vivo by using a variety of techniques. In vitro, CYT997 is shown to potently inhibit the proliferation of vascular endothelial growth factor-stimulated human umbilical vein endothelial cells (IC(50) 3.7 ± 1.8 nM) and cause significant morphological changes at 100 nM, including membrane blebbing. Using the method of corrosion casting visualized with scanning electron microscopy, a single dose of CYT997 (7.5 mg/kg i.p.) in a metastatic cancer model was shown to cause destruction of tumor microvasculature in metastatic lesions. Furthermore, repeat dosing of CYT997 at 10 mg/kg and above (intraperitoneally, b.i.d.) was shown to effectively inhibit development of liver metastases. The time and dose dependence of the antivascular effects were studied in a DLD-1 colon adenocarcinoma xenograft model using the fluorescent dye Hoechst 33342. CYT997 demonstrated rapid and dose-dependent vascular shutdown, which persists for more than 24 h after a single oral dose. Together, the data demonstrate that CYT997 possesses potent antivascular activity and support continuing development of this promising compound.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neoplasias do Colo/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Piridinas/farmacologia , Pirimidinas/farmacologia , Moduladores de Tubulina/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Camundongos Nus , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Sci Rep ; 11(1): 18930, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556703

RESUMO

Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700.


Assuntos
Antineoplásicos/farmacologia , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1B1/antagonistas & inibidores , Família 2 do Citocromo P450/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Estudos de Coortes , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismo , Família 2 do Citocromo P450/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Camundongos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Mol Cell Cardiol ; 49(6): 911-7, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20430038

RESUMO

The effect of the loss of the notch in the human action potential (AP) during heart failure was examined by voltage clamping rat ventricular myocytes with human APs and recording intracellular Ca(2+) with fluorescent dyes. Loss of the notch resulted in about a 50% reduction in the initial phase of the Ca(2+) transient due to reduced ability of the L-type Ca(2+) channel to trigger release. The failing human AP increased non-uniformity of cytosolic Ca(2+), with some cellular regions failing to elicit Ca(2+)-induced Ca(2+) release from the sarcoplasmic reticulum. In addition, there was an increase in the occurrence of late Ca(2+) sparks. Monte-Carlo simulations of spark activation by L-type Ca(2+) current supported the idea that the decreased synchrony of Ca(2+) spark production associated with the loss of the notch could be explained by reduced Ca(2+) influx from open Ca(2+) channels. We conclude that the notch of the AP is critical for efficient and synchronous EC coupling and that the loss of the notch will reduce the SR Ca(2+) release in heart failure, without changes in (for example) SR Ca(2+)-ATPase uptake.


Assuntos
Potenciais de Ação/fisiologia , Acoplamento Excitação-Contração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Miócitos Cardíacos/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Simulação por Computador , Humanos , Método de Monte Carlo , Técnicas de Patch-Clamp , Coelhos , Ratos , Ratos Wistar
13.
ChemMedChem ; 15(11): 982-987, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32237195

RESUMO

Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt-resistance mechanisms. Electron-deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron-deficient organoruthenium complex [(p-cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53-/-), and non-small cell lung H460 cancer cell lines. It shows no cross-resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53-independent. In vivo evaluation in the hollow-fibre assay across a panel of cancer cell types and subcutaneous H460 non-small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow-up, this work is the first preclinical study of electron-deficient half-sandwich complexes and highlights their promise as anticancer drug candidates.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Rutênio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Elétrons , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Relação Estrutura-Atividade
14.
Sci Rep ; 10(1): 17249, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057069

RESUMO

The formylpeptide receptor-1 (FPR1) is a member of the chemotactic GPCR-7TM formyl peptide receptor family, whose principle function is in trafficking of various leukocytes into sites of bacterial infection and inflammation. More recently, FPR1 has been shown to be expressed in different types of cancer and in this context, plays a significant role in their expansion, resistance and recurrence. ICT12035 is a selective and potent (30 nM in calcium mobilisation assay) small molecule FPR1 antagonist. Here, we demonstrate the efficacy of ICT12035, in a number of 2D and 3D proliferation and invasion in vitro assays and an in vivo model. Our results demonstrate that targeting FPR1 by a selective small molecule antagonist, such as ICT12035, can provide a new avenue for the treatment of cancers.


Assuntos
Neoplasias/tratamento farmacológico , Receptores de Formil Peptídeo/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Linhagem Celular Tumoral , Humanos , Camundongos Endogâmicos BALB C , Neoplasias/genética , Neoplasias/metabolismo , Receptores de Formil Peptídeo/genética , Receptores de Formil Peptídeo/metabolismo
15.
Prog Biophys Mol Biol ; 97(2-3): 232-49, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18367238

RESUMO

The stretch-induced increase in force production of ventricular muscle is biphasic. An abrupt increase in force coincides with the stretch, which is then followed by a slower response that develops over minutes (the slow force response or SFR). The SFR is accompanied by a slow increase in the magnitude of the intracellular Ca2+ transient, but the stretch-dependent mechanisms that give rise to this remain controversial. We characterized the SFR using right ventricular trabeculae from mouse hearts. Application of three different blockers of stretch-activated non-selective cation channels (SAC NSC) reduced the magnitude of the SFR 60s after stretch (400 microM streptomycin: from 86+/-25% to 38+/-14%, P<0.01, n=9; 10 microM GdCl3: from 65+/-21%, to 12+/-7%, P<0.01, n=7; 10 microM GsMTx-4 from 122+/-40% to 15+/-8%, P<0.05, n=6). Streptomycin also decreased the increase in Ca2+ transient amplitude 60s after the stretch from 43.5+/-12.7% to 5.7+/-3.5% (P<0.05, n=4), and reduced the stretch-dependent increase in intracellular Ca2+ in quiescent muscles when stretched. The transient receptor potential, canonical channels TRPC1 and TRPC6 are mechano-sensitive, non-selective cation channels. They are expressed in mouse ventricular muscle, and could therefore be responsible for stretch-dependent influx of Na+ and/or Ca2+ during the SFR. Expression of TRPC1 was investigated in the mdx heart, a mouse model of Duchenne's muscular dystrophy. Resting Ca2+ was raised in isolated myocytes from old mdx animals, which was blocked by application of SAC blockers. Expression of TRPC1 was increased in the older mdx animals, which have developed a dilated cardiomyopathy, and might therefore contribute to the dilated cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada/fisiopatologia , Canais Iônicos/fisiologia , Contração Miocárdica/fisiologia , Miócitos Cardíacos/fisiologia , Animais , Cálcio/fisiologia , Cardiomiopatia Dilatada/metabolismo , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular , Ativação do Canal Iônico/efeitos dos fármacos , Canais Iônicos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Peptídeos/farmacologia , Venenos de Aranha/farmacologia , Estreptomicina/farmacologia , Estresse Mecânico
16.
PLoS One ; 14(4): e0214610, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30969984

RESUMO

Glycogen synthase kinase-3 (GSK3) is over-expressed and hyperactivated in non-small cell lung carcinoma (NSCLC) and plays a role in ensuring the correct alignment of chromosomes on the metaphase plate during mitosis through regulation of microtubule stability. This makes the enzyme an attractive target for cancer therapy. We examined the effects of a selective cell-permeant GSK3 inhibitor (CHIR99021), used alone or in combination with paclitaxel, using an in vitro cell growth assay, a quantitative chromosome alignment assay, and a tumor xenograft model. CHIR99021 inhibits the growth of human H1975 and H1299 NSCLC cell lines in a synergistic manner with paclitaxel. CHIR99021 and paclitaxel promoted a synergistic defect in chromosomal alignment when compared to each compound administered as monotherapy. Furthermore, we corroborated our in vitro findings in a mouse tumor xenograft model. Our results demonstrate that a GSK3 inhibitor and paclitaxel act synergistically to inhibit the growth of NSCLC cells in vitro and in vivo via a mechanism that may involve converging modes of action on microtubule spindle stability and thus chromosomal alignment during metaphase. Our findings provide novel support for the use of the GSK3 inhibitor, CHIR99021, alongside taxol-based chemotherapy in the treatment of human lung cancer.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Aberrações Cromossômicas/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Humanos , Masculino , Camundongos , Camundongos Nus , Paclitaxel/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo
17.
Oral Oncol ; 80: 64-73, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29706190

RESUMO

BACKGROUND: The chemokine receptor CCR7 is expressed on lymphocytes and dendritic cells and is responsible for trafficking of these cells in and out of secondary lymphoid organs. It has recently been shown that CCR7 expression is elevated in a number of cancers, including head and neck cancers, and that its expression correlates to lymph node (LN) metastasis. However, little is known about the factors that can induce CCR7 expression in head and neck cancers. METHOD: We compared the protein expression and functional responses of CCR7 under normoxia and hypoxia in head and neck cancer cell lines OSC-19, FaDu, SCC-4, A-253 and Detroit-562 cultured as monolayers, spheroids, and grown in vivo as xenografts in balb/c mice. In addition, we analysed the correlation between hypoxia marker HIF-1α and CCR7 expression in a tissue microarray comprising 80 clinical samples with various stages and grades of malignant tumour and normal tissue. RESULTS: Under hypoxia, the expression of CCR7 is elevated in both in vitro and in vivo models. Furthermore, in malignant tissue, a correlation is observed between hypoxia marker HIF-1α and CCR7 across all clinical stages. This correlation is also strong in early histological grade of tumours. CONCLUSION: Hypoxia plays a role in the regulation of the expression of CCR7 and it may contribute to the development of a metastatic phenotype in head and neck cancers through this axis.


Assuntos
Hipóxia Celular/genética , Neoplasias de Cabeça e Pescoço/genética , Receptores CCR7/genética , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores CCR7/metabolismo
18.
Plant Soil ; 427(1): 5-16, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30996482

RESUMO

BACKGROUND: Phosphorus (P) fertilizer is usually applied in excess of plant requirement and accumulates in soils due to its strong adsorption, rapid precipitation and immobilisation into unavailable forms including organic moieties. As soils are complex and diverse chemical, biochemical and biological systems, strategies to access recalcitrant soil P are often inefficient, case specific and inconsistently applicable in different soils. Finding a near-universal or at least widely applicable solution to the inefficiency in agricultural P use by plants is an important unsolved problem that has been under investigation for more than half a century. SCOPE: In this paper we critically review the strategies proposed for the remobilization of recalcitrant soil phosphorus for crops and pastures worldwide. We have additionally performed a meta-analysis of available soil 31P-NMR data to establish the potential agronomic value of different stored P forms in agricultural soils. CONCLUSIONS: Soil inorganic P stocks accounted on average for 1006 ± 115 kg ha-1 (57 ± 7%), while the monoester P pool accounted for 587 ± 32 kg ha-1 (33 ± 2%), indicating the huge potential for the future agronomic use of the soil legacy P. New impact driven research is needed in order to create solutions for the sustainable management of soil P stocks.

19.
Plant Soil ; 427(1): 125-138, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30996483

RESUMO

AIMS: Intercropping can improve plant yields and soil phosphorus (P) use efficiency. This study compares inter- and intra-species intercropping, and determines whether P uptake and shoot biomass accumulation in intercrops are affected by soil P availability. METHODS: Four barley cultivars (Hordeum vulgare L.) and three legume species (Trifolium subterreneum, Ornithopus sativus and Medicago truncatula) were selected on the basis of their contrasting root exudation and morphological responses to P deficiency. Monocultures and barley-barley and barley-legume intercrops were grown for 6 weeks in a pot trial at very limiting, slightly limiting and excess available soil P. Above-ground biomass and shoot P were measured. RESULTS: Barley-legume intercrops had 10-70% greater P accumulation and 0-40% greater biomass than monocultures, with the greatest gains occurring at or below the sub-critical P requirement for barley. No benefit of barley-barley intercropping was observed. The plant combination had no significant effect on biomass and P uptake observed in intercropped treatments. CONCLUSIONS: Barley-legume intercropping shows promise for sustainable production systems, especially at low soil P. Gains in biomass and P uptake come from inter- rather than intra-species intercropping, indicating that plant diversity resulted in decreased competition between plants for P.

20.
Prog Biophys Mol Biol ; 90(1-3): 444-68, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16125216

RESUMO

Both mechanical induction and mechanical termination of arrhythmias have been reported in man. Examples include pre-cordial impacts by sports implements (baseballs, pucks) that can trigger arrhythmias, including ventricular fibrillation, or via the so-called pre-cordial thump, used as an emergency resuscitation measure to convert arrhythmias to normal sinus node rhythm. These interventions have been partially reproduced in experimental studies on whole animals. Relating observations at the system's level to underlying mechanisms has been difficult, however, largely because of: (i) a deficit in efficient and affordable pharmacological agents to selectively target (sub-)cellular responses in whole animal studies, and (ii) the lack of suitable experimental models to study the above responses at intermediate levels of functional and structural integration, such as the isolated heart or cardiac tissue. This paper presents a soft tissue impact characterisation kit (STICK), suitable for quantitative investigations into the effects of acute mechanical stimulation on cardiac electro-mechanical function in rodent isolated heart or tissue preparations. The STICK offers independent control over a range of relevant biophysical parameters, such as impact location and energy, pre-impact projectile speed and contact area, as well as over the timing of a mechanical stimulus relative to the cardiac cycle (monitored via electrocardiogram, ECG, here recorded directly from the cardiac surface). Projectile deceleration upon interaction with the tissue is monitored, contact-free, with a resolution of 175 microm, providing information on tissue deformation dynamics, force, pressure and work of the mechanical intervention. In order to study functional effects of cardiac mechanical stimulation in the absence of tissue damage, impacts must be limited (for juvenile Guinea pig heart) to 2-2.5 mJ in the slack left ventricle (diastolic impact) and 5-10 mJ in contracture (systolic impact), as confirmed by enzyme assay and histological investigation. Impacts, timed to coincide with the early T-wave of the ECG, are capable of triggering short runs of ventricular fibrillation. Thus, the STICK is a suitable tool for the study of acute cardiac mechano-electric feedback effects, caused by short impulse-like mechanical stimulation, at the level of the isolated organ or tissue.


Assuntos
Contração Miocárdica/fisiologia , Função Ventricular Esquerda , Função Ventricular , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Cateterismo Cardíaco , Creatina Quinase/metabolismo , Eletrocardiografia , Cobaias , Ventrículos do Coração/enzimologia , Estresse Mecânico , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologia
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