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1.
Nutrients ; 11(11)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652764

RESUMO

BACKGROUND: Docosahexaenoic acid (DHA) is an essential polyunsaturated fatty acid compound present in deep water fishes and dietary supplements, with a wide spectrum of potential health benefits, ranging from neurological to anti-inflammatory. METHODS: Due to the fact that DHA is considered a breast cancer risk reducer, we examined the impact of DHA on MCF-7 breast cancer cells' viability and its inhibitory properties on protein tyrosine phosphatase 1B (PTP1B), a pro-oncogenic phosphatase. RESULTS: We found that DHA is able to lower both the enzymatic activity of PTP1B phosphatase and the viability of MCF-7 breast cancer cells. We showed that unsaturated DHA possesses a significantly higher inhibitory activity toward PTP1B in comparison to similar fatty acids. We also performed a computational analysis of DHA binding to PTP1B and discovered that it is able to bind to an allosteric binding site. CONCLUSIONS: Utilizing both a recombinant enzyme and cellular models, we demonstrated that DHA can be considered a potential pharmacological agent for the prevention of breast cancer.

2.
Nitric Oxide ; 93: 102-114, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541733

RESUMO

Elevated levels of reactive nitrogen species, alteration in redox balance and deregulated redox signaling are common hallmarks of cancer progression and chemoresistance. However, depending on the cellular context, distinct reactive nitrogen species are also hypothesized to mediate cytotoxic activity and are thus used in anticancer therapies. We present here the dual face of nitric oxide and its derivatives in cancer biology. Main derivatives of nitric oxide, such as nitrogen dioxide and peroxynitrite cause cell death by inducing protein and lipid peroxidation and/or DNA damage. Moreover, they control the activity of important protein players within the pro- and anti-apoptotic signaling pathways. Thus, the control of intracellular reactive nitrogen species may become a sophisticated tool in anticancer strategies.

3.
Mol Cell Biol ; 39(20)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31332096

RESUMO

In response to perturbed DNA replication, ATR (ataxia telangiectasia and Rad3-related) kinase is activated to initiate the checkpoint signaling necessary for maintaining genome integrity and cell survival. To better understand the signaling mechanism, we carried out a large-scale genetic screen in fission yeast looking for mutants with enhanced sensitivity to hydroxyurea. From a collection of ∼370 primary mutants, we found a few mutants in which Rad3 (ATR ortholog)-mediated phospho-signaling was significantly compromised. One such mutant carried an uncharacterized mutation in tel2, a gene encoding an essential and highly conserved eukaryotic protein. Previous studies in various biological models have shown that Tel2 mainly functions in Tel2-Tti1-Tti2 (TTT) complex that regulates the steady-state levels of all phosphatidylinositol 3-kinase-like protein kinases, including ATR. We show here that although the levels of Rad3 and Rad3-mediated phospho-signaling in DNA damage checkpoint were moderately reduced in the tel2 mutant, the phospho-signaling in the DNA replication checkpoint was almost completely eliminated. In addition, the tel2 mutation caused telomere shortening. Since the interactions of Tel2 with Tti1 and Tti2 were significantly weakened by the mutation, destabilization of the TTT complex likely contributes to the observed checkpoint and telomere defects.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31247563

RESUMO

Learning from imbalanced data is among the most popular topics in the contemporary machine learning. However, the vast majority of attention in this field is given to binary problems, while their much more difficult multiclass counterparts are relatively unexplored. Handling data sets with multiple skewed classes poses various challenges and calls for a better understanding of the relationship among classes. In this paper, we propose multiclass radial-based oversampling (MC-RBO), a novel data-sampling algorithm dedicated to multiclass problems. The main novelty of our method lies in using potential functions for generating artificial instances. We take into account information coming from all of the classes, contrary to existing multiclass oversampling approaches that use only minority class characteristics. The process of artificial instance generation is guided by exploring areas where the value of the mutual class distribution is very small. This way, we ensure a smart oversampling procedure that can cope with difficult data distributions and alleviate the shortcomings of existing methods. The usefulness of the MC-RBO algorithm is evaluated on the basis of extensive experimental study and backed-up with a thorough statistical analysis. Obtained results show that by taking into account information coming from all of the classes and conducting a smart oversampling, we can significantly improve the process of learning from multiclass imbalanced data.

5.
Micron ; 119: 64-71, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30682529

RESUMO

Composite scaffolds of bioactive glass (SiO2-CaO) and bioresorbable polyesters: poly-l-lactic acid (PLLA) and polycaprolactone (PCL) were produced by polymer coating of porous foams. Their structure and mechanical properties were investigated in micro and nanoscale, by the means of scanning electron microscopy, PeakForce Quantitative Nanomechanical Property Mapping (PF-QNM) atomic force microscopy, micro-computed tomography and contact angle measurements. This is one of the first studies in which the nanomechanical properties (elastic modulus, adhesion) were measured and mapped simultaneously with topography imaging (PF-QNM AFM) for bioactive glass and bioactive glass - polymer coated scaffolds. Our findings show that polymer coated scaffolds had higher average roughness and lower stiffness in comparison to pure bioactive glass scaffolds. Such coating-dependent scaffold properties may promote different cells-scaffold interaction.


Assuntos
Materiais Biocompatíveis/síntese química , Cerâmica/síntese química , Fenômenos Mecânicos , Engenharia Tecidual/métodos , Tecidos Suporte/química , Osso e Ossos/fisiologia , Poliésteres/síntese química
6.
Pharmacol Rep ; 71(1): 175-182, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30554037

RESUMO

BACKGROUND: Diabetic retinopathy (DR) is one of the most common complications of diabetes and the leading cause of acquired blindness in adults. In diabetic patients hyperglycemia induces complex metabolic abnormalities affecting retinal homeostasis, and promotes retinal inflammation and angiogenesis. Incretin mimetic drugs such exenatide, are a relatively new group of drugs used in the treatment of diabetes. We investigated the potential direct effects of exenatide on human retinal pigment epithelium (HRPE). METHODS: cAMP production was measured after stimulation of HRPE cells with GLP-1 and exenatide. Intracellular signaling pathways were also examined. HRPE cells were stimulated with TNF-α and subsequently incubated with exenatide. The concentration of metalloproteinases, MMP-1, MMP-2 and MMP-9, and tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, and TIMP-3 were evaluated. Viability, cytotoxicity and caspase 3/7 activation were determined. Activity of dipeptidyl peptidase-4 (DPP-4), an enzyme involved in GLP-1 inactivation, was also determined. RESULTS: Both GLP-1 and exenatide stimulation in HRPE cells caused no effect in cAMP levels suggesting alternative signaling pathways. Signaling pathway analysis showed that exenatide reduced phosphorylation of Akt-Ser473, PRAS40, SAPK/JNK, Bad, and S6 proteins but not Akt-Thr308. Exenatide also decreased MMP-1, MMP-9, and TIMP-2 protein levels whereas MMP-2 level in HRPE cells was increased. Finally, we show that exenatide decreased the activity of DPP-4 in TNF-α stimulated HRPE cells. CONCLUSIONS: These findings indicate that exenatide modulates regulation of extracellular matrix components involved in retinal remodeling.


Assuntos
Colagenases/metabolismo , Células Epiteliais/efeitos dos fármacos , Exenatida/farmacologia , Hipoglicemiantes/farmacologia , Incretinas/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Inibidores Teciduais de Metaloproteinases/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Linhagem Celular , Células Epiteliais/enzimologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/enzimologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Epitélio Pigmentado da Retina/enzimologia , Transdução de Sinais/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Inibidor Tecidual de Metaloproteinase-3/metabolismo
7.
Mater Sci Eng C Mater Biol Appl ; 94: 516-523, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30423736

RESUMO

Bioactive glass-based scaffolds are commonly used in bone tissue engineering due to their biocompatibility, mechanical strength and adequate porous structure. However, their hydrophobicity and brittleness limits their practical application. In this study, to improve nanomechanical properties of such scaffolds, pure bioactive hybrid glass and two bioactive hybrid glass-polymer coated composites were fabricated. A complementary micro and nanoscale characterization techniques (SEM, AFM, µCT, FTIR, compressive test, goniometer) were implemented for detailed description of architecture and physicochemical properties of hybrid bioactive glass-based scaffolds with emphasis on nano-mechanics. The final step was in-vitro evaluation of three dimensional macroporous structures. Our findings show that after polymer addition, architecture, topography and surface properties of the scaffolds were changed and promoted favoured behaviour of the cells.


Assuntos
Osso e Ossos/fisiologia , Cerâmica/química , Materiais Revestidos Biocompatíveis/química , Polímeros/química , Engenharia Tecidual/métodos , Tecidos Suporte/química , Linhagem Celular Tumoral , Sobrevivência Celular , Módulo de Elasticidade , Humanos , Nanopartículas/química , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Estresse Mecânico , Microtomografia por Raio-X
8.
Oxid Med Cell Longev ; 2018: 2561705, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30228853

RESUMO

Oxidative stress plays an important role in the pathophysiology of many human disorders, while antioxidants prevent the development of various adverse symptoms. Diosmin is a natural flavonoid applied in vascular system disorders, especially in chronic venous insufficiency (CVI), and it plays a significant part in the alleviation of CVI symptoms. Due to antioxidant activity, it also has the ability to scavenge the oxygen free radicals and hence decreases the level of oxidative stress biomarkers, such as prostaglandins and their precursors-isoprostanes. In the study, the influence of diosmin treatment on the level of isoprostanes in plasma samples of patients suffering from CVI was examined. The qualitative analysis was performed using high-performance liquid chromatography with spectrometry detection (LC-MS). The statistically significant decrease of isoprostane content after 3 months of treatment was observed within the studied group; however, the most significant changes were observed in patients who smoke.


Assuntos
Biomarcadores/sangue , Diosmina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Venosa/sangue , Insuficiência Venosa/tratamento farmacológico , Doença Crônica , Demografia , Diosmina/farmacologia , Feminino , Humanos , Isoprostanos/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Venosa/patologia
9.
Cell Mol Biol (Noisy-le-grand) ; 64(9): 16-23, 2018 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-30030957

RESUMO

Nerve growth factor (NGF) is protein discovered by Rita Levi Montalcini in the 1950s. It plays a crucial role in the development of nervous system. NGF may be produced by a variety of cells even beyond nervous system. NGF modulate cell metabolism by binding to p75NTR and TrkA receptors. NGF is involved in psychological processes and may be the possible therapeutical agent for diabetes, cancer and cardiovascular diseases, which will be described in the article.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiopatias/dietoterapia , Neoplasias/tratamento farmacológico , Fator de Crescimento Neural/uso terapêutico , Diabetes Mellitus Tipo 2/patologia , Cardiopatias/patologia , Humanos , Neoplasias/patologia , Fator de Crescimento Neural/metabolismo , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Transdução de Sinais
10.
Sci Rep ; 8(1): 7598, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29765058

RESUMO

Computerized linguistic analyses have proven of immense value in comparing and searching through large text collections ("corpora"), including those deposited on the Internet - indeed, it would nowadays be hard to imagine browsing the Web without, for instance, search algorithms extracting most appropriate keywords from documents. This paper describes how such corpus-linguistic concepts can be extended to chemistry based on characteristic "chemical words" that span more than traditional functional groups and, instead, look at common structural fragments molecules share. Using these words, it is possible to quantify the diversity of chemical collections/databases in new ways and to define molecular "keywords" by which such collections are best characterized and annotated.

11.
Int J Mol Sci ; 19(3)2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29495598

RESUMO

Beneficial effects of natural plant polyphenols on the human body have been evaluated in a number of scientific research projects. Bioactive polyphenols are natural compounds of various chemical structures. Their sources are mostly fruits, vegetables, nuts and seeds, roots, bark, leaves of different plants, herbs, whole grain products, processed foods (dark chocolate), as well as tea, coffee, and red wine. Polyphenols are believed to reduce morbidity and/or slow down the development of cardiovascular and neurodegenerative diseases as well as cancer. Biological activity of polyphenols is strongly related to their antioxidant properties. They tend to reduce the pool of reactive oxygen species as well as to neutralize potentially carcinogenic metabolites. A broad spectrum of health-promoting properties of plant polyphenols comprises antioxidant, anti-inflammatory, anti-allergic, anti-atherogenic, anti-thrombotic, and anti-mutagenic effects. Scientific studies present the ability of polyphenols to modulate the human immune system by affecting the proliferation of white blood cells, and also the production of cytokines or other factors that participate in the immunological defense. The aim of the review is to focus on polyphenols of olive oil in context of their biological activities.


Assuntos
Azeite de Oliva/química , Azeite de Oliva/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Humanos , Olea/química , Azeite de Oliva/uso terapêutico , Compostos Fitoquímicos/química , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Polifenóis/uso terapêutico
12.
Pharmacol Rep ; 70(1): 178-183, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29414148

RESUMO

BACKGROUND: Incretin analogue drugs, a FDA-approved treatment in diabetes, has been tested for its therapeutic properties as modulators of atherosclerosis. We investigated the effects of incretin drugs on the modulation of gene expression and protein levels of matrix metalloproteinases (MMPs) as well as their inhibitors - tissue inhibitors of metalloproteinases (TIMPs) in coronary artery smooth muscle cells (hCASMC) in the context of atherosclerotic plaque formation and inflammation. METHODS: TNFα-stimulated hCASMC were treated with Glucagon-like Peptide 1 (GLP-1) (10nM and 100nM) and Exendin-4 (1nM and 10nM). Messenger RNA (mRNA) levels and protein concentrations of MMP-1, MMP-2, MMP-9 and TIMP-1, TIMP-2 were measured and the effects on extracellular matrix turnover under TNFα-mediated microenvironment were evaluated. Intracellular signaling pathways were also examined. RESULTS: Our experiments reveal that GLP-1 receptor agonists downregulate the expression of MMP-1, MMP-2, MMP-9 in hCASMC under TNFα mediated inflammatory conditions. Signaling pathway analysis show that GLP-1 receptor agonists induced inhibition of AKT-Thr308 phosphorylation, PRAS40 and S6 proteins but not AKT-Ser473. CONCLUSIONS: These findings indicate that GLP-1 receptor agonists modulate the expression of MMPs through inhibition of AKT-Thr308 phosphorylation in hCASMC. These results suggest a possible role of incretin analogue drugs in therapy of coronary atherosclerosis.


Assuntos
Colagenases/metabolismo , Incretinas/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peçonhas/farmacologia , Células Cultivadas , Microambiente Celular , Colagenases/genética , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/enzimologia , Relação Dose-Resposta a Droga , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Fosforilação , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
13.
Cardiovasc Ther ; 36(2)2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29283509

RESUMO

INTRODUCTION: Cardiovascular disease is the main cause of mortality and morbidity in the industrialized world. Incretin-mimetic compounds such as exenatide are currently used in the treatment of type 2 diabetes. AIMS: We investigated the effects of incretin drugs on apoptosis, adhesion molecule expression, and concentration of extracellular matrix (ECM) metalloproteinases under inflammatory conditions within the context of atherosclerotic plaque formation of both human coronary artery endothelial cells (hCAECs) and human aortic endothelial cells (hAoECs). TNF-α-stimulated hCAEC and hAoEC were treated with exenatide (1 and 10 nmol/L) and GLP-1 (10 and 100 nmol/L) then evaluated for caspase 3/7 activity and assayed for protein levels of adhesion molecules sICAM-1, sVCAM-1, and P-selectin. Concentrations of matrix metalloproteinases (MMPs) MMP-1, MMP-2, MMP-9, and their inhibitors-tissue inhibitor of metalloproteinases (TIMPs), TIMP-1, TIMP-2 were also measured to evaluate the effects on extracellular matrix turnover within an inflammatory environment. Intracellular signaling pathways were evaluated via transfection of endothelial cells with a GFP vector under the NF-κB promoter. RESULTS: Our experimental data suggest that GLP-1 receptor (GLP-1R) agonists downregulate activation of NF-κB and adhesion molecules ICAM and VCAM, but not P-selectin, in both endothelial cell lines. Exendin-4 and GLP-1 modulate the expression of MMPs and TIMPs, with statistically significant effects observed at high concentrations of both incretins. Expressive modulation may be mediated by NF-κB as observed by activation of the vector when stimulated under inflammatory conditions. CONCLUSION: These findings indicate that GLP-1 analogs have anti-inflammatory properties in endothelial cells that may play an important role in preventing atherosclerosis.


Assuntos
Anti-Inflamatórios/farmacologia , Moléculas de Adesão Celular/metabolismo , Células Endoteliais/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Peptídeos/farmacologia , Inibidores Teciduais de Metaloproteinases/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Peçonhas/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Moléculas de Adesão Celular/imunologia , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Exenatida , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Anticancer Res ; 37(12): 6779-6789, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29187456

RESUMO

BACKGROUND/AIM: MicroRNAs (miRNAs) transported in melanoma-derived exosomes function as intercellular messengers supporting tumor survival and progression. Hypoxia increases melanoma phenotypic plasticity, drug resistance, and metastasis. MATERIALS AND METHODS: We determined the miRNA profiles in exosomes derived from melanoma cells grown under hypoxic and normoxic conditions by microarray analyses and reverse transcription-polymerase chain reaction (RT-PCR) in order to analyze the potential influence of vesicle-transported miRNAs on cancer-related pathways and transcriptional programs. RESULTS: Despite phenotypical differences of the four cell lines used, their exosomes shared the majority of miRNAs. The levels of three miRNAs were higher in normoxic exosomes, whereas 15 miRNAs were significantly more abundant under hypoxic conditions. Pathway analysis pointed at several cellular processes contributing to proliferation, drug resistance, and modification of the tumor microenvironment, including immunosuppression. CONCLUSION: The miRNA-expression profiles of exosomes from patient-derived melanoma cells are modified by oxygen concentration and reflect the phenotypic changes of melanoma cells under different growth conditions.


Assuntos
Exossomos/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Hipóxia Celular , Linhagem Celular Tumoral , Humanos , Melanoma/genética , Melanoma/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Anticancer Res ; 37(9): 4799-4806, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28870898

RESUMO

BACKGROUND: Rapidly-dividing cancer cells have higher requirement for iron compared to non-transformed cells, making iron chelating a potential anticancer strategy. In the present study we compared the anticancer activity of uncommon iron chelator aurintricarboxylic acid (ATA) with the known deferoxamine (DFO). MATERIALS AND METHODS: We investigated the impact of ATA and DFO on the viability and proliferation of MCF-7 cancer cells. Moreover we performed enzymatic activity assays and computational analysis of the ATA and DFO effects on pro-oncogenic phosphatases PTP1B and SHP2. RESULTS: ATA and DFO decrease the viability and proliferation of breast cancer cells, but only ATA considerably reduces the activity of PTP1B and SHP2 phosphatases. Our studies indicated that ATA strongly inactivates and binds in the PTP1B and SHP2 active site, interacting with arginine residue essential for enzyme activity. CONCLUSION: We confirmed that iron chelating can be considered as a potential strategy for the adjunctive treatment of breast cancer.


Assuntos
Ácido Aurintricarboxílico/farmacologia , Neoplasias da Mama/enzimologia , Desferroxamina/farmacologia , Quelantes de Ferro/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Ácido Aurintricarboxílico/química , Sítios de Ligação , Neoplasias da Mama/patologia , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/química , Feminino , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
16.
Anticancer Res ; 37(6): 2893-2898, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28551626

RESUMO

BACKGROUND: Protein tyrosine phosphatases PTP1B and SHP2 are potential targets for anticancer therapy, because of the essential role they play in the development of tumors. PTP1B and SHP2 are overexpressed in breast cancer cells, thus inhibition of their activity can be potentially effective in breast cancer therapy. Lipoic acid has been previously reported to inhibit the proliferation of colon, breast and thyroid cancer cells. MATERIALS AND METHODS: We investigated the effect of alpha-lipoic acid (ALA) and its reduced form of dihydrolipoic acid (DHLA) on the viability of MCF-7 cancer cells and on the enzymatic activity of PTP1B and SHP2 phosphatases. RESULTS: ALA and DHLA decrease the activity of PTP1B and SHP2, and have inhibitory effects on the viability and proliferation of breast cancer cells. CONCLUSION: ALA and DHLA can be considered as potential agents for the adjunctive treatment of breast cancer.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ácido Tióctico/farmacologia , Neoplasias da Mama , Sobrevivência Celular/efeitos dos fármacos , Humanos , Antígenos Comuns de Leucócito/metabolismo , Células MCF-7
17.
J Phycol ; 53(4): 880-888, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28523651

RESUMO

We present topographical and nanomechanical characterization of single Didymosphenia geminata stalk. We compared the samples before and after adsorption of metal ions from freshwater samples. Transmission electron microscopy studies of single stalk cross-sections have shown three distinct layers and an additional thin extra coat on the external layer (called "EL"). Using scanning electron microscopy and atomic force microscopy (AFM), we found that topography of single stalks after ionic adsorption differed significantly from topography of pristine stalks. AFM nanoindentation studies in ambient conditions yielded elastic moduli of 214 ± 170 MPa for pristine stalks and 294 ± 108 MPa for stalks after ionic adsorption. Statistical tests showed that those results were significantly different. We conducted only preliminary comparisons between ionic adsorption of several stalks in air and in water. While the stalks with ions were on average stiffer than the pristine stalks in air, they became more compliant than the pristine stalks in water. We also heated the stalks and detected EL softening at 50°C ± 15°C. AFM nanoindentation in air on the softened samples yielded elastic moduli of 26 ± 9 MPa for pristine samples and 43 ± 22 MPa for stalks with absorbed metal ions. Substantial decrease of the EL elastic moduli after heating was expected. Significantly different elastic moduli for the samples after ionic adsorption in both cases (i.e., for heated and nonheated samples), as well as behavior of the stalks immersed in water, point to permanent structural EL changes due to ions.


Assuntos
Diatomáceas/fisiologia , Metais/metabolismo , Adsorção , Fenômenos Biomecânicos , Diatomáceas/citologia , Diatomáceas/ultraestrutura , Módulo de Elasticidade , Íons/metabolismo , Cinética , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura
18.
Artigo em Inglês | MEDLINE | ID: mdl-28282637

RESUMO

A simple, fast, sensitive and accurate methodology based on a LLE followed by liquid chromatography-tandem mass spectrometry for simultaneous determination of four regioisomers (8-iso prostaglandin F2α, 8-iso-15(R)-prostaglandin F2α, 11ß-prostaglandin F2α, 15(R)-prostaglandin F2α) in routine analysis of human plasma samples was developed. Isoprostanes are stable products of arachidonic acid peroxidation and are regarded as the most reliable markers of oxidative stress in vivo. Validation of method was performed by evaluation of the key analytical parameters such as: matrix effect, analytical curve, trueness, precision, limits of detection and limits of quantification. As a homoscedasticity was not met for analytical data, weighted linear regression was applied in order to improve the accuracy at the lower end points of calibration curve. The detection limits (LODs) ranged from 1.0 to 2.1pg/mL. For plasma samples spiked with the isoprostanes at the level of 50pg/mL, intra-and interday repeatability ranged from 2.1 to 3.5% and 0.1 to 5.1%, respectively. The applicability of the proposed approach has been verified by monitoring of isoprostane isomers level in plasma samples collected from young patients (n=8) subjected to hyperbaric hyperoxia (100% oxygen at 280kPa(a) for 30min) in a multiplace hyperbaric chamber.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Isoprostanos/sangue , Prostaglandinas/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Biomarcadores/análise , Biomarcadores/sangue , Humanos , Hiperóxia/sangue , Isomerismo , Isoprostanos/análise , Limite de Detecção , Modelos Lineares , Extração Líquido-Líquido/métodos , Estresse Oxidativo , Prostaglandinas/análise , Adulto Jovem
19.
Cancer Lett ; 385: 75-86, 2017 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-27836734

RESUMO

The chaperone Hsp60 is pro-carcinogenic in certain tumor types by interfering with apoptosis and with tumor cell death. In these tumors, it is not yet known whether doxorubicin anti-tumor effects include a blockage of the pro-carcinogenic action of Hsp60. We found a doxorubicin dose-dependent viability reduction in a human lung mucoepidermoid cell line that was paralleled by the appearance of cell senescence markers. Concomitantly, intracellular Hsp60 levels decreased while its acetylation levels increased. The data suggest that Hsp60 acetylation interferes with the formation of the Hsp60/p53 complex and/or promote its dissociation, both causing an increase in the levels of free p53, which can then activate the p53-dependent pathway toward cell senescence. On the other hand, acetylated Hsp60 is ubiquitinated and degraded and, thus, the anti-apoptotic effect of the chaperonin is abolished with subsequent tumor cell death. Our findings could help in the elucidation of the molecular mechanisms by which doxorubicin counteracts carcinogenesis and, consequently, it would open new roads for the development of cancer treatment protocols targeting Hsp60.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Carcinoma Mucoepidermoide/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Chaperonina 60/metabolismo , Doxorrubicina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Mitocondriais/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Apoptose/efeitos dos fármacos , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chaperonina 60/genética , Chaperoninas/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Histonas/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Mitocondriais/genética , Ligação Proteica , Proteólise , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação
20.
Curr Med Chem ; 23(28): 3136-3153, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27666934

RESUMO

MicroRNAs (miRNAs), which are small non-coding RNA molecules that post-transcriptionally regulate the expression of target genes, control the vast majority of cellular events, including proliferation, differentiation, survival, senescence, autophagy, metabolism and genome stability. Even slight alterations in miRNA expression levels may induce the development of pathological states, including cancer. Several studies have already demonstrated the importance of miRNAs in the regulation of melanocytes. Upregulation of oncogenic miRNAs (oncomiRs), mainly by amplification and translocation of miRNA genes, and downregulation of oncosuppressor miRNAs (anti-oncomiRs) by deletion and other mutations, promoter methylation and abnormal processing contributes to melanoma initiation and progression. At each phase of melanoma progression, tumor cells exhibit distinct profiles of miRNA expression, as compared with normal melanocytes. Moreover, as miRNAs are stable molecules that can be identified in bodily fluids, such as blood and saliva, they can serve as potent non-invasive prognostic markers of disease progression and response to therapy. This review summarizes recent findings regarding miRNA-mediated control of melanocytes and melanoma development, and presents miRNAs as prognostic markers for this disease.


Assuntos
Melanoma/diagnóstico , MicroRNAs/metabolismo , Antagomirs/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Melanócitos/metabolismo , Melanoma/genética , Melanoma/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Prognóstico , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
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