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1.
Mar Drugs ; 18(4)2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32295082

RESUMO

Breast cancer is the leading cause of death from cancer among women. Higher consumption of dietary marine n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) is associated with a lower risk of breast cancer. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are two n-3 LC-PUFAs found in fish and exert anticancer effects. In this study, natural marine- derived lecithin that is rich in various polyunsaturated fatty acids (PUFAs) was extracted from salmon heads and transformed into nanoliposomes. These nanoliposomes were characterized and cultured with two breast cancer lines (MCF-7 and MDA-MB- 231). The nanoliposomes decreased the proliferation and the stiffness of both cancer cell types. These results suggest that marine-derived lecithin possesses anticancer properties, which may have an impact on developing new liposomal delivery strategies for breast cancer treatment.

2.
Eur J Med Chem ; 187: 111939, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31838327

RESUMO

Breast cancer is a major medical threat which cannot be sufficiently addressed by current therapies because of spontaneous or acquired treatment resistance. Besides, triple-negative breast cancer (TNBC) tumors do not respond to targeted therapies, thus new therapeutic strategies are needed. In this context, we designed and prepared new desulfured troglitazone (TGZ)-derived molecules and evaluated them in vitro for their anti-proliferative activity, with a special focus on triple-negative breast cancer cell lines. Optimization of the synthetic strategies and deracemization of the lead compound were performed to give highly active compound 10 with low-micromolar potency. Further studies revealed that this compound triggers apoptosis rather than cell cycle arrest as observed with TGZ.

3.
J Phys Chem B ; 123(34): 7365-7371, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365827

RESUMO

The behavior of the structural parameters of DNA considering different levels of methylation in CpG islands is studied by means of full-atom molecular dynamics simulations and electronic circular dichroism, both in an artificial model system and in a gene promoter sequence. It is demonstrated that methylation although intrinsically brings quite local perturbations may, if its level is high enough, induce cooperative effects that strongly modify the DNA backbone torsional parameters altering the helicity as compared to the nonmethylated case. Because methylation of the CpG island is correlated with the regulation of gene expression, understanding the structural modifications induced in DNA is crucial to characterize all the fine equilibria into play in epigenetics phenomena.

4.
J Appl Toxicol ; 39(5): 764-772, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30605223

RESUMO

Human exposure to airborne carbon nanotubes (CNT) is increasing because of their applications in different sectors; therefore, they constitute a biological hazard. Consequently, developing studies on CNT toxicity become a necessity. CNTs can have different properties in term of length, size and charge. Here, we compared the cellular effect of multiwall (MWCNTs) and single wall CNTs (SWCNTs). MWCNTs consist of multiple layers of graphene, while SWCNTs are monolayers. The effects of MWCNTs and SWCNTs were evaluated by the water-soluble tetrazolium salt cell proliferation assay on NR8383 cells, rat alveolar macrophage cell line (NR8383). After 24 hours of exposure, MWCNTs showed higher toxicity (50% inhibitory concentration [IC50 ] = 3.2 cm2 /cm2 ) than SWCNTs (IC50  = 44 cm2 /cm2 ). Only SWCNTs have induced NR8383 cells apoptosis as assayed by flow cytometry using the annexin V/IP staining test. The expression of genes involved in oxidative burst (Ncf1), inflammation (Nfκb, Tnf-α, Il-6 and Il-1ß), mitochondrial damage (Opa) and apoptotic balance (Pdcd4, Bcl-2 and Casp-8) was determined. We found that MWCNT exposure predominantly induce inflammation, while SWCNTs induce apoptosis and impaired mitochondrial function. Our results clearly suggest that MWCNTs are ideal candidates for acute inflammation induction. In vivo studies are required to confirm this hypothesis. However, we conclude that toxicity of CNTs is dependent on their physical and chemical characteristics.

6.
Sci Rep ; 7(1): 8885, 2017 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-28827702

RESUMO

Nonsteroidal 2-arylproprionic acids are widely used, over-the-counter, anti-inflammatory drugs. Photosensitivity is a commonly overlooked adverse effect of these drugs. Based on the combined use of cell viability assays and molecular modeling, we prove and rationalize the photochemical pathways triggering photosensitization for two drugs, ibuprofen and ketoprofen. As its parent compound benzophenone, ketoprofen produces singlet oxygen, upon triplet manifold population. However, ibuprofen and ketoprofen photodissociate and hence may generate two highly reactive radicals. The formation of metastable aggregates between the two drugs and B-DNA is also directly probed by molecular dynamics. Our approach characterizes the coupled influence of the drug's intrinsic photochemistry and the interaction pattern with DNA. The photosensitization activity of nonsteroidal 2-arylproprionic acids, being added to gels and creams for topical use, should be crucially analyzed and rationalized to enact the proper preventive measures.


Assuntos
Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Ibuprofeno/farmacologia , Cetoprofeno/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Raios Ultravioleta , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Ibuprofeno/química , Cetoprofeno/química , Modelos Moleculares , Estrutura Molecular , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade , Raios Ultravioleta/efeitos adversos
7.
J Phys Chem B ; 121(32): 7586-7592, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28735538

RESUMO

We report a combined computational and experimental study to rationalize the behavior of a well-known singlet oxygen (1O2) probe, that is, the chromophore of the Singlet Oxygen Sensor Green: a fluoresceine-based sensor. In particular, we evidence that the presence of an intramoleculer charge transfer state that is no more present upon reaction with 1O2 explains the fluorescence enhancement observed in the presence of reactive oxygen species. Furthermore, we also unequivocally show the photophysical pathways leading to the fluorescence enhancement of fluoresceine upon irradiation with UVA lights and also in the absence of any oxygen activator. More specifically, we evidence that the presence of a possible intersystem crossing upon population of higher energy singlet electronic excited states will lead to the population of the fluoresceine triplet manifold and hence to the self-production of 1O2.

8.
Breast Cancer Res Treat ; 165(3): 517-527, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28681173

RESUMO

PURPOSE: 40% of triple-negative breast cancer (TNBC) do not express claudin-1, a major constituent of tight junction. Patients with these "claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors. METHODS AND RESULTS: In MDA-MB-231 and Hs578T "claudin-1-low" TNBC cells, Δ2-TGZ treatment induced claudin-1 protein expression and triggered apoptosis as measured by FACS analysis (annexin V/PI co-staining). Interestingly, in the non-tumorigenic human breast epithelial cell line MCF-10A, the basal level of claudin-1 was not modified following Δ2-TGZ treatment, which did not induce apoptosis. Furthermore, claudin-1-transfected MDA-MB-231 and Hs578T cells displayed a significant increase of cleaved PARP-1 and caspase 7, caspase 3/7 activities, and TUNEL staining. RNA interference was performed in order to inhibit Δ2-TGZ-induced claudin-1 expression in both the cells. In absence of claudin-1, a decrease of cleaved PARP-1 and caspase 7 and caspase 3/7 activities were observed in MDA-MB-231 but not in Hs578T cells. CONCLUSION: Claudin-1 overexpression and Δ2-TGZ treatment are associated to apoptosis in MDA-MB-231 and Hs578T "claudin-1-low" TNBC. Moreover, in MDA-MB-231 cells, claudin-1 is involved in the pro-apoptotic effect of Δ2-TGZ. Our results suggest that claudin-1 re-expression could be an interesting therapeutic strategy for "claudin-1-low" TNBC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Claudina-1/metabolismo , Ésteres do Ácido Sulfúrico/farmacologia , Tiazolidinedionas/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Apoptose/genética , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Claudina-1/genética , Feminino , Regulação da Expressão Gênica , Humanos , Transporte Proteico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Troglitazona
9.
Cell Cycle ; 15(24): 3402-3412, 2016 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-27753533

RESUMO

We have previously shown that Δ2-Troglitazone (Δ2-TGZ) displayed anticancer effects on breast cancer cell lines grown in low serum conditions (1% fetal calf serum (FCS)). The present study was performed in order to characterize the effects of Δ2-TGZ in high serum containing medium and to determine if starvation could influence the response of breast cancer cells to this compound, keeping in mind the potential interest for breast cancer therapy. We observed that in high serum conditions (10% FCS), a 48 h treatment with Δ2-TGZ induced a decrease in cell numbers in MDA-MB-231 and MCF-7 breast cancer cell lines. The IC50 values were higher than in low serum conditions. Furthermore, in contrast to our previous results obtained in 1% FCS conditions, we observed that in 10% FCS-containing medium, MCF-7 cells were more sensitive to Δ2-TGZ than MDA-MB-231 cells. Δ2-TGZ also induced endoplasmic reticulum (ER) stress mainly in MDA-MB-231 cells. Besides, in high serum conditions, Δ2-TGZ induced a G0/G1 cell cycle arrest, an inhibition of BrdU incorporation and a reduced level of cyclin D1. We observed a limited cleavage of PARP and a limited proportion of cells in sub-G1 phase. Thus, in high serum conditions, Δ2-TGZ displayed cytostatic effects rather than apoptosis as previously reported in 1% FCS-containing medium. Our results are in accordance with studies suggesting that serum starvation could potentiate the action of diverse anti-cancer agents.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Cromanos/farmacologia , Soro/metabolismo , Tiazolidinedionas/farmacologia , Contagem de Células , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Fator de Transcrição CHOP/metabolismo , Troglitazona , Células Tumorais Cultivadas
10.
Sci Rep ; 6: 28480, 2016 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-27329409

RESUMO

We report a molecular modeling study, coupled with spectroscopy experiments, on the behavior of two well known organic dyes, nile blue and nile red, when interacting with B-DNA. In particular, we evidence the presence of two competitive binding modes, for both drugs. However their subsequent photophysical behavior is different and only nile blue is able to induce DNA photosensitization via an electron transfer mechanism. Most notably, even in the case of nile blue, its sensitization capabilities strongly depend on the environment resulting in a single active binding mode: the minor groove. Fluorescence spectroscopy confirms the presence of competitive interaction modes for both sensitizers, while the sensitization via electron transfer, is possible only in the case of nile blue.


Assuntos
DNA de Forma B/química , Oxazinas/química , Fármacos Fotossensibilizantes/química , Sítios de Ligação , Ligação Competitiva , Simulação por Computador , Transporte de Elétrons , Corantes Fluorescentes/química , Modelos Moleculares , Conformação de Ácido Nucleico , Processos Fotoquímicos , Polidesoxirribonucleotídeos/química , Espectrometria de Fluorescência , Espectrofotometria
11.
Nanoscale ; 8(9): 5268-79, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26879405

RESUMO

DDB2, known for its role in DNA repair, was recently shown to reduce mammary tumor invasiveness by inducing the transcription of IκBα, an inhibitor of NF-κB activity. Since cellular adhesion is a key event during the epithelial to mesenchymal transition (EMT) leading to the invasive capacities of breast tumor cells, the aim of this study was to investigate the role of DDB2 in this process. Thus, using low and high DDB2-expressing MDA-MB231 and MCF7 cells, respectively, in which DDB2 expression was modulated experimentally, we showed that DDB2 overexpression was associated with a decrease of adhesion abilities on glass and plastic areas of breast cancer cells. Then, we investigated cell nanomechanical properties by atomic force microscopy (AFM). Our results revealed significant changes in the Young's Modulus value and the adhesion force in MDA-MB231 and MCF7 cells, whether DDB2 was expressed or not. The cell stiffness decrease observed in MDA-MB231 and MCF7 expressing DDB2 was correlated with a loss of the cortical actin-cytoskeleton staining. To understand how DDB2 regulates these processes, an adhesion-related gene PCR-Array was performed. Several adhesion-related genes were differentially expressed according to DDB2 expression, indicating that important changes are occurring at the molecular level. Thus, this work demonstrates that AFM technology is an important tool to follow cellular changes during tumorigenesis. Moreover, our data revealed that DDB2 is involved in early events occurring during metastatic progression of breast cancer cells and will contribute to define this protein as a new marker of metastatic progression in this type of cancer.


Assuntos
Neoplasias da Mama , Proteínas de Ligação a DNA/biossíntese , Módulo de Elasticidade , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Neoplasias da Mama/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/ultraestrutura , Adesão Celular , Feminino , Humanos , Células MCF-7 , Microscopia de Força Atômica , Metástase Neoplásica
12.
Front Chem ; 3: 67, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26734600

RESUMO

We report the characterization of the interaction between B-DNA and three terpyridin iron II complexes. Relatively long time-scale molecular dynamics (MD) is used in order to characterize the stable interaction modes. By means of molecular modeling and UV-vis spectroscopy, we prove that they may lead to stable interactions with the DNA duplex. Furthermore, the presence of larger π-conjugated moieties also leads to the appearance of intercalation binding mode. Non-covalent stabilizing interactions between the iron complexes and the DNA are also characterized and evidenced by the analysis of the gradient of the electronic density. Finally, the structural deformations induced on the DNA in the different binding modes are also evidenced. The synthesis and chemical characterization of the three complexes is reported, as well as their absorption spectra in presence of DNA duplexes to prove the interaction with DNA. Finally, their effects on human cell cultures have also been evidenced to further enlighten their biological effects.

13.
Mol Pharm ; 12(2): 554-61, 2015 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-25536094

RESUMO

S-Nitrosoglutathione (GSNO) is a good candidate for nitric oxide (NO(•)) delivery, and its nanoformulation improves NO(•) stability and bioavailability. We have compared the effect of empty Eudragit nanoparticles (eENP), GSNO-loaded ENP (gENP), and free GSNO on THP-1 human monocytic cell line. We investigated cellular viability and growth by WST-1 and trypan blue tests. ENP uptake was studied using transmission electron microscopy, confocal microscopy, and flow cytometry. Transcriptomic profiles were obtained using microarray. ENP entered cells by clathrin- and caveolae-mediated endocytosis. Exposure to either free GSNO or gENP induced an activation of genes from the same clusters, in favor of intracellular delivery of GSNO by ENP. GSNO nanoformulation might be a therapeutic option for NO(•) delivery.


Assuntos
Monócitos/metabolismo , Nanopartículas/química , S-Nitrosoglutationa/química , S-Nitrosoglutationa/metabolismo , Linhagem Celular , Endocitose/fisiologia , Humanos , Microscopia Eletrônica de Transmissão , Monócitos/ultraestrutura , Óxido Nítrico/metabolismo , Transcriptoma/genética
14.
Free Radic Biol Med ; 77: 139-51, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25224035

RESUMO

Breast cancer is one of the most common malignancies of all cancers in women worldwide. Many difficulties reside in the prediction of tumor metastatic progression because of the lack of sufficiently reliable predictive biological markers, and this is a permanent preoccupation for clinicians. Manganese superoxide dismutase (MnSOD) may represent a rational candidate as a predictive biomarker of breast tumor metastatic progression, because its gene expression is profoundly altered between early and advanced breast cancer, in contrast to expression in the normal mammary gland. In this review, we report the characterization of some gene polymorphisms and molecular mechanisms of SOD2 gene regulation, which allows a better understanding of how MnSOD is decreased in early breast cancer and increased in advanced breast cancer. Several studies display the biological significance of MnSOD level in proliferation as well as in invasive and angiogenic abilities of breast tumor cells by controlling superoxide anion radical (O2(•-)) and hydrogen peroxide (H2O2). Particularly, they report how these reactive oxygen species may activate some signaling pathways involved in breast tumor growth. Emerging understanding of these findings provides an interesting framework for guiding translational research and suggests a way to define precisely the clinical interest of MnSOD as a prognostic and/or predicting marker in breast cancer, by associating with some regulators involved in SOD2 gene regulation and other well-known biomarkers, in addition to the typical clinical parameters.


Assuntos
Neoplasias da Mama/enzimologia , Superóxido Dismutase/fisiologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células , Indução Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Estresse Oxidativo , Polimorfismo Genético , Superóxidos/metabolismo
15.
Cancer Res ; 73(16): 5040-52, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23774208

RESUMO

The DNA repair protein damaged DNA-binding 2 (DDB2) has been implicated in promoting cell-cycle progression by regulating gene expression. DDB2 is selectively overexpressed in breast tumor cells that are noninvasive, but not in those that are invasive. We found that its overexpression in invasive human breast tumor cells limited their motility and invasiveness in vitro and blocked their ability to colonize lungs in vivo, defining a new function for DDB2 in malignant progression. DDB2 overexpression attenuated the activity of NF-κB and the expression of its target matrix metalloprotease 9 (MMP9). Mechanistic investigations indicated that DDB2 decreased NF-κB activity by upregulating expression of IκBα by binding the proximal promoter of this gene. This effect was causally linked to invasive capacity. Indeed, knockdown of DDB2-induced IκBα gene expression restored NF-κB activity and MMP9 expression, along with the invasive properties of breast tumor cells overexpressing DDB2. Taken together, our findings enlighten understanding of how breast cancer cells progress to an invasive phenotype and underscore potential clinical interest in DDB2 as a prognostic marker or therapeutic target in this setting.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , NF-kappa B/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Células MCF-7 , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Invasividade Neoplásica , Prognóstico , Regiões Promotoras Genéticas , Transcrição Genética , Regulação para Cima/genética
16.
J Cell Physiol ; 227(12): 3768-77, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22392896

RESUMO

The major effect of T3 on mitochondrial activity has been partly explained by the discovery of p43, a T3-dependent transcription factor of the mitochondrial genome. P43 is imported into mitochondria in an atypical manner which is not yet fully understood. Our aim was to characterize the p43 sequences inducing its mitochondrial import, using in organello import experiments with wild-type or mutated proteins and validation in CV1 cells. We find that several sequences define the mitochondrial addressing. Two alpha helices in the C-terminal part of p43 are actual mitochondrial import sequences as fusion to a cytosolic protein induces its mitochondrial translocation. Helix 5 drives the atypical mitochondrial import process, whereas helices 10/11 induce a classical import process. However, despite its inability to drive a mitochondrial import, the N-terminal region of p43 also plays a permissive role as in the presence of the C-terminal import sequences different N-terminal regions determine whether the protein is imported or not. These results can be extrapolated to other mitochondrial proteins related to the nuclear receptor superfamily, devoid of classical mitochondrial import sequences.


Assuntos
Mitocôndrias Hepáticas/metabolismo , Receptores alfa dos Hormônios Tireóideos/química , Receptores alfa dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Masculino , Mutação , Plasmídeos , Ligação Proteica , Conformação Proteica , Estrutura Terciária de Proteína , Transporte Proteico/fisiologia , Ratos , Ratos Wistar
17.
FASEB J ; 26(2): 748-56, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22109994

RESUMO

In vertebrates, skeletal muscle myofibers display different contractile and metabolic properties associated with different mitochondrial content and activity. We have previously identified a mitochondrial triiodothyronine receptor (p43) regulating mitochondrial transcription and mitochondrial biogenesis. When overexpressed in skeletal muscle, it increases mitochondrial DNA content, stimulates mitochondrial respiration, and induces a shift in the metabolic and contractile features of muscle fibers toward a slower and more oxidative phenotype. Here we show that a p43 depletion in mice decreases mitochondrial DNA replication and respiratory chain activity in skeletal muscle in association with the induction of a more glycolytic muscle phenotype and a decrease of capillary density. In addition, p43(-/-) mice displayed a significant increase in muscle mass relative to control animals and had an improved ability to use lipids. Our findings establish that the p43 mitochondrial receptor strongly affects muscle mass and the metabolic and contractile features of myofibers and provides evidence that this receptor mediates, in part, the influence of thyroid hormone in skeletal muscle.


Assuntos
Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Receptores dos Hormônios Tireóideos/deficiência , Animais , Replicação do DNA , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Transporte de Elétrons , Hipertrofia , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Contração Muscular , Fibras Musculares de Contração Rápida/metabolismo , Músculo Esquelético/irrigação sanguínea , Consumo de Oxigênio , Fenótipo , Receptores dos Hormônios Tireóideos/genética
18.
Exp Cell Res ; 317(14): 2059-71, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21664352

RESUMO

We have previously shown that mitochondrial protein synthesis regulates myoblast differentiation, partly through the control of c-Myc expression, a cellular oncogene regulating myogenin expression and myoblast withdrawal from the cell cycle. In this study we provide evidence of the involvement of Calcineurin in this regulation. In C2C12 myoblasts, inhibition of mitochondrial protein synthesis by chloramphenicol decreases Calcineurin expression. Conversely, stimulation of this process by overexpressing the T3 mitochondrial receptor (p43) increases Calcineurin expression. Moreover, expression of a constitutively active Calcineurin (ΔCN) stimulates myoblast differentiation, whereas a Calcineurin antisense has the opposite effect. Lastly, ΔCN expression or stimulation of mitochondrial protein synthesis specifically increases slow myosin heavy chain expression. In conclusion, these data clearly suggest that, partly via Calcineurin expression, mitochondrial protein synthesis is involved in muscle development through the control of myoblast differentiation and probably the acquisition of the contractile and metabolic phenotype of muscle fibres.


Assuntos
Calcineurina/genética , Diferenciação Celular , Citocinas/metabolismo , Regulação da Expressão Gênica , Mitocôndrias Musculares/metabolismo , Mioblastos/citologia , Miosinas/biossíntese , Animais , Aves , Calcineurina/metabolismo , Células Cultivadas , Citocinas/genética , Humanos , Camundongos , Mioblastos/metabolismo , Miosinas/metabolismo , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Free Radic Biol Med ; 50(12): 1771-9, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21419216

RESUMO

A high basal expression of manganese superoxide dismutase (MnSOD) has been reported in aggressive breast cancer cells, according to an unknown mechanism, and contributes to their invasive abilities. Here, we report the involvement of Sp1 and nuclear factor-κB (NF-κB) transcription factors in this high basal expression of MnSOD in aggressive breast cancer cells. Suppression or inactivation of Sp1 showed that it plays an essential role in the high MnSOD expression in aggressive breast cancer cells through a unique binding site identified by chromatin immunoprecipitation (ChIP) assay and functional analysis of the MnSOD proximal promoter. Treatment of cells with a specific NF-κB inhibitor peptide decreased significantly high basal MnSOD expression. A ChIP assay showed binding of a constitutive p50/p65 NF-κB complex to the MnSOD intronic enhancer element, associated with hyperacetylation of the H3 histone. Finally, high basal expression of MnSOD resulted in the lack of expression of Damaged DNA binding 2 (DDB2) protein in aggressive breast cancer cells. DDB2 overexpression prevented the binding of Sp1 as well as of NF-κB to their respective elements on the MnSOD gene. These results contribute to a better understanding of MnSOD up-regulation, which may be clinically important in the prediction of breast tumor progression.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Transcrição Sp1/metabolismo , Superóxido Dismutase/genética , Acetilação , Sequência de Bases , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos , Feminino , Radicais Livres , Histonas/genética , Histonas/metabolismo , Humanos , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Estudos Retrospectivos , Fator de Transcrição Sp1/genética , Superóxido Dismutase/biossíntese , Superóxido Dismutase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima
20.
PLoS One ; 4(5): e5631, 2009 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-19462004

RESUMO

In previous studies, we characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor. In in vitro and in vivo studies, we have shown that p43 increases mitochondrial transcription and mitochondrial biogenesis. In addition, p43 overexpression in skeletal muscle stimulates mitochondrial respiration and induces a shift in metabolic and contractile features of muscle fibers which became more oxidative.Here we have studied the influence of p43 overexpression in skeletal muscle of mice during aging. We report that p43 overexpression initially increased mitochondrial mass. However, after the early rise in mitochondrial DNA occurring at 2 months of age in transgenic mice, we observed a progressive decrease of mitochondrial DNA content which became 2-fold lower at 23 months of age relatively to control animals. Moreover, p43 overexpression induced an oxidative stress characterized by a strong increase of lipid peroxidation and protein oxidation in quadriceps muscle, although antioxidant enzyme activities (catalase and superoxide dismutase) were stimulated. In addition, muscle atrophy became detectable at 6 months of age, probably through a stimulation of the ubiquitin proteasome pathway via two muscle-specific ubiquitin ligases E3, Atrogin-1/MAFbx and MuRF1.Taken together, these results demonstrate that a prolonged stimulation of mitochondrial activity induces muscle atrophy. In addition, these data underline the importance of a tight control of p43 expression and suggest that a deregulation of the direct T3 mitochondrial pathway could be one of the parameters involved in the occurrence of sarcopenia.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Atrofia Muscular/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Animais , Antioxidantes/metabolismo , Peso Corporal , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Contração Muscular , Proteínas Musculares/metabolismo , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/patologia , Cadeias Pesadas de Miosina/metabolismo , Tamanho do Órgão , Estresse Oxidativo , Condicionamento Físico Animal , Resistência Física , Isoformas de Proteínas/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Superóxido Dismutase/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Proteína Desacopladora 2 , Proteína Desacopladora 3
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