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1.
Oxid Med Cell Longev ; 2021: 6689403, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630850

RESUMO

Xeroderma pigmentosum (XP) is a rare autosomal genodermatosis that manifests clinically with pronounced sensitivity to ultraviolet (UV) radiation and the high probability of the occurrence of different skin cancer types in XP patients. XP is mainly caused by mutations in XP-genes that are involved in the nucleotide excision repair (NER) pathway that functions in the removal of bulky DNA adducts. Besides, the aggregation of DNA lesions is a life-threatening event that might be a key for developing various mutations facilitating cancer appearance. One of the key players of NER is XPC that senses helical distortions found in damaged DNA. The majority of XPC gene mutations are nonsense, and some are missense leading either to the loss of XPC protein or to the expression of a truncated nonfunctional version. Given that no cure is yet available, XPC patients should be completely protected and isolated from all types of UV radiations (UVR). Although it is still poorly understood, the characterization of the proteomic signature of an XPC mutant is essential to identify mediators that could be targeted to prevent cancer development in XPC patients. Unraveling this proteomic signature is fundamental to decipher the signaling pathways affected by the loss of XPC expression following exposure to UVB radiation. In this review, we will focus on the signaling pathways disrupted in skin cancer, pathways modulating NER's function, including XPC, to disclose signaling pathways associated with XPC loss and skin cancer occurrence.


Assuntos
Reparo do DNA/genética , Transdução de Sinais/genética , Neoplasias Cutâneas/metabolismo , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Códon sem Sentido/efeitos da radiação , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , Humanos , Incidência , Proteoma , Proteômica/métodos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Raios Ultravioleta/efeitos adversos , Xeroderma Pigmentoso/complicações
2.
J Biomed Nanotechnol ; 16(1): 111-124, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31996290

RESUMO

Radiation therapy is a mainstay in the therapeutic management of Head and Neck Squamous Cell Carcinoma (HNSCC). Despite significant progress in this field, radioresistance still accounts for most treatment failures. Gadolinium-based nanoparticles (GBNs) have shown great promises as radiosensitizers but the underlying sensitizing mechanism is still largely unknown with regards to the disparities obtained in in vitro studies. In this study, we show that a new formulation of GBNs, AGuIX®, can radiosensitize HNSCC after cell uptake and further accumulation in lysosomes. Although radiation alone triggered late apoptosis and mitochondrial impairment, the pre-treatment with GBNs led to complex DNA damage and a specific increase of autophagic cell death. In addition, a significant radio-enhancement effect was obtained after the pre-conditioning of cells with a glutathione inhibitor before GBNs treatment and radiation exposure. Overall, our results provide additional information on the radio-enhancing properties of GBNs in the management of radioresistant HNSCC.


Assuntos
Autofagia , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Apoptose , Linhagem Celular Tumoral , Gadolínio , Humanos , Nanopartículas Metálicas
3.
Oxid Med Cell Longev ; 2019: 4654206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485292

RESUMO

The continuous exposure of the human body's cells to radiation and genotoxic stresses leads to the accumulation of DNA lesions. Fortunately, our body has several effective repair mechanisms, among which is nucleotide excision repair (NER), to counteract these lesions. NER includes both global genome repair (GG-NER) and transcription-coupled repair (TC-NER). Deficiencies in the NER pathway underlie the development of several DNA repair diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). Deficiencies in GG-NER and TC-NER render individuals to become prone to cancer and neurological disorders, respectively. Therefore, NER regulation is of interest in fine-tuning these risks. Distinct signaling cascades including the NFE2L2 (NRF2), AHR, PI3K/AKT1, MAPK, and CSNK2A1 pathways can modulate NER function. In addition, several chemical and biological compounds have proven success in regulating NER's activity. These modulators, particularly the positive ones, could therefore provide potential treatments for genetic DNA repair-based diseases. Negative modulators, nonetheless, can help sensitize cells to killing by genotoxic chemicals. In this review, we will summarize and discuss the major upstream signaling pathways and molecules that could modulate the NER's activity.


Assuntos
Síndrome de Cockayne/metabolismo , Dano ao DNA , Reparo do DNA , Transdução de Sinais , Síndromes de Tricotiodistrofia/metabolismo , Raios Ultravioleta/efeitos adversos , Xeroderma Pigmentoso/metabolismo , Animais , Síndrome de Cockayne/patologia , Humanos , Síndromes de Tricotiodistrofia/patologia , Xeroderma Pigmentoso/patologia
4.
Oxid Med Cell Longev ; 2018: 5895439, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29682159

RESUMO

Few studies have focused on the protective role of selenium (Se) against skin aging and photoaging even though selenoproteins are essential for keratinocyte function and skin development. To the best of our knowledge, the impact of Se supplementation on skin cells from elderly and young donors has not been reported. Therefore, the main objective of our study was to evaluate the effects of Se supplementation on skin keratinocytes at baseline and after exposure to ultraviolet A (UVA) irradiation. Low doses of Se (30 nM) were very potently protective against UVA-induced cytotoxicity in young keratinocytes, whereas the protection efficiency of Se in old keratinocytes required higher concentrations (240 nM). Additionally, the DNA repair ability of the old keratinocytes drastically decreased compared with that of the young keratinocytes at baseline and after the UVA exposure. The Se supplementation significantly enhanced the DNA repair of 8-oxoguanine (8oxoG) only in the keratinocytes isolated from young donors. Therefore, aged keratinocytes have an increased vulnerability to oxidative DNA damage, and the Se needs in the elderly should be considered. Strengthening DNA repair activities with Se supplementation may represent a new strategy to combat aging and skin photoaging.


Assuntos
Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Selênio/uso terapêutico , Raios Ultravioleta , Adulto , Fatores Etários , Idoso , Células Cultivadas , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Humanos , Queratinócitos/efeitos da radiação , Pessoa de Meia-Idade , Adulto Jovem
5.
Br J Radiol ; 87(1035): 20130715, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24472775

RESUMO

During the last three decades, a considerable amount of work has been undertaken to determine the nature, the mechanism of formation and the biological consequences of radiation-induced DNA lesions. Most of the information was obtained via the development of chemical approaches, including theoretical, analytical and organic synthesis methods. Since it is not possible to present all the results obtained in this review article, we will focus on recent data dealing with the formation of complex DNA lesions produced by a single oxidation event, as these lesions may play a significant role in cellular responses to ionizing radiation and also to other sources of oxidative stress. Through the description of specific results, the contribution of different chemical disciplines in the assessment of the structure, the identification of the mechanism of formation and the biological impacts in terms of repair and mutagenicity of these complex radiation-induced DNA lesions will be highlighted.


Assuntos
Dano ao DNA/efeitos da radiação , Estresse Oxidativo , Reparo do DNA , Humanos , Radiação Ionizante
6.
Rev Med Brux ; 35(6): 469-75, 2014.
Artigo em Francês | MEDLINE | ID: mdl-25619045

RESUMO

OBJECTIVE: To assess the efficacy of intra-articular sodium hyaluronate, administred once weekly for 3 weeks (3 injections) in Moroccan patients with knee osteoarthritis over 6-month period. MATERIAL AND METHODS: We prospectively studied the outcome of 75 patients with painful knee osteoarthritis in grade 1, 2 and 3 on ACR radiological criteria in our rheumatology clinic in Morocco. Group 1: 45 patients were treated with 3-weekly injections of intra-articular sodium hyaluronate (1%; 2,2-2,7 MDa). Group 2 : 30 patients treated with symptomatic slow-acting drugs for osteoarthritis (SYSADOA). The efficacy parameters were Visual Analogue Scale (VAS) and Lequesne index. RESULTS: In group 1: 35/45 were female, a mean age of patients was 57.2 (± 8.2) years, and a mean Body Mass Index (BMI) was 28 (± 1.4) kg/m2. In group 2: 23/30 were female, a mean age of patients was 58.6 (± 2.8) years, and a mean of BMI was 27.8 (± 1.4) kg/m2. Before treatment in group 1, the mean of VAS was 6.5 cm (± 1), and of Lequesne index 10.5 (± 2.1). At 3 and 6 months after the third injection of sodium hyaluronate, there was a significant improvement from baseline of Lequesne index and VAS (P = 0.001). In group 2 before treatment, the mean of VAS was 7 cm (± 0,7), and of Lequesne index 8 (+ 1.1), but the improvement from baseline at 3 and 6 months of treatment was lower than group 1. CONCLUSION: The results of this prospective study, showed the efficacy of 3-weekly injections of sodium hyaluronate in the treatment of knee osteoarthritis in Moroccan patients over a 6-month period.


Assuntos
Ácido Hialurônico/administração & dosagem , Osteoartrite do Joelho/tratamento farmacológico , Idoso , Feminino , Humanos , Ácido Hialurônico/efeitos adversos , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Marrocos , Osteoartrite do Joelho/complicações , Dor/tratamento farmacológico , Dor/etiologia , Medição da Dor , Resultado do Tratamento , Viscossuplementação/efeitos adversos
7.
Biochim Biophys Acta ; 1830(6): 3399-406, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23518201

RESUMO

BACKGROUND: Significant data supports the health benefits of selenium although supplementation trials have yielded mixed results. GPx-1, whose levels are responsive to selenium availability, is implicated in cancer etiology by human genetic data. Selenium's ability to alter the phosphorylation of the H2AX, a histone protein that functions in the reduction of DNA damage by recruiting repair proteins to the damage site, following exposure to ionizing radiation and bleomycin was investigated. METHODS: Human cell lines that were either exposed to selenium or were transfected with a GPx-1 expression construct were exposed to ionizing radiation or bleomycin. Phosphorylation of histone H2AX was quantified by flow cytometry and survival by the MTT assay. Phosphorylation of the Chk1 and Chk2 checkpoint proteins was quantified by western blotting. RESULTS: In colon-derived cells, selenium increases GPx-1 and attenuated H2AX phosphorylation following genotoxic exposures while the viability of these cells was unaffected. MCF-7 cells and transfectants that express high GPx-1 levels were exposed to ionizing radiation and bleomycin, and H2AX phosphorylation and cell viability were assessed. GPx-1 increased H2AX phosphorylation and viability following the induction of DNA damage while enhancing the levels of activated Chk1 and Chk2. CONCLUSIONS: Exposure of mammalian cells to selenium can alter the DNA damage response and do so by mechanisms that are dependent and independent of its effect on GPx-1. GENERAL SIGNIFICANCE: Selenium and GPx-1 may stimulate the repair of genotoxic DNA damage and this may account for some of the benefits attributed to selenium intake and elevated GPx-1 activity.


Assuntos
Glutationa Peroxidase/metabolismo , Histonas/metabolismo , Selênio/metabolismo , Selenoproteínas/metabolismo , Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Quinase do Ponto de Checagem 2 , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Glutationa Peroxidase/genética , Histonas/genética , Humanos , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Radiação Ionizante , Selenoproteínas/genética , Glutationa Peroxidase GPX1
8.
Food Chem Toxicol ; 49(7): 1565-71, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21515331

RESUMO

This study was designed to investigate the hypothesis that the toxic effects of di(2-ethylhexyl)phthalate (DEHP), the most abundantly used plasticizer and ubiquitous environmental contaminant that cause alterations in endocrine and spermatogenic functions in animals is mediated through the induction of reactive oxygen species (ROS) and activation of nuclear p53 and p21 proteins in LNCaP human prostate adenocarcinoma cell line. Protective effects of two selenocompounds, sodium selenite (SS) and selenomethionine (SM) were also examined. It was demonstrated that 24 h exposure of the cells to 3 mM DEHP or its main metabolite, mono(2-ethylhexyl)phthalate (MEHP, 3 µM) caused strongly amplified production of ROS. Both SS (30 nM) and SM (10 µM) supplementations reduced ROS production, and p53 and p21 activation that induced significantly only by MEHP-exposure. The overall results of this study indicated that the induction of oxidative stress is one of the important mechanisms underlying the toxicity of DEHP and this is mainly through the effects of the metabolite, MEHP. Generated data also emphasized the critical role of Se in modulation of intracellular redox status, implicating the importance of the appropriate Se status in cellular response against testicular toxicity of phthalates.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dietilexilftalato/análogos & derivados , Espécies Reativas de Oxigênio/metabolismo , Selenometionina/farmacologia , Selenito de Sódio/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Citoproteção/efeitos dos fármacos , Dietilexilftalato/toxicidade , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Espermatogênese/efeitos dos fármacos , Doenças Testiculares/induzido quimicamente , Doenças Testiculares/tratamento farmacológico , Testículo/citologia , Proteína Supressora de Tumor p53/genética
9.
Pathol Biol (Paris) ; 53(4): 244-50, 2005 May.
Artigo em Francês | MEDLINE | ID: mdl-15850959

RESUMO

Prion diseases form a group of fatal neurodegenerative disorders including Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in animals. All of which are characterized by the accumulation of abnormally folded isoform of the cellular prion protein (PrP(C)), denoted PrP(Sc), which is the major component of infectious prion diseases. The function of PrP(C) remains elusive. Its amino-terminal region contains a repeated five octapeptide domain that binds copper. The protein is believed to display a superoxide dismutase like activity, and hence a possible protective function against oxidative stress. In this review, relationship between PrP, copper and oxidative stress was analysed. Thus, metal ions and oxidative stress would play an essential role in the pathogenesis of prion diseases and represent important targets for future therapeutic targets or a novel diagnostic marker.


Assuntos
Cobre/química , Príons/química , Animais , Transporte Biológico , Química Encefálica , Quelantes/metabolismo , Cobre/análise , Cobre/metabolismo , Cobre/fisiologia , Humanos , Manganês/análise , Modelos Biológicos , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , Células PC12/efeitos dos fármacos , Células PC12/metabolismo , Proteínas PrPC/química , Proteínas PrPC/metabolismo , Proteínas PrPSc/química , Príons/metabolismo , Príons/patogenicidade , Ligação Proteica , Conformação Proteica , Dobramento de Proteína , Estrutura Terciária de Proteína , Ratos , Sequências Repetitivas de Aminoácidos , Solubilidade , Superóxido Dismutase/metabolismo , Virulência
10.
Proc Natl Acad Sci U S A ; 97(25): 13937-42, 2000 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-11095725

RESUMO

The molecular mechanism of neurodegeneration in transmissible spongiform encephalopathies remains uncertain. In this study, it was demonstrated that prion-infected hypothalamic neuronal GT1 cells displayed a higher sensitivity to induced oxidative stress over noninfected cells. In addition, the infected cells presented an increased lipid peroxidation and signs of apoptosis associated with a dramatic reduction in the activities of the glutathione-dependent and superoxide dismutase antioxidant systems. This study indicates for the first time that prion infection results in an alteration of the molecular mechanisms promoting cellular resistance to reactive oxygen species. This finding is vital for future therapeutic approaches in transmissible spongiform encephalopathies and the understanding of the function of the prion protein.


Assuntos
Estresse Oxidativo , Doenças Priônicas/patologia , Western Blotting , Linhagem Celular , Fragmentação do DNA , Glutationa/metabolismo , Peroxidação de Lipídeos , Superóxido Dismutase/metabolismo
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