RESUMEN
BACKGROUND: The development and establishment of oral squamous cell carcinoma are confined to carcinogenesis, which involves oxidative stress via oxygen-free radical production as a hydroxyl radical (HOâ¢), considered the most important cause of oxidative damage to basic biomolecules since it targets DNA strands. 8-Hydroxy-2´-deoxyguanosine (8-OHdG) is considered a free radical with a promutagenic capacity due to its ability to pair with adenosine instead of cytosine during replication. MATERIAL AND METHODS: We collected 30 paraffin-embedded tissue samples of OSCC from patients treated between 2013 and 2018. We recorded risk habits, disease stage, disease free survival and death with at least 3 years of follow-up. 8-Hydroxyguanosine was evaluated by immunohistochemistry and subsequently classified as weak-moderate or strong positive expression. Additionally, we noted whether it was expressed in the cytoplasm and/or nucleus. RESULTS: Most of the cases expressed 8-OHdG with a strong intensity (80%). All neoplastic cells were preferentially stained in only the cytoplasm (70.0%), but nuclear positivity was found in 30%, independent of the intensity. Based on the location in the cytoplasm and/or nucleus, tumors >4 cm showed a high frequency (95.5%) of 8-OHdG expression in only the cytoplasm, with a significant difference (p value 0.001). Additionally, overall survival was affected when immunoexpression was present in the cytoplasm and nucleus because all deaths were in this group were statistically significant (p value = 0.001). CONCLUSIONS: All tumors showed DNA oxidative damage, and 8-OHdG was preferentially expressed in the cytoplasm. This finding was associated with tumor size and, when present in the nucleus, might also be related to death.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de la Boca , Humanos , 8-Hidroxi-2'-Desoxicoguanosina/metabolismo , Desoxiguanosina/química , Desoxiguanosina/metabolismo , Daño del ADN , Estrés Oxidativo , Radicales LibresRESUMEN
Radon gas inhalation is the main source of exposure to ionizing radiation by humans. There is still lack in knowledge concerning the chronic and indirect effects of exposure to this carcinogenic factor. Therefore, the aim of this work is to analyze the levels of oxidative genomic damage in inhabitants of a medium-high background radiation area (HBRA) (N = 82) in Northeastern Brazil and compare them with people living in a low background radiation area (LBRA) (N = 46). 8-hydroxy-2-deoxyguanosine (8-OHdG) was quantified in urine, Ser326Cys polymorphism was determined in the hOGG1 gene and indoor radon was measured. HBRA houses had 6.5 times higher indoor radon levels than those from LBRA (p-value < 0.001). The 8-OHdG mean (95% confidence interval) were significantly different, 8.42 (5.98-11.9) ng/mg creatinine and 29.91 (23.37-38.30) ng/mg creatinine for LBRA and HBRA, respectively. The variables representing lifestyle and environmental and occupational exposures did not have a significant association with oxidized guanosine concentrations. On the other hand, lower 8-OHdG values were observed in subjects that had one mutant allele (326Cys) in the hOGG1 gene than those who had both wild alleles (Ser/Ser (p-value < 0.05). It can be concluded that high radon levels have significantly influenced the genome oxidative metabolism and hOGG1 gene polymorphism would mediate the observed biological response.
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Radón , Humanos , Radón/toxicidad , Brasil , Creatinina , Desoxiguanosina , 8-Hidroxi-2'-Desoxicoguanosina , Estrés Oxidativo , GenómicaRESUMEN
OBJECTIVE: Noise-induced hearing loss is a preventable form of hearing loss that has serious social and economic impacts. This study aimed to investigate the protective effect of berberine, a potent antioxidant and anti-inflammatory agent, against Noise-induced hearing loss. METHODS: After applying distortion product otoacoustic emission, 28 female Sprague-Dawley rats were randomly divided into four groups. Group 1 was designated as acoustic trauma group, and rats in this group were exposed to white noise for 12 h at an intensity of 4 kHz 110 dB sound pressure level. Group 2 was the control group. Group 3 was designated as the berberine group, and 100 mg/kg of berberine was administered to rats in this group by intragastric lavage for five consecutive days. Group 4 was designated as the acoustic trauma+berberine group. distortion product otoacoustic emission was repeated on the 6th day of the study and cochlear tissues of rats were dissected for histopathological and immunohistochemical analyses after sacrificing rats. RESULTS: The distortion product otoacoustic emission results showed a significant decrease in signal-noise ratio values at higher frequencies in rats of the trauma group compared to those in other groups. Acoustic trauma caused severe histopathological impairment at cochlear structures together with severe 8-hydroxy-2-deoxyguanosine expression. Rats in the acoustic trauma+berberine group showed mild histopathological changes with mild 8-hydroxy-2-deoxyguanosine expression and better signal-noise ratio values. CONCLUSION: The histopathological and audiological findings of this experimental study showed that berberine provides protection in Noise-induced hearing loss and may have the potential for use in acoustic trauma-related hearing losses.
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Berberina , Pérdida Auditiva Provocada por Ruido , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Umbral Auditivo , Berberina/farmacología , Berberina/uso terapéutico , Desoxiguanosina/farmacología , Femenino , Pérdida Auditiva Provocada por Ruido/tratamiento farmacológico , Pérdida Auditiva Provocada por Ruido/patología , Pérdida Auditiva Provocada por Ruido/prevención & control , Emisiones Otoacústicas Espontáneas , Ratas , Ratas Sprague-DawleyRESUMEN
The spread of antibiotic-resistant bacteria represents a substantial health threat. Current antibiotics act on a few metabolic pathways, facilitating resistance. Consequently, novel regulatory inhibition mechanisms are necessary. Riboswitches represent promising targets for antibacterial drugs. Purine riboswitches are interesting, since they play essential roles in the genetic regulation of bacterial metabolism. Among these, class I (2'-dG-I) and class II (2'-dG-II) are two different 2'-deoxyguanosine (2'-dG) riboswitches involved in the control of deoxyguanosine metabolism. However, high affinity for nucleosides involves local or distal modifications around the ligand-binding pocket, depending on the class. Therefore, it is crucial to understand these riboswitches' recognition mechanisms as antibiotic targets. In this work, we used a combination of computational biophysics approaches to investigate the structure, dynamics, and energy landscape of both 2'-dG classes bound to the nucleoside ligands, 2'-deoxyguanosine, and riboguanosine. Our results suggest that the stability and increased interactions in the three-way junction of 2'-dG riboswitches were associated with a higher nucleoside ligand affinity. Also, structural changes in the 2'-dG-II aptamers enable enhanced intramolecular communication. Overall, the 2'-dG-II riboswitch might be a promising drug design target due to its ability to recognize both cognate and noncognate ligands.
Asunto(s)
Antibacterianos/metabolismo , Bacterias/genética , Bacterias/metabolismo , Desoxiguanosina/genética , Riboswitch/genética , Aptámeros de Nucleótidos/genética , Ligandos , Modelos Moleculares , Conformación de Ácido Nucleico , Purinas/metabolismoRESUMEN
OBJECTIVE: Reactive oxygen species and oxygen free radicals cause oxidative damage to lipids, proteins, and cell DNA in the cell membrane. Although many DNA products are produced during oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the most common one, since it can be produced in in vivo environment. In recent years, diving has been done quite frequently for business and sports purposes all over the world. Increased environmental pressure in diving leads to hyperoxia and causes oxidative stress. METHODS: The acute effects of diving on DNA damage were evaluated by comparing 8-hydroxy-2'-deoxyguanosine values of 15 professional diver groups before and after diving. In addition to the demographic characteristics, the serum 8-hydroxy-2'-deoxyguanosine levels of these 15 divers were compared with the control group consisting of nondiving medical students to examine the chronic effect of diving on DNA damage. RESULTS: After deep dive, the amount of 8-hydroxy-2'-deoxyguanosine increased significantly in the diver group and acute DNA damage was observed (T1: 38.86±4.7; T2: 51.77±4.53; p<0.05). In the control group, the amount of 8-hydroxy-2'-deoxyguanosine was insignificant (C1: 47.48±3.73; T1: 38.86±4.7; p>0.05). CONCLUSIONS: It was found that air dives caused an increase in serum 8-hydroxy-2'-deoxyguanosine levels, leading to acute oxidative stress and aging. However, there is no chronic side effect, according to the study of samples taken from the control group. This was thought to be due to the relative sedentary life of the control group. The duration of the effect or the ability to return to normal values should be investigated with further studies planned with large populations.
Asunto(s)
Daño del ADN , Desoxiguanosina , 8-Hidroxi-2'-Desoxicoguanosina , Biomarcadores , Humanos , Estrés Oxidativo , Especies Reactivas de OxígenoRESUMEN
Aldehydes are abundantly present in tobacco smoke and in urban air pollution and are endogenously generated as products of the lipid peroxidation process. These molecules can react with DNA bases forming mutagenic exocyclic adducts, which have been used as biomarkers of aldehyde exposure and as potential tools for the study of inflammation, metal storage diseases, neurodegenerative disorders, and cancer. High-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS) provides a highly precise, specific and ultrasensitive method for the detection of exocyclic DNA adducts. Here we present and describe a validated micro-HPLC-Electro Spray Ionization (ESI)-MS/MS method for the quantification of 1,N2-propanodGuo, an adduct produced following the reaction between 2'-deoxyguanosine and acetaldehyde or crotonaldehyde.
Asunto(s)
Aductos de ADN/metabolismo , Daño del ADN , Pulmón/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Animales , Cromatografía Líquida de Alta Presión , Desoxiguanosina/metabolismo , RatasRESUMEN
A queilite actínica (QA) é uma desordem potencialmente maligna que pode evoluir para o carcinoma de células escamosas de lábio inferior (CCELI). Os fatores associados à sua probabilidade de transformação maligna ainda não estão bem estabelecidos, no entanto, a exposição à radiação ultravioleta (RUV) representa o principal fator de risco tanto para ocorrência da QA como do CCELI. A RUV causa danos oxidativos ao DNA, que levam à formação de 8-hidroxi-2'desoxiguanosina (8-OHdG). Esta pesquisa objetivou avaliar a associação entre a expressão da 8-OHdG e parâmetros clínico-patológicos, em uma série de casos de QA. A amostra foi constituída de 57 casos de QA, analisadas morfologicamente e classificadas de acordo com a gradação histopatológica de displasia epitelial (OMS). Foram observados casos sem displasia (7), com displasia epitelial leve (22), displasia epitelial moderada (17) e displasia epitelial severa (11). A expressão da 8- OHdG foi analisada de forma semiquantitativa por dois examinadores calibrados (Kappa=0,79), atribuindo um escore de imunoreatividade (EIR) que variava de 0 a 6 para os casos analisados. Os dados foram analisados através dos testes não paramétricos de Mann-Withney e de Kruskall-Wallis, com nível de significância de 5% (p<0,05). Observou-se que a maioria dos casos mostrou imunorreatividade forte (64,9%). Não foram constatadas diferenças estatisticamente significativas entre a expressão de 8-OHdG e as características clínicas da QA, nem entre a expressão de 8-OHdG e a gradação da displasia epitelial (p=0,350). A forte imunoexpressão de 8-OHdG na maioria dos casos de QA, independente das alterações morfológicas presentes, sugere que o dano oxidativo ao DNA está envolvido na patogênese desta desordem (AU).
Actinic cheilitis (AC) is a potentially malignant disorder that can progress to lower lip squamous cell carcinoma (LLSCC). It is not yet well-established which factors may be associated with the probability of malignant transformation of this condition, but the exposure to ultraviolet radiation (UVR) represents the main risk factor for both AC and LLSCC. RUV causes oxidative damage to DNA, which leads to the formation of 8-hydroxy-2'deoxyguanosine (8-OHdG), This research aimed to evaluate the expression of 8-OHdG, in a series of cases of AC and to associate its expression with clinical-pathological parameters. The sample consisted of 57 cases of AC, analyzed morphologically and classified according to the histopathological gradation of epithelial dysplasia (WHO). Cases without dysplasia (7), with mild epithelial dysplasia (22), moderate epithelial dysplasia (17) and severe epithelial dysplasia (11) were observed. The analysis of the expression of 8-OHdG was performed in a semi-quantitative way by two calibrated examiners (Kappa = 0.79), assigning an immunoreactivity score for each evaluated case, which could vary from 0 to 6. The data were analyzed using Mann-Withney and KruskallWallis non-parametric tests, with a significance level of 5% (p <0.05). It was observed that most cases showed strong immunoreactivity (64.9%). There were no statistically significant differences between the expression of 8-OHdG and the clinical characteristics of QA, neither between the expression of 8-OHdG and the gradation of epithelial dysplasia present in the evaluated cases (p = 0.350). The strong immunoexpression of 8-OHdG in most cases of QA, regardless of the morphological changes present, suggests that oxidative damage to DNA is involved in the pathogenesis of this disorder (AU).
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Queilitis , Estrés Oxidativo , Desoxiguanosina/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello , Rayos Ultravioleta , Inmunohistoquímica/métodos , Estadísticas no ParamétricasRESUMEN
Chronic exposure to inorganic arsenic (As) is associated with numerous adverse effects. Argentina is one of the countries affected by arsenicism; however, there are few studies that evaluate inorganic As exposure and its effects on child population. The aim of this study is to evaluate exposure to As through water and food in child populations living in the provinces of Santiago del Estero and Chaco (nâ¯=â¯101), and to determine the impact of this exposure analysing biomarkers of exposure (urine and hair As contents) and effect [8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG)]. The populations selected live in three areas with different levels of As in the drinking water (Santa Teresa de Carballo, 0.925â¯mg/L; Taco Pozo, 0.210â¯mg/L; Jumi Pozo, 0.016â¯mg/L). The As intakes through water and food are especially high in the areas with the greatest As exposure (Santa Teresa de Carballo, 1575⯱â¯8⯵g/day; Taco Pozo, 386⯱â¯8⯵g/day; Jumi Pozo, 39⯱â¯1⯵g/day). The total As contents in most of the samples of hair (0.11-13.11â¯mg/kg) and urine (31-4258⯵g/g creatinine) are higher than the reference values (hair: 1â¯mg/kg; urine: 50⯵g/g creatinine). The increase in the level of As exposure alters the profile of metabolites in urine, with a decrease of dimethylarsinic acid (10%) and an increase in the percentages of monomethylarsonic acid (4%) and inorganic As (6%). The results also show high values of 8-OHdG (3.7-37.8⯵g/g creatinine), a oxidative DNA damage marker, in the two areas with greater As exposure.
Asunto(s)
Arsénico/metabolismo , Arsenicales/metabolismo , Desoxiguanosina/análogos & derivados , Exposición a Riesgos Ambientales , Contaminantes Ambientales/metabolismo , Cabello/química , 8-Hidroxi-2'-Desoxicoguanosina , Argentina , Preescolar , Desoxiguanosina/metabolismo , Dieta , Agua Potable , Monitoreo del Ambiente , Femenino , Humanos , Masculino , EstudiantesRESUMEN
Objective To compare the level of oxidative deoxyribonucleic acid (DNA) damage (genotoxicity) between the offspring of mothers with and without diabetes diagnosed during pregnancy and its association with maternal body mass index (BMI). Methods We measured 8-hydroxy-deoxyguanosine (8-OH-dG), a marker of DNA oxidative damage, in venous umbilical cord plasma from newborns of mothers with (n=34) and without (n=56) diabetes diagnoses obtained during pregnancy. Two markers of oxidative stress - namely, nitric oxide degradation products (NOx) and total glutathione (GSH) - were quantified in both mothers and newborns. The effects of BMI, glycated hemoglobin (HbA1c), age and delivery mode were also analyzed. Results Newborns of mothers with diabetes during pregnancy exhibited higher levels of 8-OH-dG than those of mothers without diabetes (P<0.001). The other markers of oxidative stress were also higher in both mothers with diabetes and their newborns, with the exception of NOx in the mothers. The association of diabetes with 8-OH-dG was independent of other analyzed factors. Conclusion The offspring of mothers with diabetes during pregnancy are born with increased genotoxicity than the offspring of mothers without diabetes. BMI and HbA1c display an independent association with 8-OH-dG, particularly in the offspring of mothers not diagnosed with diabetes.
Asunto(s)
Daño del ADN , Desoxiguanosina/análogos & derivados , Diabetes Gestacional/metabolismo , Recién Nacido/sangre , Obesidad/metabolismo , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Desoxiguanosina/sangre , Femenino , Humanos , Estrés Oxidativo , Embarazo , Adulto JovenRESUMEN
OBJECTIVE: This study aims to evaluate the clinical and biochemical (oxidative stress and pro-inflammatory mediators) effects of the gaseous ozone use accompanied by scaling and root planning (SRP) in periodontal treatment. MATERIAL AND METHODS: The study population consisted of 40 patients with chronic periodontitis (CP) randomly sorted into two groups of 20. The experimental group received SRP plus 3 watts gaseous ozone in two separate applications five days apart, whereas the control group received SRP plus placebo. Clinical periodontal parameters were assayed and saliva samples were taken before the initial and one month after the second treatment. Periodontal examination assessed plaque index (PI), gingival index (GI), probing depth, and clinical attachment level (CAL). Total antioxidant status (TAS), total oxidant status (TOS), nitric oxide (NO), 8-hydroxy-2'-deoxyguanosine (8-OHdG), myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), and transforming growth factor-beta (TGF-ß) levels were evaluated from saliva samples. RESULTS: Changes following treatment in PI, GI, probing depth, and CAL scores were similar for both groups (p>0.05). Of note, TGF-ß levels were observed to be higher in the treatment group than in controls (p<0.05). Changes in 8-OHdG, TAS, TOS, NO, MPO, GSH and MDA levels, however, were not significantly different between groups (p>0.05). CONCLUSION: The findings of this study indicate that SRP plus gaseous ozone versus SRP alone does not correlate to a significant improvement in periodontal recovery.
Asunto(s)
Periodontitis Crónica/terapia , Oxidantes Fotoquímicos/uso terapéutico , Ozono/uso terapéutico , Aplanamiento de la Raíz/métodos , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Antioxidantes/análisis , Periodontitis Crónica/patología , Índice de Placa Dental , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análisis , Ensayo de Inmunoadsorción Enzimática , Femenino , Glutatión/análisis , Humanos , Masculino , Malondialdehído/análisis , Persona de Mediana Edad , Óxido Nítrico/análisis , Oxidantes/antagonistas & inhibidores , Índice Periodontal , Peroxidasa/análisis , Reproducibilidad de los Resultados , Saliva/química , Estadísticas no Paramétricas , Factores de Tiempo , Factor de Crecimiento Transformador beta/análisis , Resultado del TratamientoRESUMEN
INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de nelarabina en el tratamiento de pacientes pediátricos con leucemia linfoblástica aguda de células T con recaída o refractariedad a dos líneas de quimioterapia. El tratamiento estándar en el manejo de pacientes pediátricos con leucemia linfoblástica aguda (LLA) con varias recaídas es el trasplante de progenitores hematopoyéticos (TPH), utilizado como terapia de consolidación una vez que el paciente se encuentra en remisión. En la actualidad, EsSalud cuenta con clofarabina como tratamiento que lleva a los pacientes a remisión de manera que puedan ser trasplantados. El uso por fuera del Petitorio Farmacológico de EsSalud de clofarabina para el tratamiento de pacientes con LLA (de linfocitos T [T-LLA] y de linfocitos B [B-LLA]) que han recaído luego de dos líneas de quimioterapia fue aprobado en el 2016 mediante el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 001-SDEPFyOTS-DETS-IETSI-2016 y se encuentra vigente a la fecha. Sin embargo, los especialistas de la institución sostienen que, de acuerdo a su experiencia desde la aprobación de clofarabina hace más de dos años, si bien ésta muestra tasas de respuesta moderadas en pacientes con inmunofenotipo B (i.e., B-LLA), esto no se ha logrado en pacientes con inmunofenotipo T (i.e., T-LLA), y que por lo tanto se requiere de otra alternativa terapéutica en este subgrupo especifico de pacientes. Además, afirman que los pacientes no remitirán espontáneamente y que la sobrevida general es de alrededor de tres meses con tratamiento paliativo. TECNOLOGÍA SANITARIA DE INTERÉS: Nelarabina (2-amino-9ß-D-arabinosyl-6-methoxy-9H-guanina), de nombre comercial ARRANON®, es un análogo de purina de cuarta generación. Este es un profármaco del análogo de desoxiguanosina ara-G sintetizado (9-ß-D-arabinofuranosylguanina). Este profármaco es desmetilado rápidamente por la adenosina desaminasa (ADA) a ara-G y una vez dentro de la célula es fosforilado por la desoxiguanosina quinasa y la desoxicitidina quinasa a su metabolito 5´-monofosfato. Dicho metabolito monofosfato es convertido a la forma activa 5´-trifosfato ara-GTP. Ara-GTP se acumula en los blastos leucémicos lo que lleva a la incorporación preferente de ara-GTP en el ácido desoxirribonucleico (ADN), conduciendo a la inhibición de su síntesis. La inhibición de la síntesis de ADN lleva a la muerte de los blastos leucémicos. Es este el mecanismo a través del cual nelarabina podría tener un impacto sobre la proliferación de células cancerosas en pacientes con LLA. METODOLOGÍA: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de nelarabina en el tratamiento de pacientes pediátricos con LLA de células T con recaída o refractariedad a dos líneas de quimioterapia en las bases de datos de PubMed, Cochrane Library, el metabuscador TRIPdatabase y el sitio web ww.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Instituto de Evaluación de Efectividad Clínica y Sanitaria (IECS), Instituto de Evaluación de Tecnología en Salud (IETS); así como en organizaciones especializadas en oncología como European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN) y American Society of Clinical Oncology (ASCO). RESULTADOS: Se llevó a cabo una búsqueda de evidencia científica relacionada al uso de nelarabina en el tratamiento de pacientes pediátricos con LLA de células T recurrente o refractario a dos líneas de quimioterapia. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). A la fecha, la evidencia disponible relacionada al tratamiento con nelarabina de pacientes pediátricos con T-LLA es muy escasa, y no se ha publicado ningún estudio de la eficacia comparativa entre nelarabina y clofarabina. Con ello, la evidencia identificada en la presente búsqueda sistemática e incluida en el presente dictamen corresponde principalmente a un ensayo de fase IV no controlado del uso de nelarabina, una guía de práctica clínica (GPC) y una evaluación de tecnología sanitaria (ETS). Adicionalmente, en ausencia de estudios comparativos, y frente a la preocupación de los especialistas de una eficacia diferenciada de clofarabina entre inmunofenotipos, se llevó a cabo una búsqueda de la evidencia del uso de clofarabina en la población de pacientes con T-LLA específicamente, con la finalidad de evaluar si se trata de una alternativa factible para dicha subpoblación. De ella se obtuvo únicamente un ensayo de fase II de un solo brazo que explora la respuesta diferenciada al tratamiento con clofarabina/ciclofosfamida/etopósido entre pacientes pediátricos con B-LLA y T-LLA con dos o más recaídas. CONCLUSIONES: La evidencia identificada a la fecha no permite establecer la eficacia comparativa entre nelarabina y clofarabina. A pesar de que la evidencia que apoya el uso de nelarabina en pacientes con T-LLA es escasa y de baja calidad, y la comparación con clofarabina es descriptiva e indirecta, la baja tasa de respuesta y la tasa nula de supervivencia al año observada en la población con T-LLA tras el uso de clofarabina sugieren que este no sería una alternativa de tratamiento factible para dicho inmunofenotipo y, por lo tanto, nos encontraríamos en un escenario de vacío terapéutico. Además, considerando que, de acuerdo a los especialistas de la institución y la historia natural de la enfermedad, los pacientes no remitirán espontáneamente, se tiene entonces que nelarabina podría ofrecer una tasa de respuesta de alrededor de 40 %. el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI), aprueba el uso fuera del petitorio de nelarabina en el tratamiento de pacientes pediátricos con diagnóstico de leucemia linfoblástica aguda de células T con recaída o refractariedad a dos líneas de quimioterapia. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación.
Asunto(s)
Humanos , Niño , Purinas/uso terapéutico , Desoxiguanosina/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Evaluación de la Tecnología Biomédica , Análisis Costo-EficienciaRESUMEN
Abstract Objective: This study aims to evaluate the clinical and biochemical (oxidative stress and pro-inflammatory mediators) effects of the gaseous ozone use accompanied by scaling and root planning (SRP) in periodontal treatment. Material and Methods: The study population consisted of 40 patients with chronic periodontitis (CP) randomly sorted into two groups of 20. The experimental group received SRP plus 3 watts gaseous ozone in two separate applications five days apart, whereas the control group received SRP plus placebo. Clinical periodontal parameters were assayed and saliva samples were taken before the initial and one month after the second treatment. Periodontal examination assessed plaque index (PI), gingival index (GI), probing depth, and clinical attachment level (CAL). Total antioxidant status (TAS), total oxidant status (TOS), nitric oxide (NO), 8-hydroxy-2'-deoxyguanosine (8-OHdG), myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), and transforming growth factor-beta (TGF-β) levels were evaluated from saliva samples. Results: Changes following treatment in PI, GI, probing depth, and CAL scores were similar for both groups (p>0.05). Of note, TGF-β levels were observed to be higher in the treatment group than in controls (p<0.05). Changes in 8-OHdG, TAS, TOS, NO, MPO, GSH and MDA levels, however, were not significantly different between groups (p>0.05). Conclusion: The findings of this study indicate that SRP plus gaseous ozone versus SRP alone does not correlate to a significant improvement in periodontal recovery.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Oxidantes Fotoquímicos/uso terapéutico , Ozono/uso terapéutico , Aplanamiento de la Raíz/métodos , Periodontitis Crónica/terapia , Saliva/química , Factores de Tiempo , Ensayo de Inmunoadsorción Enzimática , Índice Periodontal , Índice de Placa Dental , Reproducibilidad de los Resultados , Factor de Crecimiento Transformador beta/análisis , Resultado del Tratamiento , Oxidantes/antagonistas & inhibidores , Peroxidasa/análisis , Estadísticas no Paramétricas , Desoxiguanosina/análisis , Desoxiguanosina/análogos & derivados , Periodontitis Crónica/patología , Glutatión/análisis , Malondialdehído/análisis , Persona de Mediana Edad , Óxido Nítrico/análisis , Antioxidantes/análisisRESUMEN
Uric acid presents different roles in an organism, since it can act as an antioxidant or a pro-oxidant molecule. High serum uric acid levels may cause damage to several structures, including nucleic acids and its components. Therefore, in this study the association between increased serum uric acid concentrations and oxidation of nucleosides was investigated by assessment of urinary 8-hydroxydeoxyguanosine (8-OHdG) in patients with type 2 diabetes (T2D) and in healthy individuals. Urinary 8-OHdG and biochemical parameters were assessed in 61 patients who were initially grouped into 2 groups based on the median serum uric acid levels (<5.3 mg/dL and ≥5.3 mg/dL). Urinary 8-OHdG was higher in patients with T2D and serum uric acid levels ≥5.3 mg/dL, when compared with the patients with serum uric acid levels <5.3 mg/dL; however, co-occurrence of high serum uric acid with high urinary 8-OHdG was not observed in healthy individuals. A significant positive correlation between 8-OHdG and uric acid (r = 0.40, P < 0.01) was observed in patients with T2D. High serum uric acid levels were associated with high urinary 8-OHdG levels in patients with T2D, and this association was independent of gender, hypertension, body mass index, and serum creatinine.
Asunto(s)
Desoxiguanosina/análogos & derivados , Diabetes Mellitus Tipo 2/metabolismo , Nucleósidos/metabolismo , Ácido Úrico/sangre , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Anciano , Creatinina/sangre , Desoxiguanosina/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxidación-ReducciónRESUMEN
OBJECTIVE: Relacin is a synthetic molecule that targets RelA, an essential protein in a conserved bacterial stress response system. It was shown to inhibit bacterial growth. The aims of this study were to evaluate the antimicrobial effect of relacin combined with sodium hypochlorite (NaOCl) on Enterococcus faecalis biofilms and to evaluate the cytotoxicity of relacin. MATERIAL AND METHODS: 48-h E. faecalis OG1RF biofilms were treated by various concentrations of relacin in order to determine its inhibitory concentration. Then, the 48-h biofilms were treated either with 1-min NaOCl (0.01%, 0.05%) alone, or in combination of relacin. As a means of comparison, the biofilms of ΔrelA were also treated by 1-min NaOCl (0.01%, 0.05%, 0.25%). The treatment efficacy was determined by agar plate count assays. The cytotoxicity of relacin was examined on human gingival epithelial cells Ca9-22 and murine fibroblasts NIH-3T3 by a methyl thiazolyltetrazolium (MTT) assay and a lactate dehydrogenase assay. Statistical analysis was performed by one-way or two-way analysis of variance (ANOVA) with Bonferroni's post-hoc test and an independent Student's t-test. A significance level of p<0.05 was used. RESULTS: Relacin inhibited the growth of OG1RF biofilms partially at 8 mM and fully at 14 mM. The relacin (14 mM) and NaOCl combined treatment resulted in significantly higher treatment efficacy than NaOCl treatment alone. At 0.05% NaOCl, the combined treatment resulted in 5.65 (±0.19) log reduction in biofilm viability. The ΔrelA biofilms were more susceptible to NaOCl treatment than the wild type biofilms at 0.25% NaOCl. Relacin at 14 mM was not toxic to host epithelial cells and fibroblasts. CONCLUSIONS: The combination of relacin with a low concentration of NaOCl was effective and not cytotoxic.
Asunto(s)
Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Desoxiguanosina/análogos & derivados , Dipéptidos/farmacología , Enterococcus faecalis/efectos de los fármacos , Hipoclorito de Sodio/farmacología , Análisis de Varianza , Animales , Biopelículas/crecimiento & desarrollo , Recuento de Colonia Microbiana , Desoxiguanosina/farmacología , Enterococcus faecalis/fisiología , Células Epiteliales/efectos de los fármacos , Formazáns , Encía/citología , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Células 3T3 NIH/efectos de los fármacos , Reproducibilidad de los Resultados , Sales de Tetrazolio , Factores de TiempoRESUMEN
The progressive decline of the ovarian follicle pool leads to reproductive ageing. The latter is accompanied by age-related disorders, including various types of cancer. In fact, the highest rates of ovarian cancer (OC) occur at postmenopause while OC risk is significantly modulated by parity records during previous fertile life. We approached the age-parity relationship in the C57BL/6 mouse model and herein describe the presence of nonheme iron (hemosiderin) and deposits of the "age pigment" lipofuscin in reproductively aged mouse ovaries by applying conventional histochemical methods and autofluorescence. In addition, the 8-OHdG adduct was evaluated in ovarian genomic DNA. Both hemosiderin and lipofuscin were significantly higher in virgin compared to multiparous ovaries. The same pattern was observed for 8-OHdG. We conclude that nulliparity induces a long-term accumulation of iron and lipofuscin with concomitant oxidative damage to DNA in the mouse ovary. Since lipofuscin is a widely accepted senescence marker and given the recently postulated role of lipofuscin-associated iron as a source of reactive oxygen species (ROS) in senescent cells, these findings suggest a possible pathogenic mechanism by which nulliparity contributes to an increased OC risk in the postmenopausal ovary.
Asunto(s)
Envejecimiento/metabolismo , Hemosiderina/metabolismo , Lipofuscina/metabolismo , Ovario/crecimiento & desarrollo , Ovario/metabolismo , Paridad/fisiología , Reproducción , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Daño del ADN , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Femenino , Genoma , Ratones Endogámicos C57BL , EmbarazoRESUMEN
Exocyclic DNA adducts are considered as potential tools for the study of oxidative stress-related diseases, but an important aspect is their chemical reactivity towards oxidant species. We report here the oxidation of 1-N2-etheno-2'-deoxyguanosine (1,N2-εdGuo) by singlet molecular oxygen (1O2) generated by a non-ionic water-soluble endoperoxide [N,N'-di(2,3-dihydroxypropyl)-1,4-naphthalenedipropanamide endoperoxide (DHPNO2)] and its corresponding oxygen isotopically labeled [18O]-[N,N'-di(2,3-dihydroxypropyl)-1,4- naphthalenedipropanamide endoperoxide (DHPN18O2)], and by photosensitization with two different photosensitizers [methylene blue (MB) and Rose Bengal (RB)]. Products detection and characterization were achieved using high performance liquid chromatography (HPLC) coupled to ultraviolet and electrospray ionization (ESI) tandem mass spectrometry, and nuclear magnetic resonance (NMR) analyses. We found that dGuo is regenerated via reaction of 1O2 with the ε-linkage, and we propose a dioxetane as an intermediate, which cleaves and loses the aldehyde groups as formate residues, or alternatively, it generates a 1,2-ethanediol adduct. We also report herein the quenching rate constants of 1O2 by 1,N2-εdGuo and other etheno modified nucleosides. The rate constant (kt) values obtained for etheno nucleosides are comparable to the kt of dGuo. From these results, we suggest a possible role of 1O2 in the cleanup of etheno adducts by regenerating the normal base.
Asunto(s)
Daño del ADN , Desoxiguanosina/química , Oxígeno Singlete/química , Desoxiguanosina/análogos & derivados , Desoxiguanosina/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Oxidación-ReducciónRESUMEN
PURPOSE: Breast cancer is the most common neoplasm in women and has the highest associated mortality rate. Rapid detection programmes can provide early diagnosis and increase the chances of survival. There are no specific tumor biomarkers for the early phase of the disease. The primary aim of this study was to search a blood biomarker with levels that exceeded the normal range established in the general population that could be used to screen breast cancer. METHODS/PATIENTS: Case-control study. Conventional as well as research (NGAL, EGFR and 8-OHdG) tumor biomarkers were analyzed. RESULTS: A total of 126 women were enrolled (cases: 63 patients with local breast cancer; Controls: 63 healthy women). Significant differences were found in patients with higher levels of the conventional markers, Ca15.3, CEA, Cyfra 21.1 and NSE. However, when commercial cut-off values were used, only Ca 15.13 was significant. In the group of research biomarkers, significantly higher levels of EGFR were found in the control group, and of 8-OHdG in the case group. Using logistic regression analysis and a ROC curve, an equation composed of five markers, Ca 15.3, NSE, NGAL, EGFR and 8-OHdG, which yielded a correct diagnostic probability of breast cancer of 91.8% was obtained. CONCLUSIONS: 8-OHdG has been identified as a new potential marker for screening early stage breast cancer. In addition, a model that combines five blood markers that can be used as a diagnostic test in certain groups of patients has been developed. New studies with a larger sample size are needed to verify the results obtained.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias de la Mama/diagnóstico , Desoxiguanosina/análogos & derivados , Detección Precoz del Cáncer/métodos , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Anciano , Antígenos de Neoplasias/sangre , Neoplasias de la Mama/sangre , Antígeno CA-19-9/sangre , Antígeno Carcinoembrionario/sangre , Estudios de Casos y Controles , Desoxiguanosina/sangre , Femenino , Humanos , Queratina-19/sangre , Persona de Mediana Edad , Fosfopiruvato Hidratasa/sangre , alfa-Fetoproteínas/análisisRESUMEN
Introduction: Homocysteine (Hcy) tissue accumulation occurs in a metabolic disease characterized biochemically by cystathionine ß-synthase (CBS) deficiency and clinically by mental retardation, vascular problems, and skeletal abnormalities. Previous studies indicate the occurrence of DNA damage secondary to hyperhomocysteinemia and it was observed that DNA damage occurs in leukocytes from CBS-deficient patients. This study aimed to investigate whether an oxidative mechanism could be involved in DNA damage previously found and investigated the in vitro effect of N-acety-L-cysteine (NAC) on DNA damage caused by high Hcy levels. Methods: We evaluated a biomarker of oxidative DNA damage in the urine of CBSdeficient patients, as well as the in vitro effect of NAC on DNA damage caused by high levels of Hcy. Moreover, a biomarker of lipid oxidative damage was also measured in urine of CBS deficient patients. Results: There was an increase in parameters of DNA (8-oxo-7,8-dihydro-2'- deoxyguanosine) and lipid (15-F2t-isoprostanes levels) oxidative damage in CBS-deficient patients when compared to controls. In addition, a significant positive correlation was found between 15-F2t-isoprostanes levels and total Hcy concentrations. Besides, an in vitro protective effect of NAC at concentrations of 1 and 5 mM was observed on DNA damage caused by Hcy 50 µM and 200 µM. Additionally, we showed a decrease in sulfhydryl content in plasma from CBS-deficient patients when compared to controls. Discussion: These results demonstrated that DNA damage occurs by an oxidative mechanism in CBS deficiency together with lipid oxidative damage, highlighting the NAC beneficial action upon DNA oxidative process, contributing with a new treatment perspective of the patients affected by classic homocystinuria.
Asunto(s)
Humanos , Femenino , Niño , Adolescente , Adulto , Adulto Joven , Acetilcisteína/farmacología , Daño del ADN , Estrés Oxidativo , Cistationina/metabolismo , Desoxiguanosina/orina , Homocistinuria/genética , Antioxidantes/farmacología , Biomarcadores/orina , Estudios de Casos y Controles , Creatinina/orina , Ensayo Cometa , Cistationina/biosíntesis , Cistationina/sangre , Isoprostanos/análisis , Desoxiguanosina/análogos & derivados , Homocisteína/sangre , Homocistinuria/sangreRESUMEN
Abstract Objective Relacin is a synthetic molecule that targets RelA, an essential protein in a conserved bacterial stress response system. It was shown to inhibit bacterial growth. The aims of this study were to evaluate the antimicrobial effect of relacin combined with sodium hypochlorite (NaOCl) on Enterococcus faecalis biofilms and to evaluate the cytotoxicity of relacin. Material and Methods 48-h E. faecalis OG1RF biofilms were treated by various concentrations of relacin in order to determine its inhibitory concentration. Then, the 48-h biofilms were treated either with 1-min NaOCl (0.01%, 0.05%) alone, or in combination of relacin. As a means of comparison, the biofilms of ΔrelA were also treated by 1-min NaOCl (0.01%, 0.05%, 0.25%). The treatment efficacy was determined by agar plate count assays. The cytotoxicity of relacin was examined on human gingival epithelial cells Ca9-22 and murine fibroblasts NIH-3T3 by a methyl thiazolyltetrazolium (MTT) assay and a lactate dehydrogenase assay. Statistical analysis was performed by one-way or two-way analysis of variance (ANOVA) with Bonferroni's post-hoc test and an independent Student's t-test. A significance level of p<0.05 was used. Results Relacin inhibited the growth of OG1RF biofilms partially at 8 mM and fully at 14 mM. The relacin (14 mM) and NaOCl combined treatment resulted in significantly higher treatment efficacy than NaOCl treatment alone. At 0.05% NaOCl, the combined treatment resulted in 5.65 (±0.19) log reduction in biofilm viability. The ΔrelA biofilms were more susceptible to NaOCl treatment than the wild type biofilms at 0.25% NaOCl. Relacin at 14 mM was not toxic to host epithelial cells and fibroblasts. Conclusions The combination of relacin with a low concentration of NaOCl was effective and not cytotoxic.
Asunto(s)
Humanos , Animales , Hipoclorito de Sodio/farmacología , Enterococcus faecalis/efectos de los fármacos , Biopelículas/efectos de los fármacos , Desoxiguanosina/análogos & derivados , Dipéptidos/farmacología , Antibacterianos/farmacología , Sales de Tetrazolio , Factores de Tiempo , Recuento de Colonia Microbiana , Pruebas de Sensibilidad Microbiana , Reproducibilidad de los Resultados , Análisis de Varianza , Enterococcus faecalis/fisiología , Biopelículas/crecimiento & desarrollo , Células 3T3 NIH/efectos de los fármacos , Desoxiguanosina/farmacología , Células Epiteliales/efectos de los fármacos , Formazáns , Encía/citologíaRESUMEN
Maternal obesity has been related to adverse neonatal outcomes and fetal programming. Oxidative stress and adipokines are potential biomarkers in such pregnancies; thus, the measurement of these molecules has been considered critical. Therefore, we developed artificial neural network (ANN) models based on maternal weight status and clinical data to predict reliable maternal blood concentrations of these biomarkers at the end of pregnancy. Adipokines (adiponectin, leptin, and resistin), and DNA, lipid and protein oxidative markers (8-oxo-2'-deoxyguanosine, malondialdehyde and carbonylated proteins, respectively) were assessed in blood of normal weight, overweight and obese women in the third trimester of pregnancy. A Back-propagation algorithm was used to train ANN models with four input variables (age, pre-gestational body mass index (p-BMI), weight status and gestational age). ANN models were able to accurately predict all biomarkers with regression coefficients greater than R² = 0.945. P-BMI was the most significant variable for estimating adiponectin and carbonylated proteins concentrations (37%), while gestational age was the most relevant variable to predict resistin and malondialdehyde (34%). Age, gestational age and p-BMI had the same significance for leptin values. Finally, for 8-oxo-2'-deoxyguanosine prediction, the most significant variable was age (37%). These models become relevant to improve clinical and nutrition interventions in prenatal care.