Discriminación percibida por pacientes en seguimiento por COVID-19. Tajamar Regalado, Ecuador

Fundamento la COVID-19 tuvo repercusión en el estado biopsicosocial de la población. Entre las actitudes y comportamientos, la discriminación se manifestó como una de las respuestas a diferentes niveles de interrelación personal y social. Objetivo describir la discriminación percibida por pacientes en seguimiento por COVID-19. Métodos estudio descriptivo y transversal, realizado en el periodo septiembre de 2021 a febrero de 2022, con todos los pacientes con seguimiento por COVID-19 (N=89) residentes en el barrio de Tajamar Regalado (Tulcán, Ecuador). Mediante la encuesta se obtuvo información sobre las variables: tipo de institución donde recibió seguimiento médico, percepción de discriminación, apoyo social y apoyo comunitario. Resultados el 60,67 % de los pacientes refirió que casi siempre lamentaba haberse contagiado de COVID-19; el 59,55 %, que siempre sintió ser discriminado por haber padecido la enfermedad; el 40,45 %, que casi siempre consideró importante utilizar medidas de protección para evitar más contagios en su comunidad; el 48,31 % planteó que casi siempre recibió consejería por el personal de salud; y el 59,55 % consideró que su salud mental se vio afectada. Casi la mitad de los pacientes expresó haber recibido un apoyo social muy malo, y el 51,68 % un apoyo social malo parte de las autoridades en particular. Conclusiones durante la pandemia de COVID-19 existió un rechazo social a los pacientes contagiados, el cual provocó afectaciones en la salud mental de estos. Se evidenció una falta de apoyo por parte de la comunidad y las autoridades; y una escasa consejería por el personal de salud.

Foundation COVID-19 had an impact on the population' biopsychosocial state. Among attitudes and behaviors, discrimination manifested itself as one of the responses to different levels of personal and social interrelation. Objective to describe the discrimination perceived by patients being monitored for COVID-19. Methods descriptive and cross-sectional study, carried out from September 2021 to February 2022, in all patients monitored for COVID-19 (N=89) who live in Tajamar Regalado neighborhood (Tulcán, Ecuador). Through the survey, information was obtained on the variables: type of institution where they received medical follow-up, perception of discrimination, social support and community support. Results 60.67% of patients reported that they almost always regretted having been infected with COVID-19; 59.55%, who always felt they were discriminated against for having suffered from the disease; 40.45%, who almost always considered it important to use protective measures to avoid further infections in their community; 48.31% stated that they almost always received counseling from health personnel; and 59.55% considered that their mental health was affected. Almost half of the patients expressed having received very bad social support, and 51.68% received bad social support from the authorities in particular. Conclusions during the COVID-19 pandemic, there was social rejection of infected patients, which caused effects on their mental health. A lack of support from the community and authorities was evident; and little counseling by health personnel.

Aplicabilidad del componente lactancia materna de la normativa Establecimientos de Salud Amigos de la Madre y del Niño

Introducción: Dentro de los objetivos estratégicos del Plan de Desarrollo y Ordenamiento Territorial de la provincia de Esmeraldas, Ecuador, se plantea generar acciones afirmativas para garantizar el acceso a la salud y la promoción de derechos y deberes a favor de la población; sin embargo, apenas inicia con la normativa sanitaria para la certificación de ESAMyN. Objetivo: Describir la aplicabilidad del componente lactancia materna normativa del Establecimientos de Salud Amigos de la Madre y del Niño en el Centro de Salud Tipo C Las Palmas de Esmeraldas, Ecuador. Método: Se realizó un estudio bajo una modalidad mixta, donde se aplicó una encuesta sobre dicha normativa a 56 profesionales de la salud Resultados: El 75 % del personal tiene conocimiento sobre la normativa ESAMYN pero se identificó que el personal no aplica la normativa vigente, pues solo el 26,79 % sabe sobre su composición, solo el 43 % respondió correctamente el objetivo de la misma y el 29 % a quién va dirigida. Por otra parte, el 57 % del personal de Enfermería conoce sobre cuántas pruebas son necesarias a una mujer durante el embarazo, parto y posparto; y el 41 % manifestó conocer qué es el acompañamiento familiar durante el parto. Conclusiones: El presente estudio aporta una estrategia para mejorar el servicio de salud hacia las madres y sus hijos recién nacidos sobre la normativa de ESAMYN, lo que contribuye a la disminución de brechas intersectoriales y regionales.

Introduction: Within the strategic objectives of the Territorial Development and Planning Plan of the province of Esmeraldas, Ecuador, it is proposed to generate affirmative actions to guarantee access to health and the promotion of rights and duties in favor of the population; However, it is just beginning with the health regulations for ESAMyN certification. Objective: To describe the applicability of the normative breastfeeding component of the Mother and Child Friendly Health Establishments in the Type C Health Center Las Palmas de Esmeraldas, Ecuador. Method: A study was carried out under a mixed modality, where a survey about said regulations was applied to 56 health professionals. Results: 75% of the staff have knowledge about the ESAMYN regulations but it was identified that the staff does not apply the current regulations. since only 26.79% know about its composition, only 43% correctly answered its objective and 29% to whom it is directed. On the other hand, 57% of Nursing staff know how many tests are necessary for a woman during pregnancy, childbirth and postpartum; and 41% said they knew what family support during childbirth is. Conclusions: The present study provides a strategy to improve the health service for mothers and their newborn children based on the ESAMYN regulations, which contributes to the reduction of intersectoral and regional gaps.

Introdução: Dentro dos objetivos estratégicos do Plano de Desenvolvimento e Planejamento Territorial da província de Esmeraldas, Equador, propõe-se gerar ações afirmativas para garantir o acesso à saúde e a promoção de direitos e deveres em favor da população; No entanto, as regulamentações sanitárias para a certificação ESAMyN estão apenas começando. Objetivo: Descrever a aplicabilidade do componente normativo de amamentação dos Estabelecimentos de Saúde Amigos da Mãe e da Criança do Centro de Saúde Tipo C Las Palmas de Esmeraldas, Equador. Método: Foi realizado um estudo de modalidade mista, onde foi aplicado um levantamento sobre as referidas normas a 56 profissionais de saúde. Resultados: 75% dos funcionários têm conhecimento sobre as normas da ESAMYN, mas identificou-se que os funcionários não aplicam as normas vigentes. regulamentação. como apenas 26,79% conhecem sua composição, apenas 43% responderam corretamente seu objetivo e 29% a quem se destina. Por outro lado, 57% dos trabalhadores de Enfermagem sabem quantos exames são necessários para uma mulher durante a gravidez, parto e pós-parto; e 41% disseram saber o que é o apoio familiar durante o parto. Conclusões: O presente estudo fornece uma estratégia para melhorar o serviço de saúde para mães e seus filhos recém-nascidos com base na regulamentação da ESAMYN, o que contribui para a redução de lacunas intersetoriais e regionais.

Insatisfacción con la atención de salud en los usuarios del Centro de Salud Tajamar, Ecuador

Introducción: La OMS atribuye entre 5,7 y 8,4 millones de muertes anuales a la atención de calidad deficiente en los países de ingresos bajos y medianos, lo que representa hasta el 15 % de las muertes en esos países; es decir, que a nivel general existe un alto nivel de insatisfacción sobre todo en los países tercermundistas. Objetivo: Evaluar el grado de insatisfacción de la atención de salud en los usuarios del Centro de Salud Tajamar, Ecuador. Método: Se realizó un estudio cuantitativo observacional, descriptivo, de corte transversal en el centro de salud Tajamar de Ecuador durante el año 2022. Se trabajó con 215 usuarios por el método aleatorio simple, se utilizó los métodos científicos de observación, análisis y síntesis, empírico de encuesta. Las respuestas de la encuesta permitieron dar un grado de consecución en: muy adecuado, adecuado, poco adecuado e inadecuado, además de siempre, casi siempre y nunca. Se tuvo en cuenta criterios de inclusión y exclusión. Resultados: El 51,2 % consideró muy adecuado el trato por parte del personal de salud, solo el 32,6 % encontró adecuado el estado general de la infraestructura, el 44,2 estuvo de acuerdo con el medicamento recetado. En cuanto a la información brindada el 37,7 % siempre lo halló correcto y entendible. El 69 % alegó volvería al centro nuevamente. En sentido general el 37 % y el 29 % de los usuarios calificaron de neutra y negativa la calidad de la atención en los servicios de salud prestados. Conclusiones: Se logró evidenciar la insatisfacción de la atención en salud en los usuarios del Centro de Salud Tajamar. Se recomienda realizar intervención para mejorar la calidad de atención en dicha unidad de salud.

Introduction: WHO attributes between 5.7 and 8.4 million deaths annually to poor-quality care in low- and middle-income countries, accounting for up to 15% of deaths in these countries; That is to say, at a general level there is a high level of dissatisfaction, especially in third world countries. Objective: To evaluate the degree of dissatisfaction with health care in users of the Tajamar Health Center, Ecuador. Method: A quantitative observational, descriptive, cross-sectional study was carried out at the Tajamar health center in Ecuador during the year 2022. We worked with 215 users using the simple random method, using scientific methods of observation, analysis and synthesis. empirical survey. The survey responses made it possible to give a degree of achievement in: very adequate, adequate, slightly adequate and inadequate, as well as always, almost always and never. Inclusion and exclusion criteria were taken into account. Results: 51.2% considered the treatment by health personnel to be very adequate, only 32.6% found the general state of the infrastructure adequate, 44.2% agreed with the prescribed medication. Regarding the information provided, 37.7% always found it correct and understandable. 69% said they would return to the center again. In general, 37% and 29% of users described the quality of care in the health services provided as neutral and negative. Conclusions: Dissatisfaction with health care among users of the Tajamar Health Center was evident. It is recommended to carry out an intervention to improve the quality of care in said health unit.

Introdução: A OMS atribui anualmente entre 5,7 e 8,4 milhões de mortes a cuidados de má qualidade em países de baixo e médio rendimento, sendo responsáveis por até 15% das mortes nestes países; Isto é, a nível geral existe um elevado nível de insatisfação, especialmente nos países do terceiro mundo. Objetivo: Avaliar o grau de insatisfação com os cuidados de saúde em usuários do Centro de Saúde Tajamar, Equador. Método: Foi realizado um estudo quantitativo observacional, descritivo e transversal no centro de saúde Tajamar, no Equador, durante o ano de 2022. Trabalhamos com 215 usuários através do método aleatório simples, utilizando métodos científicos de observação, análise e síntese. As respostas ao inquérito permitiram atribuir um grau de realização em: muito adequado, adequado, pouco adequado e inadequado, bem como sempre, quase sempre e nunca. Critérios de inclusão e exclusão foram levados em consideração. Resultados: 51,2% consideraram o tratamento do pessoal de saúde muito adequado, apenas 32,6% consideraram adequado o estado geral da infraestrutura, 44,2% concordaram com a medicação prescrita. Quanto às informações prestadas, 37,7% consideraram-nas sempre corretas e compreensíveis. 69% disseram que voltariam ao centro novamente. Em geral, 37% e 29% dos utentes descreveram a qualidade dos cuidados nos serviços de saúde prestados como neutra e negativa. Conclusões: Ficou evidente a insatisfação com a assistência à saúde entre os usuários do Centro de Saúde Tajamar. Recomenda-se a realização de uma intervenção para melhorar a qualidade do atendimento na referida unidade de saúde.

Cuidados de la salud en tiempos de COVID-19 para adultos mayores del Centro de Salud San Francisco de Tulcán, Ecuador

Introducción: La pandemia de la COVID-19 tiene impacto en la salud pública, en el crecimiento económico y en el desarrollo social. En las personas, estos efectos se reflejan en la salud y situación económica, en particular en las personas adultas mayores. Objetivo: Caracterizar los cuidados de la salud durante la pandemia de COVD-19 en los adultos mayores del centro de salud San Francisco de la ciudad de Tulcán-Ecuador. Método: Se realizó un estudio observacional, descriptivo de corte transversal con técnicas cualicuantitativa. El universo constituido por 28 adultos mayores del Centro de Salud San Francisco, ciudad de Tulcán, Ecuador. Las variables utilizadas fueron sobre la atención brindada por el personal de salud a los adultos mayores. Los datos obtenidos unido a la experiencia de los autores permitieron triangular los resultados y redactar el informe final de la investigación. Resultados: El 75 % de los encuestados recibieron orientación sobre medidas para la prevención y la importancia de los cuidados; el 67,8 % señala no recibió atención oportuna ante la demanda, el 92,8 % evaluaron como adecuada la comunicación; el 45 % recibió atención mensual, el 50 % no recibió atención psicológica. Conclusiones: La COVID-19 constituye un inconveniente para el adecuado cuidado de la salud en los adultos mayores. Se necesita atención multidisciplinaria, integral, integrada y centrada en las personas mayores en la atención primaria de salud. Necesitan mayor apoyo por su vulnerabilidad y comorbilidades. La atención domiciliaria adecuada es efectiva para la prevención de la enfermedad y por tanto de las complicaciones.

Introduction: The COVID-19 pandemic has an impact on public health, economic growth and social development. In people, these effects are reflected in the health and economic situation, particularly in the elderly. Objective: To characterize health care during the COVD-19 pandemic in the elderly at the San Francisco health center in the city of Tulcán, Ecuador. Method: An observational, descriptive, cross-sectional study was carried out with qualitative-quantitative techniques. The population made up of 28 older adults from the San Francisco Health Center, city of Tulcán, Ecuador. The variables used were about the care provided by health personnel to the elderly. The data obtained together with the experience of the authors allowed triangulating the results and writing the final report of the research. Results: 75% of the respondents received guidance on measures for prevention and the importance of care; 67.8% indicated that they did not receive timely attention to the demand, 92.8% evaluated the communication as adequate; 45% received monthly care; 50% did not receive psychological care. Conclusions: COVID-19 constitutes an inconvenience for adequate health care in older adults. Multidisciplinary, comprehensive, integrated and centered care for older people in primary health care is needed. They need more support due to their vulnerability and comorbidities. Adequate home care is effective in preventing the disease and therefore its complications.

Introdução: A pandemia de COVID-19 tem impacto na saúde pública, no crescimento econômico e no desenvolvimento social. Nas pessoas, esses efeitos se refletem na situação econômica e de saúde, principalmente nos idosos. Objetivo: Caracterizar a atenção à saúde durante a pandemia de COVD-19 em idosos no centro de saúde San Francisco na cidade de Tulcán-Equador. Método: Estudo observacional, descritivo, transversal, com técnicas quali-quantitativas. O universo foi constituído por 28 idosos do Centro de Saúde San Francisco, cidade de Tulcán, Equador. As variáveis utilizadas foram sobre os cuidados prestados pelos profissionais de saúde aos idosos. Os dados obtidos juntamente com a experiência dos autores permitiram triangular os resultados e redigir o relatório final da investigação. Resultados: 75% dos entrevistados receberam orientações sobre as medidas de prevenção e a importância dos cuidados; 67,8% indicaram que não receberam atendimento oportuno à demanda, 92,8% avaliaram a comunicação como adequada; 45% recebiam atendimento mensal, 50% não recebiam atendimento psicológico. Conclusões: A COVID-19 constitui um inconveniente para os cuidados de saúde adequados aos idosos. É necessária uma atenção multidisciplinar, integral, integrada e centrada ao idoso na atenção primária à saúde. Eles precisam de mais apoio devido à sua vulnerabilidade e comorbidades. O cuidado domiciliar adequado é eficaz na prevenção da doença e, consequentemente, de suas complicações.

Cumplimiento de protocolos y técnicas de enfermería y exposición accidental a riesgos biológicos en estudiantes en las prácticas clínicas / Compliance with nursing protocols and techniques and accidental exposure to biological risks in students in clinical practices

La exposición a peligros biológicos para la salud y las medidas preventivas implementadas para evitar o minimizar esta exposición, es parcialmente desconocida en Ecuador; particularmente, por los estudiantes de enfermería, los cuales, durante sus prácticas pre-profesionales, están expuestos a factores que pueden afectar negativamente el bienestar en su lugar de trabajo. El riesgo puede ser de origen diversos, físicos, ergonómicos, químicos, psicosociales y biológicos. Entre los biológicos se incluyen pinchazos con agujas, salpicaduras de sangre y otros fluidos corporales, cortes de ampollas de medicamentos, cortes de bisturí, perforación de guantes durante la cirugía, contacto con la sangre de los pacientes con las manos sin guantes y contaminación de heridas abiertas con la sangre de los pacientes. Este estudio tuvo como objetivo establecer la relación entre el cumplimiento de los protocolos y técnicas de enfermería con la exposición accidental a riesgos biológicos en estudiantes. Los resultados demostraron asociación estadísticamente significativa entre las variables en estudios, evidenciándose que, a menor cumplimiento de los protocolos e inexperiencias en las maniobras técnicas de enfermería, mayor era la probabilidad a accidentes por riesgo biológico. Se concluye que el conocimiento de los protocolos de enfermería, la vigilancia sobre la prevención de infecciones, la adherencia a las normas de bioseguridad son algunas de las medidas a seguir para reducir la exposición de los estudiantes de enfermería a los riesgos laborales biológicos. Se recomienda, establecer sistemática para el reporte y abordaje de accidentes por riesgo biológicos que ocurran a los estudiantes de enfermería, durante su proceso formativo(AU)

Exposure to biological health hazards and the preventive measures implemented to avoid or minimize this exposure are partially unknown in Ecuador; particularly by nursing students, who, during their pre-professional practices, are exposed to factors that can negatively affect well-being in their workplace. The risk can be of various physical, ergonomic, chemical, psychosocial and biological origins. Biological include needle sticks, splashes of blood and other body fluids, cuts from medication blisters, scalpel cuts, perforation of gloves during surgery, contact with blood from patients on bare hands, and contamination of wounds opened with the blood of patients. This study aimed to establish the relationship between compliance with nursing protocols techniques and accidental exposure to biological risks in students. The results showed a statistically significant association between the variables in the studies, showing that, the less compliance with the protocols and inexperience in nursing technical maneuvers, the greater the probability of accidents due to biological risk. It is concluded that knowledge of nursing protocols, surveillance of infection prevention, adherence to biosafety standards are some of the measures to be followed to reduce the exposure of nursing students to biological occupational hazards. It is concluded that knowledge of nursing protocols, surveillance of infection prevention, adherence to biosafety standards are some of the measures to be followed to reduce the exposure of nursing students to biological occupational hazards. It is recommended to establish a system for reporting and addressing biological risk accidents that occur to nursing students during their training process(AU)

Conocimientos, prácticas y habilidades estudiantiles sobre la búsqueda bibliográfica e investigación en salud ambiental / Knowledge, practices and student skills on bibliographic search and research in environmental health

Durante el ejercicio profesional, los enfermeros les corresponden brindar educación a la comunidad para prevenir la exposición a los riesgos medioambientales e, integrarse y proponer profilaxis en pro del bienestar de la comunidad, en este sentido, les incumben consolidar destrezas que les permitan desarrollar historia ambiental valorando riesgos, diagnosticando problemas, proponiendo intervenciones, evaluando resultados, e incluso identificando los factores peligrosos de acuerdo a vulnerabilidades particulares. Para los estudiantes de enfermería de UNIANDES, el reto, en esta área de formación es doble (investigativa y académica), y lo deben asumir, de manera autodidáctica. Este trabajo pretendió explorar conocimientos, prácticas y habilidades estudiantiles sobre la búsqueda bibliográfica e investigación en salud ambiental. La muestra estuvo conformada por 120 estudiantes. Se precisó que 17,5% poseen conocimiento para realizar búsqueda básica de información, utilizando principalmente el motor web Google 40,8%. El nivel de destreza fue bajo 73,3%; percepción de los estudiantes, mala 49,2%: prácticas para realizar búsqueda, no sabe 54,2%, sin asociación estadísticamente significativa con sexo. Para la percepción del nivel de competencia en investigación y búsqueda de información en salud ambiental: lectura crítica obtuvo 3,08 puntos, seguida de búsqueda de información 2,98 puntos, lo que las clasifican como regular; mientras que, redacción de artículos y el proceso de publicación, ambas con 2,70 puntos; se catalogan deficientes. Estos resultados permiten afirmar que es necesario un acompañamiento permanente en la instrucción sobre el uso de información digital a lo largo de la carrera y con especial atención en el área de salud ambiental(AU)

During professional practice, nurses are responsible for providing education to the community to prevent exposure to environmental risks and integrate and propose prophylaxis for the well-being of the community, in this sense, they are responsible for consolidating skills that allow them to develop environmental history assessing risks, diagnosing problems, proposing interventions, evaluating results, and even identifying dangerous factors according to particular vulnerabilities. For UNIANDES nursing students, the challenge in this training area is twofold (investigative and academic), and they must assume it in a self-taught manner. This work aimed to explore student knowledge, practices and skills on bibliographic search and research in environmental health. The sample consisted of 120 students. It was specified that 17.5% have knowledge to perform basic information searches, mainly using Google web engine 40.8%. The skill level was low 73.3%; perception of the students, poor 49.2%: practices to carry out searches, do not know 54.2%, without statistically significant association with gender. For the perception of the level of competence in research and information search in environmental health: critical reading obtained 3.08 points, followed by information search 2.98 points, which classifies them as regular; while, writing articles and the publication process, both with 2.70 points; are classified as deficient. These results allow us to affirm that permanent accompaniment is necessary in the instruction on the use of digital information throughout the career and with special attention in the area of environmental health(AU)

Frequent expression of activation-induced cytidine deaminase in diffuse large B-cell lymphoma tissues from persons living with HIV.

OBJECTIVE: The increased risk for persons living with HIV to develop diffuse large B-cell lymphoma (DLBCL) even in the post-antiretroviral therapy eras suggests a role beyond immunosuppression in lymphoma development. However, the mechanisms leading to lymphoma in the HIV setting are not fully understood. HIV is known to induce activation-induced cytidine deaminase (AID) levels in nonneoplastic B cells in vitro and chronic AID expression may play an important role in lymphomagenesis. Although AID expression is observed in B-cell lymphoma, studies in HIV-associated DLBCL are limited. DESIGN: In this study, we conducted a retrospective review of DLBCL tissues from patients with and without HIV infection to compare expression of AID and B-cell receptors potentially involved in HIV and B-cell interaction. METHODS: We evaluated DLBCL formalin-fixed paraffin-embedded tissues from 72 HIV-seropositive and 58 HIV-seronegative patients for AID, DC-SIGN, and CD40 protein expression. BCL2 and MYC, two well established prognostically significant oncoproteins in DLBCL, were also assessed at the protein and mRNA levels. Subset analysis was performed according to DLBCL subtype and EBV status. RESULTS: Of note, AID expression was more frequent in HIV-associated DLBCL compared with non-HIV-associated DLBCL regardless of cell-of-origin subtype, and also displayed significantly less BCL2 expression. Despite no direct correlation with AID expression, the HIV-DLBCL tissues also exhibited high levels of the DC-SIGN receptor. CONCLUSION: Collectively, these findings support a potential role for AID in the pathogenesis of HIV-associated lymphomas and suggest the need of further investigations into the involvement of the DC-SIGN receptor-signaling pathway.

Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate.

AIMS: We aim here to demonstrate that radiation (RT) enhances tumor sensitization by only those Mn complexes that are redox active and cycle with ascorbate (Asc), thereby producing H2O2 and utilizing it subsequently in protein S-glutathionylation in a glutathione peroxidase (GPx)-like manner. In turn, such compounds affect cellular redox environment, described by glutathione disulfide (GSSG)/glutathione (GSH) ratio, and tumor growth. To achieve our goal, we tested several Mn complexes of different chemical and physical properties in cellular and animal flank models of 4T1 breast cancer cell. Four other cancer cell lines were used to substantiate key findings. RESULTS: Joint administration of cationic Mn porphyrin (MnP)-based redox active compounds, MnTE-2-PyP5+ or MnTnBuOE-2-PyP5+ with RT and Asc contributes to high H2O2 production in cancer cells and tumor, which along with high MnP accumulation in cancer cells and tumor induces the largest suppression of cell viability and tumor growth, while increasing GSSG/GSH ratio and levels of total S-glutathionylated proteins. Redox-inert MnP, MnTBAP3- and two other different types of redox-active Mn complexes (EUK-8 and M40403) were neither efficacious in the cellular nor in the animal model. Such outcome is in accordance with their inability to catalyze Asc oxidation and mimic GPx. INNOVATION: We provided here the first evidence how structure-activity relationship between the catalytic potency and the redox properties of Mn complexes controls their ability to impact cellular redox environment and thus enhance the radiation and ascorbate-mediated tumor suppression. CONCLUSIONS: The interplay between the accumulation of cationic MnPs and their potency as catalysts for oxidation of Asc, protein cysteines, and GSH controls the magnitude of their anticancer therapeutic effects.

Manganese (III) meso-tetrakis N-ethylpyridinium-2-yl porphyrin acts as a pro-oxidant to inhibit electron transport chain proteins, modulate bioenergetics, and enhance the response to chemotherapy in lymphoma cells.

The manganese porphyrin, manganese (III) meso-tetrakis N-ethylpyridinium-2-yl porphyrin (MnTE-2-PyP(5+)), acts as a pro-oxidant in the presence of intracellular H2O2. Mitochondria are the most prominent source of intracellular ROS and important regulators of the intrinsic apoptotic pathway. Due to the increased oxidants near and within the mitochondria, we hypothesized that the mitochondria are a target of the pro-oxidative activity of MnTE-2-PyP(5+) and that we could exploit this effect to enhance the chemotherapeutic response in lymphoma. In this study, we demonstrate that MnTE-2-PyP(5+) modulates the mitochondrial redox environment and sensitizes lymphoma cells to antilymphoma chemotherapeutics. MnTE-2-PyP(5+) increased dexamethasone-induced mitochondrial ROS and oxidation of the mitochondrial glutathione pool in lymphoma cells. The combination treatment induced glutathionylation of Complexes I, III, and IV in the electron transport chain, and decreased the activity of Complexes I and III, but not the activity of Complex IV. Treatment with the porphyrin and dexamethasone also decreased cellular ATP levels. Rho(0) malignant T-cells with impaired mitochondrial electron transport chain function were less sensitive to the combination treatment than wild-type cells. These findings suggest that mitochondria are important for the porphyrin's ability to enhance cell death. MnTE-2-PyP(5+) also augmented the effects of 2-deoxy-D-glucose (2DG), an antiglycolytic agent. In combination with 2DG, MnTE-2-PyP(5+) increased protein glutathionylation, decreased ATP levels more than 2DG treatment alone, and enhanced 2DG-induced cell death in primary B-ALL cells. MnTE-2-PyP(5+) did not enhance dexamethasone- or 2DG-induced cell death in normal cells. Our findings suggest that MnTE-2-PyP(5+) has potential as an adjuvant for the treatment of hematologic malignancies.

Induction of autophagy contributes to cisplatin resistance in human ovarian cancer cells.

Cisplatin resistance is a major challenge in the clinical treatment of ovarian cancer, of which the underlying mechanisms remain unknown. The aim of the present study was to explore the role of autophagy in cisplatin resistance in ovarian cancer cells. A2780cp cisplatin-resistant ovarian carcinoma cells and the A2780 parental cell line, were used as a model throughout the present study. The cell viability was determined using a water soluble tetrazolium salt-8 assay, and western blot analysis was performed to determine the protein expression levels of microtubule-associated protein 1 light chain 3 (LC3 I and LC3 II), and Beclin 1. Beclin 1 small interfering (si)RNA and 3-methyladenine (3-MA) were used to determine whether inhibition of autophagy may re-sensitize cisplatin-resistant cells to cisplatin. The ultrastructural analysis of autophagosomes was performed using transmission electron microscopy, and apoptosis was measured by flow cytometry. In both A2780cp and A2780 cells, cisplatin induced the formation of autophagosomes and upregulated the expression levels of autophagy protein markers, LC3 II and Beclin 1. However, the levels of autophagy were significantly higher in A2780cp cells, as compared with the A2780 cells. The combined treatment of cisplatin with 3-MA, the autophagy pharmacological inhibitor, increased the cell death rate, but had no effects on apoptosis, as compared with cisplatin treatment alone in A2780cp cells. However, inhibition of autophagy by siRNA knockdown of Beclin 1 expression enhanced cisplatin-induced cell death and apoptosis. The findings of the present study suggest that autophagy has a protective role in human ovarian cancer cells, and that targeting autophagy may promote chemotherapeutic sensitivity.

Mitochondria and redox homoeostasis as chemotherapeutic targets.

Characteristics of cancer cells include a more oxidized redox environment, metabolic reprogramming and apoptosis resistance. Our studies with a lymphoma model have explored connections between the cellular redox environment and cancer cell phenotypes. Alterations seen in lymphoma cells made resistant to oxidative stress include: a more oxidized redox environment despite increased expression of antioxidant enzymes, enhanced net tumour growth, metabolic changes involving the mitochondria and resistance to the mitochondrial pathway to apoptosis. Of particular importance, the cells show cross-resistance to multiple chemotherapeutic agents used to treat aggressive lymphomas. Analyses of clinical and tumour data reveal the worst prognosis when patients' lymphomas have gene expression patterns consistent with the most oxidized redox environment. Lymphomas from patients with the worst survival outcomes express increased levels of proteins involved in oxidative phosphorylation, including cytochrome c. This is consistent with these cells functioning as metabolic opportunists. Using lymphoma cell models and primary lymphoma cultures, we observed enhanced killing using genetic and drug approaches which further oxidize the cellular redox environment. These approaches include increased expression of SOD2 (superoxide dismutase 2), treatment with a manganoporphyrin that oxidizes the glutathione redox couple, or treatment with a copper chelator that inhibits SOD1 and leads to peroxynitrite-dependent cell death. The latter approach effectively kills lymphoma cells that overexpress the anti-apoptotic protein Bcl-2. Given the central role of mitochondria in redox homoeostasis, metabolism and the intrinsic pathway to apoptosis, our studies support the development of new anti-cancer drugs to target this organelle.

Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma.

UNLABELLED: Cisplatin resistance is a major problem affecting ovarian carcinoma treatment. NF-E2-related factor 2 (Nrf2), a nuclear transcription factor, plays an important role in chemotherapy resistance. However, the underlying mechanism by which Nrf2 mediates cisplatin chemoresistance is unclear. METHODS: The human ovarian carcinoma cell line, A2780, and its cisplatin-resistant variant, A2780cp were cultivated. Cell viability was determined with WST-8 assay. Western blot was applied to detect the expression of Nrf2, Nrf2 target genes, and autophagy-related proteins. RNA interference was used to knock down target genes. Annexin V and propidium iodide (PI) staining was utilized to quantify apoptosis. The ultrastructural analysis of autophagosomes was performed by transmission electron microscopy (TEM). RESULTS: Nrf2 and its targeting genes, NQO1 and HO-1, are overexpressed in A2780cp cells compared with A2780 cells. Knocking down Nrf2 sensitized A2780cp cells to cisplatin treatment and decreased autophagy-related genes, Atg3, Atg6, Atg12 and p62 in both mRNA and protein levels. Furthermore, we demonstrated that in both cell lines cisplatin could induce the formation of autophagosomes and upregulate the expression of autophagy-related genes Atg3, Atg6 and Atg12. Treatment with an autophagy inhibitor, 3-Methyladenine (3-MA), or beclin 1 siRNA enhanced cisplatin-induced cell death in A2780cp cells, suggesting that inhibition of autophagy renders resistant cells to be more sensitive to cisplatin. Taken together, Nrf2 signaling may regulate cisplatin resistance by activating autophagy. CONCLUSIONS: Nrf2-activated autophagy may function as a novel mechanism causing cisplatin-resistance.

Indolent lymphoma: follicular lymphoma and the microenvironment-insights from gene expression profiling.

As shown with gene expression profiling (GEP), the development and progression of follicular lymphoma (FL) involves complex interactions between neoplastic B cells and the surrounding microenvironment. GEP further reveals that the tumor microenvironment may predict survival in patients with FL and influence the response to therapy and the risk of transformation. Here, we briefly review GEP technology and summarize the role of the tumor microenvironment in FL diagnosis, prognosis, and transformation. Genes expressed by infiltrating T cells and macrophages appear to be the most important predictors of survival, clinical behavior, and outcome. These findings provide a basis for future studies into the pathogenesis and pathophysiology of FL and may ultimately provide guidance in the choice of therapy and the identification of potential therapeutic targets.

Poly(ADP-ribose) polymerase-1 modulates Nrf2-dependent transcription.

The basic leucine zipper transcription factor Nrf2 has emerged as a master regulator of intracellular redox homeostasis by controlling the expression of a battery of redox-balancing antioxidants and phase II detoxification enzymes. Under oxidative stress conditions, Nrf2 is induced at the protein level through redox-sensitive modifications on critical cysteine residues in Keap1, a component of an E3 ubiquitin ligase complex that targets Nrf2 for proteasomal degradation. Poly(ADP-ribose) polymerase-1 (PARP-1) is historically known to function in DNA damage detection and repair; however, recently PARP-1 has been shown to play an important role in other biochemical activities, such as DNA methylation and imprinting, insulator activity, chromosome organization, and transcriptional regulation. The exact role of PARP-1 in transcription modulation and the underlying mechanisms remain poorly defined. In this study, we report that PARP-1 forms complexes with the antioxidant response element (ARE) within the promoter region of Nrf2 target genes and upregulates the transcriptional activity of Nrf2. Interestingly, PARP-1 neither physically interacts with Nrf2 nor promotes the expression of Nrf2. In addition, PARP-1 does not target Nrf2 for poly(ADP-ribosyl)ation. Instead, PARP-1 interacts directly with small Maf proteins and the ARE of Nrf2 target genes, which augments ARE-specific DNA-binding of Nrf2 and enhances the transcription of Nrf2 target genes. Collectively, these results suggest that PARP-1 serves as a transcriptional coactivator, upregulating the transcriptional activity of Nrf2 by enhancing the interaction among Nrf2, MafG, and the ARE.

The emerging role of the Nrf2-Keap1 signaling pathway in cancer.

The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy.

Tumor protein translationally controlled 1 is a p53 target gene that promotes cell survival.

Tumor suppressor p53 maintains genome stability by differentially activating target genes that control diverse cellular responses, such as the antioxidant response, cell cycle arrest and apoptosis. Despite the fact that many p53 downstream genes have been well characterized, novel p53 target genes are continuously being identified. Here, we report that Tpt1 is a direct target gene of p53. We found that p53 upregulates the transcription of Tpt1 and identified a p53-responsive element in the promoter of the mouse Tpt1 gene. Furthermore, p53-dependent induction of Tpt1 was able to reduce oxidative stress, minimize apoptosis, and promote cell survival in response to H 2O2 challenge. In addition, a positive correlation between the expression of p53 and Tpt1 only existed in normal lung tissues, not in lung tumors. Such positive correlation was also found in lung cell lines that contain wild-type p53, but not mutated p53. Based on the important role of Tpt1 in cancer development, chemoresistance, and cancer reversion, identification of Tpt1 as a direct target gene of p53 not only adds to the complexity of the p53 network, but may also open up a new avenue for cancer prevention and intervention.

Tanshinone I activates the Nrf2-dependent antioxidant response and protects against As(III)-induced lung inflammation in vitro and in vivo.

AIMS: The NF-E2 p45-related factor 2 (Nrf2) signaling pathway regulates the cellular antioxidant response and activation of Nrf2 has recently been shown to limit tissue damage from exposure to environmental toxicants, including As(III). In an attempt to identify improved molecular agents for systemic protection against environmental insults, we have focused on the identification of novel medicinal plant-derived Nrf2 activators. RESULTS: Tanshinones [tanshinone I (T-I), tanshinone IIA, dihydrotanshinone, cryptotanshinone], phenanthrenequinone-based redox therapeutics derived from the medicinal herb Salvia miltiorrhiza, have been tested as experimental therapeutics for Nrf2-dependent cytoprotection. Using a dual luciferase reporter assay overexpressing wild-type or mutant Kelch-like ECH-associated protein-1 (Keap1), we demonstrate that T-I is a potent Keap1-C151-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. In human bronchial epithelial cells exposed to As(III), T-I displays pronounced cytoprotective activity with upregulation of Nrf2-orchestrated gene expression. In Nrf2 wild-type mice, systemic administration of T-I attenuates As(III) induced inflammatory lung damage, a protective effect not observed in Nrf2 knockout mice. INNOVATION: Tanshinones have been identified as a novel class of Nrf2-inducers for antioxidant tissue protection in an in vivo As(III) inhalation model, that is relevant to low doses of environmental exposure. CONCLUSION: T-I represents a prototype Nrf2-activator that displays cytoprotective activity upon systemic administration targeting lung damage originating from environmental insults. T-I based Nrf2-directed systemic intervention may provide therapeutic benefit in protecting other organs against environmental insults.

Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway.

Arsenic is present in the environment and has become a worldwide health concern due to its toxicity and carcinogenicity. However, the specific mechanism(s) by which arsenic elicits its toxic effects has yet to be fully elucidated. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been recognized as the master regulator of a cellular defense mechanism against toxic insults. This review highlights studies demonstrating that arsenic activates the Nrf2-Keap1 antioxidant pathway by a distinct mechanism from that of natural compounds such as sulforaphane (SF) found in broccoli sprouts or tert-butylhyrdoquinone (tBHQ), a natural antioxidant commonly used as a food preservative. Evidence also suggests that arsenic prolongs Nrf2 activation and may mimic constitutive activation of Nrf2, which has been found in several human cancers due to disruption of the Nrf2-Keap1 axis. The current literature strongly suggests that activation of Nrf2 by arsenic potentially contributes to, rather than protects against, arsenic toxicity and carcinogenicity. The mechanism(s) by which known Nrf2 activators, such as the natural chemopreventive compounds SF and lipoic acid, protect against the deleterious effects caused by arsenic will also be discussed. These findings will provide insight to further understand how arsenic promotes a prolonged Nrf2 response, which will lead to the identification of novel molecular markers and development of rational therapies for the prevention or intervention of arsenic-induced diseases. The National Institute of Environmental Health Science (NIEHS) Outstanding New Environmental Scientist (ONES) award has provided the opportunity to review the progress both in the fields of arsenic toxicology and Nrf2 biology. Much of the funding has led to (1) the novel discovery that arsenic activates the Nrf2 pathway by a mechanism different to that of other Nrf2 activators, such as sulforaphane and tert-butylhydroquinone, (2) activation of Nrf2 by chemopreventive compounds protects against arsenic toxicity and carcinogenicity both in vitro and in vivo, (3) constitutive activation of Nrf2 by disrupting Keap1-mediated negative regulation contributes to cancer and chemoresistance, (4) p62-mediated sequestration of Keap1 activates the Nrf2 pathway, and (5) arsenic-mediated Nrf2 activation may be through a p62-dependent mechanism. All of these findings have been published and are discussed in this review. This award has laid the foundation for my laboratory to further investigate the molecular mechanism(s) that regulate the Nrf2 pathway and how it may play an integral role in arsenic toxicity. Moreover, understanding the biology behind arsenic toxicity and carcinogenicity will help in the discovery of potential strategies to prevent or control arsenic-mediated adverse effects.

Mitochondria are the primary source of the H(2)O(2) signal for glucocorticoid-induced apoptosis of lymphoma cells.

Glucocorticoids are a class of steroid hormones commonly used for the treatment of hematological malignancies due to their ability to induce apoptosis in lymphoid cells. An understanding of the critical steps in glucocorticoid-induced apoptosis is required to identify sources of drug resistance. Previously, we found that an increase in hydrogen peroxide is a necessary signal for glucocorticoid-induced apoptosis. In the current study, we found that mitochondria are the source of the signal. Glucocorticoid treatment inhibited Complex I and Complex III of the electron transport chain (ETC). Mitochondrial matrix reactive oxygen species (ROS) increased concomitantly with the oxidation of the mitochondrial glutathione pool. Treatment with Tiron, a superoxide scavenger, inhibited the signal. This suggests that the hydrogen peroxide signal originates as superoxide from the mitochondria and is metabolized to hydrogen peroxide. An inability to generate mitochondrial oxidants in response to glucocorticoids could cause drug resistance.

Manganese porphyrin, MnTE-2-PyP5+, Acts as a pro-oxidant to potentiate glucocorticoid-induced apoptosis in lymphoma cells.

Using current chemotherapy protocols, over 55% of lymphoma patients fail treatment. Novel agents are needed to improve lymphoma survival. The manganese porphyrin, MnTE-2-PyP(5+), augments glucocorticoid-induced apoptosis in WEHI7.2 murine thymic lymphoma cells, suggesting that it may have potential as a lymphoma therapeutic. However, the mechanism by which MnTE-2-PyP(5+) potentiates glucocorticoid-induced apoptosis is unknown. Previously, we showed that glucocorticoid treatment increases the steady state levels of hydrogen peroxide ([H(2)O(2)](ss)) and oxidizes the redox environment in WEHI7.2 cells. In the current study, we found that when MnTE-2-PyP(5+) is combined with glucocorticoids, it augments dexamethasone-induced oxidative stress however, it does not augment the [H(2)O(2)](ss) levels. The combined treatment depletes GSH, oxidizes the 2GSH:GSSG ratio, and causes protein glutathionylation to a greater extent than glucocorticoid treatment alone. Removal of the glucocorticoid-generated H(2)O(2) or depletion of glutathione by BSO prevents MnTE-2-PyP(5+) from augmenting glucocorticoid-induced apoptosis. In combination with glucocorticoids, MnTE-2-PyP(5+) glutathionylates p65 NF-κB and inhibits NF-κB activity. Inhibition of NF-κB with SN50, an NF- κB inhibitor, enhances glucocorticoid-induced apoptosis to the same extent as MnTE-2-PyP(5+). Taken together, these findings indicate that: 1) H(2)O(2) is important for MnTE-2-PyP(5+) activity; 2) Mn-TE-2-PyP(5+) cycles with GSH; and 3) MnTE-2-PyP(5+) potentiates glucocorticoid-induced apoptosis by glutathionylating and inhibiting critical survival proteins, including NF-κB. In the clinic, over-expression of NF-κB is associated with a poor prognosis in lymphoma. MnTE-2-PyP(5+) may therefore, synergize with glucocorticoids to inhibit NF-κB and improve current treatment.