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More than 80 million people live and work (in a chronic or intermittent form) above 2500 masl, and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 100,000 people work in high-altitude shifts, where stays in the lowlands are interspersed with working visits in the highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders due to increased free radical formation and decreased antioxidant capacity. However, intermittent hypoxia (IH) induces preconditioning in animal models, generating cardioprotection. Here, we aim to describe the responses of a cardiac function to four cycles of intermittent hypobaric hypoxia (IHH) in a rat model. The twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days of hypoxia + 4 days of normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the fourth cycle, cardiac structural and functional variables were also determined by echocardiography; furthermore, cardiac oxidative stress biomarkers (4-Hydroxynonenal, HNE; nitrotyrosine, NT), antioxidant enzymes, and NLRP3 inflammasome panel expression are also determined. Our results show a higher ejection and a shortening fraction of the left ventricle function by the end of the fourth cycle. Furthermore, cardiac tissue presented a decreased expression of antioxidant proteins. However, a decrease in IL-1ß, TNF-αn, and oxidative stress markers is observed in IHH compared to normobaric hypoxic controls. Non-significant differences were found in protein levels of NLRP3 and caspase-1. IHH exposure determines structural and functional heart changes. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection.
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BACKGROUND: Cervical cancer continues to be a major public health problem worldwide, and Cisplatin is used as first-line chemotherapy for this cancer; however, malignant cells exposed to CISplatin (CIS) become insensitive to the effects of this drug. PenToXifylline (PTX) is a xanthine that sensitizes several types of tumor cells to apoptosis induced by antitumor drugs, such as Adriamycin, Carboplatin, and CIS. The effects of PTX on tumor cells have been related to the disruption of the NF-κB pathway, thus preventing the activation of cell survival mechanisms such as the expression of anti-apoptotic genes, the secretion of proinflammatory interleukins, and growth factors. OBJECTIVE: In this work, we studied the antitumor proprieties of PTX in human SiHa cervical carcinoma cells resistant to CIS. MATERIALS AND METHODS: SiHa and HeLa cervical cancer cells and their CIS-resistant derived cell lines (SiHaCIS-R and HeLaCIS-R, respectively) were used as in-vitro models. We studied the effects of PTX alone or in combination with CIS on cell viability, apoptosis, caspase-3, caspase-8, and caspase-9 activity, cleaved PARP-1, anti-apoptotic protein (Bcl-2 and Bcl-xL) levels, p65 phosphorylation, cadmium chloride (CdCl2) sensitivity, Platinum (Pt) accumulation, and glutathione (GSH) levels, as well as on the gene expression of GSH and drug transporters (influx and efflux). RESULTS: PTX sensitized SiHaCIS-R cells to the effects of CIS by inducing apoptosis, caspase activation, and PARP-1 cleavage. PTX treatment also decreased p65 phosphorylation, increased Pt levels, depleted GSH, and downregulated the expression of the ATP7A, ATP7B, GSR, and MGST1 genes. CONCLUSION: PTX reverses the acquired phenotype of CIS resistance close to the sensitivity of parental SiHa cells.
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Oxidative stress (OS) is an indispensable condition to ensure genomic instability in cancer cells. In breast cancer (BC), redox alterations have been widely characterized, but since this process results from a chain of inflammatory events, the causal molecular triggers remain to be identified. In this context, we used a microarray approach to investigate the role of the main pro-oxidant transcription factor, nuclear factor-kappa B (NF-κB), in gene profiles of BC subtypes. Our results showed that NF-κB knockdown in distinct BC subtypes led to differential expression of relevant factors involved in glutathione metabolism, prostaglandins, cytochrome P450 and cyclooxygenase, suggesting a relationship between the redox balance and NF-κB in such cells. In addition, we performed biochemical analyses to validate the microarray dataset focusing on OS and correlated these parameters with normal expression or NF-κB inhibition. Our data showed a distinct oxidative status pattern for each of the three studied BC subtype models, consistent with the intrinsic characteristics of each BC subtype. Thus, our findings suggest that NF-κB may represent an additional mechanism related to OS maintenance in BC, operating in various forms to mediate other important predominant signaling components of each BC subtype.
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Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. In addition, microorganisms, such as viruses and bacteria, cooperate in the activation of NF-κB in tumors, confirming the multifactorial role of this transcription factor as a cancer driver. Recent reports have shown that the NF-κB signaling pathway should receive attention for the development of therapies. In addition to the direct effects of NF-κB in cancer cells, it might also impact immune cells that can both promote or prevent tumor development. Currently, with the rise of cancer immunotherapy, the link among immune cells, inflammation, and cancer is a major focus, and NF-κB could be an important regulator for the success of these therapies. This review discusses the contrasting roles of NF-κB as a regulator of pro- and antitumor processes and its potential as a therapeutic target.
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OBJECTIVES: Oxidative stress is known to participate in the progression of sepsis. Definite data regarding the behavior of oxidative stress biomarkers in pediatric sepsis is still lacking. This study hypothesized that oxidative stress occurs in pediatric sepsis and that the magnitude of the redox derangement is associated with worse clinical progression. METHODS: Forty-two previously healthy pediatric patients with sepsis and a group of control subjects were included. Oxidative stress and inflammatory activity biomarkers were determined in blood samples. Patients were prospectively followed until their discharge or death. RESULTS: Patients with non-severe and severe sepsis showed higher levels of plasmatic antioxidant capacity, lower erythrocyte thiol index, lower superoxide dismutase and catalase activities, higher glutathione peroxidase activity, and higher plasmatic F2-isoprostanes concentration than controls. Patients with severe sepsis had higher NF-kappaB activation than those with non-severe sepsis. Although we observed changes in some biomarkers in patients with worse clinical evolution, the explored biomarkers did not correlate with clinical estimators of outcome. DISCUSSION: Oxidative stress occurs in pediatric sepsis, resulting in oxidative damage. The explored biomarkers are not useful as outcome predictors in the studied population. The behavior of these biomarkers still needs to be addressed in broader groups of pediatric patients with sepsis.
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Sepse/sangue , Antioxidantes/metabolismo , Biomarcadores/sangue , Catalase/sangue , Criança , Pré-Escolar , F2-Isoprostanos/sangue , Feminino , Humanos , Lactente , Masculino , Malondialdeído/sangue , NF-kappa B/sangue , Estresse Oxidativo/fisiologia , Projetos Piloto , Estudos Prospectivos , Superóxido Dismutase/sangueRESUMO
STUDY OBJECTIVES: Sleep is known to increase as an acute response to infection. However, the function of this behavioral response in host defense is not well understood. To address this problem, we evaluated the effect of acute sleep deprivation on post-infection sleep and immune function in Drosophila. SETTING: Laboratory. PARTICIPANTS: Drosophila melanogaster. METHODS AND RESULTS: Flies were subjected to sleep deprivation before (early DEP) or after (late DEP) bacterial infection. Relative to a non-deprived control, flies subjected to early DEP had enhanced sleep after infection as well as increased bacterial clearance and survival outcome. Flies subjected to late DEP experienced enhanced sleep following the deprivation period, and showed a modest improvement in survival outcome. Continuous DEP (early and late DEP) throughout infection also enhanced sleep later during infection and improved survival. However, improved survival in flies subjected to late or continuous DEP did not occur until after flies had experienced sleep. During infection, both early and late DEP enhanced NFκB transcriptional activity as measured by a luciferase reporter (κB-luc) in living flies. Early DEP also increased NFκB activity prior to infection. Flies that were deficient in expression of either the Relish or Dif NFκB transcription factors showed normal responses to early DEP. However, the effect of early DEP on post-infection sleep and survival was abolished in double mutants, which indicates that Relish and Dif have redundant roles in this process. CONCLUSIONS: Acute sleep deprivation elevated NFκB-dependent activity, increased post-infection sleep, and improved survival during bacterial infection.
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Drosophila melanogaster/microbiologia , Drosophila melanogaster/fisiologia , Privação do Sono/imunologia , Privação do Sono/fisiopatologia , Sono/imunologia , Sono/fisiologia , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/imunologia , Feminino , NF-kappa B/metabolismo , Sono/genética , Análise de Sobrevida , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
OBJECTIVE: Activation of nuclear factor kappaB by diverse bacteria regulates the secretion of chemokines and cytokines. Staphylococcus aureus (S. aureus)-infected osteoblasts can significantly increase the secretion of interleukin-6 and monocyte chemoattractant protein-1. The aim of this study was to investigate whether S. aureus can activate nuclear factor kappaB in human osteoblasts, and whether the activation of nuclear factor kappaB by S. aureus regulates the secretion of interleukin-6 and monocyte chemoattractant protein-1. METHODS: Immunoblot and electrophoretic mobility shift assay were used to detect the degradation of IκBa and activation of nuclear factor kappaB in human osteoblasts in response to S. aureus, respectively. Enzyme-linked immunosorbent assay was used to measure the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants. Lastly, carbobenzoxyl-l-leucinyl-l-leucinyl-l-leucinal, an inhibitor of the nuclear factor kappaB, was used to determine if activation of nuclear factor kappaB by S. aureus in human osteoblasts regulates the secretions of interleukin-6 and monocyte chemoattractant protein-1. RESULTS: Our results for the first time demonstrated that S. aureus can induce the degradation of IκBa and activation of nuclear factor kappaB in human osteoblasts in a time and dose-dependent manner. In addition, inhibition of nuclear factor kappaB by carbobenzoxyl-l-leucinyl-l-leucinyl-l-leucinal suppressed the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants of S. aureus-infected human osteoblasts in a dose-dependent manner. CONCLUSION: These findings suggest that S. aureus can activate nuclear factor kappaB in human osteoblasts, and subsequently regulate the secretion of interleukin-6 and monocyte chemoattractant protein-1. The nuclear factor kappaB transcription factor regulates a number of genes involved in a wide variety of biological processes. Further study of the effects of nuclear factor kappaB activation on S. aureus-infected human osteoblast may provide us new insights into discovery of the immune mechanisms in osteomyelitis.
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Humanos , NF-kappa B/metabolismo , Osteoblastos/microbiologia , Transdução de Sinais/fisiologia , Staphylococcus aureus/fisiologia , Western Blotting , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Leupeptinas/farmacologia , NF-kappa B/antagonistas & inibidoresRESUMO
Apoptosis is an essential physiological process of elimination of destined cells during the development and differentiation or after damage from external stresses such as ionizing radiation or chemotherapeutic agents. Disruption of apoptosis is proved to cause various diseases including cancer. Among numerous molecules involved in diverse anti- or pro-apoptotic signaling pathways, NF-kappaB is one of the key factors controlling anti-apoptotic responses. Its anti-apoptotic effect is thought to be mediated through not only transcriptional activation of dependent genes but also by crosstalking with the JNK pathway. Oncogenic proteins such as Ret/PTC, Ras and BRAF can induce NF-kappaB activation making it an important change in thyroid cancer. A number of specific or non-specific NF-kappaB inhibitors have been tried to take over the cascade in in vitro and in vivo experiments. These agents can induce massive apoptosis especially in combination with radio- or chemotherapy. Current results suggest that the inhibition of the NF-kappaB may be a promising strategy for advanced thyroid cancer treatment but further investigations are warranted to develop specific and clinically effective NF-kappaB inhibitors in future.
A apoptose é um processo fisiológico essencial destinado a eliminar células durante o desenvolvimento e diferenciação ou após danos decorrentes de estresses externos com a radiação ionizante ou agentes quimioterápicos. Distúrbios na apoptose têm sido demonstrados como causadores de várias doenças, incluindo câncer. Entre as inúmeras moléculas envolvidas nas várias vias de sinalização anti- ou pró-apoptoticas, NF-kapaB é um dos fatores-chave que controlam as respostas anti-apoptóticas. Acredita-se que seu efeito anti-apoptótico seja mediado não apenas pela ativação transcricional de genes dependentes mas também por crosstalking com a via JNK. Proteínas oncogênicas como Ret/PTC, Ras e BRAF podem induzir ativação de NF-kapaB promovendo importante transformação no câncer da tireóide. Uma série de inibidores específicos e não-específicos do NF-kapaB tem sido usada em experimentos in vitro e in vivo procurando inibir a cascata. Esses agentes podem induzir apoptose maciça especialmente em combinação com radio ou quimioterapia. Resultados atuais sugerem que a inibição de NF-kapaB pode ser uma estratégia promissora no tratamento do câncer da tireóide avançado, mas novas investigações são necessárias para desenvolver inibidores específicos e clinicamente efetivos do NF-kapaB.
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Animais , Humanos , Apoptose/fisiologia , Carcinoma/tratamento farmacológico , NF-kappa B/fisiologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , /metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzamidas/metabolismo , Benzamidas/farmacologia , Carcinoma/metabolismo , Cicloexanonas/metabolismo , Cicloexanonas/farmacologia , Ativação Enzimática , Proteínas Inibidoras de Apoptose/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/genética , Ativação Transcricional , Neoplasias da Glândula Tireoide/metabolismoRESUMO
Progesterone is an essential hormone for pregnancy maintenance. This hormone acts by binding to its intracellular receptor or by rapid non-genomic actions to regulate a wide variety of biological functions in the feto-placental unit. Progesterone regulates blastocyst implantation and placental development by inducing immunosupression through type Th2 cytokines secretion. This review summarizes current research about the role of progesterone as critical regulator of expression and secretion of cytokines by T-cell and other placental cells.
La progesterona es una hormona esteroide muy versátil y esencial para el mantenimiento del embarazo. El principal mecanismo de acción de la progesterona es el clásico, vía receptor intracelular, regulando diversas funciones, aspectos celulares y vías moleculares implicadas en el proceso de la implantación. Asimismo existen mecanismos adicionales que no dependen de la interacción del complejo hormona receptor con la maquinaria transcripcional y que son capaces de regular rápidamente cascadas de señalización que determinarán la respuesta de la célula. En particular se ha demostrado que la progesterona ejerce efectos inmunosupresores durante la gestación al favorecer la secreción de citocinas de tipo Th2 por los linfocitos T, evento importante para regular el sistema inmunológico materno y evitar el rechazo de la placenta. El objetivo de esta revisión se centra en analizar la influencia de la progesterona en la interfase materno-fetal sobre la expresión y secreción de citocinas por las células T y no T como es el caso del trofoblasto.
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Animais , Feminino , Camundongos , Gravidez , Manutenção da Gravidez/imunologia , Progesterona/fisiologia , Blastocisto , Citocinas/fisiologia , Implantação do Embrião/imunologia , Implantação do Embrião/fisiologia , Regulação da Expressão Gênica , Tolerância Imunológica , Inflamação , Trabalho de Parto/fisiologia , Linfócitos/metabolismo , Modelos Biológicos , Troca Materno-Fetal/imunologia , NF-kappa B/fisiologia , Placenta/crescimento & desenvolvimento , Placenta/imunologia , Manutenção da Gravidez/fisiologia , Proteínas da Gravidez/fisiologia , Receptores de Progesterona/fisiologia , Fatores Supressores Imunológicos , Baço/metabolismoRESUMO
Para la biología de hoy las vías de señalización intracelular que controlan los procesos entre la vida y la muerte celular son de gran interés. Al respecto, el NF-κB destaca como un factor de transcripción decisivo de respuesta rápida que participa en la activación de las vías de señalización de la muerte celular programada. Lo relevante es que sus efectos tienen consecuencias en el desarrollo normal y/o la homeostasis en muchas células o tejidos, que incluyen entre otros al sistema inmune, los folículos capilares, apéndices epidermales, el riñon y el sistema nervioso. En esta revisión analizamos el papel central que juega el factor de transcripción NF-κB en el funcionamiento normal de la célula cardíaca y sus implicaciones en algunas de las patologías cardíacas más frecuentes como: el daño por isquemia-reperfusión, la isquemia precondicionada, la hipertrofia, la aterosclerosis, y el paro cardíaco. El NF-κB comúnmente funciona como un agente citoprotector, aunque hay algunos casos en los cuales resulta ser pro-apoptótico dependiendo del estímulo y del contexto celular. Se han logrado avances significativos a nivel molecular, que han permitido entender su modo de acción y el papel interactivo que juega con otros factores claves. Estos estudios han identificado muchos genes anti-apoptóticos y pro-apoptóticos regulados por la actividad del NF-κB abriendo novedosas aproximaciones que se pueden hacer sobre sus efectos en el desarrollo de patologías cardíacas.
The signaling pathways that control the life-death switch of a cell are a prime interest in Modern Biology. To this respect, NF-κB has emerged as a decisive transcription factor in the cell's response to apoptotic challenge and its effects on apoptosis have far-reaching consequences for normal development and/or homeostasis in many cells and tissues, including the immune system, hair follicles, and epidermal appendages, the liver, and nervous system. In this review we analyze the pivotal role of the transcription factor NF-κB in the normal functioning of the cardiac cell and its implication on some of the most frequent cardiac pathologies, such as ischemia-reperfusion injury, ischemic precondition, hypertrophy, atherosclerosis and cardiac arrest. While NF-κB is commonly found to be cytoprotective, there are a number of instances where it is proapoptotic depending on the inducing stimulus and the cell context. Significant progress has been made in understanding its mode of action and its interplay with other key factors. These studies identified many anti- and pro-apoptotic NF-κB regulated genes that mediate its activity, these important new insights fuel hope that novel approaches will be developed to control the effects of NF-κB in cardiac pathologies.