3,377 research outputs found
NF-κB regulates DNA double-strand break repair in conjunction with BRCA1-CtIP complexes
No full textNF-κB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosis. Even though NF-κB can be activated by DNA damage via Ataxia telangiectasia-mutated (ATM) signalling, little was known about an involvement in DNA repair. In this work, we dissected distinct DNA double-strand break (DSB) repair mechanisms revealing a stimulatory role of NF-κB in homologous recombination (HR). This effect was independent of chromatin context, cell cycle distribution or cross-talk with p53. It was not mediated by the transcriptional NF-κB targets Bcl2, BAX or Ku70, known for their dual roles in apoptosis and DSB repair. A contribution by Bcl-xL was abrogated when caspases were inhibited. Notably, HR induction by NF-κB required the targets ATM and BRCA2. Additionally, we provide evidence that NF-κB interacts with CtIP-BRCA1 complexes and promotes BRCA1 stabilization, and thereby contributes to HR induction. Immunofluorescence analysis revealed accelerated formation of replication protein A (RPA) and Rad51 foci upon NF-κB activation indicating HR stimulation through DSB resection by the interacting CtIP-BRCA1 complex and Rad51 filament formation. Taken together, these results define multiple NF-κB-dependent mechanisms regulating HR induction, and thereby providing a novel intriguing explanation for both NF-κB-mediated resistance to chemo- and radiotherapies as well as for the sensitization by pharmaceutical intervention of NF-κB activatio
Hypoxia activates IKK-NF-κB and the immune response in <em>Drosophila melanogaster</em>
No full textHypoxia, or low oxygen availability, is an important physiological and pathological stimulus for multicellular organisms. Molecularly, hypoxia activates a transcriptional programme directed at restoration of oxygen homoeostasis and cellular survival. In mammalian cells, hypoxia not only activates the HIF (hypoxia-inducible factor) family, but also additional transcription factors such as NF-?B (nuclear factor ?B). Here we show that hypoxia activates the IKK–NF-?B [I?B (inhibitor of nuclear factor ?B)–NF-?B] pathway and the immune response in Drosophila melanogaster. We show that NF-?B activation is required for organism survival in hypoxia. Finally, we identify a role for the tumour suppressor Cyld, as a negative regulator of NF-?B in response to hypoxia in Drosophila. The results indicate that hypoxia activation of the IKK–NF-?B pathway and the immune response is an important and evolutionary conserved response.</p
Modulation of NF-kappaB activation in Theileria annulata-infected cloned cell lines is associated with detection of parasite-dependent IKK signalosomes and disruption of the actin cytoskeleton
No full textApicomplexan parasites within the genus <i>Theileria</i> have the ability to induce continuous proliferation and prevent apoptosis of the infected bovine leukocyte. Protection against apoptosis involves constitutive activation of the bovine transcription factor NF-kappaB in a parasite-dependent manner. Activation of NF-kappaB is thought to involve recruitment of IKK signalosomes at the surface of the macroschizont stage of the parasite, and it has been postulated that additional host proteins with adaptor or scaffolding function may be involved in signalosome formation. In this study two clonal cell lines were identified that show marked differences in the level of activated NF-kappaB. Further characterization of these lines demonstrated that elevated levels of activated NF-kappaB correlated with increased resistance to cell death and detection of parasite-associated IKK signalosomes, supporting results of our previous studies. Evidence was also provided for the existence of host- and parasite-dependent NF-kappaB activation pathways that are influenced by the architecture of the actin cytoskeleton. Despite this influence, it appears that the primary event required for formation of the parasite-dependent IKK signalosome is likely to be an interaction between a signalosome component and a parasite-encoded surface ligand
NF-κB translocation assay ImageJ macro
No full textThis is ImageJ macro used to determine the degree of NF-κB translocation in cells stained for NF-κB and nuclear signal. It is a part of publication entitled "Plasma extracellular vesicles signal spleen fibroblasts facilitating Plasmodium vivax adherence". Please see the publication for full author details.</p
Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation
No full textDeficiency of vitamin D is associated with accelerated decline in lung function. Vitamin D is a ligand for nuclear hormone vitamin D receptor (VDR), and upon binding it modulates various cellular functions. The level of VDR is reduced in lungs of patients with chronic obstructive pulmonary disease (COPD) which led us to hypothesize that deficiency of VDR leads to significant alterations in lung phenotype that are characteristics of COPD/emphysema associated with increased inflammatory response. We found that VDR knock-out (VDR(-/-)) mice had increased influx of inflammatory cells, phospho-acetylation of nuclear factor-kappaB (NF-κB) associated with increased proinflammatory mediators, and up-regulation of matrix metalloproteinases (MMPs) MMP-2, MMP-9, and MMP-12 in the lung. This was associated with emphysema and decline in lung function associated with lymphoid aggregates formation compared to WT mice. These findings suggest that deficiency of VDR in mouse lung can lead to an early onset of emphysema/COPD because of chronic inflammation, immune dysregulation, and lung destruction
Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease
No full textChronic obstructive pulmonary disease (COPD) is a global health problem. The current therapies for COPD are poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. An imbalance of oxidants/antioxidants caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g., NF-κB), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-κB pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervention in COPD
On-body to on-body channel characterization
No full textInterest in on-body communication channels is growing as the use of wireless devices increases in medical, consumer and military sensor applications. This paper presents an experimental investigation and analysis of the narrowband on-body propagation channel. This analysis considers each of the factors affecting the channel during a range of stationary and motion activities in different environments with actual wireless mote devices on the body. Use of such motes allows greater freedom in the subject's movements and the inclusion of real-world indoor and outdoor environments in a test sequence. This paper identifies and analyses the effect of the different components of the signal propagation (mean propagation path gain, large-scale fading and small-scale fading) and the cause of the losses and variation due to activities, positions or environmental factors. Our results show the effect on the received signal and the impact of voluntary and involuntary movements, which cause shadowing effects. The analysis also allows us to identify sensor positions on the body that are more reliable and those positions that may require a relay or those that may be suitable for acting as a relay
FORTUNA, VIRTÙ Y GLORIA CONSIDERACIONES SOBRE LA MORAL REPUBLICANA DE MAQUIAVELO
No full textIn this paper some key concepts, such as fortune, virtù, and glory,are considered in order to seek clarification regarding the problemof the relation between morality and politics in Machiavelli. TheMachiavellian virtù certainly includes a good deal of energy andtalent, but does not completely lack moral components. From theconcept of fortune we can derive a number of criteria for politicalaction, which form a part of the Machiavellian virtù, which, thoughdistant from the Christian morals of his time, places him within arepublican conception of morality. Starting from an inquiry into the concept of glory, we discover how glory is a reward for virtù, but itis not awarded to every politician who is successful in his ventures,but only to those who are able to save their country by benign mean
Dysregulation of Noncanonical NF-κB Signaling in Gastrointestinal Diseases
No full textRegulation of host health is intricately coordinated by a diverse interplay of immune cells detecting assaults from pathogens via recognition of pathogen associated molecular patterns (PAMPs) to mount an immune response, as well as detecting damage associated molecular patterns (DAMP) to indicate an area of damage and signal tissue repair. The gastrointestinal tract is a major signaling hub for such immune responses, as intestinal epithelial cells (IECs) compose the epithelial barrier, immune cells surveillance breached barriers to regulate the gut microbiome, and intestinal stem cells (ISCs) proliferate to replenish the IEC pool. One such method for regulating these cellular functions downstream of PAMPs/DAMPs within the gastrointestinal tract is via NF-κB signaling. This cellular signaling pathway is activated by one of two pathways: the well- defined canonical NF-κB pathway and the understudied noncanonical NF-κB pathway. The noncanonical NF-κB pathway is unique as it requires NIK, the NF-κB-inducing Kinase, to further elicit signal transduction of this pathway. Noncanonical NF-κB activation is critical to maintaining gut health, as signaling is regulated at a precise level to ensure a balance of pro-/anti-inflammatory signals to elicit a proper damage response. Any perturbations to NIK-activated signaling significantly predisposes the gastrointestinal niche towards chronic inflammatory conditions of the gastrointestinal tract.
In this work, we explore the potential involvement of dysregulated noncanonical NF-κB signaling in inducing chronic inflammatory diseases of the gut, including Eosinophilic Esophagitis (upper GI tract), Celiac Disease/Non-Celiac Gluten Sensitivities (small intestine), Inflammatory Bowel Disease (entire intestine/large intestine), and an inflammatory subtype of colorectal cancer being Colitis-Associated Colorectal Cancer (large intestine). We study this pathway via the use of murine models bearing genetic deletions, cellular models, and the generation of miniature organs (i.e. "organoids") in petri dishes. Further, we assess varying levels of NF-κB signaling through the genetic deletions of NIK and RelA to inhibit noncanonical and canonical NF-κB pathways, respectively. Reciprocally, we also examine overactivated signaling via loss of the negative regulatory NLRs, which are proteins that function to impede NF-κB signaling. Clinical relevancy of this work is evaluated using biopsy samples collected from human patients with active disease states. Culminating our work, we find that noncanonical NF-κB signaling levels is both tissue- and cell-type specific in driving disease formation. Finally, we conclude our findings by suggesting the promise of NIK as a potential candidate for disease biomarkers and a target for future drug development.Doctor of PhilosophyRedness, swelling, heat, pain, and loss of function – these are the five signs of inflammation. Under normal physiological conditions, inflammation is the body's conserved evolutionary response by serving as the first line of defense against infections propagated by foreign invaders like pathogens (i.e. bacteria, viruses, fungi), while also signaling to the immune system to resolve tissue damage. Therefore, properly maintained pro-inflammatory signaling is critical to ensuring a healthy state. However, an imbalance in pro- and anti-inflammatory signaling elicits a long-term, low-grade form of inflammation termed "chronic inflammation". Unresolved chronic inflammation can persist for several months or even years and further predisposes patients to various chronic inflammatory conditions and even inflammation-induced cancer. The NF-κB cellular signaling mechanism is a central regulator of inflammation and can be activated upon either the canonical NF-κB or noncanonical NF-κB pathways. In comparison to its canonical counterpart, the noncanonical NF-κB is vastly understudied, especially in regards to gastrointestinal health. A unique feature of the noncanonical NF-κB pathway is the required stabilization of the NF-κB-inducing Kinase (NIK) protein, which is required for further propagation of this signaling network.
As evidenced by our culmination of works, we reveal that Noncanonical NF-κB signaling is critical to gut health, as it maintains a precise cellular signaling mechanism within the gut tract by properly maintaining pro- and anti-inflammatory signaling. Additional, downstream implications include regulation of cell division and activation of cell death to elicit a proper damage response. Within this dissertation, we evaluate the understudied noncanonical NF-κB pathway in various chronic inflammatory diseases of the gut including Eosinophilic Esophagitis (upper GI tract), Celiac Disease/Non-Celiac Gluten Sensitivities (small intestine), Inflammatory Bowel Disease (entire intestine/large intestine), and an inflammatory subtype of colorectal cancer Colitis-Associated Colorectal Cancer (large intestine). Through the use of murine models bearing deletions of genes related to noncanonical NF-κB signaling (esp. NIK), cell models, and the generation of "mini-organs" organoids from isolated intestinal stem cells, we are able to model the involvement of NIK and noncanonical NF-κB signaling in maintaining gastrointestinal health. Clinical relevancy of these findings was further evaluated by quantifying noncanonical NF-κB signaling levels in human biopsies. Culminating our work, we find noncanonical NF-κB signaling to be context-specific in driving disease formation. Finally, we conclude this work by suggesting the promise of NIK as a potential candidate for disease biomarkers and target for future drug development
Environmental toxicity, redox signaling and lung inflammation:the role of glutathione
No full textGlutathione (gamma-glutamyl-cysteinyl-glycine, GSH) is the most abundant intracellular antioxidant thiol and is central to redox defense during oxidative stress. GSH metabolism is tightly regulated and has been implicated in redox signaling and also in protection against environmental oxidant-mediated injury. Changes in the ratio of the reduced and disulfide form (GSH/GSSG) can affect signaling pathways that participate in a broad array of physiological responses from cell proliferation, autophagy and apoptosis to gene expression that involve H(2)O(2) as a second messenger. Oxidative stress due to oxidant/antioxidant imbalance and also due to environmental oxidants is an important component during inflammation and respiratory diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and asthma. It is known to activate multiple stress kinase pathways and redox-sensitive transcription factors such as Nrf2, NF-kappaB and AP-1, which differentially regulate the genes for pro-inflammatory cytokines as well as the protective antioxidant genes. Understanding the regulatory mechanisms for the induction of antioxidants, such as GSH, versus pro-inflammatory mediators at sites of oxidant-directed injuries may allow for the development of novel therapies which will allow pharmacological manipulation of GSH synthesis during inflammation and oxidative injury. This article features the current knowledge about the role of GSH in redox signaling, GSH biosynthesis and particularly the regulation of transcription factor Nrf2 by GSH and downstream signaling during oxidative stress and inflammation in various pulmonary diseases. We also discussed the current therapeutic clinical trials using GSH and other thiol compounds, such as N-acetyl-l-cysteine, fudosteine, carbocysteine, erdosteine in environment-induced airways disease
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