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Danger signal

Tiffany Elizabeth Cho, Jack Uetrecht
Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-associated molecular pattern molecules that activate antigen presenting cells...
October 24, 2016: Chemical Research in Toxicology
Nicole Y K Li-Jessen, Michael Powell, Ae-Jin Choi, Byung-Joo Lee, Susan L Thibeault
OBJECTIVES/HYPOTHESIS: High-mobility group box 1 (HMGB1) is a chromatin-binding protein located in the cell nucleus. Following injury, immunocompetent cells secrete HMGB1 to the extracellular milieu under the stimulation of proinflammatory cytokines. Extracellular HMGB1 acts a danger signal that instigates the innate immunity and tissue repair. We previously reported HMGB1 in the vocal fold extracellular compartment between day 3 and day 7 following surgical injury. In this study, we further investigated the cell source of HMGB1 and the relationship of proinflammatory cytokine expression and HMGB1 translocation in wounded vocal folds...
October 24, 2016: Laryngoscope
Erica L Heipertz, Jourdan Harper, Wendy E Walker
IFN regulatory factor (IRF)3 plays a detrimental role in the cecal ligation and puncture (CLP) mouse model of sepsis. However, it is unclear which pathway activates IRF3 in this context. In this report we investigate two pathways that activate IRF3: the Stimulator of Interferon Genes (STING) pathway (which senses cytosolic DNA) and the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway (which sense dsRNA and LPS via Toll-like receptor (TLR) 3 and 4). Initially, we examine the impact of these pathways using a severe CLP model (∼90% mortality)...
October 17, 2016: Shock
Junjie Luo, Wei L Shen, Craig Montell
Avoidance of noxious ambient heat is crucial for survival. A well-known phenomenon is that animals are sensitive to the rate of temperature change. However, the cellular and molecular underpinnings through which animals sense and respond much more vigorously to fast temperature changes are unknown. Using Drosophila larvae, we found that nociceptive rolling behavior was triggered at lower temperatures and at higher frequencies when the temperature increased rapidly. We identified neurons in the brain that were sensitive to the speed of the temperature increase rather than just to the absolute temperature...
October 17, 2016: Nature Neuroscience
Lorenzo Galluzzi, Aitziber Buqué, Oliver Kepp, Laurence Zitvogel, Guido Kroemer
Immunogenicity depends on two key factors: antigenicity and adjuvanticity. The presence of exogenous or mutated antigens explains why infected cells and malignant cells can initiate an adaptive immune response provided that the cells also emit adjuvant signals as a consequence of cellular stress and death. Several infectious pathogens have devised strategies to control cell death and limit the emission of danger signals from dying cells, thereby avoiding immune recognition. Similarly, cancer cells often escape immunosurveillance owing to defects in the molecular machinery that underlies the release of endogenous adjuvants...
October 17, 2016: Nature Reviews. Immunology
Meriam Nefla, Dirk Holzinger, Francis Berenbaum, Claire Jacques
Alarmins (also known as danger signals) are endogenous molecules that are released to the extracellular milieu after infection or tissue damage. Extracellular alarmins interact with specific receptors expressed by cells that are engaged in host defence to stimulate signalling pathways that result in initiation of innate and adaptive immune responses, triggering inflammation or tissue repair. Alarmins are considered to be markers of destructive processes that occur in degenerative joint diseases (primarily osteoarthritis (OA)) and chronic inflammatory joint diseases (such as rheumatoid arthritis, psoriatic arthritis and spondylarthropathy)...
October 13, 2016: Nature Reviews. Rheumatology
Chunya Ni, Marie-Sophie Narzt, Ionela-Mariana Nagelreiter, Cheng Feng Zhang, Lionel Larue, Heidemarie Rossiter, Johannes Grillari, Erwin Tschachler, Florian Gruber
Autophagy is a recycling program which allows cells to adapt to metabolic needs and to stress. Defects in autophagy can affect metabolism, aging, proteostasis and inflammation. Autophagy pathway genes, including autophagy related 7 (Atg7), have been associated with the regulation of skin pigmentation, and autophagy defects disturb the biogenesis and transport of melanosomes in melanocytes as well as transfer and processing of melanin into keratinocytes. We have previously shown that mice whose melanocytes or keratinocytes lack Atg7 (and thus autophagy) as a result of specific gene knockout still retained functioning melanosome synthesis and transfer, and displayed only moderate reduction of pigmentation...
October 9, 2016: International Journal of Biochemistry & Cell Biology
Luigi Martino, Louise Holland, Evangelos Christodoulou, Simone Kunzelmann, Diego Esposito, Katrin Rittinger
NOD-like receptors represent an important class of germline-encoded pattern recognition receptors that play key roles in the regulation of inflammatory signalling pathways. They function as danger sensors and initiate inflammatory responses and the production of cytokines. Since NLR malfunction results in chronic inflammation and auto-immune diseases, there is a great interest in understanding how they work on a molecular level. To date, a lot of insight into the biological functions of NLRs is available but biophysical and structural studies have been hampered by the difficulty to produce soluble and stable recombinant NLR proteins...
2016: PloS One
Christian Fisahn, Marc D Moisi, Shiveindra Jeyamohan, Mary Wingerson, R Shane Tubbs, Charles Cobbs, Rod J Oskouian, Jens R Chapman
INTRODUCTION: Misdiagnosis of Brown-Séquard-like presentations can delay treatment; potentially endangering the positive outcomes a patient might otherwise have had. Stroke mimics can be perceived as signaling the end of urgent investigation and care once stroke is ruled out; however, stroke mimics themselves can require prompt care. Herein, we discuss an extremely rare case where stroke was ruled out, resulting in a lapse in care that lead to an exacerbated hemiparesis over the following week...
September 29, 2016: International Journal of Surgery Case Reports
Hye-Kyoung Jun, Young-Jung Jung, Bong-Kyu Choi
OBJECTIVE: The aim of this study was to analyze whether periodontopathogens induced inflammatory cell death and the release of diverse endogenous danger molecules in THP-1-derived macrophages. METHODS: The macrophages were treated with Treponema denticola, Porphyromonas gingivalis, and Tannerella forsythia. Activation of caspase-1 and caspase-4 was detected by Western blotting. Cell death of bacteria-stimulated macrophages was examined using a lactate dehydrogenase (LDH) assay and propidium iodide (PI)/annexin V (AV) staining...
September 26, 2016: Archives of Oral Biology
Virginie Deswaerte, Saleela M Ruwanpura, Brendan J Jenkins
Over the last decade it has emerged that inflammasome complexes provide a pivotal platform for the host innate immune system to respond to exogenous infectious microbes (viruses, bacteria, fungi) and non-infectious environmental agents (cigarette smoke, pollution), as well as endogenous "danger" signals. Upon the canonical activation of inflammasomes, a key effector function is to catalyze, via caspase-1, the maturation of the potent pro-inflammatory cytokines interleukin (IL)-1β and IL-18, which, in addition to chronic inflammatory responses have also been intimately linked to the inflammatory form of lytic cell death, pyroptosis...
September 30, 2016: Molecular Immunology
Nathalie Niyonzima, Bente Halvorsen, Bjørnar Sporsheim, Peter Garred, Pål Aukrust, Tom Eirik Mollnes, Terje Espevik
In the host a diverse collection of endogenous danger signals is constantly generated consisting of waste material as protein aggregates or crystalline materials that are recognized and handled by soluble pattern recognition receptors and phagocytic cells of the innate immune system. These signals may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation...
September 28, 2016: Molecular Immunology
Manon Wicking, Frauke Steiger, Frauke Nees, Slawomira J Diener, Oliver Grimm, Michaela Ruttorf, Lothar R Schad, Tobias Winkelmann, Gustav Wirtz, Herta Flor
BACKGROUND: Posttraumatic stress disorder (PTSD) might be maintained by deficient extinction memory. We used a cued fear conditioning design with extinction and a post-extinction phase to provoke the return of fear and examined the role of the interplay of amygdala, hippocampus and prefrontal regions. METHODS: We compared 18 PTSD patients with two healthy control groups: 18 trauma-exposed subjects without PTSD (nonPTSD) and 18 healthy controls (HC) without trauma experience...
September 26, 2016: Neurobiology of Learning and Memory
Pavan B Narayanaswamy, Sergey Tkachuk, Hermann Haller, Inna Dumler, Yulia Kiyan
Mechanisms of DNA damage and repair signaling are not completely understood that hinder the efficiency of cancer therapy. Urokinase-type plasminogen activator receptor (PLAUR) is highly expressed in most solid cancers and serves as a marker of poor prognosis. We show that PLAUR actively promotes DNA repair in cancer cells. On the contrary, downregulation of PLAUR expression results in delayed DNA repair. We found PLAUR to be essential for activation of Checkpoint kinase 1 (CHK1); maintenance of cell cycle arrest after DNA damage in a TP53-dependent manner; expression, nuclear import and recruitment to DNA-damage foci of RAD51 recombinase, the principal protein involved in the homologous recombination repair pathway...
2016: Cell Death & Disease
Amanda N Stephens, Vanessa Beanland, Nimmi Candappa, Eve Mitsopoulos-Rubens, Bruce Corben, Michael G Lenné
Intersections are typically associated with a higher level of crash risk than other types of facilities on the road network. Standard cross-road intersections are particularly hazardous because by their very design, drivers may travel through at speeds that are incompatible with human biomechanical tolerance should a crash occur. Further, drivers are exposed to dangerous conflict angles, which are likely to result in serious injury. This paper examines the effectiveness of two new intersection designs aimed at restricting potentially dangerous conflict angles while reducing driver speeds through the intersection...
September 26, 2016: Accident; Analysis and Prevention
Andrew P Bantel, Charles R Tessier
Olfactory and gustatory perception of the environment is vital for animal survival. The most obvious application of these chemosenses is to be able to distinguish good food sources from potentially dangerous food sources. Gustation requires physical contact with a chemical compound which is able to signal through taste receptors that are expressed on the surface of neurons. In insects, these gustatory neurons can be located across the animal's body allowing taste to play an important role in many different behaviors...
2016: Journal of Visualized Experiments: JoVE
Ralf Willebrand, David Voehringer
PURPOSE OF REVIEW: Eosinophils are a subset of granulocytes generally associated with type 2 immune responses. They can contribute to protection against helminths but also mediate pro-inflammatory functions during allergic immune responses. Only recently, eosinophils were also found to exert many other functions such as regulation of glucose and fat metabolism, thermogenesis, survival of plasma cells, and antitumor activity. The mechanisms that control eosinophil development and survival are only partially understood...
September 26, 2016: Current Opinion in Hematology
Angelos Papatheodorou, Adam B Stein, Matthew Bank, Cristina P Sison, Katie Gibbs, Peter Davies, Ona Bloom
Inflammation in traumatic spinal cord injury (SCI) has been proposed to promote damage acutely and oppose functional recovery chronically. However, we do not yet understand the signals that initiate or prolong inflammation in persons with SCI. High-Mobility Group Box 1 (HMGB1) is a potent systemic inflammatory cytokine, or "damage-associated molecular pattern molecule" (DAMP) studied in a variety of clinical settings. It is elevated in pre-clinical models of traumatic spinal cord injury (SCI), where it promotes secondary injury, and strategies that block HMGB1 improve functional recovery...
September 27, 2016: Journal of Neurotrauma
Krisztina Kovács, Anna Kis, Ákos Pogány, Dóra Koller, József Topál
Dogs have been proven to show several human-analogue social behaviors, and recent research raises the possibility that the oxytocin system is related to these. However, despite dogs' general tendency to excel in the domain of social cognition, there is increasing evidence that dogs' ability to utilize human signals may vary with breed. Moreover, breeds may show differences not only in their 'inborn' communicative abilities, but also in their learning skills related to these. The aim of the present study was to explore breed differences and breed-specific effects of oxytocin administration on different aspects of social responsiveness...
September 20, 2016: Psychoneuroendocrinology
Franklin L Zhong, Ons Mamaï, Lorenzo Sborgi, Lobna Boussofara, Richard Hopkins, Kim Robinson, Ildikó Szeverényi, Takuya Takeichi, Reshmaa Balaji, Aristotle Lau, Hazel Tye, Keya Roy, Carine Bonnard, Patricia J Ahl, Leigh Ann Jones, Paul Baker, Lukas Lacina, Atsushi Otsuka, Pierre R Fournie, François Malecaze, E Birgitte Lane, Masashi Akiyama, Kenji Kabashima, John E Connolly, Seth L Masters, Vincent J Soler, Salma Samir Omar, John A McGrath, Roxana Nedelcu, Moez Gribaa, Mohamed Denguezli, Ali Saad, Sebastian Hiller, Bruno Reversade
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation...
September 22, 2016: Cell
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