24 research outputs found
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Inhibitors of apoptosis proteins in injury and disease
The inhibitor of apoptosis (IAP) gene family prevents cell death by binding to and inhibiting caspases. In addition to negatively regulating apoptosis, IAPs bind to signaling intermediates and receptors, and participate in diverse cellular functions. Here, we describe the physiological functions of IAPs and their participation in injury and disease processes
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Hypothermia decreases the protein levels of TNF family members and their signaling intermediates after traumatic brain injury
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Tumor necrosis factor receptor 1 and its signaling intermediates are recruited to lipid rafts in the traumatized brain
The tumor necrosis factor (TNF) ligand-receptor system plays an essential role in apoptosis that contributes to secondary damage after traumatic brain injury (TBI). TNF also stimulates inflammation by activation of gene transcription through the IkappaB kinase (IKK)/NF-kappaB and JNK (c-Jun N-terminal protein kinase)/AP-1 signaling cascades. The mechanism by which TNF signals between cell death and survival and the role of receptor localization in the activation of downstream signaling events are not fully understood. Here, TNF receptor 1 (TNFR1) signaling complexes in lipid rafts were investigated in the cerebral cortex of adult male Sprague Dawley rats subjected to moderate (1.8-2.2 atmospheres) fluid-percussion TBI and naive controls. In the normal rat cortex, a portion of TNFR1 was present in lipid raft microdomains, where it associated with the adaptor proteins TRADD (TNF receptor-associated death domain), TNF receptor-associated factor-2 (TRAF-2), the Ser/Thr kinase RIP (receptor-interacting protein), TRAF1, and cIAP-1 (cellular inhibitor of apoptosis protein-1), forming a survival signaling complex. Moderate TBI resulted in rapid recruitment of TNFR1, but not TNFR2 or Fas, to lipid rafts and induced alterations in the composition of signaling intermediates. TNFR1 and TRAF1 were polyubiquitinated in lipid rafts after TBI. Subsequently, the signaling complex contained activated caspase-8, thus initiating apoptosis. In addition, TBI caused a transient activation of NF-kappaB, but receptor signaling interacting proteins IKKalpha and IKKbeta were not detected in raft-containing fractions. Thus, redistribution of TNFR1 in lipid rafts and nonraft regions of the plasma membrane may regulate the diversity of signaling responses initiated by these receptors in the normal brain and after TBI
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Monoubiquitination and cellular distribution of XIAP in neurons after traumatic brain injury
XIAP is a member of the inhibitor of apoptosis (IAP) gene family that, in addition to suppressing cell death by inhibition and polyubiquitination of caspases, is involved in an increasing number of signaling cascades. Moreover, the function and regulation of XIAP in the central nervous system (CNS) is poorly understood. In this study, the authors investigated the cell-type expression, the subcellular distribution, ubiquitination of XIAP, and levels of Smac/DIABLO in the normal adult rat brain and in brains subjected to moderate traumatic brain injury (TBI). In the normal brain, XIAP was predominantly expressed in the perinuclear region of neurons. Traumatized brains showed dramatic alterations in cellular and regional expression of XIAP early after injury. Stereologic analyses of the number of XIAP-positive cells within the hippocampus of both hemispheres showed a biphasic response. Immunoprecipitation and immunoblots of extracts derived from different brain regions demonstrated that a single ubiquitin modifies XIAP. Normal cortex contained significantly higher levels of monoubiquitinated XIAP than hippocampus. TBI induced alterations in levels of monoubiquitinated XIAP that correlated with changes in XIAP distribution and immunoreactivity, suggesting that monoubiquitination of XIAP may be a regulator of XIAP location or activity. Similar levels of Smac/DIABLO were present in lysates of normal and traumatized brains. These data demonstrate for the first time a region-specific regulation of XIAP monoubiquitination in the normal adult rat brain, and after TBI, that may be a key event in the regulation of XIAP function contributing to the pathogenesis following injury
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The inflammasome as a therapeutic target to improve outcomes after injury to the central nervous system (135.73)
Abstract The inflammasome constitutes one of the host's defenses against pathogens and deleterious stimuli by activating caspase-1. Inflammation with production of cytokines processed upon inflammasome activation is a crucial part of the secondary cascade of cell death induced after central nervous system (CNS) injury. The molecular mechanisms underlying trauma-induced inflammation in the CNS are poorly defined. In this study, the cellular distribution and protein association of inflammasome components were investigated in spinal cords and brains of rats subjected to moderate cervical injury and fluid-percussion brain injury, respectively. Coimmunoprecipitation experiments revealed that in the CNS, Apoptosis-Associated Speck-like protein containing a CARD (ASC) associates with caspase-1, caspase-11, NLR family, Pyrin domain containing 1 (NLRP1) and the inhibitor of apoptosis XIAP, forming the NLRP1 inflammasome. Injury to the CNS affects the composition of the inflammasome resulting in increased association of caspases-1 and -11 and NLRP1 with ASC and cleavage of XIAP. Immunohistochemistry revealed that motor neurons and cortical neurons express the NLRP1 inflammasome proteins. Therapeutic neutralization of ASC after injury inhibited inflammasome activation as shown by decreased caspase-1 activation and XIAP cleavage, resulting in reduced lesion volume and improved functional outcomes after spinal cord injury. Thus the inflammasome forms part of the innate immune response in the CNS and its inhibition may offer a novel therapeutic strategy to improve outcomes after injury and CNS inflammatory diseases. This research was supported by the NIH/NINDS and the US Army
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Apoptotic and Antiapoptotic Mechanisms after Traumatic Brain Injury
Caspase and inhibitor of apoptosis (IAP) expression was examined in rats subjected to moderate traumatic brain injury (TBI) using a parasagittal fluid-percussion brain insult (1.7 to 2.2 atm). Within 1 hour after injury, caspase-8 and −9, two initiators of apoptosis, were predominantly expressed in superficial cortical areas adjacent to the impact site and in the thalamus. Caspase-3, an effector caspase, was evident at 6 hours throughout the traumatized cerebral cortex and hippocampus. Moreover, the authors observed that XIAP, cIAP-1, and cIAP-2, members of the IAP family, were constitutively expressed in the brain. Colocalization of XIAP-immunolabled cells with cell-specific markers indicated that XIAP is expressed within neurons and a subpopulation of oligodendrocytes. Immunoblots of brain extracts revealed that the processed forms of caspase-8, −9, and −3 are present as early as 1 hour after trauma. The appearance of activated caspases corresponded with the detection of cleavage of XIAP into fragments after injury and a concomitant increase in the levels of cIAP-1 and cIAP-2 in the traumatized hemispheres. The current data are consistent with the hypotheses that caspases in both the extrinsic and intrinsic apoptotic pathways are activated after moderate TBI and that IAPs may have a protective role within the brain with alterations in levels and cleavage of IAPs that contribute to cell death in this setting
Twenty-Year Trends in the Incidence and revalence of Diagnosed Anogenital Warts in Canada
Background: A vaccine has recently been licensed in many countries that protects against the human papillomavirus types 6,11,16, and 18. Types 6 and 11 account for approximately 90% of anogenital warts (AGWs). We describe the 20-year trends in the incidence and prevalence of AGWs in Manitoba, Canada. Methods: We used linked population-based hospital and physician databases for Manitoba for 1984 to 2004. Cases were identified using tariff (billing) and ICD codes. A case was considered to be incident if it was preceded by a 12-month interval free period of AGWs care. Otherwise, it was deemed to be prevalent. An episode was considered over once a 12-month interval had elapsed without an AGW claim. Results: Approximately 25,000 Manitobans were diagnosed with AGWs between 1985 and 2004. The annual age-standardized incidence rates peaked in 1992 (men, 149.9/100,000; women 170.8/100,000). In recent years, the rates have been increasing again, particularly for men. The male:female incidence rate ratio increased from 0.76 in 1985 to 1.25 in 2004. The highest incidence rate tended to be in those aged 20 to 24 years. Trends in prevalence were similar. Prevalence in 2004 was 165.2/100,000 for men and 128.4/100,000 for women. Conclusions: These population-based findings suggest that AGWs are a substantial burden to Manitobans and that their pattern has changed over time, with incidence and prevalence becoming higher in men than women. Monitoring the future trends in AGWs will provide an early marker of the effectiveness and duration of protection of human papillomavirus vaccination at a population level