Tumor necrosis factor-α-mediated threonine 435 phosphorylation of p65 nuclear factor-κB subunit in endothelial cells induces vasogenic edema and neutrophil infiltration in the rat piriform cortex following status epilepticus

<p>Abstract</p> <p>Background</p> <p>Status epilepticus (SE) induces severe vasogenic edema in the piriform cortex (PC) accompanied by neuronal and astroglial damages. To elucidate the mechanism of SE-induced vasogenic edema, we investigated the roles of tumor necrosis factor (TNF)-α in blood-brain barrier (BBB) disruption during vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced SE.</p> <p>Methods</p> <p>SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, and soluble TNF p55 receptor (sTNFp55R) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunits.</p> <p>Results</p> <p>Following SE, most activated microglia showed strong TNF-α immunoreactivity. In addition, TNF p75 receptor expression was detected in endothelial cells as well as astrocytes. In addition, only p65-Thr435 phosphorylation was increased in endothelial cells accompanied by SMI-71 expression (an endothelial barrier antigen). Neutralization of TNF-α by soluble TNF p55 receptor (sTNFp55R) infusion attenuated SE-induced vasogenic edema and neuronal damages via inhibition of p65-Thr435 phosphorylation in endothelial cells. Furthermore, sTNFp55R infusion reduced SE-induced neutrophil infiltration in the PC.</p> <p>Conclusion</p> <p>These findings suggest that impairments of endothelial cell functions via TNF-α-mediated p65-Thr 485 NF-κB phosphorylation may be involved in SE-induced vasogenic edema. Subsequently, vasogenic edema results in extensive neutrophil infiltration and neuronal-astroglial loss.</p

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Determining Isoform Specificity of the Caenorhabditis elegans Transcription Factor DAF-19

Though the pathologies associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s have been known for many years, we still lack a complete understanding of the molecular mechanisms behind these devastating diseases. The nematode Caenorhabditis elegans is a model organism with a simple nervous system that has given biologists a better understanding of the mechanisms of cell division, apoptosis, and other fundamental concepts of cell and molecular biology. Study of the C. elegans RFX transcription factor DAF-19 has helped us better understand the development of the nervous system. Previous research demonstrated that four distinct protein isoforms are encoded for by the daf-19 gene. DAF-19C is an isoform of the transcription factor known to be necessary for cilia development of the sensory neurons of C. elegans. DAF-19M is involved in specification of male-specific sensory neurons. Recent studies have shown that the isoforms DAF-19A and/or DAF-19B function to maintain protein homeostasis at the neuronal synapses. We used extra-chromosomal transgene arrays containing the control regions of one of two target genes fused with GFP to determine if these genes are DAF-19 dependent. We compared expression of these transgenes in WT worms and in worms without functional DAF-19. Additionally, we characterized two novel daf-19a/b isoform-specific variations using RT-PCR and analyzed the expression of the DAF-19 dependent skr-12 transgene in the presence of one of these isoform-specific variations. We found that skr-12, an E3 ligase ortholog potentially involved in ubiquitin-mediated protein degradation, appears to be repressed by DAF-19A/B in non-sensory cells of the nervous system, while expression of asm-3, a gene potentially involved in the degradation of sphingomyelin, is not DAF-19 dependent

Is an antibacterial adhesive system more effective than cavity disinfectants?

WOS: 000238582200009PubMed ID: 16838482Purpose: To compare the antibacterial activity of an adhesive system containing an antibacterial monomer MDPB, Clearfil Protect Bond with three different cavity disinfectants, chlorhexidine gluconate-based Consepsis, benzalkonium chloride-based Tubulicid Red and 3% hydrogen peroxide. Methods: Materials were tested using agar well technique and a tooth cavity model. The test materials were filled in the agar wells of plates inoculated with Streptococcus mutans. After 48 hours of incubation, the zones of inhibitions were measured in millimeters. For the tooth cavity model test, cylindrical cavities were prepared in the flat occlusal dentin of human extracted molars. The teeth were left in a broth culture of Streptococcus mutans at 37 degrees C for 72 hours allowing bacteria to invade. Teeth were then randomly assigned into five groups of five teeth (10 cavity preparations) each. In the first four groups test materials were applied into the cavities following the manufacturer's instructions and the cavities in the fifth group were left untreated for control. The teeth were kept in saline for 72 hours. Standard amounts of dentin chips were obtained from the cavity walls and the number of bacteria recovered was counted. Results: The results were analyzed by ANOVA, Dunnett C and Bonferroni tests. For the agar well technique, Clearfil Protect Bond primer exhibited greater inhibition zones than all three cavity disinfectants (P 0.05). They were superior to hydrogen peroxide in the cavity test method (P< 0.05)