The endogenous neurosteroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) has protective activity in animal models of alcoholism, depression, traumatic brain injury, schizophrenia, ...multiple sclerosis, and Alzheimer's disease that is poorly understood. Because these conditions involve proinflammatory signaling through toll-like receptors (TLRs), we examined the effects of 3α,5α-THP, and pregnenolone on TLR4 activation in both the periphery and the central nervous system (CNS). We used monocytes/macrophages (RAW264.7) as a model of peripheral immune signaling and studied innately activated TLR4 in the ventral tegmental area (VTA) of selectively bred alcohol-preferring (P) rats. LPS activated the TLR4 pathway in RAW264.7 cells as evidenced by increased levels of p-TAK1, TRAF6, NF-κB p50, phospho-NF-κB- p65, pCREB, HMGB1, and inflammatory mediators, including MCP-1 and TNFα. Both 3α,5α-THP and pregnenolone (0.5-1.0μM) substantially (~80%) inhibited these effects, indicating pronounced inhibition of TLR4 signaling. The mechanism of inhibition appears to involve blockade of TLR4/MD-2 protein interactions in RAW246.7 cells. In VTA, 3α,5α-THP (15 mg/kg, IP) administration reduced TRAF6 (~20%), CRF (~30%), and MCP-1 (~20%) levels, as well as TLR4 binding to GABA
receptor α2 subunits (~60%) and MyD88 (~40%). The data suggest that inhibition of proinflammatory neuroimmune signaling underlies protective effects of 3α,5α-THP in immune cells and brain, apparently involving blocking of protein-protein interactions that initiate TLR4-dependent signaling. Inhibition of pro-inflammatory TLR4 activation represents a new mechanism of 3α,5α-THP action in the periphery and the brain.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This first-in-human, phase I clinical trial of p28 (NSC745104), a 28-amino-acid fragment of the cupredoxin azurin, investigated the safety, tolerability, pharmacokinetics and preliminary activity of ...p28 in patients with p53(+) metastatic solid tumours.
A total of 15 patients were administered p28 i.v. as a short infusion three times per week for 4 weeks followed by a 2-week rest under an accelerated titration 3+3 dose escalation design until either a grade 3-related adverse event occurred or the maximum tolerated dose (MTD) was reached. Single-dose and steady-state serum pharmacokinetics were characterised. Assessments included toxicity, best objective response by RECIST 1.1 Criteria, and overall survival.
No patients exhibited any dose-limiting toxicities (DLTs), significant adverse events or exhibited an immune response (IgG) to the peptide. The No Observed Adverse Effect Level (NOAEL) and MTD were not reached. Seven patients demonstrated stable disease for 7-61 weeks, three a partial response for 44-125 weeks, and one a complete response for 139 weeks. Three patients are still alive at 158, 140, and 110 weeks post therapy completion.
p28 was tolerated with no significant adverse events. An MTD was not reached. Evidence of anti-tumour activity indicates a highly favourable therapeutic index and demonstrates proof of concept for this new class of non-HDM2-mediated peptide inhibitors of p53 ubiquitination.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Control of Synaptic Strength by Glial TNFα Beattle, Eric C.; Stellwagen, David; Morishita, Wade ...
Science (American Association for the Advancement of Science),
03/2002, Volume:
295, Issue:
5563
Journal Article
Peer reviewed
Activity-dependent modulation of synaptic efficacy in the brain contributes to neural circuit development and experience-dependent plasticity. Although glia are affected by activity and ensheathe ...synapses, their influence on synaptic strength has largely been ignored. Here, we show that a protein produced by glia, tumor necrosis factor α (TNFα), enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the actions of endogenous TNFα has the opposite effects. Thus, the continual presence of TNFα is required for preservation of synaptic strength at excitatory synapses. Through its effects on AMPA receptor trafficking, TNFα may play roles in synaptic plasticity and modulating responses to neural injury.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Activity-mediated changes in the strength of synaptic communication are important for the establishment of proper neuronal connections during development and for the experience-dependent modification ...of neural circuitry that is believed to underlie all forms of behavioural plasticity. Owing to the wide-ranging significance of synaptic plasticity, considerable efforts have been made to identify the mechanisms by which synaptic changes are triggered and expressed. New evidence indicates that one important expression mechanism of several long-lasting forms of synaptic plasticity might involve the physical transport of AMPA-type glutamate receptors in and out of the synaptic membrane. Here, we focus on the rapidly accumulating evidence that AMPA receptors undergo regulated endocytosis, which is important for long-term depression.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
Analgesia after liver surgery remains controversial. A previous randomized trial of continuous wound infiltration (CWI) versus thoracic epidural analgesia (TEA) after liver surgery (LIVER ...trial) showed a faster recovery time in the wound infiltration group but better early postoperative pain scores in the TEA group. High‐level evidence is, however, limited and opinion remains divided. The aim was to determine whether there is a difference in functional recovery time between patients having CWI plus abdominal nerve blocks versus TEA after liver resection.
Methods
A randomized unblinded clinical trial of patients undergoing open liver resection was commenced in December 2012, with follow‐up to August 2014. Patients were randomized to receive either wound catheter and nerve block (CWI group) or TEA for 48 h after surgery. The primary outcome measure was functional recovery time. Secondary outcomes were pain scores, complication rates, inflammatory response and central venous pressure (CVP) during transection.
Results
Of 50 patients randomized initially to each group, 44 received TEA and 49 CWI. Median (i.q.r.) recovery time was 6·5 (5–9·75) and 5·75 (4–7) days in the TEA and CWI groups respectively (P = 0·036). Pain scores were not significantly different between the two groups, and there were no differences in morbidity, inflammatory response or CVP during transection.
Conclusion
Wound infiltration is associated with a reduced time to recovery after open liver resection compared with epidural analgesia. TEA does not offer an advantage over CWI in terms of attenuation of the inflammatory response or pain scores. Registration number: NCT01747122 (
http://www.clinicaltrials.gov).
Nerve block just as good
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) causes a rapid exocytosis of AMPA receptors in hippocampal pyramidal cells and is constitutively required for the maintenance of ...normal surface expression of AMPA receptors. Here we demonstrate that TNFalpha acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase-dependent process. This increases excitatory synaptic strength while changing the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNFalpha causes an endocytosis of GABA(A) receptors, resulting in fewer surface GABA(A) receptors and a decrease in inhibitory synaptic strength. These results suggest that TNFalpha can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.
Melanoma epidemic: a midsummer night's dream? Levell, N.J.; Beattie, C.C.; Shuster, S. ...
British journal of dermatology (1951),
September 2009, Volume:
161, Issue:
3
Journal Article
Peer reviewed
Summary
Background The reported incidence of melanoma has greatly increased and this has been attributed to ultraviolet exposure.
Objectives We considered the possibility that the increase was an ...artefact caused by diagnostic drift.
Methods We tested this by analysing the histological diagnosis, mortality and incidence of all lesions reported as melanomas in East Anglia between 1991 and 2004.
Results There were 3971 melanomas in all, and their annual incidence increased from 9·39 to 13·91 cases per 100 000 per year during the period studied. This increased incidence was almost entirely due to minimal, stage 1 disease. There was no change in the combined incidence of the other stages of the disease, and the overall mortality only increased from 2·16 to 2·54 cases per 100 000 per year.
Conclusions We therefore conclude that the large increase in reported incidence is likely to be due to diagnostic drift which classifies benign lesions as stage 1 melanoma. This conclusion could be confirmed by direct histological comparison of contemporary and past histological samples. The distribution of the lesions reported did not correspond to the sites of lesions caused by solar exposure. These findings should lead to a reconsideration of the treatment of ‘early’ lesions, a search for better diagnostic methods to distinguish them from truly malignant melanomas, re‐evaluation of the role of ultraviolet radiation and recommendations for protection from it, as well as the need for a new direction in the search for the cause of melanoma.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A 28 amino-acid (aa) cell-penetrating peptide (p28) derived from azurin, a redox protein secreted from the opportunistic pathogen Pseudomonas aeruginosa, produces a post-translational increase in p53 ...in cancer cells by inhibiting its ubiquitination.
In silico computational simulations were used to predict motifs within the p53 DNA-binding domain (DBD) as potential sites for p28 binding. In vitro direct and competitive pull-down studies as well as western blot and RT-PCR analyses were used to validate predictions.
The L1 loop (aa 112-124), a region within the S7-S8 loop (aa 214-236) and T140, P142, Q144, W146, R282 and L289 of the p53DBD were identified as potential sites for p28 binding. p28 decreased the level of the E3 ligase COP1 >80%, in p53wt and p53mut cells with no decrease in COP1 in p53dom/neg or p53null cells. Brief increases in the expression of the E3 ligases, TOPORS, Pirh2 and HDM2 (human double minute 2) in p53wt and p53mut cells were in response to sustained increases in p53.
These data identify the specific motifs within the DBD of p53 that bind p28 and suggest that p28 inhibition of COP1 binding results in the sustained, post-translational increase in p53 levels and subsequent inhibition of cancer cell growth independent of an HDM2 pathway.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Compounds known to disrupt exocytosis or endocytosis were introduced into CA1 pyramidal cells while monitoring excitatory postsynaptic currents (EPSCs). Disrupting exocytosis or the interaction of ...GluR2 with NSF caused a gradual reduction in the AMPAR EPSC, while inhibition of endocytosis caused a gradual increase in the AMPAR EPSC. These manipulations had no effect on the NMDAR EPSC but prevented the subsequent induction of LTD. These results suggest that AMPARs, but not NMDARs, cycle into and out of the synaptic membrane at a rapid rate and that certain forms of synaptic plasticity may utilize this dynamic process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Orange jasmine has a complex nomenclatural history and is now known as Murraya paniculata (L.) Jack. Our interest in this common ornamental stemmed from the need to resolve its identity and the ...identities of closely related taxa as hosts of the pathogen 'Candidatus Liberibacter asiaticus' and its vector Diaphorina citri. Understanding these microbe-vector-plant relationships has been hampered by taxonomic confusion surrounding Murraya at both the generic and specific levels.
To resolve the taxonomic uncertainty, six regions of the maternally-inherited chloroplastal genome and part of the nuclear-encoded ITS region were amplified from 85 accessions of Murraya and Merrillia using the polymerase chain reaction (PCR). Clustering used maximum parsimony (MP), maximum likelihood (ML) and Bayesian inference (BI). Chronograms were produced for molecular dating, and to test the monophyly of Murraya rigorously, using selected accessions of Murraya and 26 accessions of the Rutaceae and Simarubaceae. Sequence data from the ITS and chloroplastal regions suggest that Murraya paniculata (sensu (Swingle WT and Reece CR, The Citrus Industry, p. 190-430, 1967)) can be separated into four distinct but morphologically somewhat cryptic taxa: Murraya paniculata (sensu (Mabberley DJ, Taxon 65:366-371, 2016)), M. elongata, M. sumatrana and M. lucida. In addition, Murraya omphalocarpa was identified as a putative hybrid of M. paniculata and M. lucida with two geographically isolated nothovarieties representing reciprocal crosses. Murraya is monophyletic, and molecular dating suggests that it diverged from Merrillia during the Miocene (23-5 Ma) with this Murraya group speciating and dispersing during the Middle Miocene onwards.
The accessions from Asia and Australasia used in this study grouped into biogeographical regions that match herbarium specimen records for the taxa that suggest natural allopatric distributions with limited overlap and hybridity. Murraya paniculata has been distributed around the world as an ornamental plant. The division of the Murraya paniculata complex into four species with a rare hybrid also confirms morphological studies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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