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991.
Matt Husa Freyr Petursson Martin Lotz Robert Terkeltaub Ru Liu-Bryan 《Arthritis research & therapy》2013,15(6):R218
Introduction
Excess C/EBP homologous protein (CHOP) expression is one feature of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress. Here, we focused on CHOP expression and function in chondrocytes.Methods
We studied human knee osteoarthritis (OA) cartilage, bovine chondrocytes cultured in alginate and subjected to sub-lethal biomechanical injury, and knee chondrocytes of human autopsy donors. We performed siRNA knockdown and transfection.Results
UPR activation was increased in human knee OA cartilage in situ, and in biomechanically injured cultured chondrocytes in vitro. In normal human chondrocytes, CHOP “gain of function” sensitized chondrocytes to IL-1β induced nitric oxide (NO) and matrix metalloproteinase (MMP)-3 release without inducing these responses by itself. Excess CHOP expression, by itself, induced superoxide production and apoptosis. Conversely, siRNA knockdown of CHOP and the UPR-specific mediator X-box binding protein (XBP1) inhibited NO release by >80% (P <0.0005) in response to IL-1β, and blunted MMP-3 release, whereas there were only minimal effects of the UPR mediator GRP78 on these responses. The anti-inflammatory metabolic “super-regulator” AMP kinase (AMPK) is known to limit UPR activation in vascular muscle cells. Here, CHOP supported the capacity of IL-1β to suppress AMPK activity in chondrocytes. We also observed that inhibition of AMPK activity promoted an increase in chondrocyte CHOP expression. Conversely, pharmacologic activation of AMPK by 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) blunted chondrocyte CHOP expression in response to biomechanical injury.Conclusions
Biomechanical injury and IL-1 signaling stimulate UPR activation in chondrocytes. CHOP mediates chondrocyte catabolic and apoptotic responses to IL-1β, and does so partly by inhibiting AMPK activity. Conversely, development of excess CHOP activity is limited by AMPK activity in chondrocytes. Our findings suggest a mechanism for potential chondroprotection by AICAR and other AMPK activators. The work is of translational relevance for OA, since several drugs that activate AMPK are already in the clinic for arthritis (for example, allosteric AMPK activators sodium salicylate and high dose aspirin, and methotrexate, which activates AMPK by generating AICAR). 相似文献992.
David A Martin Melvin Churchill Luis Felipe Flores-Suarez Mario H Cardiel Daniel Wallace Richard Martin Kristine Phillips Jeffrey L Kaine Hua Dong David Salinger Erin Stevens Chris B Russell James B Chung 《Arthritis research & therapy》2013,15(5):R164
Introduction
The aim of this study was to evaluate the safety, pharmacokinetics, and clinical response of brodalumab (AMG 827), a human, anti-IL-17 receptor A (IL-17RA) monoclonal antibody in subjects with moderate-to-severe rheumatoid arthritis (RA).Methods
This phase Ib, randomized, placebo-controlled, double-blind multiple ascending dose study enrolled subjects with moderate to severe RA (≥6/66 swollen and ≥8/68 tender joints). Subjects were randomized 3:1 to receive brodalumab (50 mg, 140 mg, or 210 mg subcutaneously every two weeks for 6 doses per group; or 420 mg or 700 mg intravenously every 4 weeks for two doses per group) or placebo. Endpoints included incidence of adverse events (AEs) and pharmacokinetics. Exploratory endpoints included pharmacodynamics, and improvements in RA clinical metrics.Results
Forty subjects were randomized to investigational product; one subject discontinued due to worsening of RA (placebo). The study was not designed to assess efficacy. AEs were reported by 70% (7/10) of placebo subjects and 77% (22/30) of brodalumab subjects. Three serious AEs were reported in two subjects; there were no opportunistic infections. Brodalumab treatment resulted in inhibition of IL-17 receptor signaling and receptor occupancy on circulating leukocytes. No treatment effects were observed with individual measures of RA disease activity. On day 85 (week 13) 37% (11/30) of brodalumab subjects and 22% (2/9) of placebo subjects achieved ACR20; 7% (2/30) brodalumab subjects and 11% (1/9) of placebo subjects achieved ACR50; and 0% (0/30) brodalumab subjects and 0% (0/9) of placebo subjects achieved ACR70.Conclusions
Multiple dose administration of brodalumab was tolerated in subjects with active RA. There was no evidence of a clinical response to brodalumab in subjects with RA.Trial registration
ClinicalTrials.gov, NCT00771030相似文献993.
Robert Brus Dalibor Ballian Faruk Bogunić Martin Bobinac Marilena IdžOjtić 《Plant biosystems》2013,147(2):278-285
Abstract In most European countries, the service tree (Sorbus domestica L.) is a rare and threatened species and its conservation has been recognised as a priority. The aim of this study was to asses its morphologic variation in the western and central part of the Balkan Peninsula and in southern Central Europe. Three populations were analysed: one in Serbia, one in Bosnia and Herzegovina and one in Slovenia. In each population 30 trees were selected, and from each tree 30 leaves were collected for morphometric analysis based on nine leaflet morphological traits. Univariate (ANOVA) and multivariate (MANOVA) analysis of variance were used to estimate the variation within- and between populations and a discriminant analysis was performed to examine the structure of the between-population differences. The values of particular morphological traits found in our study did not differ considerably from the values reported elsewhere. The results revealed significant within- and between population variation. Variation within populations was highly significant for all the scored leaf morphological traits, while variation between populations was significant for all the studied traits except for the leaflet length. The discrimination between the three populations was significant. High percentages of correctly classified samples demonstrate good discriminating employability of the analysed leaf morphological traits and indicate differentiation of the analysed populations. 相似文献
994.
995.
Imre Berger Martin Egli Nada Spackova Jiri Sponer Alexander Rich 《Nucleosides, nucleotides & nucleic acids》2013,32(6-7):1583-1585
Abstract DNA fragments with stretches of cytosine residues can form four-stranded intercalated i-DNA molecules stabilized by hemiprotonated cytosine·cytosine+ (C·C+) base pairs. Intriguing features of this motif are the accomodation of base stacking that is unfavorable due to electrostatic repulsion and the close approach of phosphates in narrow grooves of the molecule. Unusual sources of stability in this structure involve sugar-base stacking and CH-O interribose short contacts between the backbones of adjacent strands. 相似文献
996.
Albrecht K. Kleinschmidt Gerd Baumann Rainer Martin 《Nucleosides, nucleotides & nucleic acids》2013,32(9-11):1793-1800
Abstract The strategies for packaging the T4 coliphage chromosome are presented. Our probability model based on fractality of DNA “globules” (fasces-like DNA globules) is consistent with transient condensation modelling to the final maximally condensed state. 相似文献
997.
Abstract Studies on the pH dependence of ligand binding to A1 adenosine receptors revealed that protonation of a histidine residue in the binding pocket is accompanied by high affinity agonist binding. 相似文献
998.
Abstract The synthesis of 4′-(hydroxymethyl)guanosine (7) and the phosphonate analogue 8 of guanylic acid proceed from a common intermediate, 2′, 3′-O-isopropylidene-N 2-(monomethoxytrityl)-guanosine-5′-aldehyde (13). 相似文献
999.
An efficient entry to nucleoside 3′-H-phosphonoselenoate monoesters via phosphinate intermediates was developed. It involves a reaction of suitably protected nucleosides with triethylammonium phosphinate in the presence of pivaloyl chloride, followed by selenization of the intermediate nucleoside phosphinates with triphenylphosphine selenide, to produce the corresponding nucleoside H-phosphonoselenoates in 86–92% yields. 相似文献