排序方式: 共有60条查询结果,搜索用时 15 毫秒
51.
52.
Thomas D Walko III Valentina Di Caro Jon Piganelli Timothy R Billiar Robert SB Clark Rajesh K Aneja 《Molecular medicine (Cambridge, Mass.)》2014,20(1):612-624
Pathophysiological conditions that lead to the release of the prototypic damage-associated molecular pattern molecule high mobility group box 1 (HMGB1) also result in activation of poly(ADP-ribose) polymerase 1 (PARP1; now known as ADP-ribosyl transferase 1 [ARTD1]). Persistent activation of PARP1 promotes energy failure and cell death. The role of poly(ADP-ribosyl)ation in HMGB1 release has been explored previously; however, PARP1 is a versatile enzyme and performs several other functions including cross-talk with another nicotinamide adenine dinucleotide- (NAD+) dependent member of the Class III histone deacetylases (HDACs), sirtuin-1 (SIRT1). Previously, it has been shown that the hyperacetylation of HMGB1 is a seminal event prior to its secretion, a process that also is dependent on HDACs. Therefore, in this study, we seek to determine if PARP1 inhibition alters LPS-mediated HMGB1 hyperacetylation and subsequent secretion due to its effect on SIRT1. We demonstrate in an in vitro model that LPS treatment leads to hyperacetylated HMGB1 with concomitant reduction in nuclear HDAC activity. Treatment with PARP1 inhibitors mitigates the LPS-mediated reduction in nuclear HDAC activity and decreases HMGB1 acetylation. By utilizing an NAD+-based mechanism, PARP1 inhibition increases the activity of SIRT1. Consequently, there is an increased nuclear retention and decreased extracellular secretion of HMGB1. We also demonstrate that PARP1 physically interacts with SIRT1. Further confirmation of this data was obtained in a murine model of sepsis, that is, administration of PJ-34, a specific PARP1 inhibitor, led to decreased serum HMGB1 concentrations in mice subjected to cecal ligation and puncture (CLP) as compared with untreated mice. In conclusion, our study provides new insights in understanding the molecular mechanisms of HMGB1 secretion in sepsis. 相似文献
53.
Tetraloops are a common building block for RNA tertiary structure, and most tetraloops fall into one of three well-characterized classes: GNRA, UNCG, and CUYG. Here, we present the sequence and structure of a fourth highly conserved class of tetraloop that occurs only within the ζ-ζ′ interaction of group IIC introns. This GANC tetraloop was identified, along with an unusual cognate receptor, in the crystal structure of the group IIC intron and through phylogenetic analysis of intron RNA sequence alignments. Unlike conventional tetraloop-receptor interactions, which are stabilized by extensive hydrogen-bonding interactions, the GANC-receptor interaction is limited to a single base stack between the conserved adenosine of the tetraloop and a single purine of the receptor, which consists of a one- to three-nucleotide bulge and does not contain an A-platform. Unlike GNRA tetraloops, the GANC tetraloop forms a sharp angle relative to the adjacent helix, bending by approximately 45° toward the major groove side of the helix. These structural attributes allow GANC tetraloops to fit precisely within the group IIC intron core, thereby demonstrating that structural motifs can adapt to function in a specific niche. 相似文献
54.
55.
Herbert SB Baraf Michael A Becker Sergio R Gutierrez-Urena Edward L Treadwell Janitzia Vazquez-Mellado Claudia D Rehrig Faith D Ottery John S Sundy Robert A Yood 《Arthritis research & therapy》2013,15(5):R137
Introduction
Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy.Methods
Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR.Results
Among 212 patients randomized in the RCTs, 155 (73%) had ≥1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo).Both overall tophus CR and TT-CRs increased with treatment duration in the OLE, reaching 70% (39/56) of patients and 55% (132/238) of target tophi after one year of treatment in patients receiving pegloticase during both the RCTs and OLE. At that time point, more tophi had resolved in responders (102/145 or 70% of tophi) than nonresponders (30/93; 32%).Conclusions
Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy.Trial registrations
, NCT00325195 NCT01356498相似文献56.
Stephen A Bustin Jean-François Beaulieu Jim Huggett Rolf Jaggi Frederick SB Kibenge Pål A Olsvik Louis C Penning Stefan Toegel 《BMC molecular biology》2010,11(1):74
The conclusions of thousands of peer-reviewed publications rely on data obtained using fluorescence-based quantitative real-time
PCR technology. However, the inadequate reporting of experimental detail, combined with the frequent use of flawed protocols
is leading to the publication of papers that may not be technically appropriate. We take the view that this problem requires
the delineation of a more transparent and comprehensive reporting policy from scientific journals. This editorial aims to
provide practical guidance for the incorporation of absolute minimum standards encompassing the key assay parameters for accurate
design, documentation and reporting of qPCR experiments (MIQE précis) and guidance on the publication of pure 'reference gene'
articles. 相似文献
57.
58.
59.
Phylogeny and biogeography of ratite birds inferred from DNA sequences of the mitochondrial ribosomal genes 总被引:7,自引:2,他引:5
The origin of the flightless ratite birds of the southern continents has
been debated for over a century. Whether dispersal or vicariance
(continental breakup) best explains their origin depends largely on their
phylogenetic relationships. No consensus has been reached on this issue
despite many morphological and molecular studies. To address this question
further we sequenced a 2.8-kb region of mitochondrial DNA containing the
ribosomal genes in representative ratites and a tinamou. Phylogenetic
analyses indicate that Struthio (Africa) is basal and Rhea (South America)
clusters with living Australasian ratites. This phylogeny agrees with
transferrin and DNA hybridization studies but not with sequence analyses of
some protein-coding genes. These results also require reevaluation of the
phylogenetic position of the extinct moas of New Zealand. We propose a new
hypothesis for the origin of ratites that combines elements of dispersal
and vicariance.
相似文献
60.