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991.
Daniela Schilling Michael Düwel Michael Molls Gabriele Multhoff 《Cell stress & chaperones》2013,18(2):183-191
The oncoprotein MDM2 (murine double minute 2) is often overexpressed in human tumors and thereby attenuates the function of the tumor suppressor p53. In this study, we investigated the effects of the novel MDM2-inhibitor PXN727 on p53 activation, cell proliferation, cell cycle distribution and radiosensitivity. Since the localization of heat shock protein 70 (Hsp70) exerts different effects on radioresistance of tumor cells, we investigated the impact of PXN727 on intracellular, membrane, and secreted Hsp70 levels. We could show that PXN727 exerts its effects on wildtype p53 (HCT116 p53+/+, A549) but not p53 depleted (HCT116 p53−/−) or mutated (FaDu) tumor cells. PXN727 activates p53, induces the expression of p21, reduces the proportion of cells in the radioresistant S-phase and induces senescence. Radiosensitivity was significantly increased by PXN727 in HCT116 p53+/+ tumor cells. Furthermore, PXN727 causes a downregulation of Hsp70 membrane expression and an upregulated secretion of Hsp70 in wildtype p53 tumor cells. Our data suggest that re-activation of p53 by MDM2-inhibition modulates Hsp70 membrane expression and secretion which might contribute to the radiosensitizing effect of the MDM2-inhibitor PXN727. 相似文献
992.
993.
Gabriele Hakim Diana Fiorentini Tullia Maraldi Laura Landi 《Free radical research》2013,47(2):197-204
This study demonstrates that oxidative stress induced in rat thymocytes by the hydrophilic 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH), the lipophilic cumene hydroperoxide (CumOOH) and the freely diffusible H2O2 is associated with an activation of facilitative glucose transport rate, mediated by GLUT1, the major transporter in this cell type. We compared the effects of the three tested radical sources on the kinetic transport parameters, showing that the transport rate enhancement in the treated cells can be ascribed to an increase in the Vmax value, apart from the site of generation of the oxidative stress. The enhancement of glucose transport by the three oxidants in thymocytes was significantly attenuated both by protein tyrosine kinase inhibitors as genistein and tyrphostin A23 and by U73122, a phospholipase C inhibitor. Genistein and U73122 reversed also the cited increase of Vmax values. It is concluded that the stimulation of glucose transport in response to different oxidants is mediated, at least in part, through reactive oxygen species (ROS)-induced stimulation of protein tyrosine kinase and phospholipase C pathways. 相似文献
994.
Geoffrey Paltser Xue Jun Liu Jason Yantha Shawn Winer Hubert Tsui Ping Wu Yuko Maezawa Lindsay S Cahill Christine L Laliberté Sreeram V Ramagopalan Gabriele C DeLuca A Dessa Sadovnick Igor Astsaturov George C Ebers R Mark Henkelman Michael W Salter H-Michael Dosch 《Molecular medicine (Cambridge, Mass.)》2013,19(1):149-159
Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1−/− B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy. 相似文献
995.
Ka-Weng Ieong Gabriele Indrisiunaite Arjun Prabhakar Joseph D Puglisi Mns Ehrenberg 《Nucleic acids research》2021,49(5):2684
We used quench flow to study how N6-methylated adenosines (m6A) affect the accuracy ratio between kcat/Km (i.e. association rate constant (ka) times probability (Pp) of product formation after enzyme-substrate complex formation) for cognate and near-cognate substrate for mRNA reading by tRNAs and peptide release factors 1 and 2 (RFs) during translation with purified Escherichia coli components. We estimated kcat/Km for Glu-tRNAGlu, EF-Tu and GTP forming ternary complex (T3) reading cognate (GAA and Gm6AA) or near-cognate (GAU and Gm6AU) codons. ka decreased 10-fold by m6A introduction in cognate and near-cognate cases alike, while Pp for peptidyl transfer remained unaltered in cognate but increased 10-fold in near-cognate case leading to 10-fold amino acid substitution error increase. We estimated kcat/Km for ester bond hydrolysis of P-site bound peptidyl-tRNA by RF2 reading cognate (UAA and Um6AA) and near-cognate (UAG and Um6AG) stop codons to decrease 6-fold or 3-fold by m6A introduction, respectively. This 6-fold effect on UAA reading was also observed in a single-molecule termination assay. Thus, m6A reduces both sense and stop codon reading accuracy by decreasing cognate significantly more than near-cognate kcat/Km, in contrast to most error inducing agents and mutations, which increase near-cognate at unaltered cognate kcat/Km. 相似文献
996.
Cardiac resynchronisation therapy in patients with left bundle branch block with residual conduction
Christian Grebmer Lena Friedrich Verena Semmler Marc Kottmaier Felix Bourier Amir Brkic Patrick Blazek Severin Weigand Matthew O’ Connor Isabel Deisenhofer Gabriele Hessling Christof Kolb Carsten Lennerz 《Indian pacing and electrophysiology journal》2021,21(1):14-17
AimTo evaluate whether left bundle branch block with residual conduction (rLBBB) is associated with worse outcomes after cardiac resynchronisation therapy (CRT).MethodsAll consecutive CRT implants at our institution between 2006 and 2013 were identified from our local device registry. Pre- and post-implant patient specific data were extracted from clinical records.ResultsA total of 690 CRT implants were identified during the study period. Prior to CRT, 52.2% of patients had true left bundle branch block (LBBB), 19.1% a pacing-induced LBBB (pLBBB), 11.2% a rLBBB, 0.8% a right bundle branch block (RBBB), and 16.5% had a nonspecific intraventricular conduction delay (IVCD) electrocardiogram pattern. Mean age at implant was 67.5 years (standard deviation [SD] = 10.6), mean left ventricular ejection fraction (LV EF) was 25.7% (SD = 7.9%), and mean QRS duration was 158.4 ms (SD = 32 ms). After CRT, QRS duration was significantly reduced in the LBBB (p < 0.001), pLBBB (p < 0.001), rLBBB (p < 0.001), RBBB (p = 0.04), and IVCD groups (p = 0.03). LV EF significantly improved in the LBBB (p < 0.001), rLBBB (p = 0.002), and pLBBB (p < 0.001) groups, but the RBBB and IVCD groups showed no improvement. There was no significant difference in mortality between the LBBB and rLBBB groups. LV EF post-CRT, chronic kidney disease, hyperkalaemia, hypernatremia, and age at implant were significant predictors of mortality.ConclusionCRT in patients with rLBBB results in improved LV EF and similar mortality rates to CRT patients with complete LBBB. Predictors of mortality post-CRT include post-CRT LV EF, presence of CKD, hyperkalaemia, hypernatremia, and older age at implant. 相似文献
997.
998.
De Luca Pasquale Iaconis Daniela Biffali Elio Enza Coluccia de Magistris Laura Riegler Gabriele Pappalardo Diego Amato Maria Rosaria Iardino Patrizia Montanino Concetta De Felice Bruna 《Molecular biology reports》2021,48(11):7087-7093
Molecular Biology Reports - In adulthood the activity of the lactase enzyme is inherited as autosomal dominant form associated to Single nucleotide polymorphisms (SNPs). The present research was... 相似文献
999.
1000.
Germanus S. Bah Sebastian Schneckener Steffen R. Hahnel Nicolas H. Bayang Helena Fieseler Gabriele M. Schmuck Ralph Krebber Anouk Sarr Carsten Terjung Henrietta F. Ngangyung David D. Ekale Youssouf M. Mfopit Lucien Rufener John Graham-Brown Vincent N. Tanya Martin Glenschek-Sieberth Daniel Kulke Benjamin L. Makepeace 《PLoS pathogens》2021,17(6)
Onchocerciasis (river blindness), caused by the filarial worm Onchocerca volvulus, is a neglected tropical disease mostly affecting sub-Saharan Africa and is responsible for >1.3 million years lived with disability. Current control relies almost entirely on ivermectin, which suppresses symptoms caused by the first-stage larvae (microfilariae) but does not kill the long-lived adults. Here, we evaluated emodepside, a semi-synthetic cyclooctadepsipeptide registered for deworming applications in companion animals, for activity against adult filariae (i.e., as a macrofilaricide). We demonstrate the equivalence of emodepside activity on SLO-1 potassium channels in Onchocerca volvulus and Onchocerca ochengi, its sister species from cattle. Evaluation of emodepside in cattle as single or 7-day treatments at two doses (0.15 and 0.75 mg/kg) revealed rapid activity against microfilariae, prolonged suppression of female worm fecundity, and macrofilaricidal effects by 18 months post treatment. The drug was well tolerated, causing only transiently increased blood glucose. Female adult worms were mostly paralyzed; however, some retained metabolic activity even in the multiple high-dose group. These data support ongoing clinical development of emodepside to treat river blindness. 相似文献