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651.
Koldo Garcia-Etxebarria María Alma Bracho Juan Carlos Galán Tomàs Pumarola Jesús Castilla Raúl Ortiz de Lejarazu Mario Rodríguez-Dominguez Inés Quintela Núria Bonet Marc Garcia-Garcerà Angela Domínguez Fernando González-Candelas Francesc Calafell CIBERESP Cases Controls in Pandemic Influenza Working Group 《PloS one》2015,10(10)
652.
Luis I. Angel-Chavez Eduardo I. Acosta-Gómez Mario Morales-Avalos Elena Castro Humberto Cruzblanca 《PloS one》2015,10(5)
In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K+ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K+ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K+ current (IKV). Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that IKV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K+ currents. Forskolin inhibited Kv2.1 currents and IKV with an IC50 of ~32 μM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels. 相似文献
653.
T. N. A. van den Berg S. El Messaoudi G. A. Rongen P. H. H. van den Broek A. Bilos A. R. T. Donders M. E. Gomes N. P. Riksen 《PloS one》2015,10(10)
Background and Purpose
In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo.Experimental Approach
In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation.Key Results
Ticagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations.Conclusion and Implications
In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor.Trial Registration
ClinicalTrials.gov NCT01996735 相似文献654.
Genetic variants in LEP,LEPR, and MC4R explain 30% of severe obesity in children from a consanguineous population
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655.
Mario Vitacolonna Djeda Belharazem Patrick Maier Peter Hohenberger Eric Dominic Roessner 《PloS one》2015,10(5)
IntroductionIn neoadjuvant therapy, irradiation has a deleterious effect on neoangiogenesis. The aim of this study was to examine the post-implantation effects of neoadjuvant irradiation on the survival and proliferation of autologous cells seeded onto an acellular human dermis (hAD; Epiflex). Additionally, we examined the influence of dermal hair follicle pores on viability and proliferation. We used dorsal skinfold chambers implanted in rats and in-situ microscopy to quantify cell numbers over 9 days.Methods24 rats received a skinfold chamber and were divided into 2 main groups; irradiated and unirradiated. In the irradiated groups 20Gy were applied epicutaneously at the dorsum. Epiflex pieces were cut to size 5x5mm such that each piece had either one or more visible hair follicle pores, or no such visible pores. Fibroblasts were transduced lentiviral with a fluorescent protein for cell tracking. Matrices were seeded statically with 2.5x104 fluorescent fibroblasts and implanted into the chambers. In each of the two main groups, half of the rats received Epiflex with hair follicle pores and half received Epiflex without pores. Scaffolds were examined in-situ at 0, 3, 6 and 9 days after transplantation. Visible cells on the surface were quantified using ImageJ.ResultsIn all groups cell numbers were decreased on day 3. A treatment-dependent increase in cell numbers was observed at subsequent time points. Irradiation had an adverse effect on cell survival and proliferation. The number of cells detected in both irradiated and non-irradiated subjects was increased in those subjects that received transplants with hair follicle pores.DiscussionThis in-vivo study confirms that radiation negatively affects the survival and proliferation of fibroblasts seeded onto a human dermis transplant. The presence of hair follicle pores in the dermis transplants is shown to have a positive effect on cell survival and proliferation even in irradiated subjects. 相似文献
656.
657.
Mario Campone Isabelle Valo Pascal Jézéquel Marie Moreau Alice Boissard Loic Campion Delphine Loussouarn Véronique Verriele Olivier Coqueret Catherine Guette 《Molecular & cellular proteomics : MCP》2015,14(11):2936-2946
To date, there is no available targeted therapy for patients who are diagnosed with triple-negative breast cancers (TNBC). The aim of this study was to identify a new specific target for specific treatments. Frozen primary tumors were collected from 83 adjuvant therapy-naive TNBC patients. These samples were used for global proteome profiling by iTRAQ-OFFGEL-LC-MS/MS approach in two series: a training cohort (n = 42) and a test set (n = 41). Patients who remains free of local or distant metastasis for a minimum of 5 years after surgery were classified in the no-relapse group; the others were in the relapse group. OPLS and Kaplan–Meier analyses were performed to select candidate markers, which were validated by immunohistochemistry. Three proteins were identified in the training set and validated in the test set by Kaplan–Meier method and immunohistochemistry (IHC): TrpRS as a good prognostic markers and DP and TSP1 as bad prognostic markers. We propose the establishment of an IHC test to calculate the score of TrpRS, DP, and TSP1 in TNBC tumors to evaluate the degree of aggressiveness of the tumors. Finally, we propose that DP and TSP1 could provide therapeutic targets for specific treatments.Triple-negative breast cancers (TNBC)1 are defined by a lack of expression of estrogen (ER), progesterone (PR), and HER2/neu receptors and account for about 15% of all breast cancers. This subtype is associated with poor prognosis (1) in terms of distant free survival (DFS) and overall survival (OS), and to date, there is no clinically available targeted therapy for patients diagnosed with TNBC. Because of the absence of specific treatment guidelines for this group of patients, TNBC are managed with standard adjuvant chemotherapy (2), which, however, seems to be less effective in those cancers. In order to improve survival, it is important to determine new specific-targeted treatment.A proteomic analysis has several inherent advantages over a genomic approach in that measured mRNA levels do not necessarily correlate to corresponding protein levels. In addition, protein detection is probably also more reflective of the tumor microenvironment. Several proteomic studies have been conducted on TNBC (3–5), but no proteomic study was conducted on large cohorts including the clinical outcome of the patients, except a recent comparative proteome analysis that identified a 11-protein signature for aggressive TNBC in a large cohort of 93 microdissected tumors (6). Although microdissection was necessary to elucidate the contribution of TNBC cells, it did not reflect the tumor with its microenvironment that is increasingly described as fundamental to explain the tumor outcome. Thus, it is now recognized that carcinomas derive from phenomena that occur in tissues, not in individual cancer cells. From this perspective, the microenvironment becomes an integral, essential part of the tumor (7, 8). In this context, taking into account the tumor microenvironment, we investigated a cohort of 83 TNBC samples without microdissection by a quantitative proteomic approach using iTRAQ labeling. Based on clinical data, we established a protein signature of the most aggressive tumors. From these differentially expressed proteins, some of them appeared to be potential therapeutic targets. 相似文献
658.
Barbara Salani Silvia Ravera Adriana Amaro Annalisa Salis Mario Passalacqua Enrico Millo Gianluca Damonte Cecilia Marini Ulrich Pfeffer Gianmario Sambuceti Renzo Cordera Davide Maggi 《Cell cycle (Georgetown, Tex.)》2015,14(10):1559-1567
Pyruvate kinase M2 (PKM2) acts at the crossroad of growth and metabolism pathways in cells. PKM2 regulation by growth factors can redirect glycolytic intermediates into key biosynthetic pathway. Here we show that IGF1 can regulate glycolysis rate, stimulate PKM2 Ser/Thr phosphorylation and decrease cellular pyruvate kinase activity. Upon IGF1 treatment we found an increase of the dimeric form of PKM2 and the enrichment of PKM2 in the nucleus. This effect was associated to a reduction of pyruvate kinase enzymatic activity and was reversed using metformin, which decreases Akt phosphorylation. IGF1 induced an increased nuclear localization of PKM2 and STAT3, which correlated with an increased HIF1α, HK2, and GLUT1 expression and glucose entrapment. Metformin inhibited HK2, GLUT1, HIF-1α expression and glucose consumption. These findings suggest a role of IGFIR/Akt axis in regulating glycolysis by Ser/Thr PKM2 phosphorylation in cancer cells. 相似文献
659.
660.
Verbascoside down‐regulates some pro‐inflammatory signal transduction pathways by increasing the activity of tyrosine phosphatase SHP‐1 in the U937 cell line
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Mirko Pesce Sara Franceschelli Alessio Ferrone Maria Anna De Lutiis Antonia Patruno Alfredo Grilli Mario Felaco Lorenza Speranza 《Journal of cellular and molecular medicine》2015,19(7):1548-1556
Polyphenols are the major components of many traditional herbal remedies, which exhibit several beneficial effects including anti‐inflammation and antioxidant properties. Src homology region 2 domain‐containing phosphatase‐1 (SHP‐1) is a redox sensitive protein tyrosine phosphatase that negatively influences downstream signalling molecules, such as mitogen‐activated protein kinases, thereby inhibiting inflammatory signalling induced by lipopolysaccharide (LPS). Because a role of transforming growth factor β‐activated kinase‐1 (TAK1) in the upstream regulation of JNK molecule has been well demonstrated, we conjectured that SHP‐1 could mediate the anti‐inflammatory effect of verbascoside through the regulation of TAK‐1/JNK/AP‐1 signalling in the U937 cell line. Our results demonstrate that verbascoside increased the phosphorylation of SHP‐1, by attenuating the activation of TAK‐1/JNK/AP‐1 signalling. This leads to a reduction in the expression and activity of both COX and NOS. Moreover, SHP‐1 depletion deletes verbascoside inhibitory effects on pro‐inflammatory molecules induced by LPS. Our data confirm that SHP‐1 plays a critical role in restoring the physiological mechanisms of inducible proteins such as COX2 and iNOS, and that the down‐regulation of TAK‐1/JNK/AP‐1 signalling by targeting SHP‐1 should be considered as a new therapeutic strategy for the treatment of inflammatory diseases. 相似文献