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111.
Influenza A is a single stranded (ss)RNA virus that can cause upper respiratory tract infections that in rare cases may progress to pneumonia. Toll-like receptors (TLRs) and CD14 are receptors which recognize viral proteins and nucleic acid of several viruses. CD14 is required for influenza-induced cytokine production during infection of mouse macrophages. In addition, CD14 was shown to bind ssRNA, suggesting an important role for CD14 during infection with influenza. To investigate the role of CD14 during influenza pneumonia we inoculated WT and CD14 KO mice with a non-lethal dose of a mouse adapted strain of influenza A. CD14 KO mice displayed a reduced viral load in the lungs, 2 and 14 days after infection with influenza. Pulmonary cytokine production in CD14 KO mice was reduced at day 2 and elevated at day 8 compared to WT mice. CD14 deficiency did not influence lymphocyte recruitment or lymphocyte activation in lungs and draining lymph nodes 8 days after infection. These data show that CD14 plays a limited role in host defense against infection with influenza. 相似文献
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Henri S Siret C Machy P Kissenpfennig A Malissen B Leserman L 《European journal of immunology》2007,37(5):1184-1193
Skin-draining LN contain several phenotypically distinguishable DC populations, which may be immature or mature. Mature DC are generally considered to have lost the capacity to acquire and present newly encountered Ag. Using antibody-opsonized liposomes as Ag carriers, we show that mature DC purified from skin explants are able to efficiently capture liposomes, process Ag encapsulated within them and activate Ag-specific CD4(+) T cells. Explant DC from mice with Langerhans cells (LC) expressing the primate diphtheria toxin receptor that were exposed to diphtheria toxin in vivo presented Ag as well as explant DC from wild-type mice, indicating that LC are not required and dermal DC are probably responsible for this presentation. We further show that all DC subtypes from LN that capture opsonized Ag are capable of cross-presenting it to CD8(+) T cells. Induction of additional maturation in vivo by LPS or treatment with double-stranded RNA did not alter the Ag presentation capacity of the skin or LN DC subtypes. These results suggest that mature DC present in skin-draining LN may play an important role in the induction of primary and/or secondary immune responses against Ag delivered to the LN that they take up by receptor-mediated endocytosis. 相似文献
114.
Castelli FA Leleu M Pouvelle-Moratille S Farci S Zarour HM Andrieu M Auriault C Ménez A Georges B Maillere B 《European journal of immunology》2007,37(6):1513-1523
To understand the inter-individual and virus-independent variability of CD4+ T cell responses to HCV components, we evaluated the effect on these responses of HLA II molecules in uninfected healthy donors. Using HLA II-specific binding assays, we identified, in the Core and NS3 proteins, 21 long fragments and 24 15-mer peptides that bound to four to eight of the most preponderant HLA II molecules. We then evaluated the priming capacity of eight long promiscuous peptides in 12 HLA-unrelated healthy donors. The NS3 1250-1264 peptide primed T cells in all the naive donors, while five others were stimulating in at least half of the individuals. We also report sequences that bind to multiple HLA II molecules but are weakly immunogenic. We therefore conclude that (i) broad HLA II specificity is only a prerequisite for a peptide to be stimulating in multiple individuals, and (ii) promiscuous peptides widely differ in their capacity to prime CD4+ T cells from uninfected healthy donors. We suggest that these priming differences result from inter-individual variations in the peptide-specific T cell repertoire. Interestingly, five of the most immunogenic peptides we identified correspond to frequently targeted T cell epitopes in infected patients. 相似文献
115.
Yara Nasser Philippe Fayemendy Manon Arnal Huguette Sourisseau Sandrine Bonhommo Jean-Claude Desport Béatrice Morin Pierre Jésus 《Nutrition Clinique et Métabolisme》2018,32(3):184-186
In institutions and at home, some patients may have difficulty mobilizing and undressing, or refusing to put on their underwear. It is therefore likely that weighing dressed patients is a common practice. The overestimation of the body weight thus obtained could lead to an error in the evaluation of the nutritional status. The aim of the study was to determine the extent to which adult patients dressed versus underwear could alter their nutritional status. Fifty-one patients were included. Dressed weighing overestimated the actual weight of 1.6 ± 0.6 kg and induced an overestimation of nutritional status classification in almost 14% of cases. In addition, the weight of the clothes was different according to the sex and the conditions of outside temperature. These results suggest that it is desirable as much as possible to weigh all adult patients in underwear. 相似文献
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Julien Dumurgier Jean-Louis Laplanche Francois Mouton-Liger Pauline Lapalus Sandrine Indart Magali Prévot Katell Peoc’h Jacques Hugon Claire Paquet 《Journal of neurology》2014,261(6):1187-1195
Polymorphism of the apolipoprotein E gene (APOE) plays a role in the level of neuropathological lesions and in drug response in Alzheimer’s disease (AD). The aim of this study was to investigate whether the selection of AD patients based on cerebrospinal fluid (CSF) biomarkers assessment may be biased by their APOE distribution. We studied the relationships between APOE genotype and CSF biomarkers levels in a total of 432 patients (AD, n = 244; non-AD, n = 188) explored for cognitive disorders. We studied the distribution of APOE genotypes among AD patient subgroups selected by various cut-offs of CSF biomarkers. Strategies of screening based on CSF Aβ1–42 lead to overselection of ε4/ε4 patients in the AD group. Screening based on tau levels did not change Apoe4 distribution in the AD group. CSF Aβ1–42 discriminated better AD patients with at least one ε4 than AD patients with no ε4. A strong allele-effect relationship was detected between APOE genotype and CSF amyloid-β (Aβ1–42) in AD patients. Selecting AD patients on CSF amyloid levels only may create an overselection of ε4/ε4 carriers, and might potentially bias the population of patients included in clinical trial studies. 相似文献
118.
Geurt Stokman Yu Qin Tijmen H. Booij Sreenivasa Ramaiahgari Marie Lacombe M. Emmy M. Dolman Kim M.A. van Dorenmalen Gwendoline J.D. Teske Sandrine Florquin Frank Schwede Bob van de Water Robbert J. Kok Leo S. Price 《Journal of the American Society of Nephrology : JASN》2014,25(7):1474-1485
Activation of Rap1 by exchange protein activated by cAMP (Epac) promotes cell adhesion and actin cytoskeletal polarization. Pharmacologic activation of Epac-Rap signaling by the Epac-selective cAMP analog 8-pCPT-2′-O-Me-cAMP during ischemia-reperfusion (IR) injury reduces renal failure and application of 8-pCPT-2′-O-Me-cAMP promotes renal cell survival during exposure to the nephrotoxicant cisplatin. Here, we found that activation of Epac by 8-pCPT-2′-O-Me-cAMP reduced production of reactive oxygen species during reoxygenation after hypoxia by decreasing mitochondrial superoxide production. Epac activation prevented disruption of tubular morphology during diethyl maleate–induced oxidative stress in an organotypic three-dimensional culture assay. In vivo renal targeting of 8-pCPT-2′-O-Me-cAMP to proximal tubules using a kidney-selective drug carrier approach resulted in prolonged activation of Rap1 compared with nonconjugated 8-pCPT-2′-O-Me-cAMP. Activation of Epac reduced antioxidant signaling during IR injury and prevented tubular epithelial injury, apoptosis, and renal failure. Our data suggest that Epac1 decreases reactive oxygen species production by preventing mitochondrial superoxide formation during IR injury, thus limiting the degree of oxidative stress. These findings indicate a new role for activation of Epac as a therapeutic application in renal injury associated with oxidative stress.Renal ischemia-reperfusion (IR) injury is an important cause of AKI1 and a significant risk factor for the development of renal dysfunction after kidney transplantation.2 During IR injury, morphologic and functional alterations of the proximal tubular epithelium occur that are linked to the development of renal failure and activation of immune cells via release of proinflammatory cytokines.3Exchange protein activated by cAMP (Epac) is a guanine nucleotide exchange factor for the small GTPase Rap1.4 Activation of Epac by cAMP or by the Epac-selective cAMP analog 8-pCPT-2′-O-Me-cAMP (also referred to as 007) induces functional activation of Rap1.5 Initial studies showed that Epac-Rap signaling enhances cell adhesion by supporting maturation of cell-cell junctions6,7 and promoting integrin-mediated cell-matrix adhesion.8,9 In line with these studies, we recently demonstrated that selective activation of Epac reduces proximal tubular epithelial cell (PTEC) detachment during IR injury using in vitro and in vivo models.10 Activation of Epac-Rap was associated with reduced expression of markers for cellular stress in PTECs. In addition, in vitro cisplatin-induced apoptosis of PTECs could be significantly reduced by activation of Epac and this was also associated with improved adhesion of cells.11 On the basis of these findings, we hypothesized that activation of Epac-Rap signaling may protect against a common cytotoxic event in these injury models.Unbalanced and uncontrolled production of reactive oxygen species (ROS) is an important mediator of cell injury and occurs during cisplatin nephrotoxicity,12 IR injury,13 and renal fibrosis.14 In renal pathology, intracellular ROS can be produced enzymatically such as by NADPH oxidase (NOX) complexes or derive from dysfunctional mitochondrial activity. Mitochondrial ROS production appears to be the driving force behind hypoxia-reoxygenation cell injury15 and cisplatin cytotoxicity.16Here we studied the role of specific proximal tubular activation of Epac and how this protects against renal injury in both in vitro and in vivo models for IR injury. We found that ROS production during reoxygenation after hypoxia was decreased by activation of Epac. Selective proximal tubular activation of Epac by renal targeting of 8-pCPT-2′-O-Me-cAMP conjugated to lysozyme (LZM-007) reduced oxidative stress in an in vivo model for IR injury and significantly decreased IR injury–associated renal failure and tubular damage. Our data show that Epac activation reduces ROS-mediated cellular injury in renal disease and may be a therapeutic strategy for modulation of oxidative stress. 相似文献
119.
Doriane Lorendeau Lauriane Dury Estelle Genoux-Bastide Florine Lecerf-Schmidt Claudia Simões-Pires Pierre-Alain Carrupt Raphaël Terreux Sandrine Magnard Attilio Di Pietro Ahcène Boumendjel Hélène Baubichon-Cortay 《Biochemical pharmacology》2014
The multidrug resistance protein 1 (MRP1) is involved in multidrug resistance of cancer cells by mediating drug efflux out of cells, often in co-transport with glutathione (GSH). GSH efflux mediated by MRP1 can be stimulated by verapamil. In cells overexpressing MRP1, we have previously shown that verapamil induced a huge intracellular GSH depletion which triggered apoptosis of the cells. That phenomenon takes place in the more global anticancer strategy called “collateral sensitivity” and could be exploited to eradicate some chemoresistant cancer cells. Seeking alternative compounds to verapamil, we screened a library of natural flavonoids and synthetic derivatives. A large number of these compounds stimulate MRP1-mediated GSH efflux and the most active ones have been evaluated for their cytotoxic effect on MRP1-overexpressing cells versus parental cells. Interestingly, some are highly and selectively cytotoxic for MRP1-cells, leading them to apoptosis. However, some others do not exhibit any cytotoxicity while promoting a strong GSH efflux, indicating that GSH efflux is necessary but not sufficient for MRP1-cells apoptosis. In support to this hypothesis, structure activity relationships show that the absence of a hydroxyl group at position 3 of the flavonoid C ring is an absolute requirement for induction of MRP1-cells death, but is not for GSH efflux stimulation. Chrysin (compound 8) and its derivatives, compounds 11 and 22, exhibit a high selectivity toward MRP1-cells with a IC50 value of 4.1 μM for compound 11 and 4.9 μM for chrysin and compound 22, making them among the best described selective killer compounds of multidrug ABC transporter-overexpressing cells. 相似文献