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11.
Laurence Dutot Pascaline Lécorché Fabienne Burlina Rodrigue Marquant Vanessa Point Sandrine Sagan Gérard Chassaing Jean-Maurice Mallet Solange Lavielle 《Journal of chemical biology》2010,3(2):51-65
Cell-penetrating peptides (CPPs), which are usually short basic peptides, are able to cross cell membranes and convey bioactive
cargoes inside cells. CPPs have been widely used to deliver inside cells peptides, proteins, and oligonucleotides; however,
their entry mechanisms still remain controversial. A major problem concerning CPPs remains their lack of selectivity to target
a specific type of cell and/or an intracellular component. We have previously shown that myristoylation of one of these CPPs
affected the intracellular distribution of the cargo. We report here on the synthesis of glycosylated analogs of the cell-penetrating
peptide (R6/W3): Ac-RRWWRRWRR-NH2. One, two, or three galactose(s), with or without a spacer, were introduced into the sequence of this nonapeptide via a triazole link, the Huisgen reaction being achieved on a solid support. Four of these glycosylated CPPs were coupled via a disulfide bridge to the proapoptotic KLAK peptide, (KLAKLAKKLAKLAK), which alone does not enter into cells. The effect
on cell viability and the uptake efficiency of different glycosylated conjugates were studied on CHO cells and were compared
to those of the nonglycosylated conjugates: (R6/W3)S-S-KLAK and penetratinS-S-KLAK. We show that glycosylation significantly
increases the cell viability of CHO cells compared to the nonglycosylated conjugates and concomitantly decreases the internalization
of the KLAK cargo. These results suggest that glycosylation of CPP may be a key point in targeting specific cells. 相似文献
12.
Koganti V Carroll F Ferraina R Falk R Waghmare Y Berry M Liu Y Norris K Leasure R Gaudio J 《AAPS PharmSciTech》2010,11(4):1541-1548
Liquid mixing scale-up in pharmaceutical industry has often been based on empirical approach in spite of tremendous understanding
of liquid mixing scale-up in engineering fields. In this work, we attempt to provide a model-based approach to scale-up dissolution
process from a 2 l lab-scale vessel to a 4,000 l scale vessel used in manufacturing. Propylparaben was used as a model compound
to verify the model predictions for operating conditions at commercial scale that would result in similar dissolution profile
as observed in lab scale. Geometric similarity was maintained between both of the scales to ensure similar mixing characteristics.
We utilized computational fluid dynamics (CFD) to ensure that the operating conditions at laboratory and commercial scale
will result in similar power per unit volume (P/V). Utilizing this simple scale-up criterion of similar P/V across different
scales, results obtained indicate fairly good reproducibility of the dissolution profiles between the two scales. Utilization
of concepts of design of experiments enabled summarizing scale-up results in statistically meaningful parameters, for example
−90% dissolution in lab scale at a given time under certain operating conditions will result in 75–88% at commercial scale
with 95% confidence interval when P/V is maintained constant across the two scales. In this work, we have successfully demonstrated
that scale-up of solid dissolution can be done using a systematic process of lab-scale experiments followed by simple CFD
modeling to predict commercial-scale experimental conditions. 相似文献
13.
14.
The RING finger ATPase Rad5p of Saccharomyces cerevisiae contributes to DNA double-strand break repair in a ubiquitin-independent manner 总被引:3,自引:0,他引:3 下载免费PDF全文
Tolerance to replication-blocking DNA lesions is achieved by means of ubiquitylation of PCNA, the processivity clamp for replicative DNA polymerases, by components of the RAD6 pathway. In the yeast Saccharomyces cerevisiae the ubiquitin ligase (E3) responsible for polyubiquitylation of the clamp is the RING finger protein Rad5p. Interestingly, the RING finger, responsible for the protein's E3 activity, is embedded in a conserved DNA-dependent ATPase domain common to helicases and chromatin remodeling factors of the SWI/SNF family. Here, we demonstrate that the Rad5p ATPase domain provides the basis for a function of the protein in DNA double-strand break repair via a RAD52- and Ku-independent pathway mediated by the Mre11/Rad50/Xrs2 protein complex. This activity is distinct and separable from the contribution of the RING domain to ubiquitin conjugation to PCNA. Moreover, we show that the Rad5 protein physically associates with the single-stranded DNA regions at a processed double-strand break in vivo. Our observations suggest that Rad5p is a multifunctional protein that—by means of independent enzymatic activities inherent in its RING and ATPase domains—plays a modulating role in the coordination of repair events and replication fork progression in response to various different types of DNA lesions. 相似文献
15.
From a pool of Medicago truncatula mutants—obtained by gamma-irradiation or ethyl methanesulfonate mutagenesis—impaired in symbiosis with the N-fixing bacterium Sinorhizobium meliloti, new mutants are described and genetically analysed, and for already reported mutants, complementary data are given on their phenotypic and genetic analysis. Phenotypic data relate to nodulation and mycorrhizal phenotypes. Among the five new mutants, three were classified as [Nod+ Fix– Myc+] and the mutations were ascribed to two loci, Mtsym20 (TRV43, TRV54) and Mtsym21 (TRV49). For the two other new mutants, one was classified as [Nod–/+ Myc+] with a mutation ascribed to gene Mtsym15 (TRV48), and the other as [Nod– Myc-/+] with a mutation ascribed to gene Mtsym16 (TRV58). Genetic analysis of three previously described mutants has shown that [Nod–/+ Myc+] TR74 mutant can be ascribed to gene Mtsym14, and that [Nod–/+ Myc–/+] TR89 and TRV9 mutants are ascribed to gene Mtsym2 (dmi2). Using a detailed analysis of mycorrhizal phenotype, we have observed a delayed typical arbuscular mycorrhizal formation on some mutants that present thick lens-shaped appressoria. This phenotype was called [Myc–/+] and mutants TR25, TR26, TR89, TRV9, P1 and Y6 were reclassified as [Myc–/+]. Mutant P1 was reclassified as [Nod–/+] because of a late nodulation observed on roots of this mutant. 相似文献
16.
This protocol allows the accurate quantification of cell-penetrating peptide (CPP) cellular uptake by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). Quantification is based on the use of an internal standard with same chemical structure as the analyte but labeled with a stable isotope. The analyte and the standard can both be obtained by standard solid-phase peptide synthesis using commercially available amino acids. They are functionalized by biotin to allow their easy purification before MALDI-TOF MS analysis. The method allows determination of the amount of intact internalized peptide and the identification of potential intracellular digests. It can be used to simultaneously compare the uptake of several peptides, and can also be applied to the quantification of peptidic cargoes and the study of their intracellular stability. It is therefore a potent tool to study the mechanisms of CPPs internalization and to select new carriers for drug delivery. This protocol will take approximately 5 hours for the analysis of 12 samples (not including the time for cell incubation with peptides). 相似文献
17.
Selena M Sagan Yanouchka Rouleau Cynthia Leggiadro Lubica Supekova Peter G Schultz Andrew I Su John Paul Pezacki 《Biochimie et biologie cellulaire》2006,84(1):67-79
The hepatitis C virus (HCV) replicates on a membrane protein complex composed of viral proteins, replicating RNA, and altered cellular membranes. Small-molecule inhibitors of cellular lipid-cholesterol metabolism such as 25-hydroxycholesterol, cerulenin, lovastatin, and GGTI-286 all show a negative effect on HCV replication. Perturbation of host cell lipid and cholesterol metabolism can disrupt replication complexes by altering membranous structures where replication occurs. Changes in cholesterol and (or) lipid composition can have a general effect on membrane structure. Alternatively, metabolic changes can exert a more subtle influence over replication complexes by altering localization of host proteins through alterations in lipid anchoring. Here, we use Huh-7 cells harboring subgenomic HCV replicons to demonstrate that 25-hydroxycholesterol, cerulenin, lovastatin, and GGTI-286 do not disrupt the membranous web where replication occurs, whereas cholesterol-depleting agents such as beta-cyclodextrin do. Cellular imaging suggests that the HCV RNA can remain associated with subcellular compartments connected with replication complexes in the presence of metabolic inhibitors. Therefore, at least 2 different molecular mechanisms are possible for the inhibition of HCV replication through the modulation of cellular lipid and cholesterol metabolism. 相似文献
18.
Sagan S Burlina F Delaroche D Aussedat B Aubry S Bolbach G Lavielle S Chassaing G 《Journal de la Société de Biologie》2006,200(3):213-219
Trojan peptides or cell-penetrating peptides (CPP) are natural or designed peptides identified as cellular membrane-crossing molecules, in particular through their potency to vehiculate various kinds of compounds to the cytoplasm and nucleus of living cells. The indirect methods used so far to detect these peptides in cells led to controversial hypotheses on the mechanism of their cell entry. Therefore, we have developed a MALDI-TOF mass spectrometry-based quantification method to track these peptides inside cells. This new method is presented in this review. 相似文献
19.
Schulze-Topphoff U Shetty A Varrin-Doyer M Molnarfi N Sagan SA Sobel RA Nelson PA Zamvil SS 《PloS one》2012,7(3):e33797
Laquinimod is a novel oral drug that is currently being evaluated for the treatment of relapsing-remitting (RR) multiple sclerosis (MS). Using the animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we examined how laquinimod promotes immune modulation. Oral laquinimod treatment reversed established RR-EAE and was associated with reduced central nervous system (CNS) inflammation, decreased Th1 and Th17 responses, and an increase in regulatory T cells (Treg). In vivo laquinimod treatment inhibited donor myelin-specific T cells from transferring EAE to naive recipient mice. In vivo laquinimod treatment altered subpopulations of myeloid antigen presenting cells (APC) that included a decrease in CD11c(+)CD11b(+)CD4(+) dendritic cells (DC) and an elevation of CD11b(hi)Gr1(hi) monocytes. CD11b(+) cells from these mice exhibited an anti-inflammatory type II phenotype characterized by reduced STAT1 phosphorylation, decreased production of IL-6, IL-12/23 and TNF, and increased IL-10. In adoptive transfer, donor type II monocytes from laquinimod-treated mice suppressed clinical and histologic disease in recipients with established EAE. As effects were observed in both APC and T cell compartments, we examined whether T cell immune modulation occurred as a direct effect of laquinimod on T cells, or as a consequence of altered APC function. Inhibition of Th1 and Th17 differentiation was observed only when type II monocytes or DC from laquinimod-treated mice were used as APC, regardless of whether myelin-specific T cells were obtained from laquinimod-treated or untreated mice. Thus, laquinimod modulates adaptive T cell immune responses via its effects on cells of the innate immune system, and may not influence T cells directly. 相似文献
20.