Search

The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we show that exosomes (EXs) derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca 2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen., (© 2024 The Authors.)

Two strategies for protecting body image against the negative effects of exposure to idealized media images have been proposed: (1) using labels to alert viewers to digital retouching, (2) limiting digital retouching. This study investigated the effects digitally modified vs.unmodified images and the use of labels on those images (disclaimer/retouch-free] vs. unlabeled) on appearance satisfaction and mood. Trait upwards appearance comparison, media ideal internalization, media similarity, and body appreciation were explored as moderators. Participants (n = 614, women, 18-30 years) viewed the same ten images of female figures (both thin ideal and size/shape diverse images) across four conditions: (1) unmodified, unlabelled, (2) unmodified, labelled, (3) modified, labelled, and (4) modified, unlabelled images. Exposure to unmodified images was shown to be less harmful than exposure to modified images. Neither label type was associated with more positive outcomes compared to their counterpart unlabelled conditions. State appearance comparison was highest in the two labelled conditions. Trait upwards appearance comparison and media ideal internalization to some extent moderated effects on negative mood. Findings provide additional evidence that disclaimer labels on digitally modified images are not helpful for body image, while images that depart from the thin-ideal can contribute to promoting positive body image., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Aims: Hyperphosphatemia increases the risk of cardiovascular morbidity but the use of medicines as a source of phosphate has not been investigated yet. This study aims to explore the use of absorbable phosphate-containing drugs in CKD patients., Methods and Results: Incident CKD patients were identified within the Arianna database (containing data from 158,510 persons in Caserta (Southern Italy) registered with 123 general practitioners) from 2005 to 2011. Drugs prescribed to these patients were classified as phosphate-containing based on the summary of product characteristics (SPC), PubChem and Micromedex. The number and duration of prescriptions for these drugs as well as the overall intake of phosphate were estimated. Out of 1989 CKD patients, 1381 (70%) were prescribed 266 medicinal products containing absorbable phosphate over a median follow-up of 6 years (interquartile range (IQR) = 5.2-6.0). Most patients were prescribed ATC A (650; 47.1%) and C (660; 47.8%) phosphate-containing drug products targeting the gastrointestinal and cardiovascular system for a median of 232 (IQR: 56-656) and 224 (IQR: 56-784) days respectively., Conclusions: Several medications, especially chronically prescribed ones, contain absorbable phosphate. This study's findings confirm the relevance of medicines as a phosphate source for the first time., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The counter-regulatory hormone glucagon inhibits lipogenesis via downregulation of sterol regulatory element binding protein 1 (SREBP-1). The effect of glucagon is mediated via protein kinase A (PKA). To determine if SREBP-1 is a direct phosphorylation target of PKA, we conducted mass spectrometry analysis of recombinant n-terminal SREBP-1a following PKA treatment in vitro. This analysis identified serines 331/332 as bona-fide phosphorylation targets of PKA. To determine the functional consequences of phosphorylation at these sites, we constructed mammalian expression vector for both nSREBP-1a and 1c isoforms in which the candidate PKA phosphorylation sites were mutated to active phosphomimetic or non-phosphorylatable amino acids. The transcriptional activity of SREBP was reduced by the phosphomimetic mutation of S332 of nSREBP-1a and the corresponding serine (S308) of nSREBP-1c. This site is a strong candidate for mediating the negative regulatory effect of glucagon on SREBP-1 and lipogenesis., (Published by Elsevier Inc.)

Inactivation of the enzyme L-aspartase from Escherichia coli by the substrate analog aspartate beta-semialdehyde has previously been shown to occur by the mechanism-based conversion to the corresponding product aldehyde, followed by covalent modification of cysteine-273 (F. Giorgianni et al. (1995) Biochemistry 34, 3529). Inactivation by the product analog, fumaric acid aldehyde (FAA), has now been examined directly by adding a reduction step to the modification protocol in order to stabilize the resulting enzyme-FAA derivative(s). HPLC and mass spectrometric analyses of proteolytic digests of inactivated L-aspartase have confirmed the modification at cysteine-273, and have also identified an additional modified peptide. The inactivation at this additional site involves a crosslink between cysteine-140 and an adjacent lysine. Site-directed mutagenesis studies have shown that cysteine-140 is a very reactive and accessible nucleophile that is not, however, directly involved in enzyme activity. The adjacent lysine-139 that is modified does appear to play a role in substrate binding. A double mutant in which both of the reactive cysteines have been replaced is almost completely insensitive to modification by these substrate and product analogs.

Single crystals of L-aspartate ammonia-lyase (L-aspartase) from Escherichia coli have been obtained by microdialysis at room temperature using polyethylene glycol 3350 and sodium acetate as co-precipitants. The crystals exhibit the symmetry of space group P2(1)2(1)2 with a = 156.5 A, b = 147.6 A, c = 102.5 A and diffract at least to 2.8 A.