Hesskirkpatrick0053

The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high Peff marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol's solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product.The self-emulsifying acrylate-based emulsions with solid content 45 wt.% were prepared in 3.5 h by reverse iodine transfer polymerization (RITP), and the polymer molecular weight (Mn) could be 30,000 g·mol-1. The influences of methacrylic acid (MAA) amount, soft/hard monomer mass ratio, and iodine amount on polymerization and latex were investigated. A moderate amount of ionized MAA was needed to stabilize the emulsion. Glass transition temperature (Tg) was decreased with the increasing mass ratio of soft/hard monomer. A higher iodine amount resulted in lower Mn. The increased Mn after chain extension of the polymer with water-insoluble monomers in iterative one-pot method proved the living of polymer. Compared with conventional emulsion polymerization, molecular weight (Mn) could be controlled, and Mn of polymer synthesized in RITP emulsion polymerization is higher; emulsion of polyacrylate-containing hydroxyl monomer units prepared by RITP emulsifier-free radical polymerization is more stable. Good properties, such as hardness, water resistance, adhesion, and increased value of maximum tensile of films modified by reaction of polyacrylate with melamine-formaldehyde (MF) resin, indicated potential application in baking coating.To improve the interfacial adhesion and dispersion of a poplar fiber in a polylactic acid (PLA) matrix, maleic anhydride (MA) and a silane coupling agent (KH550) were used to modify the poplar fiber. The poplar fiber/PLA composites were produced with different modifier contents. The mechanical, thermal, rheological, and physical properties of composites were investigated. A comparison of different natural fiber modifications on the properties of composites was also analyzed. The results showed that both MA and KH550 could improve the interfacial adhesion between the poplar fiber and PLA, resulting in the enhanced mechanical properties of the composite, with 17% and 23% increases of tensile strength for 0.5% MA and 2% KH550, respectively. The thermal properties of the composites were improved at 6% KH550 (a 9% enhancement of T90%) and decreased at 0.5% MA (a 6% decrement of T90%). The wettability of the composites obtained a 11.3% improvement at 4% KH550 and a 5% reduction at 4% MA. Therefore, factors such as mechanical properties, economic efficiency, and durability should be carefully considered when choosing the modifier to improve the property of the composite.Dietary habits are crucially important to prevent the development of lifestyle-associated diseases. Diets supplemented with chickpeas have numerous benefits and are known to improve body fat composition. The present study was undertaken to characterize two genetically and phenotypically distinct accessions, MG_13 and PI358934, selected from a global chickpea collection. Rat hepatoma FaO cells treated with a mixture of free fatty acids (FFAs) (O/P) were used as an in vitro model of hepatic steatosis. In parallel, a high-fat diet (HFD) animal model was also established. In vitro and in vivo studies revealed that both chickpea accessions showed a significant antioxidant ability. However, only MG_13 reduced the lipid over-accumulation in steatotic FaO cells and in the liver of HFD fed mice. Moreover, mice fed with HFD + MG_13 displayed a lower level of glycemia and aspartate aminotransferase (AST) than HFD mice. Interestingly, exposure to MG_13 prevented the phosphorylation of the inflammatory nuclear factor kappa beta (NF-kB) which is upregulated during HFD and known to be linked to obesity. To conclude, the comparison of the two distinct chickpea accessions revealed a beneficial effect only for the MG_13. These findings highlight the importance of studies addressing the functional characterization of chickpea biodiversity and nutraceutical properties.Extracellular vesicles (EVs) have recently emerged as a relevant way of cell to cell communication, and its analysis has become an indirect approach to assess the cell/tissue of origin status. However, the knowledge about their nature and role on metabolic diseases is still very scarce. We have established an insulin resistant (IR) and two lipid (palmitic/oleic) hypertrophied adipocyte cell models to isolate EVs to perform a protein cargo qualitative and quantitative Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis by mass spectrometry. Our results show a high proportion of obesity and IR-related proteins in pathological EVs; thus, we propose a panel of potential obese adipose tissue EV-biomarkers. Among those, lipid hypertrophied vesicles are characterized by ceruloplasmin, mimecan, and perilipin 1 adipokines, and those from the IR by the striking presence of the adiposity and IR related transforming growth factor-beta-induced protein ig-h3 (TFGBI). Onvansertib Interestingly, functional assays show that IR and hypertrophied adipocytes induce differentiation/hypertrophy and IR in healthy adipocytes through secreted EVs. Finally, we demonstrate that lipid atrophied adipocytes shed EVs promote macrophage inflammation by stimulating IL-6 and TNFα expression. Thus, we conclude that pathological adipocytes release vesicles containing representative protein cargo of the cell of origin that are able to induce metabolic alterations on healthy cells probably exacerbating the disease once established.Single-crystal quartz material is widely applied in the manufacture of resonators and sensors, but it is difficult to process because of its high hardness. A novel way to fabricate single-crystal quartz structures is proposed in this paper; the method includes quartz-on-silicon (QoS) technology and inductively coupled plasma (ICP) etching, which makes it feasible to fabricate complex structures with crystal quartz. The QoS method encompasses the bonding of silicon and quartz, followed by the thinning and polishing of quartz, which can enable the fabrication of an ultra-thin quartz wafer on silicon. In this way, instead of the conventional wet etching with hydrofluoric acid, the quartz layer can be easily etched using the ICP dry-etching method. Then, the structure of the pure quartz material is obtained by removing the silicon wafer. In addition, the silicon layer can be processed into the appropriate structure. This aspect overcomes the difficulty of processing a complex structure of single-crystal quartz with different crystal orientations. Thin single-crystal quartz wafers of Z-cut with a thickness of less than 40 μm were obtained by using this method, and a complex three-dimensional structure with an 80 μm width was also acquired by the ICP etching of the quartz wafer. The method can be applied to make both crystal-oriented quartz-based sensors and actuators, such as quartz resonant accelerometers.Despite instrument and algorithmic improvements, the untargeted and accurate assignment of metabolites remains an unsolved problem in metabolomics. New assignment methods such as our SMIRFE algorithm can assign elemental molecular formulas to observed spectral features in a highly untargeted manner without orthogonal information from tandem MS or chromatography. However, for many lipidomics applications, it is necessary to know at least the lipid category or class that is associated with a detected spectral feature to derive a biochemical interpretation. Our goal is to develop a method for robustly classifying elemental molecular formula assignments into lipid categories for an application to SMIRFE-generated assignments. Using a Random Forest machine learning approach, we developed a method that can predict lipid category and class from SMIRFE non-adducted molecular formula assignments. Our methods achieve high average predictive accuracy (>90%) and precision (>83%) across all eight of the lipid categories in the LIPIDMAPS database. Classification performance was evaluated using sets of theoretical, data-derived, and artifactual molecular formulas. Our methods enable the lipid classification of non-adducted molecular formula assignments generated by SMIRFE without orthogonal information, facilitating the biochemical interpretation of untargeted lipidomics experiments. This lipid classification appears insufficient for validating single-spectrum assignments, but could be useful in cross-spectrum assignment validation.Binding peptides for given target molecules are often selected in vitro during drug discovery and chemical biology research. Among several display technologies for this purpose, complementary DNA (cDNA) display (a covalent complex of a peptide and its encoding cDNA linked via a specially designed puromycin-conjugated DNA) is unique in terms of library size, chemical stability, and flexibility of modification. However, selection of cDNA display libraries often suffers from false positives derived from non-specific binding. Although rigorous washing is a straightforward solution, this also leads to the loss of specific binders with moderate affinity because the interaction is non-covalent. To address this issue, herein, we propose a method to covalently link cDNA display molecules with their target proteins using light irradiation. We designed a new puromycin DNA linker that contains a photocrosslinking nucleic acid and prepared cDNA display molecules using the linker. Target proteins were also labeled with a short single-stranded DNA that should transiently hybridize with the linker.