Riggs Robles (horsebrow22)

Benzbromarone (BBR), a potent uricosuric agent for the management of gout, is known to cause fatal fulminant hepatitis. Although the mechanism of BBR-induced idiosyncratic hepatotoxicity remains unelucidated, cytochrome P450 enzyme-mediated bioactivation of BBR to electrophilic reactive metabolites is commonly regarded as a key molecular initiating event. However, apart from causing aberrant toxicities, reactive metabolites may result in mechanism-based inactivation (MBI) of cytochrome P450. Here, we investigated and confirmed that BBR inactivated CYP3A4 in a time-, concentration-, and NADPH-dependent manner with K I, k inact, and partition ratio of 11.61 µM, 0.10 minutes-1, and 110, respectively. Coincubation with ketoconazole, a competitive inhibitor of CYP3A4, attenuated the MBI of CYP3A4 by BBR, whereas the presence of glutathione and catalase did not confer such protection. The lack of substantial recovery of enzyme activity postdialysis and after oxidation with potassium ferricyanide, combined with the evelops a unique covalent docking methodology to predict the structural molecular determinants underpinning the inactivation for the first time. These findings lay the groundwork for future investigation of clinically relevant drug-drug interactions implicating BBR and mechanisms of BBR-induced idiosyncratic hepatotoxicity.RNA sequencing (RNA-seq) has matured into a reliable and low-cost assay for transcriptome profiling and has been deployed across a range of systems. see more The computational tool space for the analysis of RNA-seq data has kept pace with advances in sequencing. Yet tool development has largely centered around the human transcriptome. While eukaryotic and prokaryotic transcriptomes are similar, key differences in transcribed units limit the transfer of wet-lab and computational tools between the two domains. The article by M. Chung, R. S. Adkins, J. S. A. Mattick, K. R. Bradwell, et al. (mSystems 6e00917-20, 2021, https//doi.org/10.1128/mSystems.00917-20), demonstrates that integrating prokaryote-specific strategies into existing RNA-seq analyses improves read quantification. Unlike in eukaryotes, polycistronic transcripts derived from operons lead to sequencing reads that span multiple neighboring genes. Chung et al. introduce FADU, a software tool that performs a correction for such reads and thereby improves read quantification and biological interpretation of prokaryotic RNA sequencing.The impact of gut fungi and (1→3)-β-d-glucan (BG), a major fungal cell wall component, on uremia was explored by Candida albicans oral administration in bilateral nephrectomy (BiNx) mice because of the prominence of C. albicans in the human intestine but not in mice. As such, BiNx with Candida administration (BiNx-Candida) enhanced intestinal injury (colon cytokines and apoptosis), gut leakage (fluorescein isothiocyanate [FITC]-dextran assay, endotoxemia, serum BG, and bacteremia), systemic inflammation, and liver injury at 48 h postsurgery compared with non-Candida BiNx mice. Interestingly, uremia-induced enterocyte apoptosis was severe enough for gut translocation of viable bacteria, as indicated by culture positivity for bacteria in blood, mesenteric lymph nodes (MLNs), and other organs, which was more severe in BiNx-Candida than in non-Candida BiNx mice. Candida induced alterations in the gut microbiota of BiNx mice as indicated by (i) the higher fungal burdens in the feces of BiNx-Candida mice than in shred to the liver and induced hepatocyte inflammatory responses with a reduced energy production capacity, resulting in acute uremia-induced liver injury. In addition, Lactobacillus rhamnosus attenuated intestinal injury through reduced gut Candida and improved intestinal bacterial conditions.An outer membrane protein A (OmpA) from Acinetobacter sp. strain SA01 was identified and characterized in-depth based on the structural and functional characteristics already known of its homologues. In silico structural st