Deciphering structural bases of intestinal and hepatic selectivity in targeting pregnane X receptor with indole-based microbial mimics.

Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.

Imaging in Interventional Radiology: Applications of Contrast-Enhanced Ultrasound.

This review explores the applications of contrast-enhanced ultrasound (CEUS) in interventional radiology, focusing on its role in endoleak detection after endovascular abdominal aortic aneurysm repair (EVAR), periprocedural thermal ablation guidance, and transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). CEUS offers a dynamic assessment for the detection of endoleak following EVAR, facilitating accurate diagnosis and classification. In periprocedural thermal ablation, CEUS enhances target lesion delineation with the visualization of real-time perfusion changes, optimizing treatment strategies and reducing residual tumor rates. Finally, CEUS has demonstrated efficacy in intraprocedural evaluation and postprocedural follow-up in TACE for HCC, offering early detection of residual tumor enhancement and providing an alternative for patients with contraindications to contrast-enhanced computed tomography or magnetic resonance imaging. Overall, CEUS is a versatile and valuable tool with many applications to offer interventional radiologists enhanced diagnostic capabilities and improved patient management.