Microbial indoles have been demonstrated as selective or dual agonists and ligands of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR). However, structural determinants of microbial indoles selectivity towards both receptors remain elusive. Here, we studied the effects of existing and newly synthesized derivatives of indole microbial metabolite tryptamine on the activity of AhR and PXR receptors. We show that the elongation of indolyl-3-alkaneamine chain, indole N-methylation and conversion of indolyl-3-alkaneamines to oleamides resulted in a major increase of PXR activity and in parallel loss of AhR activity. Using reporter gene assays, RT-PCR and TR-FRET techniques, we have characterized in detail the activation of PXR by novel indolyl-3-alkanyl-oleamides, 1-methyltryptamine and 1-methyltryptamine-acetamide. As a proof of concept, we demonstrated anti-inflammatory and epithelial barrier-protective activity of lead derivatives in intestinal Caco-2 cells, employing the measurement of expression of pro-inflammatory chemokines, tight junction genes, trans-epithelial electric resistance TEER, and dextran-FITC permeability assay. In conclusion, we show that a subtle chemical modifications of simple microbial indole metabolite tryptamine, leads to substantial changes in AhR and PXR agonist activities.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.toxlet.2023.09.012 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Molecular insights into a distinct class of terpenoid cyclases.
Nat Commun
January 2025
State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Hongshan Laboratory, School of Life Sciences, Hubei University, Wuhan, China.
Article Synopsis
- Terpenoid cyclases (TCs) are crucial for producing diverse natural compounds, with the BcABA3 enzyme from the fungus Botrytis cinerea representing a unique type that deviates from typical TCs.
- Crystal structures of BcABA3 and related enzymes show they have an all-α-helix fold and interact with specific substrates through a unique binding mechanism.
- Findings suggest significant potential for exploring more uncharacterized terpenoids synthesized by these enzymes, highlighting the need for further research in this area.
Photoinduced Regiodivergent and Enantioselective Cross-Coupling of Glycine Derivatives with Hydrocarbon Feedstocks.
J Am Chem Soc
January 2025
Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China.
Regiodivergent asymmetric synthesis represents a transformative strategy for the efficient generation of structurally diverse chiral products from a single set of starting materials, significantly enriching their enantiomeric composition. However, the design of radical-mediated regiodivergent and enantioselective reactions that can accommodate a wide range of functional groups and substrates has posed significant challenges. The obstacles primarily lie in switching the regioselectivity and achieving high enantiodiscrimination, especially when dealing with high-energy intermediates.
View Article and Find Full Text PDFN-Doped Zigzag-Type Aromatic Truncated Cone Belts.
J Am Chem Soc
January 2025
Key Laboratory of Bioorganic Phosphorous and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.
Zigzag aromatic hydrocarbon belts, ultrashort segments of zigzag carbon nanotubes, have been fascinating in the chemistry community for more than a half century because of their aesthetically appealing molecular nanostructures and tantalizing applications. Precise introduction of heteroatoms of distinct electronegativity and electronic configuration can create various heterocyclic aromatic nanobelts with novel physical and chemical properties. Here, we report the synthesis of unprecedented N-doped zigzag-type aromatic belts, belt[]pyrrole[]pyridines ( = 6-8), from multiple intramolecular C-C homocoupling reactions of readily available azacalix[](3,5-dibromopyridine)s.
View Article and Find Full Text PDFComprehensive assessment of the safety of bisphenol A and its analogs based on multi-toxicity tests in vitro.
J Hazard Mater
December 2024
National Engineering Research Center of Industrial Wastewater Detoxication and Resource Recovery, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:
As substitutes for bisphenol A (BPA), bisphenol analogs (BPs) have raised concerns due to their frequent environmental detection and unclear safety. Here, the cytotoxicity, endocrine disruption, neurotoxicity, aryl hydrocarbon receptor (AhR) activity, and genotoxicity of nine BPs and BPA were evaluated in three types of cell lines. Over half of the tested BPs exhibited greater cytotoxicity than BPA, with IC50 values showing a linear correlation with Log (R²=0.
View Article and Find Full Text PDFRevealing and mitigating the inhibitory effect of serotonin on HRP-mediated protein labelling.
Sci Rep
December 2024
Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Proximity-dependent biotinylation coupled with mass spectrometry enables the characterization of subcellular proteomes. This technique has significantly advanced neuroscience by revealing sub-synaptic protein networks, such as the synaptic cleft and post-synaptic density. Profiling proteins at this detailed level is essential for understanding the molecular mechanisms of neuronal connectivity and transmission.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!