AbstractUpon epithelial barrier dysfunction, lipopolysaccharide (LPS) stimulates glucagon‐like peptide‐1 (GLP‐1) secretion from enteroendocrine L cells by activating Toll‐like receptor 4 (TLR4). Because GLP‐1 accelerates peristalsis in the proximal colon, the present study aimed to explore whether LPS facilitates colonic peristalsis by stimulating L cell‐derived GLP‐1 release. In isolated segments of rat proximal colon that were serosally perfused with physiological salt solution and luminally perfused with 0.9% saline, peristaltic wall motion was video recorded and converted into spatio‐temporal maps. Fluorescence immunohistochemistry was also carried out. Intraluminal administration of LPS (100 or 1 µg mL−1 but not 100 ng mL−1) increased the frequency of oro‐aboral propagating peristaltic contractions. The LPS‐induced acceleration of colonic peristalsis was blocked by TAK‐242 (the TLR4 antagonist), exendin‐3 (the GLP‐1 receptor antagonist) or BIBN4096 (the calcitonin gene‐related peptide receptor antagonist). GLP‐1‐positive epithelial cells co‐expressed TLR4 immunoreactivity. In aspirin‐pretreated preparations where epithelial barrier function had been impaired, a lower dose of LPS (100 ng mL−1) became capable of accelerating peristalsis. By contrast, luminally applied dimethyl sulphoxide, a reactive oxygen species scavenger that protects epithelial integrity, attenuated the prokinetic effects of a higher dose of LPS (100 µg mL−1). In colonic segments of a stress rat model leading to a leaky gut, LPS induced more pronounced prokinetic effects. Colonic L cells may well sense luminal LPS via TLR4 triggering the release of GLP‐1 that stimulates calcitonin gene‐related peptide‐containing neurons. The resultant acceleration of peristalsis would facilitate excretion of Gram‐negative bacteria from the intestine, and thus L cells may have a protective role against intestinal bacterial infections.

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Key points

Colonic epithelial cells form a barrier against bacterial invasion but also may contribute more actively to the exclusion of luminal pathogen by stimulating colonic motility.

Luminal lipopolysaccharide (LPS) accelerated colonic peristalsis by stimulating calcitonin gene‐related peptide‐containing neurons.

The prokinetic effect of LPS was mediated by the secretion of glucagon‐like peptide‐1 from enteroendocrine L cells in which Toll‐like receptor 4 was expressed.

The LPS‐mediated acceleration of peristalsis depended on epithelial barrier integrity.

L cells have a defensive role against Gram‐negative bacterial infections by facilitating faecal excretion, and could be a potential therapeutic target for gastrointestinal infections.

01 Aug 2023·Diabetes, Obesity and Metabolism

Control of human pancreatic beta cell kinome by glucagon‐like peptide‐1 receptor biased agonism

Article

Author: El Eid, Liliane ; Boutry, Raphaël ; Buenaventura, Teresa ; Jones, Ben ; Bonnefond, Amélie ; Tomas, Alejandra ; Rutter, Guy A. ; Xiao, Jiannan ; Froguel, Philippe

AbstractAimTo determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon‐like peptide‐1 receptor (GLP‐1R) balanced versus biased agonist stimulations.Materials and MethodsThis study analysed the kinomic profiles of human EndoC‐βh1 cells following vehicle and GLP‐1R stimulation with the pharmacological agonist exendin‐4, as well as exendin‐4–based biased derivatives exendin‐phe1 and exendin‐asp3 for acute (10‐minute) versus sustained (120‐minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase‐substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis.ResultsThe present analysis reveals that kinomic responses are distinct for acute versus sustained GLP‐1R agonist exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP‐1R signalling mediators, constituting potential targets for further research on biased GLP‐1R downstream signalling.ConclusionThe results from this study suggest that differentially biased exendin‐phe1 and exendin‐asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti‐type 2 diabetes therapies with optimized downstream kinomic profiles.

01 Jun 2023·Molecular and Cellular Neuroscience

Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception

Article

Author: Morton, Paul D. ; Arellano, Eric ; Chang, Yuxuan ; Li, Jing Jing ; Shishikura, Kyosuke ; Gregus, Ann M. ; Buczynski, Matthew W. ; Wang, Xie ; Lin, Zongtao ; Matthews, Megan L. ; Pei, Liming ; Chen, Irene ; Bustin, Katelyn A. ; McKnight, Nate

Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors) in vivo using chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil®). We show the probes are in vivo active and can map proteome-wide tissue-specific target engagement of the drug. In addition to engaging targets (flavoenzymes monoamine oxidase A/B) that are associated with the known therapeutic mechanism as well as several other members of the flavoenzyme family, the probes captured the previously discovered N-terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3) in vivo through a divergent mechanism, indicating this functional feature has biochemical activity in the brain. SCRN3 protein is ubiquitously expressed in the brain, yet gene expression is regulated by inflammatory stimuli. In an inflammatory pain mouse model, behavioral assessment of nociception showed Scrn3 male knockout mice selectively exhibited impaired thermal nociceptive sensitivity. Our study provides a guided workflow to entangle molecular (off)targets and pharmacological mechanisms for therapeutic development.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Preclinical	US	Amylin Pharmaceuticals, Inc.	-

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