Ke Xing

Aims Glucokinase activators (GKAs) lower glucose by directly activating glucokinase (GK) or dissociating it from GK regulatory protein (GK-GKRP). Their long-term effects on gastrointestinal (GI) diseases remain unclear. This study explores how two approaches influence GI disorders through metabolic-immune interplay. Methods We used genetic variants near GCK and GCKR associated with fasting glucose as proxies for direct GK activation and GK-GKRP dissociation. Using Mendelian Randomization and meta-analysis, we assessed their associations with 20 GI diseases and explored mediation by lipid traits and inflammatory proteins (pQTL). MR-prioritized lipid and immune mediators underwent multi-omics analysis including functional enrichment, protein-protein interaction networks, single-cell RNA sequencing (scRNA-seq) and Cellchat in disease models, investigating metabolic-immune interactions and intercellular signaling. Results Direct GK activation and GK-GKRP dissociation exerted distinct causal effects on GI diseases. GK-GKRP dissociation increased risks of irritable bowel syndrome, Crohn’s disease, ulcerative colitis, beyond its established association with metabolic dysfunction-associated steatotic liver disease (MASLD). Lipid traits and inflammatory proteins interconnected through PPAR and NF-κB signaling, mediating GCKR’s associations with GI diseases. Key mediators such as FGF-21, CSF1, CD40, CXCL9 were localized to disease-specific niches in MASLD and IBD scRNA-seq models, highlighting GCKR-centered metabolic-immune crosstalk. Intercellular communication via CSF, CXCL, CCL, TGFβ, Visfatin, Galectin, and MIF signaling linked immune, parenchymal, and stromal cells in disease pathogenesis. Conclusions GK-GKRP dissociation, but not direct GK activation, increases IBD and MASLD risks through metabolic-immune interplay in gut-liver axis. Tailoring GKA therapies for patients with comorbidities is essential.

Rationale: Phenylethylamines are one of the most common types of new psychoactive substances, following synthetic cannabinoids and synthetic cathinones. They are regulated in many countries because of their strong hallucinogenic effects, which can cause serious nerve damage. There is a wide variety of phenylethylamines, exhibiting rapid renewal and extremely similar structures, therefore accurate qualitative analysis of isomers is a difficult problem in current drug analysis. Methods: The dissociation pathways of the position isomers 2‐(2‐methylaminoprolyl)benzofuran (2‐MAPB) and 5‐(2‐methylaminopropyl)benzofuran (5‐MAPB) were investigated by gas chromatography–mass spectrometry and liquid chromatography coupled to high‐resolution quadrupole Orbitrap MS. The dissociation patterns of the phenethylamine‐based designer drugs 2‐MAPB and 5‐MAPB were explored and extended in this work based on MS combined with density functional theory studies. Results: For electron ionization mass spectrometry (EI‐MS) analysis, the dissociation patterns of 2‐MAPB were similar to those of 5‐MAPB. For electrospray ionization mass spectrometry (ESI‐MS ⁿ ) analysis, the hydrogen atom on amino group was facile to form a intramolecular hydrogen bond with the oxygen atom on the parent nucleus of benzofuran in the structure of 2‐MAPB, leading to higher abundance of the product ion at m / z 58. However, there was a conjugated system between the positive charge formed by the cleavage of the 5‐MAPB side chain and the benzofuran ring, enabling the 5‐MAPB to generate a product ion at m / z 131. Computational study showed that energy barrier and spin density difference distribution jointly control the selective dissociation in EI‐MS, while different types of orbital interaction induced by intramolecular hydrogen bond led to different dissociation results in ESI‐MS ⁿ . Conclusions: These different dissociation patterns could be used to distinguish 2‐MAPB from 5‐MAPB. This could assist forensic laboratories in the differentiation and characterization of potential isomers in these kinds of compounds, especially in mixtures.

Arctium lappa L. is one of the medicinal and food homologous plants in China, which is rich in nutrients and medicinal ingredients. The use of plant growth-promoting (PGP) endophytic bacteria is an alternative to reducing chemical fertilizers in agricultural production. The aim of this study was to analyze the diversity of endophytic bacteria in different cultivars of A. lappa L. collected from two geographical locations in China and evaluate PGP traits of the isolates and their potential PGP ability in greenhouse condition. Endophytic bacterial community was investigated by culture-dependent and culture-independent methods. Isolates were screened and investigated for multiple PGP traits, and representative strains were inoculated host seedlings to evaluate the growth promoting effect. A total of 348 endophytic bacteria were obtained and they were distributed into 4 phyla and 30 genera. In addition, high throughput sequencing revealed more abundant bacterial community, including 17 bacterial phyla and 207 genera. A high proportion of PGP traits were detected, including production of indole acetic acid, siderophore, ammonia and phosphate solubilization. Four representative strains with multiple PGP traits of the most dominant genera (Bacillus, Pantoea, Microbacterium and Pseudomonas) were further selected for host inoculation and growth promoting evaluation, and they significantly increase seedlings length, root length and fresh weight. This study demonstrated that A. lappa L. harbors abundant endophytic bacteria, and some endophytic bacteria showed good potential for the development of microbial fertilizer in the future.