Patients with ulcerative colitis (UC) exhibit heightened depression risk, linked to microbiota-gut-brain axis dysfunction. This study isolated a novel low-molecular-weight Schisandra chinensis polysaccharide (SCP) that ameliorated UC and comorbid depression by remodeling gut microbiota, redirecting tryptophan (Trp) metabolism toward the indole pathway, and activating aryl hydrocarbon receptor (AhR). Structurally, SCP features a →4)-α-D-Glcp backbone with O-6 branched chains. In dextran sulfate sodium-induced UC mice, SCP mitigated colonic inflammation, restored intestinal barrier integrity, and improved depression-like behaviors by repairing blood-brain barrier, reducing neuroinflammation, preserving hippocampal neurons, and modulating synaptic plasticity. Multi-omics revealed SCP enriched beneficial microbiota (e.g., Limosilactobacillus reuteri) and rebalanced Trp metabolism along the gut-brain axis. SCP suppressed the hyperactive kynurenine (Kyn) pathway (reduced Kyn/Trp ratio) while elevating indole-3-propionic acid (IPA) levels in colon, serum, and hippocampus. Functioning as a pivotal molecule, IPA exerted dual anti-inflammatory effects in both colon and hippocampus via AhR activation and NF-κB inhibition. Antibiotic depletion and fecal microbiota transplantation validated SCP's microbiota-dependent efficacy, while IPA supplementation recapitulated SCP's benefits. AhR inhibition abolished SCP's therapeutic actions, confirming AhR as the critical target. Collectively, these findings propose a novel therapeutic strategy for UC and associated depression, highlighting SCP's potential value in targeting the Trp metabolism-AhR axis.
The allylic moiety is a prevalent structural motif in pharmaceuticals and bioactive molecules, offering significant synthetic versatility. The conventional Tsuji-Trost reaction relies on transition metal catalysis and preactivated carbon nucleophiles (such as malonates), which often constrain functional group compatibility and reaction diversity. This study introduces a direct radical-radical cross-coupling strategy that capitalizes on polarity matching between π-allylic radicals and amine α-alkyl radicals to facilitate C(sp3)-C(sp3) bond formation. The approach demonstrates remarkable substrate versatility and functional group compatibility, enabling late-stage derivatization of diverse natural products. The reaction also achieves enantioselective control through chiral auxiliaries, such as (-)-menthol, underscoring its synthetic potential.
Based on a novel targeted protein degradation platform, Protein-Radical-Oxidation Targeting Enediyne Chimera (PROTEC), a series of chimeric enediyne compounds targeting the oncogenic protein nicotinamide phosphoribosyltransferase (NAMPT) were designed and synthesized. These compounds feature different linker lengths and cyclopropane modifications at the alkyne terminus. Computational studies showed that incorporating the cyclopropane group at the propargyl position facilitates the "radical clock" mechanism, achieving greater spatial separation and weaker orbital interactions between the two radical centers, thereby enhancing hydrogen abstraction ability. The PROTEC-4 compound exhibiting the strongest interaction with NAMPT, as demonstrated by docking studies, established significant cytotoxicity against human ovarian cancer A2780 cells with a half-inhibitory concentration (IC50) of 0.24 μM, indicating great potential for future antitumor drug development.
Rapid, accurate and convenient detection of illegally added drugs are of critical importance in food safety. Herein, based on the host-guest recognition strategy, we establish a novel label-free fluorescence lateral flow assay (LF-LFA) platform for detection of amantadine (AMD) in egg samples. Specially, two fluorescence reporters-BSA-β-CD@BER (formed via host-guest interaction) and BER-BSA (generated through AIE effect), are effectively designed. This platform can enable "turn-on" FL detection through host-guest interaction between cucurbit[7]uril (CB[7]) and AMD, as well as between CB[7] and BSA-β-CD@BER, without the need for fluorescent labeling of target molecule (AMD). As a result, it has successfully achieved sensitive detection of AMD with a low limit of detection (LOD = 2.1 ng mL-1), wide linear detection range (2.5-100 ng mL-1), high specificity (CR ≤ 4%) and fast response (only 8 min). It will be expected to provide a novel avenue for rapid on-site detection of more illegal drugs in practices.
Lysine acetyl-methylation (Kam) is a novel protein post-translational modification (PTM) recently identified on histone H4, yet its biological functions on non-histone proteins remain largely unexplored. Here, we engineered an orthogonal Methanosarcina barkeri pyrrolysyl-tRNA synthetase (MbPylRS) variant and tRNACUAPyl pair for site-specific Kam incorporation into proteins in mammalian cells. Using this system, we identified endogenous Kam sites at K28 of adenylate kinase 2 (AK2) and K207 of pyruvate kinase M2 (PKM2) through proteomic analysis. Functional characterization revealed that Kam at these evolutionarily conserved residues significantly attenuated enzymatic activity. These findings demonstrate that Kam serves as a regulatory mechanism for non-histone proteins, and the ability to generate proteins harboring Kam at defined sites provides a valuable approach for investigating the biological roles of this newly identified PTM.
