Introduction: Acute liver failure (ALF) is a clinical condition with many causes, fast progression, and a poor prognosis. Previous research has indicated that microbial factors have a role in ALF, but a clear picture has yet to emerge.Methods: To investigate the specific involvement of microbial metabolites in ALF development, we pretreated D-GalN/LPS-induced ALF mice with indole derivatives, an influential class of gut microbial metabolites.Results: Contrary to their typical role as anti-inflammatory agents in the host, indole-3-acetic acid (IAA), indole-3-lactic acid (ILA), and indolepropionic acid (IPA) gavage sensitize mice to D-GalN/LPS-induced-ALF with a rapid rise in serum transaminases and histologic lesion. For a clearer picture, we performed comprehensive analysis for the IAA therapy. IAA markedly amplified inflammatory response and cellular damage. The transcriptome analysis indicated the participation of the TNF-α/NF-κB signaling pathway. The structure of gut microbiota in ileum and the expression of Toll-like receptor 2 (Tlr2) in the liver were also significantly changed.Discussion: In conclusion, IAA pretreatment can exacerbate D-GalN/LPS-induced ALF via probable Tlr2/NF-κB pathway involvement and ileac dysbiosis characterized by enriched gram-positive genus with potential pathogenesis. Microbial metabolites IAA may aggravate individual susceptibility to D-GalN/LPS-induced ALF. Further investigation of the underlying mechanism is needed, and intervention with indole derivatives and related commensal species should be undertaken with caution.
Min Li,Jia-Yao Si,Peng-Fei Xie,Zhen-Jie Feng,Sheng-Jie Li,Feng Zhou,Jian-Mei Li
The global aging crisis has increased the risk of atherosclerosis (AS), positioning vascular senescence as a critical therapeutic target. Procyanidin C1 (PCC1), a bioactive polyphenol from hawthorn, demonstrates dual senolytic and longevity-enhancing effects. This study explored the regulatory role and mechanisms of PCC1 in AS using an ApoE −/− mouse model fed a high-fat diet (HFD) and a D-galactose (D-Gal)-induced cellular senescence model. Hawthorn oligomeric proanthocyanidins (HOPCs), as well as PCC1, showed potent anti-atherosclerotic and anti-aging effects by improving serum lipid metabolism and reducing aortic root plaque, vascular senescence markers and inflammatory adhesion molecules. Metabolomic analysis demonstrated that PCC1 significantly suppresses key enzymes in arachidonic acid (AA) metabolism, thereby decreasing downstream pro-inflammatory mediators. Target identification studies, including drug affinity responsive target stability (DARTS) assay, liquid chromatography-tandem mass spectrometry (LC-MS/MS), cellular thermal shift assay (CETSA), and molecular docking, identified heat shock protein 90 (HSP90) as a direct target of PCC1, leading to inhibition of its downstream signaling. In vitro, PCC1 selectively cleared senescent cells, suppressed the senescence-associated secretory phenotype (SASP), enhanced endothelial nitric oxide synthase (eNOS) phosphorylation, and inhibited the toll-like receptor 2 (TLR2)/nuclear factor kappa-B (NF-κB) pathway, demonstrating multimodal anti-aging and anti-inflammatory effects. Together, these findings indicate that PCC1 mitigates atherosclerosis by targeting both metabolic and inflammatory pathways through senescent cell clearance and HSP90-mediated blockade of the TLR2/NF-κB signaling axis. This dual mechanism highlights PCC1 as a promising vasoprotective agent and supports the potential application of hawthorn extracts in functional foods aimed at preventing aging-related cardiovascular diseases.
危险品化学品经营许可证（带存储）