MK-2206

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with notable clinical challenges, necessitating the search for innovative therapeutic strategies. FB-15, a derivative incorporating flavonoid and benzimidazole structures, has demonstrated significant anti-tumor activity in prior research. However, its effects on NPC remain unexplored. In this research, we explored the anti-cancer potential of FB-15 in NPC and elucidated its molecular mechanisms. Our results, based on CCK-8 assays, colony formation assays, EdU staining, cell cycle analysis, wound healing and Transwell assays, as well as Western blotting, demonstrated that FB-15 markedly inhibited NPC cell proliferation, migration, and invasion, and induced G0/G1 phase cell cycle arrest. Transcriptome sequencing and KEGG pathway analysis suggested that FB-15 exerts its anti-cancer activities primarily by suppressing the PI3K-Akt signaling pathway, a conclusion reinforced by Western blot analysis showing reduced phosphorylation levels of PI3K and Akt proteins. Rescue experiments further confirmed the involvement of this pathway: the PI3K-Akt activator 740 Y-P partially reversed the inhibitory effects of FB-15 in 5-8F cells, whereas co-treatment with the PI3K-Akt inhibitor MK-2206 and FB-15 in HK1 cells did not produce additive effects compared to MK-2206 alone. These findings support the notion that FB-15 exerts its anti-tumor effects primarily through inhibition of the PI3K-Akt signaling axis. Animal studies demonstrated that FB-15 significantly suppressed the growth of subcutaneous NPC tumors in nude mice while maintaining stable body weight. Immunohistochemical analysis confirmed that FB-15 downregulated Ki67 and Vimentin expression while upregulating the epithelial marker E-cadherin, suggesting its role in inhibiting epithelial-mesenchymal transition. These results highlight FB-15 as a potential therapeutic agent for NPC, underscoring its potential clinical application as a monotherapy or in combination with existing treatments.

Ulcerative colitis (UC) is a non-specific inflammatory bowel disease. Unlike any single form of cell death reported previously, macrophage PANoptosis, a unique programmed cell death characterized by inflammation and necrosis, plays a crucial role in the pathogenesis of colitis. Changdiqing Decoction (CDQD), an empirical hospital prescription enema, has been used to treat UC for decades. This study aimed to investigate the multi-target anti-colitic effects of CDQD by examining its impact on intestinal homeostasis and its anti-inflammatory properties.

A dextran sulfate sodium (DSS)-induced mouse model of acute colitis was employed. Interferon-gamma (IFN-γ) and KPT-330 were used to induce macrophage PANoptosis. Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLCHRMS) was utilized to identify the chemical constituents of CDQD. Multi-omics analysis and fecal microbiota transplantation (FMT) were used to explore the therapeutic targets and gut microbiota alterations induced by CDQD.

CDQD treatment significantly alleviated colitis symptoms in mice, with a dose-dependent therapeutic effect. The decoction mitigated PANoptosis in colon tissues and bone marrow-derived macrophages (BMDMs). 16S rRNA sequencing analysis and metabonomics revealed that CDQD administration significantly altered the gut microbiota composition and metabolite profiles. Notably, CDQD-modulated gut microbiota exhibited anti-colitic effects through FMT. Integrated transcriptomics and network pharmacology analysis revealed that CDQD significantly downregulated the PI3K/Akt signaling pathway in colitis. This finding was further validated using the inhibitors LY294002 and MK2206.

CDQD alleviates colitis by suppressing inflammatory macrophage activation and modulating the gut microbiota. Our research provides a novel traditional Chinese medicine strategy for the treatment of UC via enema administration.