Zhang Shouqing, Qiu Quanyuan, Yuan Mengzhen, Yu Jiajia, Gao Weiwei, Wang Xi, Liu Zhen, Yu Peng, Xiang Cen, Teng Yuou
China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China.
Curr Issues Mol Biol. 2025 Apr 1;47(4):243. doi: 10.3390/cimb47040243.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by complex pathogenesis involving dysregulated immunity and gut microbiota imbalance, demanding innovative therapeutic strategies. This study investigates the synergistic therapeutic potential of pomegranate peel-hawthorn combinations and their active constituents (ellagic acid and maslinic acid) through an integrative approach combining network pharmacology, in vitro/in vivo experiments, and gut microbiota analysis. Network pharmacology identified 61 shared therapeutic targets ( < 0.05 for pathway enrichment) and revealed complementary mechanisms: pomegranate peel primarily modulated AGE-RAGE/PI3K-Akt pathways, while hawthorn targeted IL-17/NF-κB signaling. Experimental validation demonstrated potent synergistic anti-inflammatory effects (combination index < 1), with optimal combinations reducing nitric oxide production by 52.35% (herbal extracts, < 0.05) and 74.4% (active monomers, < 0.05). In DSS-induced UC mice, combinatorial therapies significantly suppressed pro-inflammatory cytokines (TNF-α: 204.78 vs. 446.52 pg/mL in UC group, < 0.05; IL-6: 33.19 vs. 64.86 pg/mL, < 0.05), restored colonic SOD activity (72.31 vs. 50.10 U/mg·prot in UC group, < 0.01), and alleviated histopathological damage, outperforming monotherapeutics. Gut microbiota analysis revealed the recovery of α-diversity indices and normalized Bacteroidota/Bacillota ratios. Mechanistically, the combinations suppressed MAPK/NF-κB signaling cascades, reducing p-p38/p38 ( < 0.01 vs. UC group) and p-ERK1/2/ERK1/2 ( < 0.01 vs. UC group) phosphorylation. These findings establish that pomegranate peel-hawthorn formulations exert multi-modal therapeutic effects through the synergistic inhibition of pathways, mitigation of oxidative stress, and restoration of the microbiota, offering a scientifically validated approach for UC management rooted in traditional medicine principles.
溃疡性结肠炎（UC）是一种慢性炎症性肠病，其发病机制复杂，涉及免疫失调和肠道微生物群失衡，需要创新的治疗策略。本研究通过整合网络药理学、体外/体内实验和肠道微生物群分析等方法，研究石榴皮-山楂组合及其活性成分（鞣花酸和齐墩果酸）的协同治疗潜力。网络药理学确定了61个共同的治疗靶点（通路富集<0.05），并揭示了互补机制：石榴皮主要调节AGE-RAGE/PI3K-Akt通路，而山楂靶向IL-17/NF-κB信号通路。实验验证表明其具有强大的协同抗炎作用（联合指数<1），最佳组合可使一氧化氮生成减少52.35%（草药提取物，<0.05）和74.4%（活性单体，<0.05）。在DSS诱导的UC小鼠中，联合疗法显著抑制促炎细胞因子（TNF-α：UC组为204.78 vs. 446.52 pg/mL，<0.05；IL-6：33.19 vs. 64.86 pg/mL，<0.05），恢复结肠SOD活性（UC组为72.31 vs. 50.10 U/mg·prot，<0.01），并减轻组织病理学损伤，优于单一疗法。肠道微生物群分析显示α多样性指数恢复，拟杆菌门/厚壁菌门比率正常化。从机制上讲，这些组合抑制了MAPK/NF-κB信号级联反应，降低了p-p38/p38（与UC组相比<0.01）和p-ERK1/2/ERK1/2（与UC组相比<0.01）的磷酸化。这些发现表明，石榴皮-山楂制剂通过协同抑制信号通路、减轻氧化应激和恢复微生物群发挥多模式治疗作用，为基于传统医学原则的UC管理提供了一种经过科学验证的方法。
