University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Münster, Germany.
University of Basel, Department Pharmaceutical Sciences, Molecular Pharmacy, Basel, Switzerland.
J Ethnopharmacol. 2020 Jul 15;257:112889. doi: 10.1016/j.jep.2020.112889. Epub 2020 Apr 18.
Extracts from Cranberry fruits (Vaccinium macrocarpon) are traditionally used against urinary tract infections, mainly due to antiadhesive activity against uropathogenic E. coli (UPEC), but the exact mode of action and compounds, responsible for the activity, are unknown.
i. To investigate if cranberry extract acts only by a single component or must be assessed as a multi-active-compound preparation; ii to screen isolated cranberry-related natural products under in vitro conditions to pinpoint natural products with antiadhesive effects against UPEC, followed by in silico calculations (QSAR) to predict potential antiadhesive compounds; iii. investigations by using urine samples from cranberry treated volunteers for evaluation on the bacterial transcriptome and the mannose-binding side of FimH, iv. to investigate if besides Tamm Horsfall Protein induction in the kidney, the extract acts also directly against UPEC.
Antiadhesive activity of 105 compounds was determined by flow cytometric adhesion assay (UPEC UTI89 on T24 bladder cells). Urine samples from 16 volunteers treated with cranberry extract (p.o., 7 days, 900 mg/day) were used for ex vivo testing concerning influence on the bacterial transcriptome (Illumina RNA-seq) and interaction with the mannose binding domain of type-1 fimbriae.
i. The antiadhesive effect of cranberry extract cannot be attributed to a single compound or to a single fraction. ii. Unglycosylated flavones and flavonols with bulky substitution of the B ring contribute to the antiadhesive activity. 3'-8″-biflavones and flavolignans (not related to cranberry fruits) were identified as potent antiadhesive compounds against UPEC. iii. QSAR yielded a model with good statistical performance and sufficient internal and external predictive ability. iv. Urine samples from male cranberry-treated volunteers indicated significant interaction with the mannose binding domain of type-1 fimbriae, which correlated with the amount of Tamm-Horsfall Protein in the test samples. v Cranberry extract did not influence the UPEC transcriptome; gene expression of bacterial adhesins (P-, S-fimbrae, curli) was not influenced by the urine samples, while a slight, but non-significant upregulation of type 1 fimbriae was observed.
B-ring substituted flavones and flavonols from cranberry contribute to the antiadhesive activity against UPEC by inhibition of the FimH-mediated interaction with the host cell bladder epithelium.
蔓越莓（Vaccinium macrocarpon）的提取物传统上被用于治疗尿路感染，主要是因为其对尿路致病性大肠杆菌（UPEC）具有抗粘附活性，但确切的作用机制和负责这种活性的化合物尚不清楚。
i. 研究蔓越莓提取物是否仅由单一成分起作用，还是必须被评估为多活性化合物制剂；ii. 在体外条件下筛选分离的蔓越莓相关天然产物，以确定具有抗 UPEC 粘附作用的天然产物，然后进行定量构效关系（QSAR）计算，以预测潜在的抗粘附化合物；iii. 使用来自蔓越莓治疗志愿者的尿液样本进行细菌转录组和 FimH 中甘露糖结合侧的评估；iv. 研究提取物除了在肾脏中诱导 Tamm Horsfall 蛋白外，是否还直接作用于 UPEC。
通过流式细胞术粘附试验（UPEC UTI89 在 T24 膀胱细胞上）测定 105 种化合物的抗粘附活性。使用 16 名志愿者的尿液样本（口服，7 天，每天 900mg）进行离体试验，以研究其对细菌转录组（Illumina RNA-seq）的影响以及与 I 型菌毛甘露糖结合结构域的相互作用。
i. 蔓越莓提取物的抗粘附作用不能归因于单一化合物或单一馏分。ii. 未糖基化的黄酮和黄酮醇，B 环具有较大的取代基，有助于抗粘附活性。3'-8″-双黄酮和黄烷醇（与蔓越莓果实无关）被鉴定为具有抗 UPEC 粘附活性的有效化合物。iii. QSAR 得到了一个具有良好统计学性能和足够内部和外部预测能力的模型。iv. 来自男性蔓越莓治疗志愿者的尿液样本表明与 I 型菌毛甘露糖结合结构域有显著相互作用，这与测试样本中的 Tamm-Horsfall 蛋白含量相关。v. 蔓越莓提取物不影响 UPEC 的转录组；细菌粘附素（P-、S-菌毛、卷曲菌）的基因表达不受尿液样本的影响，而 I 型菌毛的表达略有上调，但无统计学意义。
蔓越莓中的 B 环取代黄酮和黄酮醇通过抑制 FimH 介导的与宿主膀胱上皮细胞的相互作用，有助于对抗 UPEC 的粘附活性。
