Department of Urology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264000, China.
Department of Hematologic Lymphoma, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264000, China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Aug;397(8):5819-5830. doi: 10.1007/s00210-024-02987-y. Epub 2024 Feb 7.
Interstitial cystitis (IC) is a chronic bladder inflammation. Inhibition of prostaglandin G/H synthase 2 (PTGS2) is the most common method for controlling inflammation-related diseases. This study aimed to analyze the effects of hispidulin on the PTGS2 and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammation in experimental IC models. A binding activity between hispidulin and PTGS2 was measured using molecular docking. Human urothelial cells (SV-HUC-1) were stimulated by 2 ng/mL of interleukin (IL)-1β for 24 h and cultured in a medium with different concentrations of hispidulin (2.5, 5, 10, 20 µM) for 24 h to observe the expressions of PTGS2 and NLRP3 protein. Cells overexpressing PTGS2 were established by PTGS2 cDNA transfection. In the IL-1β-treated cells, the NLRP3 inflammasome was measured after 20 µM hispidulin treatment. In rats, animals were performed with three injections of 40 mg/kg cyclophosphamide (CYP) and orally treated with 50 mg/kg/day hispidulin or ibuprofen for 3 days. The bladder pain was measured using Von Frey filaments, and the bladder pathology was observed using hematoxylin and eosin (H&E) staining. The expressions of PTGS2 and NLRP3 inflammasome were also observed in the bladder tissues. A good binding activity was found between hispidulin and PTGS2 (score = - 8.9 kcal/mol). The levels of PTGS2 and NLRP3 inflammasome were decreased with the hispidulin dose increase in the IL-1β-treated cells (p < 0.05). Cells overexpressing PTGS2 weakened the protective effects of hispidulin in the IL-1β-treated cells (p < 0.01). In the CYP-treated rats, hispidulin treatment improved the bladder pain through decreasing the nociceptive score (p < 0.01) and suppressed the bladder inflammation through suppressing the expressions of PTGS2 and NLRP3 inflammasome in bladder tissues (p < 0.01). Additionally, the results of ibuprofen treatment were similar to the effects of hispidulin in the CYP-treated rats. This study demonstrates that hispidulin may be a new alternative drug for the IC treatment that binds PTGS2 to perform its functions.
间质性膀胱炎（IC）是一种慢性膀胱炎症。抑制前列腺素 G/H 合酶 2（PTGS2）是控制炎症相关疾病最常用的方法。本研究旨在分析白杨素对实验性 IC 模型中 PTGS2 和 NOD 样受体热蛋白域相关蛋白 3（NLRP3）炎症的影响。使用分子对接测量白杨素与 PTGS2 的结合活性。用 2ng/mL 白细胞介素（IL）-1β刺激人尿路上皮细胞（SV-HUC-1）24h，然后在含有不同浓度白杨素（2.5、5、10、20µM）的培养基中培养 24h，观察 PTGS2 和 NLRP3 蛋白的表达。通过 PTGS2 cDNA 转染建立过表达 PTGS2 的细胞。在 IL-1β 处理的细胞中，用 20µM 白杨素处理后测量 NLRP3 炎性体。在大鼠中，用 40mg/kg 环磷酰胺（CYP）进行三次注射，并每天口服 50mg/kg 白杨素或布洛芬治疗 3 天。使用 Von Frey 细丝测量膀胱疼痛，并使用苏木精和伊红（H&E）染色观察膀胱病理。还观察了膀胱组织中 PTGS2 和 NLRP3 炎性体的表达。发现白杨素与 PTGS2 之间具有良好的结合活性（评分=-8.9kcal/mol）。在 IL-1β 处理的细胞中，随着白杨素剂量的增加，PTGS2 和 NLRP3 炎性体的水平降低（p<0.05）。过表达 PTGS2 的细胞削弱了白杨素在 IL-1β 处理的细胞中的保护作用（p<0.01）。在 CYP 处理的大鼠中，白杨素治疗通过降低疼痛评分（p<0.01）改善了膀胱疼痛，并通过抑制膀胱组织中 PTGS2 和 NLRP3 炎性体的表达抑制了膀胱炎症（p<0.01）。此外，布洛芬治疗的结果与 CYP 处理大鼠中白杨素的作用相似。本研究表明，白杨素可能是一种新的 IC 治疗替代药物，通过与 PTGS2 结合发挥作用。
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