Flavonoid Nobiletin Attenuates Cyclophosphamide-Induced Cystitis in Mice through Mechanisms That Involve Inhibition of IL-1β Induced Connexin 43 Upregulation and Gap Junction Communication in Urothelial Cells.
Flavonoid Nobiletin Attenuates Cyclophosphamide-Induced Cystitis in Mice through Mechanisms That Involve Inhibition of IL-1β Induced Connexin 43 Upregulation and Gap Junction Communication in Urothelial Cells.
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DOI：
10.3390/ijms23095037
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发表时间：
2022-05-01
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
膀胱炎性疾病会导致各种泌尿症状，如尿频和排尿疼痛，这些症状会影响生活质量。本研究采用环磷酰胺(CYP)诱导的小鼠膀胱炎模型和永生化人尿路上皮细胞(TRT-HU1)模型，探讨橙皮多甲氧基黄酮(nobiletin，NOB)对小鼠膀胱炎的预防作用，并探讨其作用机制。用PMF90(60%NOB)预防可减轻CYP治疗小鼠的膀胱炎和尿路症状。PMF90还减少了CYP处理的小鼠膀胱粘膜中缝隙连接通道的主要成分--连接蛋白43(Cx43)的上调。用促炎细胞因子IL-1β刺激TRT-HU1细胞，可增加Cx43mRNA和蛋白的表达，并增强缝隙连接偶联反应，而这一作用可被Nob预先处理所阻止。在尿路上皮特异性Cx43基因敲除(UCx43KO)小鼠中，与对照组相比，CYP治疗引起的膀胱炎症和排尿行为改变的肉眼迹象显著减弱。这些结果表明尿路上皮Cx43参与了CYP治疗的小鼠膀胱炎和泌尿症状的发生发展，并为Nob通过抗炎作用对IL-1β信号和尿路上皮Cx43表达的预防作用提供了临床前证据。
Bladder inflammatory diseases cause various urinary symptoms, such as urinary frequency and painful urination, that impair quality of life. In this study, we used a mouse model of cyclophosphamide (CYP)-induced bladder inflammation and immortalized human urothelial (TRT-HU1) cells to explore the preventive potential of nobiletin (NOB), a polymethoxylated flavone enriched in citrus fruit peel, and investigate its mechanism of action in the bladder. Prophylaxis with PMF90 (60% NOB) attenuated the development of bladder inflammation and urinary symptoms in CYP-treated mice. PMF90 also reduced the upregulation of connexin 43 (Cx43), a major component of gap junction channels, in the bladder mucosa of CYP-treated mice. Stimulation of TRT-HU1 cells with the pro-inflammatory cytokine IL-1β increased Cx43 mRNA and protein expression and enhanced gap junction coupling—responses that were prevented by pre-treatment with NOB. In urothelium-specific Cx43 knockout (uCx43KO) mice, macroscopic signs of bladder inflammation and changes in voiding behavior induced by CYP treatment were significantly attenuated when compared to controls. These findings indicate the participation of urothelial Cx43 in the development of bladder inflammation and urinary symptoms in CYP-treated mice and provide pre-clinical evidence for the preventive potential of NOB through its anti-inflammatory effects on IL-1β signaling and urothelial Cx43 expression.
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影响因子：
2.7
作者：
Birder, Lori A.
通讯作者：
Birder, Lori A.
影响因子：
6.6
作者：
Boucher, M;Meen, M;Eschalier, A
通讯作者：
Eschalier, A
DOI：
10.1152/ajprenal.00297.2013
发表时间：
2014-02-01
影响因子：
4.2
作者：
Hughes, Francis M., Jr.;Vivar, Nivardo P.;Purves, J. Todd
通讯作者：
Purves, J. Todd
影响因子：
5.6
作者：
Cliff CL;Williams BM;Chadjichristos CE;Mouritzen U;Squires PE;Hills CE
通讯作者：
Hills CE
DOI：
10.1016/j.juro.2015.12.068
发表时间：
2016-05
期刊：
The Journal of urology
影响因子：
--
作者：
Hughes FM Jr;Hill HM;Wood CM;Edmondson AT;Dumas A;Foo WC;Oelsen JM;Rac G;Purves JT
通讯作者：
Purves JT