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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

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 pre...

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Autores principales: Kono, Jin, Ueda, Masakatsu, Sengiku, Atsushi, Suadicani, Sylvia O., Woo, Je Tae, Kobayashi, Takashi, Ogawa, Osamu, Negoro, Hiromitsu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102543/
https://www.ncbi.nlm.nih.gov/pubmed/35563427
http://dx.doi.org/10.3390/ijms23095037
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author Kono, Jin
Ueda, Masakatsu
Sengiku, Atsushi
Suadicani, Sylvia O.
Woo, Je Tae
Kobayashi, Takashi
Ogawa, Osamu
Negoro, Hiromitsu
author_facet Kono, Jin
Ueda, Masakatsu
Sengiku, Atsushi
Suadicani, Sylvia O.
Woo, Je Tae
Kobayashi, Takashi
Ogawa, Osamu
Negoro, Hiromitsu
author_sort Kono, Jin
collection PubMed
description 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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spelling pubmed-91025432022-05-14 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 Kono, Jin Ueda, Masakatsu Sengiku, Atsushi Suadicani, Sylvia O. Woo, Je Tae Kobayashi, Takashi Ogawa, Osamu Negoro, Hiromitsu Int J Mol Sci Article 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. MDPI 2022-05-01 /pmc/articles/PMC9102543/ /pubmed/35563427 http://dx.doi.org/10.3390/ijms23095037 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kono, Jin
Ueda, Masakatsu
Sengiku, Atsushi
Suadicani, Sylvia O.
Woo, Je Tae
Kobayashi, Takashi
Ogawa, Osamu
Negoro, Hiromitsu
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102543/
https://www.ncbi.nlm.nih.gov/pubmed/35563427
http://dx.doi.org/10.3390/ijms23095037
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