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

doi:10.3390/ijms23095037

Cited by 10 publications

(4 citation statements)

References 64 publications

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“…Increased variance in IL-18 and IFNγ at early time points suggests inflammasome activation in the urothelium in response to damage associated molecular pattern molecules generated as a consequence of pathologic tissue injury akin to a flare up of IC/BPS in patients. 24,25 Interleukin-18 emerges as one of the most highly connected nodes in DyNA during the interval 570-630 min. The implication of IL-18's role in IC/BPS and its potentiation of downstream inflammation is supported by studies in patients with IC/BPS, in which this cytokine was elevated relative to controls.…”

Section: Discussionmentioning

confidence: 99%

“…IL‐5, IFNγ, and IL‐18 account for large amounts of variance in the inflammatory response at early and intermediate time intervals according to TI‐PCA. Increased variance in IL‐18 and IFNγ at early time points suggests inflammasome activation in the urothelium in response to damage associated molecular pattern molecules generated as a consequence of pathologic tissue injury akin to a flare up of IC/BPS in patients 24,25 …”

Section: Discussionmentioning

confidence: 99%

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Temporally complex inflammatory networks in an animal model reveal signatures for interstitial cystitis and bladder pain syndrome phenotype

Shah,

Vodovotz,

Yoshimura

et al. 2023

Neurourology and Urodynamics

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Introduction and ObjectiveInterstitial cystitis and bladder pain syndrome (IC/BPS) presents with symptoms of debilitating bladder pain and is typically a diagnosis of exclusion. The cystoscopic detection of Hunner's lesions increases the likelihood of detecting tissue inflammation on bladder biopsy and increases the odds of therapeutic success with anti‐inflammatory drugs. However, the identification of this subgroup remains challenging with the current lack of surrogate biomarkers of IC/BPS. On the path towards identifying biomarkers of IC/BPS, we modeled the dynamic evolution of inflammation in an experimental IC/BPS rodent model using computational biological network analysis of inflammatory mediators (cytokines and chemokines) released into urine. The use of biological network analysis allows us to identify urinary proteins that could be drivers of inflammation and could therefore serve as therapeutic targets for the treatment of IC/BPS.MethodsRats subjected to cyclophosphamide (CYP) injection (150 mg/kg) were used as an experimental model for acute IC/BPS (n = 8). Urine from each void was collected from the rats over a 12‐h period and was assayed for 13 inflammatory mediators using Luminex™. Time‐interval principal component analysis (TI‐PCA) and dynamic network analysis (DyNA), two biological network algorithms, were used to identify biomarkers of inflammation characteristic of IC/BPS over time.ResultsCompared to vehicle‐treated rats, nearly all inflammatory mediators were elevated significantly (p < 0.05) in the urine of CYP treated rats. TI‐PCA highlighted that GRO‐KC, IL‐5, IL‐18, and MCP‐1 account for the greatest variance in the inflammatory response. At early time points, DyNA indicated a positive correlation between IL‐4 and IL‐1β and between TNF‐α and IL‐1β. Analysis of TI‐PCA and DyNA at later time points showed the emergence of IL‐5, IL‐6, and IFNγ as additional key mediators of inflammation. Furthermore, DyNA network complexity rose and fell before peaking at 9.5 h following CYP treatment. This pattern of inflammation may mimic the fluctuating severity of inflammation associated with IC/BPS flares.ConclusionsComputational analysis of inflammation networks in experimental IC/BPS analysis expands on the previously accepted inflammatory signatures of IC by adding IL‐5, IL‐18, and MCP‐1 to the prior studies implicating IL‐6 and GRO as IC/BPS biomarkers. This analysis supports a complex evolution of inflammatory networks suggestive of the rise and fall of inflammation characteristic of IC/BPS flares.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Temporally complex inflammatory networks in an animal model reveal signatures for interstitial cystitis and bladder pain syndrome phenotype

Shah,

Vodovotz,

Yoshimura

et al. 2023

Neurourology and Urodynamics

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“…Cells and cell culture. The hTERT-immortalized human urothelial (TRT-HU1) cell-line was used in this study, as previously reported 62,63 . The pBmal1-dLuc lentiviral reporter was a kind gift from Prof. Andrew C. Liu (Department of Biological Sciences, University of Memphis, Tennessee, USA).…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoids coordinate the bladder peripheral clock and diurnal micturition pattern in mice

et al. 2023

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Peripheral clocks function to regulate each organ and are synchronized though various molecular and behavioral signals. However, signals that entrain the bladder clock remain elusive. Here, we show that glucocorticoids are a key cue for the bladder clock in vitro and in vivo. A pBmal1-dLuc human urothelial cell-line showed significant shifts in gene expression after cortisol treatment. In vivo, rhythmic bladder clock gene expression was unchanged by bilateral adrenalectomy but shifted 4 h forward by corticosterone administration at the inactive phase. Moreover, the bladder clock shifted 8–12 h in mice that underwent both bilateral adrenalectomy and corticosterone administration at the inactive phase. These mice showed decreases in the diurnal rhythm of volume voided per micturition, while maintaining diurnal activity rhythms. These results indicate that the diurnal rhythm of glucocorticoid signaling is a zeitgeber that overcomes other bladder clock entrainment factors and coordinates the diurnal rhythm of volume voided per micturition.

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“…The hTERT-immortalized human urothelial (TRT-HU1) cell-line was used in this study, as previously reported 58,59 . The pBmal1-dLuc lentiviral reporter was a kind gift from Prof. Andrew C. Liu (Department of Biological Sciences, University of Memphis, Tennessee, USA).…”

Section: Cells and Cell Culturementioning

confidence: 99%

Coordination of bladder peripheral clock and diurnal micturition pattern by glucocorticoids

Chihara

Negoro

Kono³

et al. 2022

Preprint

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Peripheral clocks function to regulate each organ and are synchronized though various molecular and behavioral signals. However, signals that entrain the bladder clock remain elusive. Here, we show that glucocorticoids are a key cue for the bladder clock in vitro and in vivo. A pBmal1-dLuc human urothelial cell-line showed significant shifts in gene expression after cortisol treatment. In vivo, rhythmic bladder clock gene expression was unchanged by bilateral adrenalectomy but shifted 4 hours forward by corticosterone administration at the inactive phase. Moreover, the bladder clock shifted 8–12 hours in mice that underwent both bilateral adrenalectomy and corticosterone administration at the inactive phase. These mice saw decreases in the diurnal rhythm of volume voided per micturition, while maintaining diurnal activity rhythms. These results indicate that the diurnal rhythm of glucocorticoid signaling is a zeitgeber that overcomes other bladder clock entrainment factors and coordinates the diurnal rhythm of volume voided per micturition.

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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

Cited by 10 publications

References 64 publications

Temporally complex inflammatory networks in an animal model reveal signatures for interstitial cystitis and bladder pain syndrome phenotype

Temporally complex inflammatory networks in an animal model reveal signatures for interstitial cystitis and bladder pain syndrome phenotype

Glucocorticoids coordinate the bladder peripheral clock and diurnal micturition pattern in mice

Coordination of bladder peripheral clock and diurnal micturition pattern by glucocorticoids

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