Quercetin inhibits transcriptional up-regulation of histamine H1 receptor via suppressing protein kinase C-δ/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 signaling pathway in HeLa cells

Hattori, Masashi; Mizuguchi, Hiroyuki; Baba, Yuko; Ono, Shohei; Nakano, Tomohiro; Zhang, Qian; Sasaki, Yohei; Kitamura, Yoshiaki; Takeda, Noriaki; Fukui, Hirokazu

doi:10.1016/j.intimp.2012.12.030

Cited by 31 publications

(24 citation statements)

References 34 publications

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“…Previously, we reported that quercetin is a PKCδ signaling inhibitor (18). We also reported that heat shock protein 90 (Hsp90) regulated PKCδ signaling in HeLa cells (24).…”

Section: Effect Of Quercetin On Glucagon Secretion From Isolated Isletsmentioning

confidence: 91%

“…We have demonstrated that PKCδ signaling is involved in PMAinduced upregulation of histamine H1 receptor (H1R) gene expression in HeLa cells and compounds, including quercetin and (-)-maackiain, suppressed H1R gene expression through the inhibition of PKCδ signaling (17)(18)(19). Thus, suppression of PKCδ signaling by these compounds could improve diabetic symptoms and help to further elucidate the mechanisms underlying these actions to better understand the role of PKCδ signaling in diabetes onset and progression.…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

et al. 2017

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: Accumulating evidence supports the "glucagonocentric hypothesis", in which antecedent α-cell failure and inhibition of glucagon secretion are responsible for diabetes progression. Protein kinase C (PKC) is involved in glucagon secretion from α-cells, although which PKC isozyme is involved and the mechanism underlying this PKC-regulated glucagon secretion remains unknown. Here, the involvement of PKCδ in the onset and progression of diabetes was elucidated. Immunofluorescence studies revealed that PKCδ was expressed and activated in α-cells of STZ-induced diabetic model mice. Phorbol 12-myristate 13-acetate (PMA) stimulation significantly augmented glucagon secretion from isolated islets. Pre-treatment with quercetin and rottlerin, PKCδ signaling inhibitors, significantly suppressed the PMA-induced elevation of glucagon secretion. While Go6976, a Ca 2+ -dependent PKC selective inhibitor did not suppress glucagon secretion. Quercetin suppressed PMA-induced phosphorylation of Tyr 311 of PKCδ in isolated islets. However, quercetin itself had no effect on either glucagon secretion or glucagon mRNA expression. Our data suggest that PKCδ signaling inhibitors suppressed glucagon secretion. Elucidation of detailed signaling pathways causing PKCδ activation in the onset and progression of diabetes followed by the augmentation of glucagon secretion could lead to the identification of novel therapeutic target molecules and the development of novel therapeutic drugs for diabetes.

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“…Previously, we reported that quercetin is a PKCδ signaling inhibitor (18). We also reported that heat shock protein 90 (Hsp90) regulated PKCδ signaling in HeLa cells (24).…”

Section: Effect Of Quercetin On Glucagon Secretion From Isolated Isletsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

et al. 2017

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“…Rats-Previously, we have demonstrated that pretreatment with racemic maackiain and quercetin suppresses TDI-induced nasal symptoms and up-regulation of H1R and IL-4 gene expression in TDI-sensitized rats (8,14). In the present study, we investigated the effect of an additional Hsp90 inhibitor, celastrol, on TDI-induced nasal symptoms and up-regulation of H1R and IL-4 gene expression in the nasal mucosa of TDIsensitized rats.…”

Section: Effect Of Celastrol On Tdi-induced Nasal Symptoms and Upregumentioning

confidence: 90%

“…Effect of Quercetin on the Interaction of Hsp90 with PKC␦-We reported that quercetin suppresses PMA-induced up-regulation of H1R gene expression in HeLa cells (8). Quercetin inhibited the phosphorylation of Tyr 311 residue on PKC␦.…”

Section: Effect Of Hsp90 Inhibitors On Pma-induced Up-regulation Of Hmentioning

confidence: 97%

“…Recently, we reported that the H1R gene expression strongly correlated with the severity of allergic symptoms in toluene-2,4-diisocyanate (TDI)-sensitized rats, a commonly used allergy model, and patients with Japanese cedar pollinosis (3,4). We also demonstrated that compounds that suppress up-regulation of H1R gene expression alleviate allergy symptoms (5)(6)(7)(8). These findings strongly suggest that H1R signaling is very important for the development of pollinosis and that drugs targeting H1R signaling will be effective for allergic diseases.…”

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confidence: 99%

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Disruption of Heat Shock Protein 90 (Hsp90)-Protein Kinase Cδ (PKCδ) Interaction by (−)-Maackiain Suppresses Histamine H1 Receptor Gene Transcription in HeLa Cells

Nariai

Mizuguchi

Ogasawara

et al. 2015

Journal of Biological Chemistry

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Background:The molecular mechanism of anti-allergic (Ϫ)-maackiain remains unknown. Results: (Ϫ)-Maackiain and Hsp90 inhibitors inhibited PKC␦ activation and suppressed H1R gene expression. Conclusion: (Ϫ)-Maackiain is a novel Hsp90 pathway inhibitor, and its anti-allergic activity underlies the disruption of Hsp90-PKC␦ interaction. Significance: Hsp90 is involved in H1R gene up-regulation, and its inhibition could be a novel therapeutic strategy for allergic rhinitis.

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Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H₁ receptor and interleukin‐4 genes

Mizuguchi

Nariai

Kato

et al. 2015

Pharmacology Res & Perspec

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Kujin contains antiallergic compounds that inhibit upregulation of histamine H1 receptor (H1R) and interleukin (IL)-4 gene expression. However, the underlying mechanism remains unknown. We sought to identify a Kujin-derived antiallergic compound and investigate its mechanism of action. The H1R and IL-4 mRNA levels were determined by real-time quantitative RT-PCR. To investigate the effects of maackiain in vivo, toluene-2,4-diisocyanate (TDI)-sensitized rats were used as a nasal hypersensitivity animal model. We identified (−)-maackiain as the responsible component. Synthetic maackiain showed stereoselectivity for the suppression of IL-4 gene expression but not for H1R gene expression, suggesting distinct target proteins for transcriptional signaling. (−)-Maackiain inhibited of PKCδ translocation to the Golgi and phosphorylation of Tyr311 on PKCδ, which led to the suppression of H1R gene transcription. However, (−)-maackiain did not show any antioxidant activity or inhibition of PKCδ enzymatic activity per se. Pretreatment with maackiain alleviated nasal symptoms and suppressed TDI-induced upregulations of H1R and IL-4 gene expressions in TDI-sensitized rats. These data suggest that (−)-maackiain is a novel antiallergic compound that alleviates nasal symptoms in TDI-sensitized allergy model rats through the inhibition of H1R and IL-4 gene expression. The molecular mechanism underlying its suppressive effect for H1R gene expression is mediated by the inhibition of PKCδ activation.

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Quercetin inhibits transcriptional up-regulation of histamine H1 receptor via suppressing protein kinase C-δ/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 signaling pathway in HeLa cells

Cited by 31 publications

References 34 publications

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

Disruption of Heat Shock Protein 90 (Hsp90)-Protein Kinase Cδ (PKCδ) Interaction by (−)-Maackiain Suppresses Histamine H1 Receptor Gene Transcription in HeLa Cells

Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H₁ receptor and interleukin‐4 genes

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Quercetin inhibits transcriptional up-regulation of histamine H1 receptor via suppressing protein kinase C-δ/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 signaling pathway in HeLa cells

Cited by 31 publications

References 34 publications

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

Disruption of Heat Shock Protein 90 (Hsp90)-Protein Kinase Cδ (PKCδ) Interaction by (−)-Maackiain Suppresses Histamine H1 Receptor Gene Transcription in HeLa Cells

Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin‐4 genes

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Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H₁ receptor and interleukin‐4 genes