Redox-dependent internalization of the purinergic P2Y
            <sub>6</sub>
            receptor limits colitis progression

Nishiyama, Kazuhiro; Nishimura, Akiyoshi; Shimoda, Kakeru; Tanaka, Tomohiro; Kato, Yuri; Shibata, Takahiro; Tanaka, Hiroshi; Kurose, Hitoshi; Azuma, Yasutaka; Ihara, Hideshi; Kumagai, Yoshito; Akaike, Takaaki; Eaton, Philip; Uchida, Kôji; Nishida, Motohiro

doi:10.1126/scisignal.abj0644

Cited by 19 publications

(14 citation statements)

References 63 publications

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“…Endothelial-dependent vasorelaxation, induced by UDP stimulation, and contraction, induced by UDP upon the inhibition of endothelial nitric oxide synthase, were abolished in P2Y 6 R-deficient aortas [ 21 ]. P2Y 6 R KO mice did not display atherosclerosis, vascular inflammation, age-related hypertension and intestinal inflammation [ 14 , 15 , 22 ]. Compared to wild-type mice, P2Y 6 R KO mice show a significant resistance to the skin papilloma-inducing effects of 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, cardiomyocyte-specific overexpression of P2Y 6 R exacerbates pressure overload-induced heart failure [ 13 ]. We also reported that P2Y 6 R contributes to the progression of age-related hypertension and inflammatory bowel disease, and P2Y 6 R knockout mice show the prevention of tissue remodeling, including fibrosis and inflammation [ 14 , 15 ]. These results suggest a positive relationship between P2Y 6 R expression and the severity of tissue fibrosis and inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Knockout of Purinergic P2Y6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis

Nishiyama

Ariyoshi

Nishimura

et al. 2023

IJMS

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Nonalcoholic steatohepatitis (NASH) is a disease that progresses from nonalcoholic fatty liver (NAFL) and which is characterized by inflammation and fibrosis. The purinergic P2Y6 receptor (P2Y6R) is a pro-inflammatory Gq/G12 family protein-coupled receptor and reportedly contributes to intestinal inflammation and cardiovascular fibrosis, but its role in liver pathogenesis is unknown. Human genomics data analysis revealed that the liver P2Y6R mRNA expression level is increased during the progression from NAFL to NASH, which positively correlates with inductions of C-C motif chemokine 2 (CCL2) and collagen type I α1 chain (Col1a1) mRNAs. Therefore, we examined the impact of P2Y6R functional deficiency in mice crossed with a NASH model using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Feeding CDAHFD for 6 weeks markedly increased P2Y6R expression level in mouse liver, which was positively correlated with CCL2 mRNA induction. Unexpectedly, the CDAHFD treatment for 6 weeks increased liver weights with severe steatosis in both wild-type (WT) and P2Y6R knockout (KO) mice, while the disease marker levels such as serum AST and liver CCL2 mRNA in CDAHFD-treated P2Y6R KO mice were rather aggravated compared with those of CDAHFD-treated WT mice. Thus, P2Y6R may not contribute to the progression of liver injury, despite increased expression in NASH liver.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Knockout of Purinergic P2Y6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis

Nishiyama

Ariyoshi

Nishimura

et al. 2023

IJMS

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“…It is unknown how cells recognize 6-MSITC. However, sulforaphane, an isothiocyanate, has recently been reported to bind to P2Y6 receptors [ 16 ], and it is possible that 6-MSITC may bind to cells by the same mechanism. We think further studies are needed to prove the hypothesis.…”

Section: Discussionmentioning

confidence: 99%

6-(Methylsulfinyl) Hexyl Isothiocyanate Inhibits IL-6 and CXCL10 Production in TNF-α-Stimulated Human Oral Epithelial Cells

Shimoyama

Hosokawa

et al. 2022

CIMB

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6-(Methylsulfinyl) hexyl isothiocyanate (6-MSITC) is a bioactive substance found in wasabi (Wasabia japonica) and has been reported to have some bioactive effects including anticancer and antioxidant effects. However, there are no reports on its effects on periodontal resident cells, and many points remain unclear. In this study, we aimed to investigate whether 6-MSITC exerts anti-inflammatory effects on human oral epithelial cells, including effects on signal transduction pathway activation. 6-MSITC inhibited interleukin (IL)-6 and C-X-C motif chemokine ligand 10 (CXCL10) production in TNF-α-stimulated TR146 cells, which are a human oral epithelial cell line. Moreover, we found that 6-MSITC could suppress signal transducer and activator of transcription (STAT)3, nuclear factor (NF)-κB, and p70S6 kinase (p70S6K)-S6 ribosomal protein (S6) pathways activation in TNF-α-stimulated TR146 cells. Furthermore, STAT3 and NF-κB inhibitors could suppress IL-6 and CXCL10 production in TNF-α-treated TR146 cells. In summary, 6-MSITC could decrease IL-6 and CXCL10 production in human oral epithelial cell by inhibiting STAT3 and NF-κB activation.

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“…Reactions were prepared following the manufacturer’s protocol. For BMDMs, total RNA was extracted and cDNA was synthesized as previously described [ 64 ]. Quantitative real-time PCR was performed as previously described [ 64 ].…”

Section: Methodsmentioning

confidence: 99%

“…For BMDMs, total RNA was extracted and cDNA was synthesized as previously described [ 64 ]. Quantitative real-time PCR was performed as previously described [ 64 ]. Primer sequences used are summarized in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

Echinochrome Prevents Sulfide Catabolism-Associated Chronic Heart Failure after Myocardial Infarction in Mice

et al. 2023

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Abnormal sulfide catabolism, especially the accumulation of hydrogen sulfide (H2S) during hypoxic or inflammatory stresses, is a major cause of redox imbalance-associated cardiac dysfunction. Polyhydroxynaphtoquinone echinochrome A (Ech-A), a natural pigment of marine origin found in the shells and needles of many species of sea urchins, is a potent antioxidant and inhibits acute myocardial ferroptosis after ischemia/reperfusion, but the chronic effect of Ech-A on heart failure is unknown. Reactive sulfur species (RSS), which include catenated sulfur atoms, have been revealed as true biomolecules with high redox reactivity required for intracellular energy metabolism and signal transduction. Here, we report that continuous intraperitoneal administration of Ech-A (2.0 mg/kg/day) prevents RSS catabolism-associated chronic heart failure after myocardial infarction (MI) in mice. Ech-A prevented left ventricular (LV) systolic dysfunction and structural remodeling after MI. Fluorescence imaging revealed that intracellular RSS level was reduced after MI, while H2S/HS- level was increased in LV myocardium, which was attenuated by Ech-A. This result indicates that Ech-A suppresses RSS catabolism to H2S/HS- in LV myocardium after MI. In addition, Ech-A reduced oxidative stress formation by MI. Ech-A suppressed RSS catabolism caused by hypoxia in neonatal rat cardiomyocytes and human iPS cell-derived cardiomyocytes. Ech-A also suppressed RSS catabolism caused by lipopolysaccharide stimulation in macrophages. Thus, Ech-A has the potential to improve chronic heart failure after MI, in part by preventing sulfide catabolism.

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Redox-dependent internalization of the purinergic P2Y ₆ receptor limits colitis progression

Abstract: Cysteine modification of the purinergic receptor P2Y 6 R promotes internalization and degradation and limits colitis progression.

Cited by 19 publications

References 63 publications

Knockout of Purinergic P2Y6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis

Knockout of Purinergic P2Y6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis

6-(Methylsulfinyl) Hexyl Isothiocyanate Inhibits IL-6 and CXCL10 Production in TNF-α-Stimulated Human Oral Epithelial Cells

Echinochrome Prevents Sulfide Catabolism-Associated Chronic Heart Failure after Myocardial Infarction in Mice

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Redox-dependent internalization of the purinergic P2Y 6 receptor limits colitis progression

Abstract: Cysteine modification of the purinergic receptor P2Y 6 R promotes internalization and degradation and limits colitis progression.

Cited by 19 publications

References 63 publications

Knockout of Purinergic P2Y6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis

Knockout of Purinergic P2Y6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis

6-(Methylsulfinyl) Hexyl Isothiocyanate Inhibits IL-6 and CXCL10 Production in TNF-α-Stimulated Human Oral Epithelial Cells

Echinochrome Prevents Sulfide Catabolism-Associated Chronic Heart Failure after Myocardial Infarction in Mice

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Redox-dependent internalization of the purinergic P2Y ₆ receptor limits colitis progression