Sofalcone, a gastric mucosa protective agent, increases vascular endothelial growth factor via the Nrf2-heme-oxygenase-1 dependent pathway in gastric epithelial cells

Shibuya, Akira; Onda, Kenji; Kawahara, Hirofumi; Uchiyama, Yuka; Nakayama, Hiroko; Omi, Takamasa; Nagaoka, Masayoshi; Matsui, Hirofumi; Hirano, Toshihiko

doi:10.1016/j.bbrc.2010.06.124

Cited by 35 publications

(30 citation statements)

References 16 publications

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“…Nrf2 is a basic leucine zipper transcription factor that regulates a number of ARE-driven genes (85). Induction of HO-1 has been shown to occur via Nrf2 in a number of cell types (24,55,86,87) including gastric mucosal epithelial cells (23), epithelial cells (88), monocytes (89), and mouse embryo fibroblasts (90). Under normal conditions, Nrf2 remains bound to Keap1 in the cytosol.…”

Section: Table 2 Effect Of Copp On Indomethacin-induced Gastric Mucosmentioning

confidence: 99%

Translocation of Heme Oxygenase-1 to Mitochondria Is a Novel Cytoprotective Mechanism against Non-steroidal Anti-inflammatory Drug-induced Mitochondrial Oxidative Stress, Apoptosis, and Gastric Mucosal Injury

Bindu

Pal

Dey

et al. 2011

Journal of Biological Chemistry

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Background:The inherent cytoprotective mechanism involved in repair of injured gastric mucosa is not clear. Results: HO-1 is induced and translocated to mitochondria to favor repair of gastric mucosal injury induced by non-steroidal anti-inflammatory drug-mediated mitochondrial oxidative stress (MOS). Conclusion: Mitochondrial localization of HO-1 is a novel cytoprotective mechanism against MOS-mediated gastric mucosal injury. Significance: Induction of HO-1 in gastric mucosa is beneficial for gastroprotection.

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Section: Table 2 Effect Of Copp On Indomethacin-induced Gastric Mucosmentioning

confidence: 99%

Translocation of Heme Oxygenase-1 to Mitochondria Is a Novel Cytoprotective Mechanism against Non-steroidal Anti-inflammatory Drug-induced Mitochondrial Oxidative Stress, Apoptosis, and Gastric Mucosal Injury

Bindu

Pal

Dey

et al. 2011

Journal of Biological Chemistry

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“…The consolidated results suggest that Nrf2 can regulate angiogenesis via HO-1-mediated HIF-1α/VEGF signaling pathways. In addition, certain investigations252829 indeed indicate that HO-1 knockdown by HO-1-specific shRNA or HO-1 inhibitors ZnPP and tin-protoporphyrin may reduce the effects of Nrf2 on angiogenesis. However, the effects of Nrf2 on the pathogenesis of cerebral AVM, particularly under venous hypertension, have yet to be ecaluated mechanistically.…”

Section: Discussionmentioning

confidence: 99%

Interplay between VEGF and Nrf2 regulates angiogenesis due to intracranial venous hypertension

Liu

Pān

Wang

et al. 2016

Sci Rep

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Venous hypertension(VH) plays an important role in the pathogenesis of cerebral arteriovenous malformations (AVMs) and is closely associated with the HIF-1α/VEGF signaling pathway. Nuclear factor erythroid 2-related factor 2(Nrf2) significantly influences angiogenesis; however, the interplay between Nrf2 and VEGF under VH in brain AVMs remains unclear. Therefore, our study aimed to investigate the interplay between Nrf2 and VEGF due to VH in brain AVMs. Immunohistochemistry indicated that Nrf2 and VEGF were highly expressed in human brain AVM tissues. In vivo, we established a VH model in both wild-type (WT) and siRNA-mediated Nrf2 knockdown rats. VH significantly increased the expression of Nrf2 and VEGF. Loss of Nrf2 markedly inhibited the upregulation of VEGF, as determined by Western blot analysis and qRT-PCR. In vitro, primary brain microvascular endothelial cells (BMECs) were isolated from WT and Nrf2−/− mice, and a VEGF-Nrf2 positive feed-back loop was observed in BMECs. By trans well assay and angiogenesis assay, Nrf2 knockout significantly inhibited the migration and vascular tube formation of BMECs. These findings suggest that the interplay between Nrf2 and VEGF can contribute to VH-induced angiogenesis in brain AVMs pathogenesis.

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“…18,19 We have previously reported that sofalcone, which is currently used to treat gastric ulcers or gastritis in Japan and South Korea, can potently induce HO-1 expression in gastric epithelial cells and adipocyte cells. 11,20 Given that HO-1 is a promising therapeutic target for preeclampsia, 17,18,[21][22][23] we set out to investigate the effects of this clinical drug in several pathophysiological models of preeclampsia in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated that sofalcone is a potent inducer of HO-1 in gastric epithelium. 11 Thus, we hypothesized that sofalcone can induce HO-1 (and other antioxidant genes) in placental tissues leading to a reduction of the antiangiogenic factors, such as sFlt-1 or sEng. We also investigated whether sofalcone ameliorates endothelial dysfunction induced by tumor necrosis factor α (TNF-α).…”

Section: Hypertensionmentioning

confidence: 99%

Sofalcone Upregulates the Nuclear Factor (Erythroid-Derived 2)–Like 2/Heme Oxygenase-1 Pathway, Reduces Soluble fms–Like Tyrosine Kinase-1, and Quenches Endothelial Dysfunction

et al. 2015

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P reeclampsia is a pregnancy specific condition affecting ≈5% to 8% of all pregnancy in women and a leading cause of maternal and perinatal morbidity and mortality.1 An imbalance between angiogenic and antiangiogenic factors leading to endothelial dysfunction is proposed to be a key mechanism of preeclampsia. Previous landmark studies identified that antiangiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), play crucial roles in the development of preeclampsia.2,3 Administration of both sFlt-1 and sEng causes severe preeclamptic phenotype in rodents. Furthermore, sFlt-1 and sEng have also been shown to have predictive significance in clinic in women who go onto to develop preeclampsia. 4Heme oxygenase-1 (HO-1) is an inducible rate-limiting enzyme, which catalyzes free heme into carbon monoxide, free iron, and biliverdin. It is known that HO-1-derived carbon monoxide and biliverdin have strong anti-inflammatory and antioxidant properties.5 Transcription of HO-1 mRNA is Abstract-Preeclampsia is a severe complication of pregnancy, characterized by hypertension, oxidative stress, and severe endothelial dysfunction. Antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin, play key pathophysiological roles in preeclampsia. Heme oxygenase-1 (HO-1) is a cytoprotective, antioxidant enzyme reported to be downregulated in preeclampsia. Studies propose that inducing HO-1 may also decrease sFlt-1 production. Sofalcone, a gastric antiulcer agent in clinical use, is known to induce HO-1 in gastric epithelium. We aimed to investigate whether sofalcone induces HO-1 and reduces sFlt-1 release from primary human placental and endothelial cells and blocks endothelial dysfunction in vitro. We isolated human trophoblasts and endothelial cells (human umbilical vein endothelial cells) and also used uterine microvascular cells. We investigated the effects of sofalcone on (1) HO-1 production, (2) activation of the nuclear factor (erythroid-derived 2)-like 2 pathway, (3) sFlt-1 and soluble endoglin release, (4) tumor necrosis factor α-induced monocyte adhesion and vascular cell adhesion molecule upregulation, and (5) endothelial tubule formation. Sofalcone potently increased HO-1 mRNA and protein in both primary trophoblasts and human umbilical vein endothelial cells. Furthermore, sofalcone treatment caused nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and transactivation of other nuclear factor (erythroid-derived 2)-like 2 responsive genes (NQO1, TXN, and GCLC). Importantly, sofalcone significantly decreased the secretion of sFlt-1 from primary human trophoblasts. Sofalcone potently suppressed endothelial dysfunction in 2 in vitro models, blocking tumor necrosis factor α-induced monocyte adhesion and vascular cell adhesion molecule 1 expression in human umbilical vein endothelial cells. These results indicate that in primary human tissues, sofalcone can potently activate antioxidant nuclear factor (erythroid-derived 2)-like 2/HO-1 pathw...

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Sofalcone, a gastric mucosa protective agent, increases vascular endothelial growth factor via the Nrf2-heme-oxygenase-1 dependent pathway in gastric epithelial cells

Cited by 35 publications

References 16 publications

Translocation of Heme Oxygenase-1 to Mitochondria Is a Novel Cytoprotective Mechanism against Non-steroidal Anti-inflammatory Drug-induced Mitochondrial Oxidative Stress, Apoptosis, and Gastric Mucosal Injury

Translocation of Heme Oxygenase-1 to Mitochondria Is a Novel Cytoprotective Mechanism against Non-steroidal Anti-inflammatory Drug-induced Mitochondrial Oxidative Stress, Apoptosis, and Gastric Mucosal Injury

Interplay between VEGF and Nrf2 regulates angiogenesis due to intracranial venous hypertension

Sofalcone Upregulates the Nuclear Factor (Erythroid-Derived 2)–Like 2/Heme Oxygenase-1 Pathway, Reduces Soluble fms–Like Tyrosine Kinase-1, and Quenches Endothelial Dysfunction

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