Fisetin induces Nrf2‐mediated HO‐1 expression through PKC‐δ and p38 in human umbilical vein endothelial cells

Lee, Seung Eun; Jeong, Seong Il; Yang, Hana; Park, Cheung Seog; Jin, Young Ho; Park, Yong Seek

doi:10.1002/jcb.23158

Cited by 102 publications

(59 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, fisetin induces the transcription factor Nrf2, which results in increased expression of many cellular protective and antioxidant genes in cells other than OCLs (35). A previous study reported that fisetin induces enhanced expression of Nrf2 and HO-1 in primary cultured HUVECs (17). Upregulation of HO-1 is directly mediated by Nrf2 since Nrf2 siRNA blocked fisetin-induced HO-1 up-regulation.…”

Section: Discussionmentioning

confidence: 93%

“…Interestingly, fisetin also attenuates IκBα and p38 MAPK phosphorylation in LPS-stimulated microglia (31). In HUVECs, the p38 signaling pathway is primarily involved in Nrf2-mediated HO-1 expression induced by fisetin (17). Therefore, fisetin uniquely inhibits OCL differentiation through down-regulation of Erk, Akt, and JNK phosphorylation.…”

Section: Discussionmentioning

confidence: 94%

“…Although over-expression of HO-1 by transient gene vector suppresses the OCL differentiation, down-regulation of HO-1 by RNA interference enhances osteoclastogenesis (7). In addition, a recent study has shown that fisetin induces HO-1 in HUVECs (17). Therefore, we investigated whether fisetin up-regulates HO-1 gene expression in OCLs, thereby inhibiting OCL differentiation.…”

Section: Effects Of Fisetin On the Expression Levels Of Oxidative Strmentioning

confidence: 95%

“…A recent study has reported that fisetin treatment in HUVEC enhances expression of the Nrf2 gene (17). To test whether Nrf2 is involved in fisetin-mediated suppression of osteoclastogenesis, we performed knockdown experiments with siRNA and examined the effects on OCL differentiation.…”

Section: Effects Of Fisetin On the Expression Levels Of Oxidative Strmentioning

confidence: 99%

“…These cellular protective effects are due to up-regulation of HO-1, which plays a critical role in cellular protection against oxidative stress. This idea is based on the report that fisetin induces HO-1 upregulation through PKCδ-and p38 MAPK-dependent pathways in human umbilical vein endothelial cells (HUVECs) (17). These findings suggest that fisetin may inhibit osteoclastogenesis via an HO-1-dependent pathway.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Fisetin Inhibits Osteoclastogenesis Through Prevention of RANKL-Induced ROS Production by Nrf2-Mediated Up-regulation of Phase II Antioxidant Enzymes

et al. 2013

View full text Add to dashboard Cite

Abstract. Osteoclasts (OCLs) are multinucleated bone-resorbing cells that are differentiated by stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor. We recently demonstrated that regulation of heme-oxygenase 1 (HO-1), a stress-induced cytoprotective enzyme, also functions in OCL differentiation. In this study, we investigated effects of fisetin, a natural bioactive flavonoid that has been reported to induce HO-1 expression, on the differentiation of macrophages into OCLs. Fisetin inhibited the formation of OCLs in a dose-dependent manner and suppressed the bone-resorbing activity of OCLs. Moreover, fisetin-treated OCLs showed markedly decreased phosphorylation of extracellular signal-regulated kinase, Akt, and Jun N-terminal kinase, but fisetin did not inhibit p38 phosphorylation. Fisetin up-regulated mRNA expression of phase II antioxidant enzymes including HO-1 and interfered with RANKL-mediated reactive oxygen species (ROS) production. Studies with RNA interference showed that suppression of NF-E2-related factor 2 (Nrf2), a key transcription factor for phase II antioxidant enzymes, rescued fisetin-mediated inhibition of OCL differentiation. Furthermore, fisetin significantly decreased RANKL-induced nuclear translocation of cFos and nuclear factor of activated T cells cytoplasmic-1 (NFATc1), which is a transcription factor critical for osteoclastogenic gene regulation. Therefore, fisetin inhibits OCL differentiation through blocking RANKLmediated ROS production by Nrf2-mediated up-regulation of phase II antioxidant enzymes.

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Section: Effects Of Fisetin On the Expression Levels Of Oxidative Strmentioning

confidence: 95%

Section: Effects Of Fisetin On the Expression Levels Of Oxidative Strmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Fisetin Inhibits Osteoclastogenesis Through Prevention of RANKL-Induced ROS Production by Nrf2-Mediated Up-regulation of Phase II Antioxidant Enzymes

et al. 2013

View full text Add to dashboard Cite

show abstract

Nrf2 Activation as a Protective Feedback to Limit Cell Death in High Glucose‐Exposed Cardiomyocytes

Tsai

Cheng

et al. 2017

J of Cellular Biochemistry

View full text Add to dashboard Cite

Hyperglycemia leads to excess reactive oxygen species (ROS) generation, which causes many diabetic complications, such as cardiomyopathy. Nuclear factor erythroid 2-related factor 2 (Nrf2), a redox-sensing transcription factor, can up-regulate its downstream antioxidant gene expressions in response to oxidative stress. However, the regulatory signal pathway in which high glucose (HG) induces Nrf2 activation is still unclear. Our results demonstrated that HG (33 mM) can indeed stimulate Nrf2 protein expression and translocation into the nucleus in cardiomyocytes, enhancing the downstream antioxidant protein levels. Using siRNAs, p38, JNK, PKCα, and PKCδ, as well as ROS scavengers, it was observed that the dependence of PKCα/PKCδ on ROS production to enhance JNK and p38 phosphorylation mediated HG-induced cardiac Nrf2 expression and activation. Knockdown of Nrf2 by siRNA transfection increased cleaved-caspase3, reduced Bcl2 in the cellular protein level and further exacerbated HG-induced apoptosis. In addition, all of these proteins induced by HG in vitro were also increased in STZ-induced diabetic rat ventricles in vivo. Our study demonstrated that HG-induced cardiac Nrf2 activation occurs through PKCα/PKCδ-ROS-JNK/p38 signaling. These findings may provide a therapeutic target to counteract the oxidative stress associated with diabetic cardiomyopathy. J. Cell. Biochem. 118: 1659-1669, 2017. © 2016 Wiley Periodicals, Inc.

show abstract

Small Molecule Modulators of Keap1‐Nrf2‐ARE Pathway as Potential Preventive and Therapeutic Agents

Magesh

Chen

2012

Medicinal Research Reviews

653

551

View full text Add to dashboard Cite

Keap1-Nrf2-ARE pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, over-activation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction.

show abstract

Fisetin induces Nrf2‐mediated HO‐1 expression through PKC‐δ and p38 in human umbilical vein endothelial cells

Cited by 102 publications

References 42 publications

Fisetin Inhibits Osteoclastogenesis Through Prevention of RANKL-Induced ROS Production by Nrf2-Mediated Up-regulation of Phase II Antioxidant Enzymes

Fisetin Inhibits Osteoclastogenesis Through Prevention of RANKL-Induced ROS Production by Nrf2-Mediated Up-regulation of Phase II Antioxidant Enzymes

Nrf2 Activation as a Protective Feedback to Limit Cell Death in High Glucose‐Exposed Cardiomyocytes

Small Molecule Modulators of Keap1‐Nrf2‐ARE Pathway as Potential Preventive and Therapeutic Agents

Contact Info

Product

Resources

About