Licochalcone A activates Keap1-Nrf2 signaling to suppress arthritis via phosphorylation of p62 at serine 349

Su, Xiaohui; Li, Ting; Liu, Zhongqiu; Huang, Qingchun; Liao, Kangsheng; Ren, Rutong; Lu, Linlin; Qi, Xiaoxiao; Wang, Maojie; Chen, Jianyu; Zhou, Hua; Leung, Elaine Lai‐Han; Pan, Hudan; Liu, Juan; Wang, Hui; Huang, Lufen; Liu, Liang

doi:10.1016/j.freeradbiomed.2017.12.004

Cited by 64 publications

(37 citation statements)

References 54 publications

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“…The synovial cells of RA patients present abnormal proliferation characteristics compared with normal synovial cells, and the abnormal proliferation of synovial cells is the pathological feature of RA. Therefore, suppressing proliferation and inducing apoptosis of RA‐FLSs to relieve hyperplasia of synovia could be an important strategy when treating RA patients . In our present study, we found that Res inhibited the proliferation of 5 µM H 2 O 2 ‐treated RA‐FLSs and reduced the expression of antiapoptotic protein Bcl‐2 in a dose‐dependent manner and enhanced the expression of proapoptotic protein Bax, while the ratio of Bcl‐2/Bax (reflecting the degree of apoptosis) decreased with treatment of increasing concentrations of Res.…”

Section: Discussionsupporting

confidence: 58%

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Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes

Zhang

Wang

et al. 2019

Annals of the New York Academy of Sciences

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Resveratrol (Res) is a polyphenolic compound that has a variety of biological functions and activities. This study aimed to explore the mechanisms of the antioxidant and proapoptotic effects of Res in H2O2‐treated rheumatoid arthritis fibroblast‐like synoviocytes (RA‐FLSs) by the Nrf2–Keap1 signaling pathway. We found that 5 µM H2O2 promoted cell proliferation and increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content in RA‐FLSs. However, Res could reverse these effects in 5 µMH2O2‐treated RA‐FLSs by (1) promoting expression of nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1), (2) reducing expression of Kelch‐like ECH–related protein 1 (Keap1), (3) inhibiting production of ROS and MDA, (4) blocking activation of nuclear factor‐κB (NF‐κB) p65, (5) inhibiting cell proliferation and migration, and (6) activating Bcl‐2/Bax to induce apoptosis. After lentiviral silencing of Nrf2 (siNrf2) mRNA expression in RA‐FLSs, Res addition did not increase the expression of Nrf2 or HO‐1 to reduce the production of mitochondrial ROS caused by 5 µM H2O2. Res reduced the Bcl‐2/Bax ratio, but siNrf2 reduced the ability of Res to promote apoptosis. We conclude that Res inhibits ROS production by activating the Nrf2 pathway, thereby inhibiting activation of NF‐κB and proliferation and migration of RA‐FLSs, to induce apoptosis. Targeting the Nrf2–Keap1 pathway may be a relevant aim of using Res in the treatment of RA.

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Section: Discussionsupporting

confidence: 58%

“…Therefore, we speculated activation of Nrf2 might be a promising therapeutic approach for treating RA and other autoimmune conditions . This study was conducted to investigate the effect of Res on H 2 O 2 ‐induced oxidative stress, apoptosis in RA‐FLSs, and their correlation with the Nrf2–Keap1 pathway.…”

Section: Introductionmentioning

confidence: 99%

Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes

Zhang

Wang

et al. 2019

Annals of the New York Academy of Sciences

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“…The results of related studies have indicated that by physically isolating Keap1 and impairing the ubiquitylation of Nrf2, p62 mediates the activation of Nrf2 and its downstream pathways and plays an important role in antioxidative processes (Jiang et al, 2015). In the process of exploring new drugs, up-regulation of autophagy has been found in numerous disease-model studies (Yang et al, 2018a;Rusmini and Cortese, 2019) and activation of the p62/Keap1/Nrf2 pathway has been shown to play a role in alleviating systemic diseases (Sun et al, 2016;Su et al, 2018) and in ameliorating brain injury, such as ischemic stroke (Wu et al, 2019). Our present findings were similar to those described above.…”

Section: Discussionmentioning

confidence: 99%

Luteolin Exerts Neuroprotection via Modulation of the p62/Keap1/Nrf2 Pathway in Intracerebral Hemorrhage

Tan

et al. 2020

Front. Pharmacol.

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Upregulation of neuronal oxidative stress is involved in the progression of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). In this study, we investigated the potential effects and underlying mechanisms of luteolin on ICH-induced SBI. Autologous blood and oxyhemoglobin (OxyHb) were used to establish in vivo and in vitro models of ICH, respectively. Luteolin treatment effectively alleviated brain edema and ameliorated neurobehavioral dysfunction and memory loss in vivo. Also, in vivo, we found that luteolin promoted the activation of the sequestosome 1 (p62)/kelch-like enoyl-coenzyme A hydratase (ECH)-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by enhancing autophagy and increasing the translocation of Nrf2 to the nucleus. Meanwhile, luteolin inhibited the ubiquitination of Nrf2 and increased the expression levels of downstream antioxidant proteins, such as heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate (NADPH): quinine oxidoreductase 1 (NQO1). This effect of luteolin was also confirmed in vitro, which was reversed by the autophagy inhibitor, chloroquine (CQ). Additionally, we found that luteolin inhibited the production of neuronal mitochondrial superoxides (MitoSOX) and alleviated neuronal mitochondrial injury in vitro, as indicated via tetrachloro-tetraethylbenzimidazol carbocyanine-iodide (JC-1) staining and MitoSOX staining. Taken together, our findings demonstrate that luteolin enhances autophagy and anti-oxidative processes in both in vivo and in vitro models of ICH, and that activation of the p62-Keap1-Nrf2 pathway, is involved in such luteolin-induced neuroprotection. Hence, luteolin may represent a promising candidate for the treatment of ICH-induced SBI.

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“…found that LCA activated Keap1‐Nrf2 signaling to suppress arthritis by phosphorylation of p62 at Ser349. It is a promising strategy that LCA as a lead compound for activating the Keap1‐Nrf2 pathway to inhibit arthritis . Clinical study have shown that moisturizer containing licochalcone A could be used both for treatment of acute and maintenance phase in mild‐to‐moderate childhood atopic dermatitis .…”

Section: Natural Polyphenols Nrf2 Activators In Multiple Disease Modelsmentioning

confidence: 99%

“…It is a promising strategy that LCA as a lead compound for activating the Keap1-Nrf2 pathway to inhibit arthritis. [92] Clinical study have shown that moisturizer containing licochalcone A could be used both for treatment of acute and maintenance phase in mild-tomoderate childhood atopic dermatitis. [93] Xanthohumol (Xn, 32) is a major isoprene flavonoid with antiinflammatory and antioxidant activities.…”

Section: Chalconementioning

confidence: 99%

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

Zhou

Jiang

et al. 2019

Chemistry & Biodiversity

140

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The Keap1‐Nrf2/ARE signaling pathway is an important defense system against exogenous and endogenous oxidative stress injury. The dysregulation of the signaling pathway is associated with many diseases, such as cancer, diabetes, and respiratory diseases. Over the years, a wide range of natural products has provided sufficient resources for the discovery of potential therapeutic drugs. Among them, polyphenols possess Nrf2 activation, not only inhibit the production of ROS, inhibit Keap1‐Nrf2 protein–protein interaction, but also degrade Keap1 and regulate the Nrf2 related pathway. In fact, with the continuous improvement of natural polyphenols separation and purification technology and further studies on the Keap1‐Nrf2 molecular mechanism, more and more natural polyphenols monomer components of Nrf2 activators have been gradually discovered. In this view, we summarize the research status of natural polyphenols that have been found with apparent Nrf2 activation and their action modes. On the whole, this review may guide the design of novel Keap1‐Nrf2 activator.

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Licochalcone A activates Keap1-Nrf2 signaling to suppress arthritis via phosphorylation of p62 at serine 349

Cited by 64 publications

References 54 publications

Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes

Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes

Luteolin Exerts Neuroprotection via Modulation of the p62/Keap1/Nrf2 Pathway in Intracerebral Hemorrhage

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

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