Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells

Kang, Kyoung Ah; Piao, Mei Jing; Hyun, Yu Jae; Zhen, Ao Xuan; Cho, Suk Ju; Ahn, Meejung; Yi, Joo Mi; Hyun, Jin Won

doi:10.1038/s12276-019-0238-y

Cited by 101 publications

(83 citation statements)

References 41 publications

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“…However, other studies have demonstrated that luteolin can induce the demethylation of the Nrf2 gene promoter region, upregulate the Nrf2 gene expression, activate the Nrf2/ARE pathway, increase the antioxidant capacity, inhibit the transformation and promote apoptosis of colon cancer cells (52,53), which is not supported by the results of the present study. In the current study, it was speculated that the antioxidant capacity served a different role at different stages of cancer development.…”

Section: Discussioncontrasting

confidence: 99%

Luteolin induces mitochondrial apoptosis in HT29 cells by inhibiting the Nrf2/ARE signaling pathway

et al. 2020

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The aim of the current study was to investigate luteolin-induced apoptosis and the molecular mechanisms underlying it in HT29 cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to assess the cytotoxicity of luteolin on HT29 cells, and a dichloro-dihydro-fluorescein diacetate assay was used to measure cellular levels of reactive oxygen species (ROS). The effects of luteolin on the mitochondrial membrane potential were also evaluated. Bax and Bcl-2 mRNA expression were determined using reverse transcription-quantitative PCR. Additionally, western blot analysis was performed to assess changes in cytochrome c and caspase-3 protein expression. Localization of nuclear factor erythroid 2-related factor 2 (Nrf2) in the nucleus was also assessed using immunofluorescence. Luteolin exhibited cytotoxicity on HT29 cells in a time-and concentration-dependent manner. Additionally, ROS production was indicated to be increased and ROS scavenging was decreased, which resulted in a significant increase in the levels of ROS in the cells. The mitochondrial membrane potential was indicated to decrease following luteolin treatment. At the molecular level, luteolin significantly increased the mRNA expression of Bax and the protein expression of cytochrome c, caspase-3, p47 phox and p22 phox . The results revealed that luteolin decreased Bcl-2 protein expression and inhibited the nuclear localization of Nrf2. In conclusion, the current study indicated that luteolin inhibited HT29 cell proliferation and induced apoptosis via the mitochondrial pathway.

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Section: Discussioncontrasting

confidence: 99%

Luteolin induces mitochondrial apoptosis in HT29 cells by inhibiting the Nrf2/ARE signaling pathway

et al. 2020

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“…Luteolin is a member of the naturally occurring flavonoid family and has various beneficial bioactivities. Numerous studies have revealed anti-inflammatory, antioxidative, anti-apoptotic, autophagic-regulatory, anti-viral, anticancer, and metabolic effects of luteolin, which have been confirmed in many different disease models (Hu et al, 2016;Zhang et al, 2016;Peng et al, 2017;Du et al, 2018;Liu et al, 2018;Tan et al, 2018b;Yang et al, 2018b;Kang et al, 2019). In addition, in studies on ischemic stroke (Qiao et al, 2012;Tan et al, 2018a;Luo et al, 2019), traumatic brain injury (Xu et al, 2014), neurodegenerative diseases (Kwon, 2017;Zhang et al, 2017), and other neurological diseases, luteolin has been shown to exert therapeutic effects.…”

Section: Discussionmentioning

confidence: 92%

“…In this study, we demonstrated that luteolin enhanced the activation of the Nrf2 pathway and enhanced Nrf2 nuclear translocation after ICH. Nrf2 is known to regulate various antioxidant enzymes to protect cells against oxidative stress and is essential for the clearance of hematomas (Zhao et al, 2015;Kang et al, 2019). Numerous studies have demonstrated that activation of the Nrf2 signaling pathway is beneficial in alleviating ICH-induced SBI.…”

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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“…In support of this, it was observed an increased expression of DNA demethylases, TET (ten eleven translocation) enzymes, combined with TET1 physical interaction with Nrf2 promoter. The interaction between Nrf2 and p53 proteins seems to be important for the induction of apoptosis [128].…”

Section: Luteolinmentioning

confidence: 99%

Citrus Flavones: An Update on Sources, Biological Functions, and Health Promoting Properties

Barreca

Mandalari

Calderaro

et al. 2020

Plants

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Citrus spp. are among the most widespread plants cultivated worldwide and every year millions of tons of fruit, juices, or processed compounds are produced and consumed, representing one of the main sources of nutrients in human diet. Among these, the flavonoids play a key role in providing a wide range of health beneficial effects. Apigenin, diosmetin, luteolin, acacetin, chrysoeriol, and their respective glycosides, that occur in concentrations up to 60 mg/L, are the most common flavones found in Citrus fruits and juices. The unique characteristics of their basic skeleton and the nature and position of the substituents have attracted and stimulated vigorous investigations as a consequence of an enormous biological potential, that manifests itself as (among other properties) antioxidant, anti-inflammatory, antiviral, antimicrobial, and anticancer activities. This review analyzes the biochemical, pharmacological, and biological properties of Citrus flavones, emphasizing their occurrence in Citrus spp. fruits and juices, on their bioavailability, and their ability to modulate signal cascades and key metabolic enzymes both in vitro and in vivo. Electronic databases including PubMed, Scopus, Web of Science, and SciFinder were used to investigate recent published articles on Citrus spp. in terms of components and bioactivity potentials.

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Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells

Cited by 101 publications

References 41 publications

Luteolin induces mitochondrial apoptosis in HT29 cells by inhibiting the Nrf2/ARE signaling pathway

Luteolin induces mitochondrial apoptosis in HT29 cells by inhibiting the Nrf2/ARE signaling pathway

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

Citrus Flavones: An Update on Sources, Biological Functions, and Health Promoting Properties

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