A physiological concentration of luteolin induces phase II drug-metabolizing enzymes through the ERK1/2 signaling pathway in HepG2 cells

Kitakaze, Tomoya; Makiyama, Atsushi; Samukawa, Yumi; Jiang, Songyan; Yamashita, Yoko; Ashida, Hitoshi

doi:10.1016/j.abb.2019.01.012

Cited by 29 publications

(22 citation statements)

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“…The activation of Nrf2 is regulated by multiple steps, such as transcription, translation and protein stability. Our previous study has demonstrated that luteolin at the physiological concentration range activates Nrf2 nuclear translocation by reduction of Nrf2 ubiquitination through increasing modified Keap1 and phosphorylation of Nrf2 in HepG2 cells [23]. This result supports our finding that the low dose of luteolin increased nuclear accumulation of Nrf2 independently of its mRNA transcription in the liver.…”

Section: Plos Onesupporting

confidence: 90%

“…Luteolin possesses a lot of physiological functions including antioxidative activity [21,22], while the number of cultured cells and animal studies evaluate the effects in the concentration that exceeds the amount taken from the daily meal. On the other hand, our previous study revealed that the physiological nanomolarconcentration range of luteolin induces Nrf2/ARE pathway in human hepatoma HepG2 cells [23]. However, the effect of the low dose of luteolin that can be taken from a dietary meal on the Nrf2 activation remain unclear.After intake of flavonoids, including luteolin, they are metabolized to glucuronide, sulfate and methylated conjugates by glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and catechol O-methyl transferases (COMTs), respectively [24][25][26][27].…”

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Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase

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A flavone luteolin has various health-promoting activities. Several studies reported that high dose of luteolin activates the Nrf2/ARE pathway in the liver. However, the effect of the low dose of luteolin that can be taken from a dietary meal on the Nrf2 activation remain unclear. It is expected that the flavonoid metabolism possesses a circadian rhythm, since nutritional metabolism processes daily cycle. In this study we investigated whether an administration affects the Nrf2 activation. ICR mice were orally administered 0.01-10 mg/kg body weight of luteolin once a day for 7 days at two time-points: at the start of active phase (ZT12) or at that of inactive phase (ZT0). Luteolin increased the nuclear translocation of Nrf2, resulting in the increases in its target gene products HO-1 and NQO1 at ZT12 but not at ZT0. The expression level of Nrf2 was lower at ZT12 than at ZT0 in the liver. We also found that the level of luteolin aglycon in the plasma is higher at ZT12 than at ZT0. These results suggest that the low dose of luteolin can activate Nrf2 pathway and the aglycon form of luteolin may mainly contribute to activate the Nrf2 pathway at ZT12 in the liver. OPEN ACCESSCitation: Kitakaze T, Makiyama A, Yamashita Y, Ashida H (2020) Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase. PLoS ONE 15(4): e0231403. https://doi.org/10.beneficial functions for human health. However, most of study have not considered feeding time of flavonoids. Thus, the involvement of feeding time on the function of flavonoids remain unclear.Flavonoids possess various health-promoting activities as antioxidants. Evidences from the cultured cells and animal studies revealed that individual flavonoids have many health benefits, such as prevention of oxidative stress, inflammation and lipid accumulation [5,6]. Epidemiological studies suggest that high dietary intake of flavonoids is associated with lower risk of diseases including cardiovascular disease and several types of cancer [7,8]. The mean daily intake of flavonoids has been estimated in many countries; e.g., US (207.0 mg/day), Korea (318.0 mg/ day) and Spain (376.69 mg/day) [9][10][11]. A number of animal studies are intended to evaluate the effects of high dose of flavonoids (more than 10 mg/kg), but little is known about the function of low dose of flavonoids that can be taken from a dietary meal.Many flavonoids have antioxidant activity not only by its free radical scavenging ability but also by inducing the expression of antioxidant enzymes. Nuclear factor-erythroid-2-related factor 2 (Nrf2) belongs to the cap'n'collar basic leucine zipper family, and is a key regulator of oxidative stress in numerous types of cells, as well as hepatocytes. Nrf2 is primarily regulated by Kelch-like ECH-associated protein 1 (Keap1), a substrate adaptor for a cul3-containing E3 ubiquitin ligase [12]. Under the normal condition, Nrf2 interacts with Keap1 in the cytoplasm and is rapidly degraded by the ubiquitin-proteasome pathway ...

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Section: Plos Onesupporting

confidence: 90%

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Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase

et al. 2020

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“…The sample that was not treated with luteolin was employed as the control. The mixture was incubated at 37 ºC at a speed of 150 rpm and the absorption of the bacterial suspension at 600 nm was measured after 2,4,8,12,16,20,24,28,32,36, and 40 h of incubation. The bacterial growth curve was plotted to analyse the effect of luteolin on T. pyogenes growth.…”

Section: Determination Of the Growth Curvementioning

confidence: 99%

“…[19][20][21][22] Luteolin could hamper the progression of cancer through multiple mechanisms including the suppression of kinases, regulation of cell cycle, induction of apoptotic cell death, and reduction of transcription factors. [23][24][25][26] Many researchers have focused on the antiinflammatory and anti-tumour properties of luteolin; however, only minor attention has been paid to its good antibacterial activity. Nonetheless, luteolin has been demonstrated to exhibit good antibacterial activity against Bacillus subtilis, Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Pseudomonas fluorescens.…”

Section: Introductionmentioning

confidence: 99%

<p>The Antibacterial Activity and Mechanism of Action of Luteolin Against <em>Trueperella pyogenes</em></p>

Guo¹,

Liu²,

Zhang³

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Purpose: This research aimed to investigate the antibacterial activity and potential mechanism of luteolin against T. pyogenes. Materials and Methods: The broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of luteolin against various T. pyogenes strains. The potential mechanism of action of luteolin was elucidated through testing and analysing the luteolin-induced alterations of T. pyogenes in several aspects, including cell wall, cell membrane, protein expression, nucleic acid content, topoisomerase activity and energy metabolism. Results: The MIC values of luteolin against various T. pyogenes isolates and ATCC19411 were 78 µg/mL. The increased cell membrane permeability, destruction of cell wall integrity and TEM images after exposure to luteolin showed that the cell wall and membrane were damaged. The content of total protein and nucleic acid in T. pyogenes decreased significantly after treatment with luteolin (1/2 MIC) for 12, 24, and 36 h. Moreover, a hypochromic effect was observed in the absorption spectrum of luteolin when deoxyribonucleic acid (DNA) was added. In addition, after treatment with luteolin, a decrease in nicked or relaxed DNA content, which was catalysed by T. pyogenes-isolated DNA topoisomerase, was observed. In addition, the adenosine triphosphate (ATP) content in cells and the activity of succinate dehydrogenase (SDH) both decreased when T. pyogenes was exposed to different concentrations (1/4 MIC, 1/2 MIC, 1 MIC, 2 MIC) of luteolin for 1 h. Conclusion: Luteolin showed distinct antibacterial activity against T. pyogenes by multiple actions, which mainly include destroying the integrity of the cell wall and cell membrane, influencing the expression of proteins, inhibiting nucleic acid synthesis, and interfering with energy metabolism.

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“…Moreover, an imbalance of oxidative stress and the limitation of the intestinal antioxidant defense system have been observed in colitis (Yasukawa et al, 2019). NF-E2-related factor 2 (Nrf2), a key factor in oxidative stress response of cells regulated by Kelch-like ECH-associated protein 1 (Keap1), moderates the expression of antioxidant proteins and phase II detoxification enzymes (Kitakaze et al, 2019). UC is connected with the Keap1/Nrf2 signaling pathway, and influences Nrf2, Keap1, and Nrf2-related target genes and their expression (Lu et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Bruguiera gymnorrhiza (L.) Lam. Fruit on Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice: Role of Keap1/Nrf2 Pathway and Gut Microbiota

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homeostasis. BGF possessed protective effect against DSS-induced colitis. The potential mechanism of BGF may involve the amelioration of inflammatory and oxidative status, activation of Keap1/Nrf2 signaling pathway, and maintenance of micro-ecological balance of the host. This study provides experimental evidence for the traditional application of BGF in the treatment of diarrhea, and indicates that BGF may be a promising candidate against colitis.

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A physiological concentration of luteolin induces phase II drug-metabolizing enzymes through the ERK1/2 signaling pathway in HepG2 cells

Cited by 29 publications

References 50 publications

Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase

Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase

<p>The Antibacterial Activity and Mechanism of Action of Luteolin Against <em>Trueperella pyogenes</em></p>

Protective Effect of Bruguiera gymnorrhiza (L.) Lam. Fruit on Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice: Role of Keap1/Nrf2 Pathway and Gut Microbiota

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