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

Abstract

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 ...

Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management?

“…Therefore, ERK1-mediated influences may be due to the improved stability of Nrf2 upon Nrf2 phosphorylation, which prevents Nrf2 ubiquitination and degradation [ 117 ]. However, the tested concentrations of luteolin (mouse testis Sertoli TM4 cells), epicatechin (primary astrocytes from mice), quercetin (rat hepatocytes) and chrysin (IEC-6 cells) in the above murine cells are higher than the achievable physiological concentrations in murine models upon oral administration [ 51 , 125 , 126 , 127 ]. Baicalein upregulates the Nrf2 nuclear translocation against high glucose-induced oxidative stress in L-02 liver cells [ 119 , 120 ].…”

“…Furthermore, promising results on the upregulation of Nrf2 nuclear translocation were observed in several pre-clinical studies (ICR mice, Sprague-Dawley rats, Kunming mice, and broiler chicken) [ 51 , 111 , 120 , 131 , 132 ]. Luteolin, baicalein, myricetin, quercetin and genistein demonstrate their ability in upregulating Nrf2 nuclear translocation [ 51 , 111 , 120 , 131 , 132 ].…”

“…Furthermore, promising results on the upregulation of Nrf2 nuclear translocation were observed in several pre-clinical studies (ICR mice, Sprague-Dawley rats, Kunming mice, and broiler chicken) [ 51 , 111 , 120 , 131 , 132 ]. Luteolin, baicalein, myricetin, quercetin and genistein demonstrate their ability in upregulating Nrf2 nuclear translocation [ 51 , 111 , 120 , 131 , 132 ]. Luteolin increases Nrf2 nuclear translocation in male Sprague-Dawley rats with intracerebral hemorrhage-induced secondary brain damage (intraperitoneal administration) and male ICR mice (oral administration) at concentrations which are not toxic [ 51 , 131 , 133 , 134 , 135 ].…”

“…Luteolin, baicalein, myricetin, quercetin and genistein demonstrate their ability in upregulating Nrf2 nuclear translocation [ 51 , 111 , 120 , 131 , 132 ]. Luteolin increases Nrf2 nuclear translocation in male Sprague-Dawley rats with intracerebral hemorrhage-induced secondary brain damage (intraperitoneal administration) and male ICR mice (oral administration) at concentrations which are not toxic [ 51 , 131 , 133 , 134 , 135 ]. Similarly, the oral administration of baicalein facilitates Nrf2 nuclear translocation in male type 2 diabetes mellitus (T2DM) Kunming mice with high glucose-induced oxidative stress, at a concentration much lower than the maximum tolerable levels for mice [ 120 , 136 ].…”

“…Among many other phytochemicals, flavonoids have shown the potential to activate the Nrf2/ARE pathway in the absence of oxidative inducers [ 38 , 51 ]. However, the activation of the Nrf2/ARE pathway has not always been beneficial because the same flavonoids may promote the growth of cancer cells as well [ 52 ].…”