Anti-inflammatory effects of 4′-demethylnobiletin, a major metabolite of nobiletin

Wu, Xian; Song, Mingyue; Rakariyatham, Kanyasiri; Zheng, Jinkai; Guo, Shan-Shan; Tang, Zhonghai; Zhou, Shi‐Ping; Xiao, Hang

doi:10.1016/j.jff.2015.09.035

Cited by 54 publications

(45 citation statements)

References 32 publications

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“…This finding accorded with the previous in vitro results. 19 Inhibition of TPA-Induced Expression of iNOS, COX-2, and MMP-9 by 4DN. To further investigate the molecular mechanisms underlying the in vivo anti-inflammatory of 4DN, we utilized Western blotting to analyze the effect of 4DN on multiple proteins related with inflammatory pathways in TPAtreated mice, including iNOS, COX-2, and matrix metalloproteinase-9 (MMP-9).…”

Section: ■ Resultsmentioning

confidence: 99%

“…Recently, nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes HO-1 and NQO1 have been demonstrated to play inhibitory roles in TPA-treated mouse skin epidermal JB6 cells. 29 Because 4DN resulted in the induction of the Nrf2 pathway in RAW 264.7 cells, 19 we next investigated whether 4DN exerts any interference with HO-1 and NQO1 expression in TPA-treated mouse ears. As shown in Figure 4, TPA treatment slightly enhanced the protein level of HO-1, whereas it reduced the level of NQO1, in comparison to the control group.…”

Section: ■ Resultsmentioning

confidence: 99%

“…These results were consistent with our previous finding on RAW 264.7 cells. 19 Inhibition of the Phosphorylation of PI3K, Akt, and ERK by 4DN. The activation of phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) MAP kinase pathways plays important roles in inflammatory response.…”

Section: ■ Resultsmentioning

confidence: 99%

“…These effects were associated with inhibition of PGE 2 , IL-6, IL-1β, and COX-2 signaling pathways. 19 Therefore, TPA-induced acute skin inflammation mouse model is an ideal animal model for us to further investigate the in vivo anti-inflammatory properties of 4DN. We first evaluated and compared the in vivo anti-inflammatory effects of NOB and 4DN by using this TPA model.…”

Section: ■ Discussionmentioning

confidence: 99%

“…7 Recently, we demonstrated that 4DN, the major metabolite of NOB, effectively inhibited LPS-induced inflammatory response in RAW 264.7 macrophages, which was evidenced by reduced production of NO, PGE 2 , IL-1β, and IL-6 and suppressed gene expression of iNOS and COX-2, as well as elevated gene expression of antioxidant enzymes heme oxygenase-1 (HO-1) and NADH quinone oxidoreductase 1 (NQO1). 19 However, information on the in vivo anti-inflammatory effects of 4ND and its molecular mechanisms remains unavailable. Therefore, the aim of this study was to determine the inhibitory effects of 4DN on TAP-stimulated skin inflammation in mice and elucidate the underlying molecular mechanisms.…”

Section: ■ Introductionmentioning

confidence: 99%

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Inhibitory Effects of 4′-Demethylnobiletin, a Metabolite of Nobiletin, on 12-O-Tetradecanoylphorbol-13-acetate (TPA)-Induced Inflammation in Mouse Ears

Song

Rakariyatham

et al. 2015

J. Agric. Food Chem.

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Nobiletin (NOB) is major citrus flavonoid with many health-promoting benefits. We reported previously that 4'-demethylnobiletin (4DN), a major metabolite of NOB, significantly inhibited lipopolysaccharide (LPS)-stimulated inflammation in RAW 264.7 macrophages. In this study, we further studied the anti-inflammatory effects of 4DN in TPA-induced skin inflammation in mice. We demonstrated that topical application of 4DN decreased TPA-induced ear edema by >88 ± 4.77% in mice. This inhibitory effect was associated with inhibition on TPA-induced up-regulation of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Immunoblotting results showed that 4DN resulted in profound effects on multiple proteins related with inflammation and carcinogenesis. 4DN significantly decreased the expression levels of iNOS, COX-2, and MMP-9, suppressed phosphorylation of PI3K/Akt and ERK, and increased the levels of HO-1 and NQO1 in TPA-treated mice. Overall, the results demonstrated that 4DN had strong anti-inflammatory effects in vivo, which provided a scientific basis for using NOB to inhibit inflammation-driven diseases.

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Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inhibitory Effects of 4′-Demethylnobiletin, a Metabolite of Nobiletin, on 12-O-Tetradecanoylphorbol-13-acetate (TPA)-Induced Inflammation in Mouse Ears

Song

Rakariyatham

et al. 2015

J. Agric. Food Chem.

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Nobiletin suppresses high‐glucose–induced inflammation and ECM accumulation in human mesangial cells through STAT3/NF‐κB pathway

Liu

Han

Zhao

et al. 2018

J of Cellular Biochemistry

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Diabetic nephropathy (DN) is a complication of chronic diabetes and the main cause of end-stage renal disease all over the world. Inflammation and extracellular matrix (ECM) accumulation play important roles in the pathogenesis of DN.Evidence suggested that nobiletin acts anti-inflammatory role and plays a critical role in diabetes; however, its role in DN remains unclear. In the current study, we promulgated the nobiletin involved in high-glucose-induced glomerular mesangial cell inflammation and ECM accumulation. Nobiletin treatment significantly abrogated high-glucose-induced glomerular mesangial cell proliferation. Nobiletin treatment markedly suppressed inflammation cytokine secretion, including interleukin (IL)-1β, IL-6, tumor necrosis factor α, and monocyte chemoattractant protein 1 in high-glucose-induced glomerular mesangial cell. Also, exposed nobiletin to high-glucose-induced glomerular mesangial cell considerably reduced ECM accumulation through inhibited ECM-associated protein type 4 collagen and fibronectin expression. Furthermore, nobiletin treatment abolished nuclear factor κB (NF-κB) pathway activation through signal transducer and activator of transcription 3 (STAT3) inhibition. Overexpression STAT3 reversed the effects of nobiletin on high-glucose-induced glomerular mesangial cell proliferation, inflammation, ECM accumulation, and NF-κB pathway activation. Hence, our results suggest that nobiletin play roles in high-glucose-induced glomerular mesangial cells through inhibiting inflammation and ECM accumulation, and the STAT3/NF-κB pathway was involved in the function of nobiletin. K E Y W O R D S diabetic nephropathy, extracellular matrix accumulation, inflammation, nuclear factor κB pathway, nobiletin, signal transducer and activator of transcription 3

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A polymethoxy flavonoids-rich Citrus aurantium extract ameliorates ethanol-induced liver injury through modulation of AMPK and Nrf2-related signals in a binge drinking mouse model

et al. 2015

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Nobiletin and tangeretin are polymethoxy flavonoids (PMFs), found in rich quantities in the peel of citrus fruits. In the present study, we assessed the biological effect of the PMFs on liver damage using a mouse model of binge drinking. First, we extracted PMFs from the peels of Citrus aurantium to make Citrus aurantium extract (CAE). Male C57BL/6 mice were orally treated with silymarin and CAE (50, 100, and 200 mg/kg) for 3 days prior to ethanol (5 g/kg, total of 3 doses) oral gavage. Liver injury was observed in the ethanol alone group, as evidenced by increases in serum hepatic enzymes and histopathologic alteration, as well as by hepatic oxidative status disruption. CAE improved serum marker and hepatic structure and restored oxidative status by enhancing antioxidant enzyme levels and by reducing lipid peroxidation levels. In addition, CAE evidently suppressed inflammation and apoptosis in the livers of mice administered with ethanol, by 85% (tumor necrosis factor-α) and 44% compared to the control group, respectively. Furthermore, CAE activated lipid metabolism related signals and enhanced phosphorylation of AMP-activated protein kinase (AMPK) and nuclear factor E2-related factor 2 (Nrf2) with several cytoprotective proteins including heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, and γ-glutamylcysteine synthetase. Taken together, the present study demonstrated that, CAE possesses antioxidant, anti-inflammatory, and antiapoptotic activity against ethanol-induced liver injury.

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Anti-inflammatory effects of 4′-demethylnobiletin, a major metabolite of nobiletin

Cited by 54 publications

References 32 publications

Inhibitory Effects of 4′-Demethylnobiletin, a Metabolite of Nobiletin, on 12-O-Tetradecanoylphorbol-13-acetate (TPA)-Induced Inflammation in Mouse Ears

Inhibitory Effects of 4′-Demethylnobiletin, a Metabolite of Nobiletin, on 12-O-Tetradecanoylphorbol-13-acetate (TPA)-Induced Inflammation in Mouse Ears

Nobiletin suppresses high‐glucose–induced inflammation and ECM accumulation in human mesangial cells through STAT3/NF‐κB pathway

A polymethoxy flavonoids-rich Citrus aurantium extract ameliorates ethanol-induced liver injury through modulation of AMPK and Nrf2-related signals in a binge drinking mouse model

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