Citrus flavonoid 5‐demethylnobiletin suppresses scavenger receptor expression in THP‐1 cells and alters lipid homeostasis in HepG2 liver cells

Yen, Jui-Hung; Weng, Ching-Yi; Li, Shiming; Lo, Ya-Hsuan; Pan, Min‐Hsiung; Fu, Shih-Hang; Ho, Chi‐Tang; Wu, Ming-Jiuan

doi:10.1002/mnfr.201000226

Cited by 38 publications

(35 citation statements)

References 74 publications

(86 reference statements)

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“…Polymethoxyflavones (PMFs) exist almost exclusively in the peels of citrus such as sweet orange ( Citrus sinensis (L.) Osbeck) and mandarin orange ( Citrus reticulate Blanco). The roles of PMFs in prevention and treatment of diseases have received considerable attention recently, with particular interest in the use of these citrus flavonoids as antioxidant, anti-inflammatory, anti-cancer, and anti-atherogenic agents [22]–[26]. Nobiletin ( Figure 1 ), the most abundant and studied PMF in orange peel extract [23], has been found to induce neurite outgrowth through cAMP and ERK/MAPK-dependent mechanism [27], to stimulate CRE transcription activity [28], to enhance long-term potentiation (LTP) in the hippocampal slices [29], and to improve impaired memory in animal models including olfactory-bulbectomized, Alzheimer's disease, and brain-ischemia mice [30]–[32].…”

Section: Introductionmentioning

confidence: 99%

Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells

Lai

Chen

et al. 2011

PLoS ONE

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5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-OH-HxMF), a hydroxylated polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. In this research, we report the first investigation of the neurotrophic effects and mechanism of 5-OH-HxMF in PC12 pheochromocytoma cells. We found that 5-OH-HxMF can effectively induce PC12 neurite outgrowth accompanied with the expression of neuronal differentiation marker protein growth-associated protein-43(GAP-43). 5-OH-HxMF caused the enhancement of cyclic AMP response element binding protein (CREB) phosphorylation, c-fos gene expression and CRE-mediated transcription, which was inhibited by 2-naphthol AS-E phosphate (KG-501), a specific antagonist for the CREB-CBP complex formation. Moreover, 5-OH-HxMF-induced both CRE transcription activity and neurite outgrowth were inhibited by adenylate cyclase and protein kinase A (PKA) inhibitor, but not MEK1/2, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K) or calcium/calmodulin-dependent protein kinase (CaMK) inhibitor. Consistently, 5-OH-HxMF treatment increased the intracellular cAMP level and downstream component, PKA activity. We also found that addition of K252a, a TrKA antagonist, significantly inhibited NGF- but not 5-OH-HxMF-induced neurite outgrowth. These results reveal for the first time that 5-OH-HxMF is an effective neurotrophic agent and its effect is mainly through a cAMP/PKA-dependent, but TrKA-independent, signaling pathway coupling with CRE-mediated gene transcription. A PKC-dependent and CREB-independent pathway was also involved in its neurotrophic action.

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Section: Introductionmentioning

confidence: 99%

Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells

Lai

Chen

et al. 2011

PLoS ONE

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“…Treatment of endothelial cells with the antioxidant flavonoid, luteolin, protects them from the effects of oxLDL effects by downregulation of the lectin-like oxidised LDL receptor [47]. Similarly, the citrus-derived flavonoid nobiletin has recently been reported to inhibit monocyte to macrophage differentiation and scavenger receptor activity in THP-1 cells via inhibition of PKC [48]. Although we cannot completely rule out the possibility that the effects observed in the present work are specifically due to the presence of probucol, rather than protection of the particles from oxidation, our previous work with macrophages showing that probucol and lycopene, a chemically unrelated antioxidant, have remarkably similar effects on lipid accumulation suggest that this is not the case.…”

Section: Resultsmentioning

confidence: 99%

The Oxidative State of Chylomicron Remnants Influences Their Modulation of Human Monocyte Activation

Lopez

Botham

2012

International Journal of Vascular Medicine

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Chylomicron remnants (CMRs) contribute directly to human monocyte activation in vitro, by increasing reactive oxygen species (ROS) production and cell migration. In this study, the effects of the oxidative state of CMR on the degree of monocyte activation was investigated. CMR-like particles (CRLPs) were prepared in three different oxidative states, normal (CRLPs), protected from oxidation by incorporation of the antioxidant, probucol (pCRLPs), or oxidised with CuSO4 (oxCRLPs). Lipid accumulation and ROS production were significantly increased in primary human monocytes incubated with CRLPs, whilst secretion on monocyte chemoattractant protein-1 was reduced, but oxCRLPs had no additional effect. In contrast, pCRLPs were taken up by monocytes to a lesser extent and had no significant effect on ROS or MCP-1 secretion. These studies suggest that the oxidative state of CMRs modulates their stimulation of the activation of peripheral blood human monocytes and that dietary antioxidants may provide some protection against these atherogenic effects.

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“…Molecular studies have demonstrated that incubation of lipopolysaccharide-treated RAW-264.7 macrophages with naringenin, dose-dependently decreased the production of tumour necrosis factor (TNF α ) and monocyte chemoattractant protein 1 (MCP-1) [72]. Nobiletin and its derivatives have been shown to reduce the expression and activity of macrophage scavenger receptors [73] including CD36 and SRAI/II and decrease the uptake of acetylated LDL [74]. These studies suggest that in addition to decreased exposure of the vessel wall to increased plasma lipoproteins, flavonoids directly decrease both lipoprotein uptake and the inflammatory response within macrophages of the arterial intima.…”

Section: Prevention Of Atherosclerosis By Citrus Flavonoidsmentioning

confidence: 99%

Protection from Metabolic Dysregulation, Obesity, and Atherosclerosis by Citrus Flavonoids: Activation of Hepatic PGC1α-Mediated Fatty Acid Oxidation

Mulvihill

Huff

2012

PPAR Research

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Studies in a multitude of models including cell culture, animal and clinical studies demonstrate that citrus-derived flavonoids have therapeutic potential to attenuate dyslipidemia, correct hyperinsulinemia and hyperglycemia, and reduce atherosclerosis. Emerging evidence suggests the metabolic regulators, PPARα and PGC1α, are targets of the citrus flavonoids, and their activation may be at least partially responsible for mediating their metabolic effects. Molecular studies will add significantly to the concept of these flavonoids as viable and promising therapeutic agents to treat the dysregulation of lipid homeostasis, metabolic disease, and its cardiovascular complications.

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Citrus flavonoid 5‐demethylnobiletin suppresses scavenger receptor expression in THP‐1 cells and alters lipid homeostasis in HepG2 liver cells

Cited by 38 publications

References 74 publications

Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells

Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells

The Oxidative State of Chylomicron Remnants Influences Their Modulation of Human Monocyte Activation

Protection from Metabolic Dysregulation, Obesity, and Atherosclerosis by Citrus Flavonoids: Activation of Hepatic PGC1α-Mediated Fatty Acid Oxidation

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