Nobiletin

The peel of Citrus nobilis Lour.

Nobiletin, a natural polymethoxylated flavone, is identified as a clock amplitude-enhancing small molecule. IC50 value: Target: In vitro: Although NGF alone had little effect on the CRE-dependent transcription, NGF markedly enhanced the CRE-dependent transcription induced by nobiletin[1]. Nobiletin, up to 100 μM without cytotoxicity, significantly decreased motility, migration and invasion as well as enzymatic activities, protein levels and mRNA expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in U2OS and HOS cells[3]. In vivo: When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders[2].

References:
[1]. Takito J, et al. Nerve growth factor enhances the CRE-dependent transcriptional activity activated by nobiletin in PC12 cells. Can J Physiol Pharmacol. 2016 Feb 12:1-6. [2]. He B, et al. The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. Cell Metab. 2016 Apr 12;23(4):610-21. [3]. Cheng HL, et al. Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression. Oncotarget. 2016 Apr 29.

Nobiletin inhibits invasion and migration of human nasopharyngeal carcinoma cell lines by involving ERK1/2 and transcriptional inhibition of MMP-2.[Pubmed:25563790]

Expert Opin Ther Targets. 2015 Mar;19(3):307-20.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) is known for its high incidence of neck lymph node metastasis, which represents poor prognosis. Nobiletin is a citrus polymethoxyflavonoid that suppresses tumor growth and metastasis, both of which depend on angiogenesis in previous studies. However, the effect of Nobiletin on human NPC cells metastasis has not been clearly clarified. RESEARCH DESIGN AND METHODS: In this study, we determine the effects of Nobiletin on the migration and invasion in NPC cells. RESULTS: Nobiletin significantly inhibited migration/invasion capacities of HONE-1 and NPC-BM cell lines. The results of gelatin zymography and western blotting revealed that the activities and protein levels of the MMP-2 were inhibited by Nobiletin. Nobiletin also showed that inhibits phosphorylation of ERK1/2. Tests of the real-time PCR and promoter assays evaluated the inhibitory effects of Nobiletin on MMP-2 expression in human NPC cells. Nobiletin inhibits MMP-2 expression, up-regulating tissue inhibitor of metalloproteinase-2 and down-regulation of the transcription factors of NF-kappaB and activator protein 1 (AP-1) signaling pathways. Finally, an administration of Nobiletin effectively suppressed the tumor formation and metastasis in the NPC xenograft model in vivo. CONCLUSIONS: Nobiletin may have potential use as a chemo-preventive agent against nasopharyngeal cancer metastasis.

Nobiletin suppresses the proliferation and induces apoptosis involving MAPKs and caspase-8/-9/-3 signals in human acute myeloid leukemia cells.[Pubmed:25164609]

Tumour Biol. 2014 Dec;35(12):11903-11.

Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative that was shown to have anti-inflammatory and anticancer activities in various solid tumors. The anticancer effect of Nobiletin on nonsolid tumor remains unclear. Herein, the molecular mechanisms by which Nobiletin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. The results showed that Nobiletin suppressed cell proliferation in various types of AML cell lines. Moreover, Nobiletin induced cell-cycle arrest of HL-60 AML cells at the G0/G1 phase by suppressing extracellular signal-regulated kinase (ERK) activity. Furthermore, Nobiletin effectively induced apoptosis of HL-60 cells through caspase-8, caspase-9, and caspases-3 activation concomitantly with a marked induction of p38 mitogen-activated protein kinase (MAPK) activation, but without affecting expression levels of Bcl-2, Bax, or Bid. Taken together, our results suggest that Nobiletin inhibited HL-60 cell proliferation through inducing cell-cycle arrest and apoptosis and could serve as a potential additional chemotherapeutic agent for treating AML.

Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages.[Pubmed:12787887]

Biochem Pharmacol. 2003 Jun 15;65(12):2065-71.

We previously reported that Nobiletin (5,6,7,8,3',4'-hexamethoxy flavone), a citrus polymethoxy flavonoid, effectively interferes with the production of promatrix metalloproteinase (proMMP)-9/progelatinase B in rabbit synovial fibroblasts [J. Rheumatol. 27 (2000) 20]. In this paper, we further examine the effects of Nobiletin on the production of cyclooxygenases (COXs), prostaglandin (PG) E(2), and proinflammatory cytokines in human synovial fibroblasts and the mouse macrophage J774A.1 cell line. Nobiletin suppressed the interleukin (IL)-1-induced production of PGE(2) in human synovial cells in a dose-dependent manner (<64 microM). Additionally, it selectively downregulated COX-2, but not COX-1 mRNA expression. Nobiletin also interfered with the lipopolysaccharide-induced production of PGE(2) and the gene expression of proinflammatory cytokines including IL-1alpha, IL-1beta, TNF-alpha and IL-6 in mouse J774A.1 macrophages. In addition, Nobiletin downregulated the IL-1-induced gene expression and production of proMMP-1/procollagenase-1 and proMMP-3/prostromelysin-1 in human synovial fibroblasts. In contrast, production of the endogenous MMP inhibitor, TIMP-1, was augmented by Nobiletin. These anti-inflammatory actions of Nobiletin are very similar to those of anti-inflammatory steroids such as dexamethasone, and the upregulation of TIMP-1 production is a unique action of Nobiletin. Therefore, these results further support the notion that Nobiletin is likely to be a candidate for characterization as a novel immunomodulatory and anti-inflammatory drug.

Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer's disease.[Pubmed:18544674]

J Pharmacol Exp Ther. 2008 Sep;326(3):739-44.

Increasing evidence suggests that the elevation of beta-amyloid (Abeta) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that Nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signal-regulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates Abeta-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice]. Our enzyme-linked immunosorbent assay (ELISA) also showed that administration of Nobiletin to the transgenic mice for 4 months markedly reduced quantity of guanidine-soluble Abeta(1-40) and Abeta(1-42) in the brain. Furthermore, consistent with the results of ELISA, by immunohistochemistry with anti-Abeta antibody, it was evidently shown that the administration of Nobiletin decreased the Abeta burden and plaques in the hippocampus of APP-SL 7-5 Tg mice. These findings suggest that this natural compound has potential to become a novel drug for fundamental treatment of AD.

Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation.[Pubmed:15298613]

Aliment Pharmacol Ther. 2004 Jul;20 Suppl 1:95-101.

AIM: To demonstrate the antitumour effects of Nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), a citrus flavonoid extracted from Citrus depressa Hayata, on human gastric cancer cell lines TMK-1, MKN-45, MKN-74 and KATO-III. MATERIALS AND METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the TdT-mediated dUTP biotin nick-end labelling (TUNEL) method and cell-cycle analysis revealed that Nobiletin acted on these cells in several ways, namely by direct cytotoxicity, induction of apoptosis and modulation of cell cycle. The efficacy of combined treatment of Nobiletin with a conventional anticancer drug, CDDP, was also examined. Treatment with Nobiletin 24 h prior to CDDP administration showed a synergistic effect compared to the control. CONCLUSIONS: Although the effective dose and administration route of Nobiletin require further investigation, our study represents a potential successful linking of this compound with the treatment of gastric cancer.

Nobiletin Inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration and attenuates neointimal hyperplasia in a rat carotid artery injury model.[Pubmed:25452110]

Drug Dev Res. 2014 Dec;75(8):489-96.

Preclinical Research The abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) plays a pivotal role in the development of neointimal hyperplasia after vascular injury. Nobiletin, a citrus bioflavonoid, exhibits anti-inflammatory and anti-oxidative activities. The present study evalutaed whether Nobiletin could inhibit platelet-derived growth factor (PDGF)-BB- stimulated VSMC proliferation and migration and decrease neointimal hyperplasia in a rat carotid artery injury model. Cultured VSMCs from rat thoracic aortas were treated with Nobiletin before being stimulated with 20 ng/ml PDGF-BB, and rats were subjected to carotid artery injury. Nobiletin inhibited PDGF-BB-induced VSMC proliferation and migration, attenuated reactive oxygen species (ROS) production and reduced phosphorylation of ERK1/2 and the expression of nuclear NF-kappaB p65 in PDGF-BB-stimulated VSMCs. Nobiletin decreased the intima area and the ratio of neointima to media in balloon-injured rat carotid arteries. Serum levels of TNF-alpha and IL-6 in Nobiletin-treated rats were decreased. These results indicated that Nobiletin could be a potential protective agent for the prevention and treatment of restenosis after angioplasty.

Citrus nobiletin ameliorates experimental colitis by reducing inflammation and restoring impaired intestinal barrier function.[Pubmed:25655748]

Mol Nutr Food Res. 2015 May;59(5):829-42.

SCOPE: Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract. Citrus Nobiletin can exert robust anti-inflammatory effects in vivo and in vitro. We evaluated the impact of Nobiletin on the excessive inflammatory response and impaired barrier function in a rodent colitis model. METHODS AND RESULTS: Colitis was established by infusion with 1 mL 2,4,6-trinitrobenzene sulfonic acid (TNBS) dissolved in ethanol (40% v/v) in rats at a 125 mg/kg dose. Caco-2 cell monolayer exposed to LPSs is used as a culture model for intestinal permeability measurements. Nobiletin decreased rat epithelial proinflammatory cytokines and mediators production. Nobiletin restored impaired barrier function in colitic rats and Caco-2 monolayer. Nobiletin decreased protein expressions of Akt, nuclear factor-kappa B (NF-kappaB), and myosin light chain kinase (MLCK) isolated from rat intestinal epithelial tissue and Caco-2 cell, respectively. PI3K inhibitor or siRNA targeting of either Akt or NF-kappaB mitigated the impact of Nobiletin on MLCK expression and barrier function in Caco-2 monolayer, respectively. CONCLUSION: Nobiletin exerted anti-inflammatory effects in TNBS-induced colitis through the downregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expression. Nobiletin restored barrier function, which had been damaged after TNBS administration, through the inhibition of the Akt-NF-kappaB-MLCK pathway.

Nobiletin suppresses cell viability through AKT pathways in PC-3 and DU-145 prostate cancer cells.[Pubmed:25342300]

BMC Pharmacol Toxicol. 2014 Oct 24;15:59.

BACKGROUND: Nobiletin is a non-toxic dietary flavonoid that possesses anti-cancer properties. Nobiletin has been reported to reduce the risk of prostate cancer, but the mechanism is not well understood. In this study, we investigated the effects of Nobiletin in prostate cancer cell lines PC-3 and DU-145. METHODS: Nobiletin was isolated from a polymethoxy flavonoid mixture using HPLC, cell viability was analyzed with MTS-based assays. Protein expression was examined by ELISA and western blotting. Gene expression was examined by luciferase assay. And the pathways were examined by manipulating genetic components with plasmid transfection. RESULTS: Data showed that Nobiletin decreased cell viability in both prostate cell lines, with a greater reduction in viability in PC-3 cells. HIF-1alpha expression and AKT phosphorylation were decreased in both cell lines. The VEGF expression was inhibited in PC-3 but not DU-145 cells. cMyc expression was decreased in DU-145 cells. Nobiletin down-regulated NF-kappaB (p50) expression in nuclei of DU145 cells but not whole cells. It also suppressed NF-kappaB expression in both whole cells and nuclei of PC-3 cells. Increasing HIF-1alpha levels reversed Nobiletin's inhibitory effects on VEGF expression, and up-regulating AKT levels reversed its inhibitory effects on HIF-1alpha expression. We speculate that AKT influences cell viability probably by its effect on NF-kappaB in both prostate cells. The effect of Nobiletin on VEGF expression in PC-3 cell lines was through the AKT/HIF-1alpha pathway. CONCLUSION: Taken together, our results show that Nobiletin suppresses cell viability through AKT pathways, with a more profound effect against the more metastatic PC-3 line. Due to this enhanced action against a more malignant cell type, Nobiletin may be used to improve prostate cancer survival rates.

Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice.[Pubmed:11016629]

Cancer Res. 2000 Sep 15;60(18):5059-66.

The intake of citrus fruits has been suggested as a way to prevent the development of some types of human cancer. Nitric oxide (NO) is closely associated with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Citrus unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O2-) generation was induced by a combination of lipopolysaccharide and IFN-gamma in mouse macrophage RAW 264.7 cells, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocyte HL-60, respectively. Expression of inducible NO synthase and cyclooxygenase 2 proteins were detected by Western blotting. The in vivo anti-inflammatory and antitumor promoting activities were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, leukocyte infiltration, hydrogen peroxide production, and the rate of proliferating cell nuclear antigen-stained cells. As a result, Nobiletin, a polymethoxyflavonoid, was identified as an inhibitor of both NO and O2- generation. Nobiletin significantly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second stage activation (oxidative insult by leukocytes)] by decreasing the inflammatory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E2 release. Nobiletin inhibited dimethylbenz[a]anthracene (0.19 micromol)/TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumors per mouse by 61.2% (P < 0.001) and 75.7% (P < 0.001), respectively. The present study suggests that Nobiletin is a functionally novel and possible chemopreventive agent in inflammation-associated tumorigenesis.

Nobiletin is a poly-methoxylated flavone from the citrus peel that improves memory loss. Nobiletin is a retinoid acid receptor-related orphan receptors (RORs) agonist. Nobiletin can reduce reactive oxygen species (ROS) levels in differentiated C2C12 myotubes and has anti-inflammation and anti-cancer properties, including anti-angiogenesis, anti-proliferation, anti-metastasis and induced apoptosis.

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