Noble Nobiletin: Top 5 Health Benefits from this Citrus Flavonoid

Noble Nobiletin: Top 5 Health Benefits from this Citrus Flavonoid

Nobiletin, like tangeretin, is a type of flavonoid known as a polymethoxylated flavone, which is
found in citrus fruit, including its peel. In addition to its antioxidant property, nobiletin has antitumor, anti-inflammatory and other effects.


1) Anti-Inflammatory

Research has determined that nobiletin’s anti-inflammatory effect is similar to that of corticosteroid drugs and that its upregulation of the matrix metalloproteinase inhibitor TIMP-1 is a unique action. (Matrix metalloproteinases are enzymes responsible for the degradation of collagen, one of the main structural components of connective tissue.) In rats with induced rheumatoid arthritis, treatment with nobiletin lowered proinflammatory cytokines that included interleukin-1 beta, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), while downregulating the expression of the p38/nuclear factor kappa beta signaling pathway (involved in inflammation) in the synovial membrane.1 Nobiletin has also shown an ability to prevent life-threatening endotoxic shock, a severe response generated in the body in response to inflammatory molecules.2 Aside from its ability to inhibit IL-6 and TNF-alpha, research has shown that nobiletin inhibits the production of HMGB1, a mediator of endotoxin lethality with significant ability to indirectly stimulate inflammation.

In rabbit synovial fibroblasts and joint chondrocytes, nobiletin was the most effective of six flavonoids tested at suppressing the expression of matrix metalloproteinases. Nobiletin also reduced the production of the inflammatory mediator prostaglandin E2 (PGE2). The authors concluded, based on these results, that nobiletin is a novel anti-inflammatory candidate with the potential to inhibit PGE2 production and matrix degradation of the articular cartilage in osteoarthritis and rheumatoid arthritis.3

2) Anti-Cancer

As is the case with tangeretin, nobiletin has been associated with anticancer effects. In cancer cells, nobiletin and other citrus flavonoids have shown a protective effect against invasion. An experiment that tested the effects of four anti-invasive agents in seven human brain tumor-derived cell lines revealed that nobiletin was among the flavonoids with the greatest ability to inhibit invasion, migration, and adhesion in four of the cell lines and was also the most effective at downregulating the secretion of matrix metalloproteinases.4 In human squamous cell carcinoma cells, nobiletin inhibited cell growth after five days of administration at several concentrations that were tested.5 In mouse skin exposed to the tumor-promoting compound TPA, nobiletin inhibited two stages of skin inflammation, the expression of cyclooxygenase-2 (COX-2, an enzyme associated with inflammation) and the release of prostaglandin E2. Nobiletin helped inhibit skin tumor formation induced by the carcinogens DMBA and TPA by decreasing the number of tumors per mouse by 61.2% to 75.7%. These findings suggest that nobiletin could be a new chemopreventive agent in the tumorigenesis associated with inflammation.6

In rats given azoxymethane, a compound that induces aberrant crypt foci of the colon (a precursor of colon cancer), nobiletin given for five weeks prior to azoxymethane administration lowered the formation of aberrant crypt foci as well as prostaglandin E2 in the colon mucosa.7 In other research, which evaluated nobiletin’s effect in human colorectal cancer cells, nobiletin was shown to induce apoptosis (programmed cell death).8

In immunodeficient mice, administration of nobiletin was associated with a reduction in the mass and number of peritoneal dissemination nodules from a stomach cancer cell line in comparison with treatment with a control substance, suggesting its use as a drug to combat metastasis of gastric cancer.9

Research has found an increase in the uptake of the chemotherapeutic drugs vincristine in human myelogenous leukemia cells, and vinblastine in human colorectal cells in association with the administration of nobiletin. This has led to the conclusion that nobiletin and other methoxyflavones have potential as agents for reversing multidrug resistance in chemotherapy. When consumed regularly along with the drug atorvastatin, nobiletin has shown a protective effect against colon cancer in rats treated with a carcinogen by modulating cellular signaling regulators associated with inflammation, cell proliferation, cell cycle progression, apoptosis, angiogenesis and metastasis.

3) Prevents Clotting

Another area of benefit for nobiletin is in the inhibition of platelet adhesiveness and clot formation, that was confirmed in research involving mice. Investigation of nobiletin’s ability to modulate platelet function revealed mechanisms that include suppression of platelet aggregation, calcium mobilization, clot formation and more.10

4) Supports the Brain

Recent research suggests a protective effect for nobiletin against neurotoxic neuronal calcium overload. J. H. Lee and colleagues at Jeju National University reported that mitochondrial calcium overload is crucial in determining neuronal cell survival and death, processes that have been implicated in neurodegenerative diseases.11

In human stem cell-derived neurons that generate an excess of amyloid beta, and are used to study Alzheimer’s disease, nobiletin significantly reduced the amyloid beta content in the neurons as well as the extracellular amyloid beta. According to the researchers involved in the study, nobiletin appears to be a promising new prophylactic agent or functional food for Alzheimer’s disease.12 A review of nobiletin’s neuroprotective actions in Alzheimer’s and Parkinson’s disease noted that the flavonoid has been demonstrated to modify cholinergic deficits, reduce amyloid beta accumulation, help heal injury due to low blood flow, prevent tau protein hyperphosphorylation, and more.13 In a rat model of Parkinson’s disease, treatment with nobiletin protected dopaminergic neurons in the substantia nigra of the brain in addition to other benefits.14

5) Preservation and Regulation

Other potential uses for nobiletin include those of a food preservative; in cataract prevention; as a sunscreen; as a preventive agent and treatment for nonalcoholic fatty liver; as a therapy to prevent bone loss in postmenopausal women; and as a nutritional therapy for circadian clock disorders. Concerning the latter, the authors of an article in Cell Metabolism concluded that, based on their work, nobiletin activates RORs (retinoid acid receptor-related orphan receptors) and protects against metabolic syndrome in a clock-dependent manner. They predicted that their proof-of-principle study will accelerate the future use of nobiletin for other diseases, such as mood and sleep disorders, and for aging, in which the circadian amplitude is changed.”15

Summary

Nobiletin is a polymethoxyflavonoid that occurs exclusively in citrus fruits and has shown many benefits, including its ability to induce the differentiation of mouse myeloid leukemia cells, to exhibit antiproliferative activity toward a human squamous cell carcinoma cell line, to show anti-mutagenic activity, and to suppress the release pf matrix metalloproteinase-9 and prostaglandin E2 release. The authors of a study reported that nobiletin suppressed the combined endotoxin and cytokine-induced expression of nitric oxide synthase and cyclooxygenase-2 proteins, and thanks to these and several other benefits, they concluded that nobiletin emerges as a promising anti-inflammatory and/or chemopreventive agent.17

In addition to these prominent anticancer and anti-inflammatory benefits, nobiletin shows promise in other areas. Since not everyone consumes citrus fruit, a stand-alone nobiletin supplement is something we look forward to!

References

  1. Yang G et al. Food Funct. 2017 Dec 13;8(12):4668-4674.
  2. Li W et al. Inflammation. 2016 Apr;39(2):786-97.
  3. Ishiwa J et al. J Rheumatol. 2000 Jan;27(1):20-5.
  4. Rooprai HK et al. Neuropathol Appl Neurobiol. 2001 Feb;27(1):29-39.
  5. Kandaswani C et al. Cancer Lett. 1991 Feb;56(2):147-52.
  6. Murakami A et al. Cancer Res. 2000 Sep 15;60(18):5059-66.
  7. Kohno H et al. Life Sci. 2001 Jul 13;69(8):901-13.
  8. Zheng Q et al. J Cancer Res Clin Oncol. 2002 Oct;128(10):539-46.
  9. Minagawa A et al. Jpn J Cancer Res. 2001 Dec;92(12):1322-8.
  10. Vaiyapuri S et al. Br J Pharmacol. 2015 Aug;172(16):4133-45.
  11. Lee JH et al. Korean J Physiol Pharmacol. 2018 May;22(3):311-319.
  12. Kimura J et al. Biol Pharm Bull. 2018;41(4):451-457.
  13. Braidy N et al. CNS Neurol Disord Drug Targets. 2017;16(4):387-397.
  14. Jeong KH et al. J Med Food. 2015 Apr;18(4):409-14.
  15. He B et al. Cell Metab. 2016 Apr 12;23(4):610-21.
  16. Murakami A et al. Biosci Biotechnol Biochem. 2001 Jan;65(1):194-7.

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