New Insights into Health-Promoting Effects of Nobiletin from Citrus Fruits

References

• Gupta, B.; Sadaria, D.; Warrier, V. U.; Kirtonia, A.; Kant, R.; Awasthi, A.; Baligar, P.; Pal, J. K.; Yuba, E.; Sethi, G., et al. Plant Lectins and Their Usage in Preparing Targeted Nanovaccines for Cancer Immunotherapy. Semin. Cancer Biol. 2022, 80, 87–106. DOI: 10.1016/j.semcancer.2020.02.005.
   PubMed Web of Science ®Google Scholar
• Banik, K.; Ranaware, A. M.; Harsha, C.; Nitesh, T.; Girisa, S.; Deshpande, V.; Fan, L.; Nalawade, S. P.; Sethi, G.; Kunnumakkara, A. B. Piceatannol: A Natural Stilbene for the Prevention and Treatment of Cancer. Pharmacol. Res. 2020, 153, 104635. DOI: 10.1016/j.phrs.2020.104635.
   PubMed Web of Science ®Google Scholar
• Diwan, A.; Ninawe, A.; Harke, S. Gene Editing (CRISPR-Cas) Technology and Fisheries Sector. Can J Biotech. 2017, 1(2), 65–72. DOI: 10.24870/cjb.2017-000108.
   Google Scholar
• Wang, Y.; Chen, S.; Yu, O. Metabolic Engineering of Flavonoids in Plants and Microorganisms. Appl. Microbiol. Biotechnol. 2011, 91(4), 949–956. DOI: 10.1007/s00253-011-3449-2.
   PubMed Web of Science ®Google Scholar
• Jin, J.; Jie, L.; Zheng, L.; Cheng, M.; Xie, D.; Jin, Q.; Wang, X. Characteristics of Palm Mid-Fractions Produced from Different Fractionation Paths and Their Potential Usages. Int. J. Food Prop. 2018, 21(1), 58–69. DOI: 10.1080/10942912.2018.1437632.
   Web of Science ®Google Scholar
• Ullah, A.; Munir, S.; Badshah, S.L.; Khan, N.; Ghani, L.; Poulson, B.G.; Emwas, A.H.; Jaremko, M. Important Flavonoids and Their Role as a Therapeutic Agent. Mol. 2020, 25(22), 1–39.
   Web of Science ®Google Scholar
• Šamec, D.; Karalija, E.; Šola, I.; Vujčić Bok, V.; Salopek-Sondi, B. The Role of Polyphenols in Abiotic Stress Response: The Influence of Molecular Structure. Plants. 2021, 10(1), 118. DOI: 10.3390/plants10010118.
   Google Scholar
• Barreca, D.; Mandalari, G.; Calderaro, A.; Smeriglio, A.; Trombetta, D.; Felice, M. R.; Gattuso, G. Citrus Flavones: An Update on Sources. Biological Functions, and Health Promoting Properties. Plants (Basel). 2020, 9(3), 288. DOI: 10.3390/plants9030288.
   Google Scholar
• Dias, M. C.; Pinto, D. C. G. A.; Silva, A. M. S. Plant Flavonoids: Chemical Characteristics and Biological Activity. Mol. 2021, 26(17), 5377. DOI: 10.3390/molecules26175377.
   PubMed Web of Science ®Google Scholar
• Yi, L.; Ma, S.; Ren, D. Phytochemistry and Bioactivity of Citrus Flavonoids: A Focus on Antioxidant, Anti-Inflammatory, Anticancer and Cardiovascular Protection Activities. Phytochem. Rev. 2017, 16(3), 479–511. DOI: 10.1007/s11101-017-9497-1.
   Web of Science ®Google Scholar
• Gao, Z.; Gao, W.; Zeng, S. -L.; Li, P.; Liu, E. -H. Chemical Structures, Bioactivities and Molecular Mechanisms of Citrus Polymethoxyflavones. J. Funct. Foods. 2018, 40, 498–509. DOI: 10.1016/j.jff.2017.11.036.
   Web of Science ®Google Scholar
• Wang, Y.; Zang, W.; Ji, S.; Cao, J.; Sun, C. Three Polymethoxyflavones Purified from Ougan (Citrus Reticulata Cv. Suavissima) Inhibited LPS-Induced NO Elevation in the Neuroglia BV-2 Cell Line via the JAK2/STAT3 Pathway. Nutrients. 2019, 11(4), 791. DOI: 10.3390/nu11040791.
   PubMed Web of Science ®Google Scholar
• Huang, Y.; Wu, D.; Bao, M.; Li, B.; Liang, H. Coordination Driven Self-Assembly for Enhancing the Biological Stability of Nobiletin. J. Mol. Liq. 2019, 292, 111420. DOI: 10.1016/j.molliq.2019.111420.
   Web of Science ®Google Scholar
• Wu, X.; Song, M.; Gao, Z.; Sun, Y.; Wang, M.; Li, F.; Zheng, J.; Xiao, H. Nobiletin and Its Colonic Metabolites Suppress Colitis-Associated Colon Carcinogenesis by Down-Regulating iNOS, Inducing Antioxidative Enzymes and Arresting Cell Cycle Progression. J. Nutr. Biochem. 2017, 42, 17–25. DOI: 10.1016/j.jnutbio.2016.12.020.
   PubMed Web of Science ®Google Scholar
• Eguchi, A.; Murakami, A.; Li, S.; Ho, C. -T.; Ohigashi, H. Suppressive Effects of Demethylated Metabolites of Nobiletin on Phorbol Ester‐induced Expression of Scavenger Receptor Genes in THP‐1 Human Monocytic Cells. BioFactors. 2007, 31(2), 107–116. DOI: 10.1002/biof.5520310201.
   PubMed Web of Science ®Google Scholar
• Lee, Y. -S.; Asai, M.; Choi, S. -S.; Yonezawa, T.; Teruya, T.; Nagai, K.; Woo, J. -T.; Cha, B. -Y. Nobiletin Prevents Body Weight Gain and Bone Loss in Ovariectomized C57BL/6J Mice. Pharmacol. Pharm. 2014, 5(10), 959. DOI: 10.4236/pp.2014.510108.
   Google Scholar
• Lellupitiyage Don, S. S.; Robertson, K. L.; Lin, H. -H.; Labriola, C.; Harrington, M. E.; Taylor, S. R.; Farkas, M. E. Nobiletin Affects Circadian Rhythms and Oncogenic Characteristics in a Cell-Dependent Manner. PLoS One. 2020, 15(7), e0236315. DOI: 10.1371/journal.pone.0236315.
   PubMed Web of Science ®Google Scholar
• Teng, H.; Zheng, Y., Cao, H., Huang, Q., Xiao, J.; Chen, L. Enhancement of Bioavailability and Bioactivity of Diet-Derived Flavonoids by Application of Nanotechnology: A ReviewCrit. Rev. Food Sci. Nutr. 2021. 63(3), 1–16.
   PubMed Web of Science ®Google Scholar
• Theile, D.; Hohmann, N.; Kiemel, D.; Gattuso, G.; Barreca, D.; Mikus, G.; Haefeli, W. E.; Schwenger, V.; Weiss, J. Clementine Juice Has the Potential for Drug Interactions–In Vitro Comparison with Grapefruit and Mandarin Juice. Eur. J. Pharm. Sci. 2017, 97, 247–256. DOI: 10.1016/j.ejps.2016.11.021.
   PubMed Web of Science ®Google Scholar
• Barreca, D.; Gattuso, G.; Bellocco, E.; Calderaro, A.; Trombetta, D.; Smeriglio, A.; Laganà, G.; Daglia, M.; Meneghini, S.; Nabavi, S. M. Flavanones: Citrus Phytochemical with Health‐promoting Properties. BioFactors. 2017, 43(4), 495–506. DOI: 10.1002/biof.1363.
   PubMed Web of Science ®Google Scholar
• Yuk, T.; Kim, Y.; Yang, J.; Sung, J.; Jeong, H. S.; Lee, J. Nobiletin Inhibits Hepatic Lipogenesis via Activation of AMP-Activated Protein Kinase. Evid. Based Complement. Altern. Med. 2018, 2018, 1–8. DOI: 10.1155/2018/7420265.
   Web of Science ®Google Scholar
• Yasuda, N.; Ishii, T.; Oyama, D.; Fukuta, T.; Agato, Y.; Sato, A.; Shimizu, K.; Asai, T.; Asakawa, T.; Kan, T., et al. Neuroprotective Effect of Nobiletin on Cerebral Ischemia–Reperfusion Injury in Transient Middle Cerebral Artery-Occluded Rats. Brain Res. 2014, 1559, 46–54. DOI: 10.1016/j.brainres.2014.02.007.
   PubMed Web of Science ®Google Scholar
• Zhang, N.; Yang, Z.; Xiang, S. -Z.; Jin, Y. -G.; Wei, W. -Y.; Bian, Z. -Y.; Deng, W.; Tang, Q. -Z. Nobiletin Attenuates Cardiac Dysfunction, Oxidative Stress, and Inflammatory in Streptozotocin: Induced Diabetic Cardiomyopathy. Mol. Cell. Biochem. 2016, 417(1), 87–96. DOI: 10.1007/s11010-016-2716-z.
   PubMed Web of Science ®Google Scholar
• Zheng, J.; Bi, J.; Johnson, D.; Sun, Y.; Song, M.; Qiu, P.; Dong, P.; Decker, E.; Xiao, H. Analysis of 10 Metabolites of Polymethoxyflavones with High Sensitivity by Electrochemical Detection in High-Performance Liquid Chromatography. J. Agric. Food Chem. 2015, 63(2), 509–516. DOI: 10.1021/jf505545x.
   PubMed Web of Science ®Google Scholar
• Wiener, A. BitterDb: A Database of Bitter Compounds. Nucleic Acids Res. 2012, 40(Database issue), D413–9.
   PubMedGoogle Scholar
• Panche, A. N.; Diwan, A. D.; Chandra, S. R. Flavonoids: An Overview. J. Nutr. Sci. 2016, 5, e47.
   PubMed Web of Science ®Google Scholar
• Ju, S. N. Characterization, Stability, Digestion and Absorption of a Nobiletin Nanoemulsion Using DHA-Enriched Phosphatidylcholine as an Emulsifier in vivo and in vitro. Food Chem. 2022, 397, 133787.
   PubMed Web of Science ®Google Scholar
• Williamson, G.; Kay, C. D.; Crozier, A. The Bioavailability, Transport, and Bioactivity of Dietary Flavonoids: A Review from a Historical Perspective. Compr. Rev. Food Sci. Food Saf. 2018, 17(5), 1054–1112. DOI: 10.1111/1541-4337.12351.
   PubMed Web of Science ®Google Scholar
• Hattori, T.; Tagawa, H.; Inai, M.; Kan, T.; Kimura, S. -I.; Itai, S.; Mitragotri, S.; Iwao, Y. Transdermal Delivery of Nobiletin Using Ionic Liquids. Sci. Rep. 2019, 9(1), 1–11. DOI: 10.1038/s41598-019-56731-1.
   PubMedGoogle Scholar
• Uckoo, R. M.; Jayaprakasha, G. K.; Vikram, A.; Patil, B. S. Polymethoxyflavones Isolated from the Peel of Miaray Mandarin (Citrus Miaray) Have Biofilm Inhibitory Activity in Vibrio Harveyi. J. Agric. Food. Chem. 2015, 63(32), 7180–7189. DOI: 10.1021/acs.jafc.5b02445.
   PubMed Web of Science ®Google Scholar
• Kohno, H.; Yoshitani, S. -I.; Tsukio, Y.; Murakami, A.; Koshimizu, K.; Yano, M.; Tokuda, H.; Nishino, H.; Ohigashi, H.; Tanaka, T. Dietary Administration of Citrus Nobiletin Inhibits Azoxymethane-Induced Colonic Aberrant Crypt Foci in Rats. Life. sci. 2001, 69(8), 901–913. DOI: 10.1016/S0024-3205(01)01169-9.
   PubMed Web of Science ®Google Scholar
• Murakami, A.; Nakamura, Y.; Torikai, K.; Tanaka, T.; Koshiba, T.; Koshimizu, K.; Kuwahara, S.; Takahashi, Y.; Ogawa, K.; Yano, M., et al. Inhibitory Effect of Citrus Nobiletin on Phorbol Ester-Induced Skin Inflammation, Oxidative Stress, and Tumor Promotion in Mice. Cancer Res. 2000, 60(18), 5059–5066.
   PubMed Web of Science ®Google Scholar
• Itoh, N.; Iwata, C.; Toda, H. J. B. P. B. Molecular Cloning and Characterization of a Flavonoid-O-Methyltransferase with Broad Substrate Specificity and Regioselectivity from Citrus Depressa. BMC Plant Biol. 2016, 16(1), 1–13. DOI: 10.1186/s12870-016-0870-9.
   PubMedGoogle Scholar
• Lee, Y. -H.; Charles, A. L.; Kung, H. -F.; Ho, C. -T.; Huang, T. -C. Extraction of Nobiletin and Tangeretin from Citrus Depressa Hayata by Supercritical Carbon Dioxide with Ethanol as Modifier. Ind. Crops Prod. 2010, 31(1), 59–64. DOI: 10.1016/j.indcrop.2009.09.003.
   Web of Science ®Google Scholar
• Uckoo, R. M.; Jayaprakasha, G. K.; Patil, B. S. Rapid Separation Method of Polymethoxyflavones from Citrus Using Flash Chromatography. Sep. Purif. Techn. 2011, 81(2), 151–158. DOI: 10.1016/j.seppur.2011.07.018.
   Web of Science ®Google Scholar
• Goh, J. X. H.; Tan, L.T.H.; Goh, J.K.; Chan, K.G.; Pusparajah, P.; Lee, L.H. and Goh, B.H. Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention. Cancers (Basel). 2019, 11(6), 867. DOI: 10.3390/cancers11060867.
   PubMed Web of Science ®Google Scholar
• Williamson, G.; Holst, B. Dietary Reference Intake (DRI) Value for Dietary Polyphenols: Are We Heading in the Right Direction? Br. J. Nutr. 2008, 99(S3), S55–58. DOI: 10.1017/S0007114508006867.
   PubMedGoogle Scholar
• Li, S.; Wang, H.; Guo, L.; Zhao, H.; Ho, C. -T. Chemistry and Bioactivity of Nobiletin and Its Metabolites. J. Funct. Foods. 2014, 6, 2–10. DOI: 10.1016/j.jff.2013.12.011.
   Web of Science ®Google Scholar
• Singh, A. Systematic Review on Nobiletin a Phyto-Constitu-Ent Having Potential to Prevent and Manage Multiple Ailments. Japanese J Gstro Hepato. 2021, 5(14), 1–5.
   Google Scholar
• Peterson, J. J.; Dwyer, J. T.; Jacques, P. F.; McCullough, M. L. Improving the Estimation of Flavonoid Intake for Study of Health Outcomes. Nutr. Rev. 2015, 73(8), 553–576. DOI: 10.1093/nutrit/nuv008.
   PubMed Web of Science ®Google Scholar
• Zamora-Ros, R.; Knaze, V.; Rothwell, J. A.; Hémon, B.; Moskal, A.; Overvad, K.; Tjønneland, A.; Kyrø, C.; Fagherazzi, G.; Boutron-Ruault, M. -C., et al. Dietary Polyphenol Intake in Europe: The European Prospective Investigation into Cancer and Nutrition (EPIC) Study. Eur. J. Nutr. 2016, 55(4), 1359–1375.
   PubMed Web of Science ®Google Scholar
• Gabriele, M.; Frassinetti, S.; Caltavuturo, L.; Montero, L.; Dinelli, G.; Longo, V.; Di Gioia, D.; Pucci, L. Citrus Bergamia Powder: Antioxidant, Antimicrobial and Anti-Inflammatory Properties. J. Funct. Foods. 2017, 31, 255–265. DOI: 10.1016/j.jff.2017.02.007.
   Web of Science ®Google Scholar
• Oteiza, P.; Fraga, C. G.; Mills, D. A.; Taft, D. H. Flavonoids and the Gastrointestinal Tract: Local and Systemic Effects. Molecular Aspects of Medicine. Mol. Aspects. Med. 2018, 61, 41–49. DOI: 10.1016/j.mam.2018.01.001.
   PubMed Web of Science ®Google Scholar
• Wang, M., Zheng, J.; Zhong, Z.; Song, M.; Wu, X.Tissue Distribution of Nobiletin and Its Metabolites in Mice After Oral Administration of Nobiletin. 2013, Wiley Online Library.
   Google Scholar
• Koga, N.; Ohta, C.; Kato, Y.; Haraguchi, K.; Endo, T.; Ogawa, K.; Ohta, H.; Yano, M. In vitro Metabolism of Nobiletin, a Polymethoxy-Flavonoid, by Human Liver Microsomes and Cytochrome P450. Xenobiotica. 2011, 41(11), 927–933. DOI: 10.3109/00498254.2011.593208.
   PubMed Web of Science ®Google Scholar
• Zhang, M.; Zhu, S.; Yang, W.; Huang, Q.; Ho, C. -T. The Biological Fate and Bioefficacy of Citrus Flavonoids: Bioavailability, Biotransformation, and Delivery Systems. Food & Function. 2021, 12(8), 3307–3323. DOI: 10.1039/D0FO03403G.
   PubMed Web of Science ®Google Scholar
• Wen, X.; Walle, T. Methylated Flavonoids Have Greatly Improved Intestinal Absorption and Metabolic Stability. Drug Metabolism and Disposition. Drug Metab. Dispos. 2006, 34(10), 1786–1792. DOI: 10.1124/dmd.106.011122.
   PubMed Web of Science ®Google Scholar
• Kesharwani, S.; Mallya, P.; Kumar, V. A.; Jain, V.; Sharma, S.; Dey, S. Nobiletin as a Molecule for Formulation Development: An Overview of Advanced Formulation and Nanotechnology-Based Strategies of Nobiletin. AAPS PharmScitech. 2020, 21(6). DOI: 10.1208/s12249-020-01767-0.
   PubMed Web of Science ®Google Scholar
• Mayorga-Gross, A. L.; Esquivel, P. Impact of Cocoa Products Intake on Plasma and Urine Metabolites: A Review of Targeted and Non-Targeted Studies in Humans. Nutrients. 2019, 11(5), 1163. DOI: 10.3390/nu11051163.
   PubMed Web of Science ®Google Scholar
• Wu, X.; Song, M.; Wang, M.; Zheng, J.; Gao, Z.; Xu, F.; Zhang, G.; Xiao, H. Chemopreventive Effects of Nobiletin and Its Colonic Metabolites on Colon Carcinogenesis. Molecular Nutrition & Food Research. Mol Nutr Food Res. 2015, 59(12), 2383–2394. DOI: 10.1002/mnfr.201500378.
   PubMed Web of Science ®Google Scholar
• Murakami, A.; Koshimizu, K.; Ohigashi, H.; Kuwahara, S.; Kuki, W.; Takahashi, Y.; Hosotani, K.; Kawahara, S.; Matsuoka, Y. Characteristic Rat Tissue Accumulation of Nobiletin, a Chemopreventive Polymethoxyflavonoid, in Comparison with Luteolin. BioFactors. 2002, 16(3–4), 73–82. DOI: 10.1002/biof.5520160303.
   PubMed Web of Science ®Google Scholar
• Zhang, M.; Xin, Y.; Feng, K.; Yin, B.; Kan, Q.; Xiao, J.; Cao, Y.; Ho, C. -T.; Huang, Q. Comparative Analyses of Bioavailability, Biotransformation, and Excretion of Nobiletin in Lean and Obese Rats. J. Agric. Food Chem. 2020, 68(39), 10709–10718. DOI: 10.1021/acs.jafc.0c04425.
   PubMed Web of Science ®Google Scholar
• Arshad, R.; Gulshad, L.; Haq, I. -U.; Farooq, M. A.; Al‐farga, A.; Siddique, R.; Manzoor, M. F.; Karrar, E. Nanotechnology: A Novel Tool to Enhance the Bioavailability of Micronutrients. Food Sci. Nutr. 2021, 9(6), 3354–3361. DOI: 10.1002/fsn3.2311.
   PubMed Web of Science ®Google Scholar
• Buya, A. B.; Beloqui, A.; Memvanga, P. B.; Préat, V. Self-Nano-Emulsifying Drug-Delivery Systems: From the Development to the Current Applications and Challenges in Oral Drug Delivery. Pharmaceutics. 2020, 12(12), 1194. DOI: 10.3390/pharmaceutics12121194.
   PubMed Web of Science ®Google Scholar
• Mehanna, M. M.; Mneimneh, A. T. Formulation and Applications of Lipid-Based Nanovehicles: Spotlight on Self-Emulsifying Systems. Adv. Pharm. Bull. 2021, 11(1), 56–67. DOI: 10.34172/apb.2021.006.
   PubMed Web of Science ®Google Scholar
• McClements, D. J. J. J. O. F. S. Nanoscale Nutrient Delivery Systems for Food Applications: Improving Bioactive Dispersibility, Stability, and Bioavailability. J. Food Sci. 2015, 80(7), N1602–1611. DOI: 10.1111/1750-3841.12919.
   PubMed Web of Science ®Google Scholar
• Feng, S. -L.; Tian, Y.; Huo, S.; Qu, B.; Liu, R. -M.; Xu, P.; Li, Y. -Z.; Xie, Y. Nobiletin Potentiates Paclitaxel Anticancer Efficacy in A549/T Xenograft Model: Pharmacokinetic and Pharmacological Study. Phytomedicine. 2020, 67, 153141. DOI: 10.1016/j.phymed.2019.153141.
   PubMed Web of Science ®Google Scholar
• Ma, W.; Feng, S.; Yao, X.; Yuan, Z.; Liu, L.; Xie, Y. Nobiletin Enhances the Efficacy of Chemotherapeutic Agents in ABCB1 Overexpression Cancer Cells. Sci. Rep. 2015, 5(1), 18789. DOI: 10.1038/srep18789.
   PubMedGoogle Scholar
• Zhang, D. M.; Li, Y. -J.; Shu, C.; Ruan, Z. -X.; Chen, W. -M.; Yiu, A.; Peng, Y. -H.; Wang, J.; Lan, P.; Yao, Z., et al. Bipiperidinyl Derivatives of 23-Hydroxybetulinic Acid Reverse Resistance of HepG2/ADM and MCF-7/ADR Cells. Anticancer Drugs. 2013, 24(5), 441–454.
   PubMed Web of Science ®Google Scholar
• Liu, R.; Song, Y.; Li, C.; Zhang, Z.; Xue, Z.; Huang, Q.; Yu, L.; Zhu, D.; Cao, Z.; Lu, A., et al. The Naturally Occurring Flavonoid Nobiletin Reverses Methotrexate Resistance via Inhibition of P-Glycoprotein Synthesis. J. Biol. Chem. 2022, 298(4), 101756.
   PubMed Web of Science ®Google Scholar
• Dusabimana, T.; Kim, S. R.; Kim, H. J.; Park, S. W.; Kim, H. Nobiletin Ameliorates Hepatic Ischemia and Reperfusion Injury Through the Activation of SIRT-1/FOXO3a-Mediated Autophagy and Mitochondrial Biogenesis. Exp. Mol. Med. 2019, 51(4), 1–16. DOI: 10.1038/s12276-019-0245-z.
   PubMed Web of Science ®Google Scholar
• Rizzo, G. E. M.; Cabibbo, G.; Craxì, A. Hepatitis B Virus-Associated Hepatocellular Carcinoma. Viruses. 2022, 14(5), 986. DOI: 10.3390/v14050986.
   PubMed Web of Science ®Google Scholar
• Hu, Y. Ca2±induced Whey Protein Emulgels for the Encapsulation of Crystalline Nobiletin: Effect of Nobiletin Crystals on the Viscoelasticity. Food Hydrocolloids. 2019, 94, 57–62.
   Web of Science ®Google Scholar
• Morrow, N. M. The Citrus Flavonoid Nobiletin Confers Protection from Metabolic Dysregulation in High-Fat-Fed Mice Independent of AMPK [S]. J. Lipid Res. 2020, 61(3), 387–402.
   PubMed Web of Science ®Google Scholar
• Tsuboi, T. Molecular Mechanism for Nobiletin to Enhance ABCA1/G1 Expression in Mouse Macrophages. Atherosclerosis. 2020, 297, 32–39.
   PubMed Web of Science ®Google Scholar
• Kou, G. Nobiletin Activates Thermogenesis of Brown and White Adipose Tissue in High‐fat Diet‐fed C57BL/6 Mice by Shaping the Gut Microbiota. Faseb. J. 2021, 35(2), e21267.
   PubMed Web of Science ®Google Scholar
• Shimano, H. Sterol Regulatory Element-Binding Protein-1 as a Key Transcription Factor for Nutritional Induction of Lipogenic Enzyme Genes. J. Biol. Chem. 1999, 274(50), 35832–35839.
   PubMed Web of Science ®Google Scholar
• Xiong, J. Fluoxetine Suppresses AMP-Activated Protein Kinase Signaling Pathway to Promote Hepatic Lipid Accumulation in Primary Mouse Hepatocytes. Int. J. Biochem. Cell Biol. 2014, 54, 236–244.
   PubMed Web of Science ®Google Scholar
• Mhyre, T. R. Parkinson’s Disease. Subcell Biochem. 2012, 65, 389–455.
   PubMedGoogle Scholar
• Evans, J. A.; Mendonca, P.; Soliman, K. F. A. Neuroprotective Effects and Therapeutic Potential of the Citrus Flavonoid Hesperetin in Neurodegenerative Diseases. Nutrients. 2022,14(11), 2228.
   PubMed Web of Science ®Google Scholar
• Youn, K.; Lee, S.; Jun, M. Discovery of Nobiletin from Citrus Peel as a Potent Inhibitor of β-Amyloid Peptide Toxicity. Nutrients. 2019, 11(11), 2648.
   PubMed Web of Science ®Google Scholar
• Nakajima, A.; Ohizumi, Y. Potential Benefits of Nobiletin, a Citrus Flavonoid, Against Alzheimer’s Disease and Parkinson’s Disease. Int. J. Mol. Sci. 2019, 20(14), 3380.
   PubMed Web of Science ®Google Scholar
• Onozuka, H. Nobiletin, a Citrus Flavonoid, Improves Memory Impairment and Aβ Pathology in a Transgenic Mouse Model of Alzheimer’s Disease. J. Pharmacol. Exp. Ther. 2008, 326(3), 739–744.
   PubMed Web of Science ®Google Scholar
• Potue, P. Nobiletin Alleviates Vascular Alterations Through Modulation of Nrf-2/HO-1 and MMP Pathways in L-NAME Induced Hypertensive Rats. Food & Function. 2019, 10(4), 1880–1892.
   PubMed Web of Science ®Google Scholar
• Kim, J. -J. Co-Existence of Hypertensive and Anti-Hypertensive Constituents, Synephrine, and Nobiletin in Citrus Unshiu Peel. Molecules. 2019, 24(7), 1197.
   PubMed Web of Science ®Google Scholar
• Josefs, T., Barrett, T. J.; Brown, E. J.; Quezada, A.; Wu, X.; Voisin, M.; Amengual, J.; Fisher, E. A. Neutrophil Extracellular Traps Promote Macrophage Inflammation and Impair Atherosclerosis Resolution in Diabetic Mice. JCI Insight. 2020, 5(7), e134796. Apr 9. doi:10.1172/jci.insight.134796.
   PubMed Web of Science ®Google Scholar
• Nguyen-Ngo, C. Nobiletin Exerts Anti-Diabetic and Anti-Inflammatory Effects in an in vitro Human Model and in vivo Murine Model of Gestational Diabetes. Clinical Sci. 2020, 134(6), 571–592.
   PubMed Web of Science ®Google Scholar
• Liu, F. Nobiletin Suppresses Oxidative Stress and Apoptosis in H9c2 Cardiomyocytes Following Hypoxia/Reoxygenation Injury. Eur. J. Pharmacol. 2019, 854, 48–53.
   PubMed Web of Science ®Google Scholar
• Lebre, M. C. Synovial IL‐21/Tnf‐producing CD4+ T Cells Induce Joint Destruction in Rheumatoid Arthritis by Inducing Matrix Metalloproteinase Production by Fibroblast‐like Synoviocytes. J. Leukocyte Biol. 2017, 101(3), 775–783.
   PubMed Web of Science ®Google Scholar
• Parkar, N.; Bhatt, L.; Addepalli, V. Efficacy of Nobiletin, a Citrus Flavonoid, in the Treatment of the Cardiovascular Dysfunction of Diabetes in Rats. Food & Function. 2016, 7(7), 3121–3129.
   PubMed Web of Science ®Google Scholar
• Vergès, B. Pathophysiology of Diabetic Dyslipidaemia: Where are We? Diabetologia. 2015, 58(5), 886–899.
   PubMed Web of Science ®Google Scholar
• Mulvihill, E. E. Nobiletin Attenuates VLDL Overproduction, Dyslipidemia, and Atherosclerosis in Mice with Diet-Induced Insulin Resistance. Diabetes. 2011, 60(5), 1446–1457.
   PubMed Web of Science ®Google Scholar
• Yen, J. H.; Lin, C. Y.; Chuang, C. H.; Chin, H. K.; Wu, M. J.; Chen, P. Y. Nobiletin Promotes Megakaryocytic Differentiation Through the MAPK/ERK-Dependent EGR1 Expression and Exerts Anti-Leukemic Effects in Human Chronic Myeloid Leukemia (CML) K562 Cells. Cells. 2020, 9(4), 877. https://doi.org/10.3390/cells9040877.
   PubMed Web of Science ®Google Scholar
• Saito, T.; Abe, D.; Nogata, Y. Polymethoxylated Flavones Potentiate the Cytolytic Activity of NK Leukemia Cell Line KHYG-1 via Enhanced Expression of Granzyme B. Biochem. Biophys. Res. Commun. 2015, 456(3), 799–803.
   PubMed Web of Science ®Google Scholar
• Nohara, K. Ammonia-Lowering Activities and Carbamoyl Phosphate Synthetase 1 (Cps1) Induction Mechanism of a Natural Flavonoid. Nutrition & Metabolism. 2015, 12(1), 1–12.
   PubMedGoogle Scholar
• Huang, H. The Multifunctional Effects of Nobiletin and Its Metabolites in vivo and in Vitro. Evid Based Complement Alternat Med. 2016, 2016, 2918796.
   PubMed Web of Science ®Google Scholar
• Song, M. The Chemopreventive Effect of 5-Demethylnobiletin, a Unique Citrus Flavonoid, on Colitis-Driven Colorectal Carcinogenesis in Mice is Associated with Its Colonic Metabolites. Food & Function. 2020, 11(6), 4940–4952.
   PubMed Web of Science ®Google Scholar
• Moon, J. Y.; Cho, S. K. Nobiletin Induces Protective Autophagy Accompanied by ER-Stress Mediated Apoptosis in Human Gastric Cancer SNU-16 Cells. Molecules. 2016, 21(7), 914.
   PubMed Web of Science ®Google Scholar
• Yang, G. Nobiletin Prevents Trimethylamine Oxide-Induced Vascular Inflammation via Inhibition of the NF-Κb/MAPK Pathways. J. Agric. Food Chem. 2019, 67(22), 6169–6176.
   PubMed Web of Science ®Google Scholar
• Ouyang, Y.; Li, L.; Ling, P. Nobiletin Inhibits Helicobacterium Pylori Infection-Induced Gastric Carcinogenic Signaling by Blocking Inflammation, Apoptosis, and Mitogen-Activated Protein Kinase Events in Gastric Epithelial-1 Cells. J. Environ. Pathol. Toxicol. Oncol. 2020, 39(1), 77–88. https://doi.org/10.1615/JEnvironPatholToxicolOncol.2020031272.
   PubMed Web of Science ®Google Scholar
• Zhang, R. Nobiletin Triggers Reactive Oxygen Species-Mediated Pyroptosis Through Regulating Autophagy in Ovarian Cancer Cells. J. Agric. Food Chem. 2020, 68(5), 1326–1336.
   PubMed Web of Science ®Google Scholar
• Sp, N. Nobiletin Inhibits CD36-Dependent Tumor Angiogenesis, Migration, Invasion, and Sphere Formation Through the Cd36/Stat3/Nf-Κb Signaling Axis. Nutrients. 2018, 10(6), 772.
   PubMed Web of Science ®Google Scholar
• Jiang, H. Nobiletin Flavone Inhibits the Growth and Metastasis of Human Pancreatic Cancer Cells via Induction of Autophagy, G0/G1 Cell Cycle Arrest and Inhibition of NF-Kb Signalling Pathway. J. Bu On. 2020, 25(2), 1070–1075.
   PubMed Web of Science ®Google Scholar
• Wu, C. A Comparison of Volatile Fractions Obtained from Lonicera Macranthoides via Different Extraction Processes: Ultrasound, Microwave, Soxhlet Extraction, Hydrodistillation, and Cold Maceration. Integr. Med. Res. 2015, 4(3), 171–177.
   PubMed Web of Science ®Google Scholar
• Wu, X. A Metabolite of Nobiletin, 4′-Demethylnobiletin and Atorvastatin Synergistically Inhibits Human Colon Cancer Cell Growth by Inducing G0/G1 Cell Cycle Arrest and Apoptosis. Food & Function. 2018, 9(1), 87–95.
   PubMed Web of Science ®Google Scholar
• DiMarco‐crook, C. Synergistic Anticancer Effects of Curcumin and 3’, 4‘‐didemethylnobiletin in Combination on Colon Cancer Cells. J. Food Sci. 2020, 85(4), 1292–1301.
   PubMed Web of Science ®Google Scholar
• Morley, K. L.; Ferguson, P. J.; Koropatnick, J. Tangeretin and Nobiletin Induce G1 Cell Cycle Arrest but Not Apoptosis in Human Breast and Colon Cancer Cells. Cancer Lett. 2007, 251(1), 168–178.
   PubMed Web of Science ®Google Scholar
• Chiou, Y. -S. 5-Demethylnobiletin More Potently Inhibits Colon Cancer Cell Growth Than Nobiletin in vitro and in vivo. J. Food Bioactives. 2018, 2, 91–97.
   Google Scholar
• Sousa, D. P. Nobiletin Alone or in Combination with Cisplatin Decreases the Viability of Anaplastic Thyroid Cancer Cell Lines. Nutr. Cancer. 2020, 72(2), 352–363.
   PubMed Web of Science ®Google Scholar
• Sp, N.; Kang, D. Y.; Joung, Y. H.; Park, J. H.; Kim, W. S.; Lee, H. K.; Yang, Y. M. Nobiletin Inhibits Angiogenesis by Regulating Src/fak/stat3-Mediated Signaling Through PXN in ER+ Breast Cancer Cells. International Journal of Molecular Sciences. 2017, 18(5), 935.
   PubMed Web of Science ®Google Scholar
• Sp, N.; Kang, D. Y.; Kim, D. H.; Park, J. H.; Lee, H. G.; Kim, H. J.; Darvin, P.; Park, Y. M.; Yang, Y. M. Nobiletin Inhibits CD36-Dependent Tumor Angiogenesis, Migration, Invasion, and Sphere Formation Through the Cd36/Stat3/Nf-Κb Signaling Axis. Nutrients. 2018,10(6), 772. https://doi.org/10.3390/nu10060772.
   PubMed Web of Science ®Google Scholar
• Chen, C. Antiproliferative and Apoptosis-Inducing Activity of Nobiletin Against Three Subtypes of Human Breast Cancer Cell Lines. Anticancer Res. 2014, 34(4), 1785–1792.
   PubMed Web of Science ®Google Scholar
• Sun, Y. Inhibitory Effects of Nobiletin and Its Major Metabolites on Lung Tumorigenesis. Food & Function. 2019, 10(11), 7444–7452.
   PubMed Web of Science ®Google Scholar
• Guney Eskiler, G. Synergistic Effects of Nobiletin and Sorafenib Combination on Metastatic Prostate Cancer Cells. Nutr. Cancer. 2019, 71(8), 1299–1312.
   PubMed Web of Science ®Google Scholar
• Deveci Ozkan, A. Anti-Inflammatory Effects of Nobiletin on TLR4/TRIF/IRF3 and TLR9/IRF7 Signaling Pathways in Prostate Cancer Cells. Immunopharmacol. Immunotoxicol. 2020, 42(2), 93–100.
   PubMed Web of Science ®Google Scholar
• Jordan, S.; Murty, M.; Pilon, K. Products Containing Bitter Orange or Synephrine: Suspected Cardiovascular Adverse Reactions. Can. Med. Assoc. J. 2004, 171(8), 993.
   PubMedGoogle Scholar
• Roza, J.; Xian-Liu, Z.; Guthrie, N. Effect of Citrus Flavonoids and Tocotrienols on Serum Cholesterol Levels in Hypercholesterolemic Subjects. Alternative Therapies in Health. Med. 2007, 13, 44–48.
   PubMed Web of Science ®Google Scholar
• Mao, Q. Nobiletin Protects Against Myocardial Injury and Myocardial Apoptosis Following Coronary Microembolization via Activating PI3K/Akt Pathway in Rats. Naunyn Schmiedebergs Arch Pharmacol. 2019, 392(9), 1121–1130.
   PubMed Web of Science ®Google Scholar
• Qi, G. Nobiletin Protects Against Systemic Inflammation-Stimulated Memory Impairment via MAPK and NF-Κb Signaling Pathways. J. Agric. Food. Chem. 2019, 67(18), 5122–5134.
   PubMed Web of Science ®Google Scholar
• Solnier, J.; Martin, L.; Bhakta, S.; Bucar, F. Flavonoids as Novel Efflux Pump Inhibitors and Antimicrobials Against Both Environmental and Pathogenic Intracellular Mycobacterial Species. Molecules (Basel, Switzerland). 2020, 25(3), 734. https://doi.org/10.3390/molecules25030734.
   PubMed Web of Science ®Google Scholar
• Badavath, V. N. 2016, Synthesis and Antiviral Activity of 2-Aryl- 4H-Chromen- 4-One Derivatives Against Chikungunya Virus. Lett. Drug Des. Discov. 13, 1019–1024.
   Web of Science ®Google Scholar
• Nakamoto, A. Nobiletin Enhances Induction of Antigen-Specific Immune Responses in BALB/C Mice Immunized with Ovalbumin. J. Nutr. Sci. Vitaminol. (Tokyo). 2019, 65(3), 278–282.
   PubMed Web of Science ®Google Scholar