Anti-inflammatory effects of polymethoxyflavones from citrus peels: a review

Inflammation is a non-specific kind of biological immune response of body tissues to any type of external or internal injuries, such as pathogens, irritants and immune stress reactions. There are two types of inflammation, namely acute and chronic. Acute inflammation starts and develops rapidly, and is aroused by various factors, including injuries, infection, toxins or immune reactions. Chronic inflammation usually lasts for an extended long period of time and results from elimination failure of acute inflammation, autoimmune disorders, various pathogens and pathogenic environments. Except for the damage itself, there exists a direct and intimate connection between chronic inflammation and various clinic common diseases, such as neurodegeneration, as well as metabolic and cardiovascular ailments. Citrus peel is a by-product generated in citrus juice processing. Polymethoxyflavones (PMFs) exist abundantly and almost exclusively in citrus peels, and their biological activities have been broadly investigated in recent years. PMFs have proven to possess potential inhibitory bioactivities towards a number of functional and immune diseases including inflammation. The two most abundant PMFs exhibiting prominent bioactivities in citrus peels are nobiletin and tangeretin, ubiquitously detected in various citrus species. In this review, the beneficial health effects and the underlying molecular mechanisms of ten main citrus PMFs were illustrated against numerous inflammatory diseases, including inflammatory bowel disease (IBD), neuroinflammation and organ inflammation, among others.

[1]  S. Bischoff,et al.  Nobiletin acts anti-inflammatory on murine IL-10−/− colitis and human intestinal fibroblasts , 2019, European Journal of Nutrition.

[2]  Chi-Tang Ho,et al.  Absorption of polymethoxyflavones and their derivatives , 2018, Journal of Food Bioactives.

[3]  Wenbing Zhi,et al.  Nobiletin-Ameliorated Lipopolysaccharide-Induced Inflammation in Acute Lung Injury by Suppression of NF-κB Pathway In Vivo and Vitro , 2018, Inflammation.

[4]  Jing Wu,et al.  Tangeretin ameliorates renal failure via regulating oxidative stress, NF-κB–TNF-α/iNOS signalling and improves memory and cognitive deficits in 5/6 nephrectomized rats , 2017, Inflammopharmacology.

[5]  N. Lee,et al.  Tetramethyl-O-scutellarin isolated from peels of immature Shiranuhi fruit exhibits anti-inflammatory effects on LPSinduced RAW264.7 cells , 2017 .

[6]  Wenbing Zhi,et al.  The gastroprotective effect of nobiletin against ethanol-induced acute gastric lesions in mice: impact on oxidative stress and inflammation , 2017, Immunopharmacology and immunotoxicology.

[7]  Junsoo Lee,et al.  Nobiletin Attenuates the Inflammatory Response Through Heme Oxygenase-1 Induction in the Crosstalk Between Adipocytes and Macrophages. , 2017, Journal of medicinal food.

[8]  Peiju Qiu,et al.  Synergistic chemopreventive effects of nobiletin and atorvastatin on colon carcinogenesis , 2017, Carcinogenesis.

[9]  S. Bischoff,et al.  Citrus peel polymethoxyflavones nobiletin and tangeretin suppress LPS- and IgE-mediated activation of human intestinal mast cells , 2017, European Journal of Nutrition.

[10]  J. Gong,et al.  Nobiletin attenuates lipopolysaccharide/D‑galactosamine‑induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF‑κB‑mediated cytokine production. , 2016, Molecular medicine reports.

[11]  T. Sugahara,et al.  Nobiletin suppresses monocyte chemoattractant protein-1 (MCP-1) expression by regulating MAPK signaling in 3T3-L1 cells , 2016 .

[12]  Weifu Lei,et al.  Nobiletin ameliorates isoflurane-induced cognitive impairment via antioxidant, anti-inflammatory and anti-apoptotic effects in aging rats. , 2016, Molecular medicine reports.

[13]  Dong-Hyun Kim,et al.  Tangeretin Inhibits IL-12 Expression and NF-κB Activation in Dendritic Cells and Attenuates Colitis in Mice , 2016, Planta Medica.

[14]  H. Arab,et al.  Tangeretin attenuates cisplatin-induced renal injury in rats: Impact on the inflammatory cascade and oxidative perturbations. , 2016, Chemico-biological interactions.

[15]  Q. Tang,et al.  Nobiletin attenuates cardiac dysfunction, oxidative stress, and inflammatory in streptozotocin: induced diabetic cardiomyopathy , 2016, Molecular and Cellular Biochemistry.

[16]  Hang Xiao,et al.  Enhanced Anti-Inflammatory Activities by the Combination of Luteolin and Tangeretin. , 2016, Journal of food science.

[17]  Ting Zhao,et al.  Nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo , 2016, Brain Research.

[18]  H. Arab,et al.  Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis , 2016, PloS one.

[19]  Yu Young Lee,et al.  Anti-Inflammatory and Antioxidant Mechanism of Tangeretin in Activated Microglia , 2016, Journal of Neuroimmune Pharmacology.

[20]  Wei Tang,et al.  Tangeretin from Citrus reticulate Inhibits Respiratory Syncytial Virus Replication and Associated Inflammation in Vivo. , 2015, Journal of agricultural and food chemistry.

[21]  Chi-Tang Ho,et al.  Disease chemopreventive effects and molecular mechanisms of hydroxylated polymethoxyflavones , 2015, BioFactors.

[22]  B. Patil,et al.  Polymethoxyflavones Isolated from the Peel of Miaray Mandarin (Citrus miaray) Have Biofilm Inhibitory Activity in Vibrio harveyi. , 2015, Journal of agricultural and food chemistry.

[23]  A. Dinda,et al.  Nobiletin ameliorates cisplatin-induced acute kidney injury due to its anti-oxidant, anti-inflammatory and anti-apoptotic effects. , 2015, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[24]  Jung-hee Kim,et al.  Callicarpa japonica Thunb. reduces inflammatory responses: a mouse model of lipopolysaccharide-induced acute lung injury. , 2015, International immunopharmacology.

[25]  Jinyong Peng,et al.  Citrus nobiletin ameliorates experimental colitis by reducing inflammation and restoring impaired intestinal barrier function. , 2015, Molecular nutrition & food research.

[26]  Takashi Yoshida,et al.  3,5,6,7,8,3′,4′-Heptamethoxyflavone, a Citrus Polymethoxylated Flavone, Attenuates Inflammation in the Mouse Hippocampus , 2015, Brain sciences.

[27]  Jinn-Moon Yang,et al.  5-Demethyltangeretin is more potent than tangeretin in inhibiting dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumorigenesis , 2014 .

[28]  Su-Chen Ho,et al.  Hesperidin, nobiletin, and tangeretin are collectively responsible for the anti-neuroinflammatory capacity of tangerine peel (Citri reticulatae pericarpium). , 2014, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[29]  M. Morita,et al.  3,5,6,7,8,3′,4′-Heptamethoxyflavone, a citrus flavonoid, on protection against memory impairment and neuronal cell death in a global cerebral ischemia mouse model , 2014, Neurochemistry International.

[30]  Chi-Tang Ho,et al.  Chemistry and bioactivity of nobiletin and its metabolites , 2014 .

[31]  J. Woo,et al.  Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-κB, AP-1 and p38. , 2013, International immunopharmacology.

[32]  Yung-Hyun Choi,et al.  5-Hydroxy-3,6,7,8,3'4'-hexamethoxyflavone inhibits nitric oxide production in lipopolysaccharide-stimulated BV2 microglia via NF-κB suppression and Nrf-2-dependent heme oxygenase-1 induction. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[33]  Chi-Tang Ho,et al.  Effects of citrus flavonoids, 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone and 3,5,6,7,8,3',4'-heptamethoxyflavone, on the activities of macrophage scavenger receptors and the hepatic LDL receptor. , 2013, Food & function.

[34]  K. Onda,et al.  Polymethoxyflavonoids Tangeretin and Nobiletin Increase Glucose Uptake in Murine Adipocytes , 2013, Phytotherapy research : PTR.

[35]  Se-Jae Kim,et al.  Effects of Sinensetin on Lipid Metabolism in Mature 3T3‐L1 Adipocytes , 2013, Phytotherapy research : PTR.

[36]  A. Crozier Flavonoids and Related Compounds : Bioavailability and Function , 2012 .

[37]  Se-Jae Kim,et al.  Sinensetin Attenuates LPS-Induced Inflammation by Regulating the Protein Level of IκB-α , 2012, Bioscience, biotechnology, and biochemistry.

[38]  H. Vapaatalo,et al.  Flavonoids Eupatorin and Sinensetin Present in Orthosiphon stamineus Leaves Inhibit Inflammatory Gene Expression and STAT1 Activation , 2012, Planta Medica.

[39]  A. Tsuji,et al.  Sudachitin, a Polymethoxyflavone from Citrus sudachi, Suppresses Lipopolysaccharide-Induced Inflammatory Responses in Mouse Macrophage-Like RAW264 Cells , 2012, Bioscience, biotechnology, and biochemistry.

[40]  Xin Xin,et al.  Anti-diabetic effects of pentamethylquercetin in neonatally streptozotocin-induced diabetic rats. , 2011, European journal of pharmacology.

[41]  H. Matsuda,et al.  Suppressive effects of methoxyflavonoids isolated from Kaempferia parviflora on inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. , 2011, Journal of ethnopharmacology.

[42]  Si Jin,et al.  Pentamethylquercetin Improves Adiponectin Expression in Differentiated 3T3-L1 Cells via a Mechanism that Implicates PPARγ together with TNF-α and IL-6 , 2011, Molecules.

[43]  N. Lee,et al.  Preparation of a polymethoxyflavone-rich fraction (PRF) of Citrus sunki Hort. ex Tanaka and its antiproliferative effects , 2010 .

[44]  J. Liao,et al.  NF‐κB and innate immunity in ischemic stroke , 2010, Annals of the New York Academy of Sciences.

[45]  B. Cha,et al.  Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. , 2010, Biochemical pharmacology.

[46]  P. Tansakul,et al.  Anti-inflammatory mechanism of Kaempferia parviflora in murine macrophage cells (RAW 264.7) and in experimental animals. , 2009, Journal of ethnopharmacology.

[47]  Sarot Cheenpracha,et al.  Anti-inflammatory effects of compounds from Kaempferia parviflora and Boesenbergia pandurata , 2009 .

[48]  Chi-Tang Ho,et al.  Polymethoxyflavones activate Ca2+-dependent apoptotic targets in adipocytes. , 2009, Journal of agricultural and food chemistry.

[49]  S. Tewtrakul,et al.  Effects of compounds from Kaempferia parviflora on nitric oxide, prostaglandin E2 and tumor necrosis factor-alpha productions in RAW264.7 macrophage cells. , 2008, Journal of ethnopharmacology.

[50]  C. Chai,et al.  Inhibitory effect of citrus 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone on 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumor promotion in mice. , 2007, Carcinogenesis.

[51]  S. Kanaoka,et al.  Cyclooxygenase-2 and tumor biology. , 2007, Advances in clinical chemistry.

[52]  M. Catalano,et al.  Oxidative stress-dependent impairment of cardiac-specific transcription factors in experimental diabetes. , 2006, Endocrinology.

[53]  Chi-Tang Ho,et al.  Hydroxylated polymethoxyflavones and methylated flavonoids in sweet orange (Citrus sinensis) peel. , 2006, Journal of agricultural and food chemistry.

[54]  Tao Wang,et al.  Structural requirements of flavonoids for inhibition of protein glycation and radical scavenging activities. , 2003, Bioorganic & medicinal chemistry.

[55]  F. Bach,et al.  Heme oxygenase-1: unleashing the protective properties of heme. , 2003, Trends in immunology.

[56]  D. Podolsky,et al.  Inflammatory bowel disease. , 2002, The New England journal of medicine.

[57]  S. Ghosh,et al.  Molecular mechanisms of NF-κB activation induced by bacterial lipopolysaccharide through Toll-like receptors: , 2000 .

[58]  C. Manthey,et al.  Polymethoxylated flavones derived from citrus suppress tumor necrosis factor-alpha expression by human monocytes. , 1999, Journal of natural products.

[59]  J. Dean,et al.  p38 Mitogen-activated Protein Kinase Regulates Cyclooxygenase-2 mRNA Stability and Transcription in Lipopolysaccharide-treated Human Monocytes* , 1999, The Journal of Biological Chemistry.

[60]  A. Baldwin,et al.  THE NF-κB AND IκB PROTEINS: New Discoveries and Insights , 1996 .