Abstract
Aurantii Fructus (called Zhiqiao, ZQ in Chinese), the dried unripe fruit of Citrus aurantium L. or its cultivated variety, is a common traditional edible-medicinal herb in regulating visceral functions for thousands of years. As a widely used ethnomedicine in Asia including China, Japan and Korea, ZQ possesses ideal therapeutic effect on digestive system diseases, and is also used as a condiment in food for regular consumption to benefit health. Amounts of investigations on different aspects have been done for ZQ in the past decades. However, there has no literature systematic comparison on the similarity concerning research achievements of ZQ. Herein, this review comprehensively presents the up-to-date information on botany, ethnopharmacology, phytochemistry, pharmacological activity, clinical use, quality control and toxicology of ZQ to identify their therapeutic potential and directs future research opportunities. So far, about 62 compounds has been isolated and identified from ZQ, in which flavonoids, alkaloids and coumarins would be the main bioactive ingredients for its pharmacological properties, such as regulating gastrointestinal motility, anti-gastric ulcer effect, regulating blood pressure, cardioprotective effects, anti-atherosclerotic activity, anti-vascular damage activity, anti-depression activity, anti-obesity activity, anti-inflammatory, anti-oxidant, anti-tumor, immunomodulatory activity and affecting enzyme activities. Even so, the variety of sources and origins, ZQ has defects in quality control and clinical application.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data material
Not applicable.
References
Adams DO, Hamilton TA (1984) The cell biology of macrophage activation. Ann Rev Immunol 2(1):283–318. https://doi.org/10.1146/annurev.iy.02.040184.001435
Adriane FB (2004) Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research. Exp Biol Med 229(8):698–704. https://doi.org/10.1177/153537020422900802
Akao Y, Itoh T, Ohguchi K, Iinuma M, Nozawa Y (2008) Interactive effects of polymethoxy flavones from Citrus on cell growth inhibition in human neuroblastoma SH-SY5Y cells. Bioorg Med Chem 16(6):2803–2810. https://doi.org/10.1016/j.bmc.2008.01.058
Al-Omar MA, Al-Arifi MN (2005) Comparative effects of scopoletin and menadione on aldehyde oxidase activity of guinea pig liver. J Biol Sci 5(4):525–531. https://doi.org/10.3923/jbs.2005.525.531
Andrade AS, Schmitt GC, Rossato LG, Russowsky D, Limberger RP (2009) Gas chromatographic method for analysis of p-synephrine in Citrus aurantium L. Prod Chromatogr 69(S2):225–229. https://doi.org/10.1365/s10337-009-0991-5
Andrew P, Breksa GDM (2006) Evaluation of the antioxidant capacity of limonin, nomilin, and limonin glucoside. J Agric Food Chem 54(11):3827–3831
Anso E, Zuazo A, Irigoyen M, Urdaci MC, Rouzaut A, Martinez-Irujo JJ (2010) Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism. Biochem Pharmacol 79(11):1600–1609. https://doi.org/10.1016/j.bcp.2010.02.004
Appelhans MS, Reichelt N, Groppo M, Paetzold C, Wen J (2018) Phylogeny and biogeography of the pantropical genus Zanthoxylum and its closest relatives in the proto-Rutaceae group (Rutaceae). Mol Phylogenet Evol 126:31–44. https://doi.org/10.1016/j.ympev.2018.04.013
Arbo MD, Larentis ER, Linck VM, Aboy AL, Pimentel AL, Henriques AT, Dallegrave E, Garcia SC, Leal MB, Limberger RP (2008) Concentrations of p-synephrine in fruits and leaves of Citrus species (Rutaceae) and the acute toxicity testing of Citrus aurantium extract and p-synephrine. Food Chem Toxicol 46(8):2770–2775. https://doi.org/10.1016/j.fct.2008.04.037
Arbo MD, Schmitt GC, Limberger MF, Charao MF, Moro AM, Ribeiro GL, Dallegrave E, Garcia SC, Leal MB, Limberger RP (2009) Subchronic toxicity of Citrus aurantium L. (Rutaceae) extract and p-synephrine in mice. Regul Toxicol Pharmacol 54(2):114–117. https://doi.org/10.1016/j.yrtph.2009.03.001
Arigoni D, Barton DHR, Corey EJ, Jeger O, Caglioti L, Dev S, Ferrini PG, Glazier ER, Melera A, Pradhan SK, Schaffner K, Sternhell S, Templeton JF, Tobinaga S (1960) The constitution of limonin. Cell Mol Life Sci 16(2):41–49
Asamoto M, Ota T, Toriyama-Baba H, Hokaiwado N, Naito A, Tsuda H (2002) Mammary carcinomas induced in human c-Ha-ras proto-oncogene transgenic rats are estrogen-independent, but responsive to d-limonene treatment. Jpn J Cancer Res 93(1):32–35. https://doi.org/10.1111/j.1349-7006.2002.tb01197.x
Bai Y, Zheng Y, Pang W, Peng W, Wu H, Yao H, Li P, Deng W, Cheng J, Su W (2018) Identification and comparison of constituents of Aurantii Fructus and Aurantii Fructus Immaturus by UFLC-DAD-triple TOF-MS/MS. Molecules. https://doi.org/10.3390/molecules23040803
Bai YF, Wang SW, Wang XX, Weng YY, Fan XY, Sheng H, Zhu XT, Lou LJ, Zhang F (2019) The flavonoid-rich Quzhou Fructus Aurantii extract modulates gut microbiota and prevents obesity in high-fat diet-fed mice. Nutr Diabetes 9(1):30. https://doi.org/10.1038/s41387-019-0097-6
Balakrishnan A, Menon VP (2007) Antioxidant properties of hesperidin in nicotine-induced lung toxicity. Fundam Clin Pharmacol 21(5):535–546. https://doi.org/10.1111/j.1472-8206.2007.00477.x
Barreca D, Bellocco E, Caristi C, Leuzzi U, Gattuso G (2011) Distribution of C- and O-glycosyl flavonoids, (3-hydroxy-3-methylglutaryl)glycosyl flavanones and furocoumarins in Citrus aurantium L. juice. Food Chem 124(2):576–582. https://doi.org/10.1016/j.foodchem.2010.06.076
Barreca D, Bellocco E, Caristi C, Leuzzi U, Gattuso G (2012a) Flavonoid distribution in neglected Citrus species grown in the Mediterranean basin. In: Flavonoids: dietary sources, properties and health benefits, Nova Science Publishers, Inc., pp 491–509
Barreca D, Gattuso G, Bellocco E, Calderaro A, Trombetta D, Smeriglio A, Lagana G, Daglia M, Meneghini S, Nabavi SM (2017) Flavanones: Citrus phytochemical with health-promoting properties. BioFactors 43(4):495–506. https://doi.org/10.1002/biof.1363
Barreca D, Mandalari G, Calderaro A, Smeriglio A, Trombetta D, Felice MR, Gattuso G (2020) Citrus flavones: an update on sources, biological functions, and health promoting properties. Plants (Basel) 9(3):288. https://doi.org/10.3390/plants9030288
Barreca D, Bellocco E, Caristi C, Leuzzi U, Gattuso G (2012b) Flavonoids and furocoumarins in bergamot, myrtle-leaved orange and sour orange juices: distribution and properties. In: Emerging trends in dietary components for preventing and combating disease—ACS symposium series. American Chemical Society, pp 17–35
Barreca D, Bellocco E, Leuzzi U, Gattuso G (2014) Flavonoid C-glycosides in Citrus Juices from Southern Italy: distribution and influence on the antioxidant activity. In: Instrumental methods for the analysis and identification of bioactive molecules ACS symposium series. American Chemical Society, pp 189–200
Basu A, Das AS, Majumder M, Mukhopadhyay R (2016) Antiatherogenic roles of dietary flavonoids chrysin, quercetin, and luteolin. J Cardiovasc Pharmacol 68(1):89–96. https://doi.org/10.1097/FJC.0000000000000380
Battinelli L, Mengoni F, Lichtner M, Mazzanti G, Saija A, Mastroianni CM, Vullo V (2003) Effect of limonin and nomilin on HIV-1 replication on infected human mononuclear cells. Planta Med 69(10):910–913. https://doi.org/10.1055/s-2003-45099
Bent S, Padula A, Neuhaus J (2004) Safety and efficacy of Citrus aurantium for weight loss. Am J Cardiol 94(10):1359–1361. https://doi.org/10.1016/j.amjcard.2004.07.137
Bi J, Zhang H, Lu J, Lei W (2016) Nobiletin ameliorates isoflurane-induced cognitive impairment via antioxidant, anti-inflammatory and anti-apoptotic effects in aging rats. Mol Med Rep 14(6):5408–5414. https://doi.org/10.3892/mmr.2016.5919
Bouchard NC, Howland MA, Greller HA, Hoffman RS, Nelson LS (2005) Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. Mayo Clin Proc 80(4):541–545. https://doi.org/10.4065/80.4.541
Braidy N, Behzad S, Habtemariam S, Ahmed T, Daglia M, Nabavi SM, Sobarzo-Sanchez E, Nabavi SF (2017) Neuroprotective effects of citrus fruit-derived flavonoids, nobiletin and tangeretin in Alzheimer’s and Parkinson’s disease. CNS Neurol Disord Drug Targets 16(4):387–397. https://doi.org/10.2174/1871527316666170328113309
Bush JA, Ratamess NA, Stohs SJ, Ellis NL, Vought IT, O’Grady EA, Kuper JD, Kang J, Faigenbaum AD (2018) Acute hematological and mood perception effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine: a placebo-controlled, double-blind study. Phytother Res 32(8):1593–1607. https://doi.org/10.1002/ptr.6090
Cai Y, Chen Y, Fan C (1999) Studies on Chinese Drugs Zhiqiao and zhishi origin investigation and merchandise ldentification. China J Chin Mater Med 24(5):259–262
Cai YZ, Mei S, Jie X, Luo Q, Corke H (2006) Structure-radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants. Life Sci 78(25):2872–2888. https://doi.org/10.1016/j.lfs.2005.11.004
Correll WA (2015) Warning letter to TruVision health LLC. FDA Center for Food Safety and Applied Nutrition. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/truvision-health-llc-09212015. Accessed 21 Sept 2015
Chen P (1998) Investigation, development and protection of C. aurantium ‘Chuluan.’ J Zhejiang For Sci Technol 03:75–78
Chen Y-C, Shen S-C, Lin H-Y (2003) Rutinoside at C7 attenuates the apoptosis-inducing activity of flavonoids. Biochem Pharmacol 66(7):1139–1150. https://doi.org/10.1016/s0006-2952(03)00455-6
Chen KH, Weng MS, Lin JK (2007) Tangeretin suppresses IL-1beta-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells. Biochem Pharmacol 73(2):215–227. https://doi.org/10.1016/j.bcp.2006.09.018
Chen HF, Zhang WG, Yuan JB, Li YG, Yang SL, Yang WL (2012) Simultaneous quantification of polymethoxylated flavones and coumarins in Fructus Aurantii and Fructus Aurantii immaturus using HPLC–ESI–MS/MS. J Pharm Biomed Anal 59(1):90–95. https://doi.org/10.1016/j.jpba.2011.10.013
Choi J-S, Choi Y-J, Shin S-Y, Li J, Kang S-W, Bae J-Y, Kim DS, Ji G-E, Kang J-S, Kang Y-H (2008) Dietary flavonoids differentially reduce oxidized LDL-induced apoptosis in human endothelial cells: role of MAPK- and JAK/STAT-signaling. J Nutr 138(6):983–990
Choi Y, Kim Y, Ham H, Park Y, Jeong HS, Lee J (2011) Nobiletin suppresses adipogenesis by regulating the expression of adipogenic transcription factors and the activation of AMP-activated protein kinase (AMPK). J Agric Food Chem 59(24):12843–12849. https://doi.org/10.1021/jf2033208
Choi JE, Park DM, Chun E, Choi JJ, Seo JH, Kim S, Son J, Do M, Kim SY, Park YC, Jung IC, Jin M (2017) Control of stress-induced depressive disorders by So-ochim-tang-gamibang, a Korean herbal medicine. J Ethnopharmacol 196:141–150. https://doi.org/10.1016/j.jep.2016.12.025
Choudhury R, Chowrimootoo G, Srai K, Debnam E, Rice-Evans CA (1999) Interactions of the flavonoid naringenin in the gastrointestinal tract and the influence of glycosylation. Biochem Biophys Res Commun 265(2):410–415. https://doi.org/10.1006/bbrc.1999.1695
Chuang CC, Wen WC, Sheu SJ (2007) Classification of Aurantii Fructus samples by multivariate analysis. J Sep Sci 30(12):1827–1832. https://doi.org/10.1002/jssc.200700016
Dai CB, Liu N, Chen WM, Qian W, Hou XH (2012) Simo decoction promotes contraction of antral circular smooth muscle mainly via muscarinic M3 receptor. J Ethnopharmacol 144(2):270–276. https://doi.org/10.1016/j.jep.2012.09.008
Deng N, Lan Q (2011) Observation on the curative effect of tongxuanlifei pill in treating 36 cases of chronic cough in children. J New Chin Med 43(02):96
Di Lorenzo C, Dos Santos A, Colombo F, Moro E, Dell’Agli M, Restani P (2014) Development and validation of HPLC method to measure active amines in plant food supplements containing Citrus aurantium L. Food Control 46:136–142. https://doi.org/10.1016/j.foodcont.2014.05.017
Dreyer DL (1965) Citrus bitter principles. III. Isolation of deacetylnomilin and deoxylimonin. J Organ Chem 30(3):749–751. https://doi.org/10.1021/jo01014a022
Edwards DJ, Bellevue FH, Woster PM (1996) Identification of 6′,7′-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos Biol Fate Chem 24(12):1287–1290
Edwards DJ, Fitzsimmons ME, Schuetz EG, Yasuda K, Ducharme MP, Warbasse LH, Woster PM, Schuetz JD, Watkins P (1999) 6′,7′-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther 65(3):237–244
Emerson OH (1948) The bitter principles of Citrus fruit. I. Isolation of nomilin, a new bitter principle from the seeds of oranges and lemons. J Am Chem Soc 70(2):545–549. https://doi.org/10.1021/ja01182a034
Emerson OH (1951) Bitter principles of citrus II relation of nomilin and obacunone. J Am Chemi Soc 73(6):2621–2623. https://doi.org/10.1021/ja01150a059
Epifano F, Molinaro G, Genovese S, Ngomba RT, Nicoletti F, Curini M (2008) Neuroprotective effect of prenyloxycoumarins from edible vegetables. Neurosci Lett 443(2):57–60. https://doi.org/10.1016/j.neulet.2008.07.062
Fan R, Huang X, Wang Y, Chen X, Ren P, Ji H, Xie Y, Zhang Y, Huang W, Qiu X, Liu Z, Zhou H, Fan L, Gao L (2012) Ethnopharmacokinetic- and activity-guided isolation of a new antidepressive compound from Fructus Aurantii found in the traditional Chinese medicine Chaihu–Shugan–San: a new approach and its application. Evid Based Complement Alternat Med. https://doi.org/10.1155/2012/607584
Fan S, Zhang C, Luo T, Wang J, Tang Y, Chen Z, Yu L (2019) Limonin: a review of its pharmacology, toxicity, and pharmacokinetics. Molecules. https://doi.org/10.3390/molecules24203679
Fernandez-Lopez J, Zhi N, Aleson-Carbonell L, Perez-Alvarez JA, Kuri V (2005) Antioxidant and antibacterial activities of natural extracts: application in beef meatballs. Meat Sci 69(3):371–380. https://doi.org/10.1016/j.meatsci.2004.08.004
Fouotsa H, Mbaveng AT, Mbazoa CD, Nkengfack AE, Farzana S, Iqbal CM, Marion JJ, Meyer NL, Kuete V (2013) Antibacterial constituents of three Cameroonian medicinal plants: Garcinia nobilis, Oricia suaveolens and Balsamocitrus camerunensis. Complement Altern Med 13:81–91
Gange CA, Madias C, Felix-Getzik EM, Weintraub AR, Estes NAM (2006) Variant angina associated with bitter orange in a dietary supplement. Mayo Clin Proc 81(4):545–548. https://doi.org/10.4065/81.4.545
Gattuso G, Barreca D, Gargiulli C, Leuzzi U, Caristi C (2007) Flavonoid composition of Citrus juices. Molecules 12:1641–1673
Ghorbani A, Nazari M, Jeddi-Tehrani M, Zand H (2011) The citrus flavonoid hesperidin induces p53 and inhibits NF-κB activation in order to trigger apoptosis in NALM-6 cells: involvement of PPARγ-dependent mechanism. Eur J Nutr 51(1):39–46. https://doi.org/10.1007/s00394-011-0187-2
Girennavar B, Jayaprakasha GK, Jadegoud Y, Nagana Gowda GA, Patil BS (2007) Radical scavenging and cytochrome P450 3A4 inhibitory activity of bergaptol and geranylcoumarin from grapefruit. Bioorg Med Chem 15(11):3684–3691. https://doi.org/10.1016/j.bmc.2007.03.047
Guan F, Wang R, Wang J (2002) Effect of Zhiqiao and synephrine on rats ’ gastric emptying function and small intestinal propulsive function. Mod J Integr Tradit Chin West Med 11(11):1001–1003
Gui Q, Jiang H, Ruan Y (2016) RAPD analysis of seven species of Rutaceae plants. J Anhui Agric Sci 44(30):101–103
Guo LX, Chen G, Yin ZY, Zhang YH, Zheng XX (2019) p-Synephrine exhibits anti-adispogenic activity by activating the Akt/GSK3beta signaling pathway in 3T3-L1 adipocytes. J Food Biochem 43(11):e13033. https://doi.org/10.1111/jfbc.13033
Guo Z, Li W, Li Z (2012) Determination of naringin and neohesperidin in Aurantii Fructus from different habitats. Chin Tradit Herb Drugs 43(7):1347–1348
Guo W (2019) Huoxiang Zhengqi Oral Liquid and Jizhi Syrup of Tai Chi Group were allowed to enter Pakistan. China Econ Net. https://www.ce.cn/cysc/yy/hydt/201911/27/t20191127_33712928.shtml. Accessed 27 Nov 2019
Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean-Chaney S, Allison DB (2006) Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update. Obes Rev 7(1):79–88
Haller CA, Benowitz NL, Jacob P 3rd (2005) Hemodynamic effects of ephedra-free weight-loss supplements in humans. Am J Med 118(9):998–1003. https://doi.org/10.1016/j.amjmed.2005.02.034
Hasegawa S, Herman Z, Orme E, Ou P (1986b) Biosynthesis of limonoids in Citrus: sites and translocation. Phytochemistry 25(12):2783–2785
Hasegawa S, Maier VP, Herman Z, Peter Ou (1986a) Phytohormone bioregulation of nomilin biosynthesis in Citrus limon seedlings. Phytochemistry 25(6):1323–1325. https://doi.org/10.1016/S0031-9422(00)81281-9
He W, Li Y, Liu M, Yu H, Chen Q, Chen Y, Ruan J, Ding Z, Zhang Y, Wang T (2018) Citrus aurantium L. and its flavonoids regulate TNBS-induced inflammatory bowel disease through anti-inflammation and suppressing isolated jejunum contraction. Int J Mol Sci. https://doi.org/10.3390/ijms19103057
He Y, Li Z, Wang W, Sooranna SR, Shi Y, Chen Y, Wu C, Zeng J, Tang Q, Xie H (2018) Chemical profiles and simultaneous quantification of Aurantii Fructus by use of HPLC-Q-TOF-MS combined with GC–MS and HPLC methods. Molecules. https://doi.org/10.3390/molecules23092189
Hebert PD, Cywinska A, Ball SL, deWaard JR (2003) Biological identifications through DNA barcodes. Proc Biol Sci 270(1512):313–321. https://doi.org/10.1098/rspb.2002.2218
Hosseinimehr SJ, Tavakoli H (2003) Radioprotective effects of citrus extract against gamma-irradiation in mouse bone marrow cells. J Radiat Res 44(3):237–241
Hu B (2019) Clinical study of danshitong capsule in the treatment of cholelithiasis with chronic cholecystitis. Electron J Clin Med Lit 6(42):55. https://doi.org/10.16281/j.cnki.jocml.2019.42.037
Hu R, Li Z, Xiao C, Li Y, Zhan Z (2019) The change of origin and genuine area for Aurantii Fructus Immaturus and Aurantii Fructus. J Chin Med Mater 42(3):686–689
Hu S, Wang D, Qiu P, Yu H, Tu X (1992) Effects of volatile oil of Aurantii Fructus and Aurantii Fructus Immaturus on gastrointestinal tract of animals. Jiangxi Med J 27(3):158-159+152
Huang W, Huang X, Xing Z, Qiu X, Wang Y, Fan R, Liu W, Ren P, Liu Z, Zhou H (2011) Meranzin hydrate induces similar effect to Fructus Aurantii on intestinal motility through activation of H1 histamine receptors. J Gastrointest Surg 15(1):87–96. https://doi.org/10.1007/s11605-010-1374-9
Huang YT, Wang GF, Chen C-F, Chen C-C, Hong C-Y, Yang MCM (1995) Fructus Aurantii reduced portal pressure in portal hypertensive rats. Life Sci 57(22):2011–2020
Hui R, Hou D, Li T, Diao Q (2019) Comparative analysis of antioxidant activity of rutin, quercetin and mulberry pigment. J Anshan Normal Univ 21(4):38–41. https://doi.org/10.3969/j.issn.1008-2441.2019.04.008
Jang SE, Ryu KR, Park SH, Chung S, Teruya Y, Han MJ, Woo JT, Kim DH (2013) Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-kappaB, AP-1 and p38. Int Immunopharmacol 17(3):502–507. https://doi.org/10.1016/j.intimp.2013.07.012
Jia H, Wan Q (2015) The clinical research into central retinal vein occlusion treated with Danhong Huayu oral solution in combination with laser. Henan Tradit Chin Med 35(8):1897–1899
Jiang Y, Bai X, Zhu X, Li J (2014) The effects of Fructus Aurantii extract on the 5-hydroxytryptamine and vasoactive intestinal peptide contents of the rat gastrointestinal tract. Pharm Biol 52(5):581–585. https://doi.org/10.3109/13880209.2013.854396
Jiang MH, Yang L, Zhu L, Piao JH, Jiang JG (2011) Comparative GC/MS analysis of essential oils extracted by 3 methods from the bud of Citrus aurantium L. var. amara Engl. J Food Sci 76(9):C1219-1225. https://doi.org/10.1111/j.1750-3841.2011.02421.x
Julio-Pieper M, O’Connor RM, Dinan TG, Cryan JF (2013) Regulation of the brain–gut axis by group III metabotropic glutamate receptors. Eur J Pharmacol 698(1–3):19–30. https://doi.org/10.1016/j.ejphar.2012.10.027
Kang S, Deng H (2012) Study on the contents of naringin, hesperidin and neohesperidin in Aurantii Fructus at different growing stages. Lishizhen Med Mater Medica Res 23(8):1918–1919
Kang M, Kim JH, Cho C, Chung HS, Kang CW, Kim Y, Shin M, Hong M, Bae H (2007) Anti-ischemic effect of Aurantii Fructus on contractile dysfunction of ischemic and reperfused rat heart. J Ethnopharmacol 111(3):584–591. https://doi.org/10.1016/j.jep.2007.01.007
Karabıyıklı Ş, Değirmenci H, Karapınar M (2014) Inhibitory effect of sour orange (Citrus aurantium) juice on Salmonella typhimurium and Listeria monocytogenes. LWT Food Sci Technol 55(2):421–425. https://doi.org/10.1016/j.lwt.2013.10.037
Kawabata K, Murakami A, Ohigashi H (2006) Citrus auraptene targets translation of MMP-7 (matrilysin) via ERK1/2-dependent and mTOR-independent mechanism. FEBS Lett 580(22):5288–5294. https://doi.org/10.1016/j.febslet.2006.08.072
Kelly C, Jewell C, O’Brien NM (2003) The effect of dietary supplementation with the citrus limonoids, limonin and nomilin on xenobiotic-metabolizing enzymes in the liver and small intestine of the rat. Nutr Res 23(5):681–690. https://doi.org/10.1016/s0271-5317(03)00021-6
Kenneth F, Kiple KCO (2000) The Cambridge world history of food, vol 2. Cambridge University Press, Cambridge
Kim JH, Kim JK, Ahn EK, Ko HJ, Cho YR, Lee CH, Kim YK, Bae GU, Oh JS, Seo DW (2015) Marmesin is a novel angiogenesis inhibitor: regulatory effect and molecular mechanism on endothelial cell fate and angiogenesis. Cancer Lett 369(2):323–330. https://doi.org/10.1016/j.canlet.2015.09.021
Kobayashi S, Tanabe S (2006) Evaluation of the anti-allergic activity of Citrus unshiu using rat basophilic leukemia RBL-2H3 cells as well as basophils of patients with seasonal allergic rhinitis to pollen. Int J Mol Med 17(3):511–515. https://doi.org/10.3892/ijmm.17.3.511
Kusu F, Li X-D, Takamura K (1992) Determination of synephrine and N-methyltyramine in Zhishi and Zhike (Immature Citrus fruits) by high-performance liquid chromatography with electrochemical detection. Chem Pharm Bull 40(12):3284–3286
Lam KH, Alex D, Lam IK, Tsui SK, Yang ZF, Lee SM (2011) Nobiletin, a polymethoxylated flavonoid from citrus, shows anti-angiogenic activity in a zebrafish in vivo model and HUVEC in vitro model. J Cell Biochem 112(11):3313–3321. https://doi.org/10.1002/jcb.23257
Lee CH, Jeong TS, Choi YK, Hyun BH, Oh GT, Kim EH, Kim JR, Han JI, Bok SH (2001) Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits. Biochem Biophys Res Commun 284(3):681–688. https://doi.org/10.1006/bbrc.2001.5001
Li J (2018) Clinical effect of dextromethorphan guaifenesin combined with Tongxuan Lifei pills in treating cough after cold. J Clin Med Lit 5(46):148–167
Li Y, Li Y, Shi F, Wang L, Li L, Yang D (2018) Osthole attenuates right ventricular remodeling via decreased myocardial apoptosis and inflammation in monocrotaline-induced rats. Eur J Pharmacol 818:525–533. https://doi.org/10.1016/j.ejphar.2017.11.006
Li X, Liang Q, Sun Y, Diao L, Qin Z, Wang W, Lu J, Fu S, Ma B, Yue Z (2015) Potential mechanisms responsible for the antinephrolithic effects of an aqueous extract of Fructus Aurantii. Evid Based Complem Alternat Med 2015:491409. https://doi.org/10.1155/2015/491409
Li DM, Lu JX, Yue JQ (2015) Analysis of production and marketing situation of lemon and lime in the world and China. World Agric 2:106–116. https://doi.org/10.13856/j.cn11-1097/s.2015.02.022
Li S, Pan MH, Lai CS, Lo CY, Dushenkov S, Ho CT (2007) Isolation and syntheses of polymethoxyflavones and hydroxylated polymethoxyflavones as inhibitors of HL-60 cell lines. Bioorg Med Chem 15(10):3381–3389. https://doi.org/10.1016/j.bmc.2007.03.021
Li S, Sang S, Pan MH, Lai CS, Lo CY, Yang CS, Ho CT (2007) Anti-inflammatory property of the urinary metabolites of nobiletin in mouse. Bioorg Med Chem Lett 17(18):5177–5181. https://doi.org/10.1016/j.bmcl.2007.06.096
Li P, Zeng SL, Duan L, Ma XD, Dou LL, Wang LJ, Li P, Bi ZM, Liu EH (2016) Comparison of Aurantii Fructus Immaturus and Aurantii Fructus based on multiple chromatographic analysis and chemometrics methods. J Chromatogr A 1469:96–107. https://doi.org/10.1016/j.chroma.2016.09.061
Li L, Zhang S, Xin Y, Sun J, Xie F, Yang L, Chen Z, Chen H, Liu F, Xuan Y, You Z (2018) Role of Quzhou Fructus Aurantii extract in preventing and treating acute lung injury and inflammation. Sci Rep 8(1):1698. https://doi.org/10.1038/s41598-018-20083-z
Lin HY, Shen SC, Chen YC (2005) Anti-inflammatory effect of heme oxygenase 1: glycosylation and nitric oxide inhibition in macrophages. J Cell Physiol 202(2):579–590. https://doi.org/10.1002/jcp.20160
Lin Z, Wang H, Xu Y, Dong J, Hashi Y, Chen S (2012) Identification of antioxidants in Fructus Aurantii and its quality evaluation using a new on-line combination of analytical techniques. Food Chem 134(2):1181–1191. https://doi.org/10.1016/j.foodchem.2012.02.161
Liu JJ (2020) Clinical study on treatment of chronic gastritis with qizhiweitong granules combined with hydrotalcite. Drugs Clin 35(07):1412–1416
Liu XY, Fan ML, Wang HY, Yu BY, Liu JH (2017) Metabolic profile and underlying improved bio-activity of Fructus Aurantii Immaturus by human intestinal bacteria. Food Funct 8(6):2193–2201. https://doi.org/10.1039/c6fo01851c
Liu J, Gao J, Chen H, Jiang H, Zhang Y, Liu X, Xia L (2014) The protective effects of Zhiqiao Jianwei granules on gastric lesion in rats. Pharmacol Clin Chin Mater Medica 30(2):115–118
Liu H, Li P, Lin J, Chen W, Guo H, Lin J, Liu J, Lu Z, Yao X, Chen Y, Lin B (2019) Danhong Huayu Koufuye prevents venous thrombosis through antiinflammation via Sirtuin 1/NF-kappaB signaling pathway. J Ethnopharmacol 241:111975. https://doi.org/10.1016/j.jep.2019.111975
Liu Z Liu Y,, Wang C, Zha Q, Cheng Lu, Song Z, Ning Z, Zhao S, Xinmiao Lu, Aiping Lu (2014) Study on essential oils from four species of Zhishi with gas chromatography–mass spectrometry. Chem Cent J 8(1):22–29. https://doi.org/10.1186/1752-153X-8-22
Liu XQ, Wei SS, Bai WS, Jin JX, Huang WJ, Lu CZ (2003) Studies on constituents of Rutaceae plants growing in China comparied with those in Korea. Chin Tradit Herbal Drugs 34(7):586–589
Liu S (2017) The national standardization construction project for 10 kinds of Chinese medicine decoction pieces including Aurantii Fructus. China News of Traditional Chinese Medicine. https://paper.cntcm.com.cn/html/content/2017-01/09/content_584609.htm. Accessed 9 Jan 2017
Lopez-Posadas R, Ballester I, Abadia-Molina AC, Suarez MD, Zarzuelo A, Martinez-Augustin O, Sanchez de Medina F (2008) Effect of flavonoids on rat splenocytes: a structure–activity relationship study. Biochem Pharmacol 76(4):495–506. https://doi.org/10.1016/j.bcp.2008.06.001
Lu X, Wang Y, Liu C, Wang Y (2017) Depressive disorder and gastrointestinal dysfunction after myocardial infarct are associated with abnormal tryptophan-5-hydroxytryptamine metabolism in rats. PLoS ONE 12(2):e0172339. https://doi.org/10.1371/journal.pone.0172339
Luo K, Chen S, Chen K, Song J, Yao H, Ma X, Zhu Y, Pang X, Yu H, Li X, Liu Z (2010a) Assessment of candidate plant DNA barcodes using the Rutaceae family. Sci China Life Sci 53(6):701–708. https://doi.org/10.1007/s11427-010-4009-1
Luo K, Chen S, Chen K, Song J, Yao H, Ma X, Zhu Y, Pang X, Yu H, Li X, Liu Z (2010b) Research on plant general DNA barcode based on Rutaceae. Scientia Sinica (Vitae) 40(4):342–358
Ma X, Li C, Yuan L, Wang S, Liu X, (2013) Pharmacokinetics of naringin and neohesperidin in the total flavanones of Zhishi extract in rats. J China Pharm Univ 44(2):161–166
Mattoli L, Cangi F, Maidecchi A, Ghiara C, Tubaro M, Traldi P (2006) A rapid liquid chromatography electrospray ionization mass spectrometryn method for evaluation of synephrine in Citrus aurantium L. samples. J Agric Food Chem 53(26):9860–9866
Mazzei M, Nieddu E, Miele M, Balbi A, Ferrone M, Fermeglia M, Mazzei MT, Pricl S, La Colla P, Marongiu F, Ibba C, Loddo R (2008) Activity of Mannich bases of 7-hydroxycoumarin against Flaviviridae. Bioorg Med Chem 16(5):2591–2605. https://doi.org/10.1016/j.bmc.2007.11.045
Mchalce D, Khopkar PP, Sheridan JB (1987) Coumarin glycosides from Citrus flavedo. Phytochemistry 26(9):2547–2549
Md Othman SNA, Hassan MA, Nahar L, Basar N, Jamil S, Sarker SD (2016) Essential oils from the Malaysian Citrus (Rutaceae) Med Plants. Medicines (Basel). https://doi.org/10.3390/medicines3020013
Mercader J, Wanecq E, Chen J, Carpene C (2011) Isopropylnorsynephrine is a stronger lipolytic agent in human adipocytes than synephrine and other amines present in Citrus aurantium. J Physiol Biochem 67(3):443–452. https://doi.org/10.1007/s13105-011-0078-2
Min L, Xi H, Yang W, Ping R (2015) Zhiqiaochuanxiong decoction for major depressive disorder complicated by functional dyspepsia: a case report with fast-acting efficacy. J Tradit Chin Med 35(6):697–702. https://doi.org/10.1016/S0254-6272(15)30162-X
Miyata Y, Sato T, Imada K, Dobashi A, Yano M, Ito A (2008) A citrus polymethoxyflavonoid, nobiletin, is a novel MEK inhibitor that exhibits antitumor metastasis in human fibrosarcoma HT-1080 cells. Biochem Biophys Res Commun 366(1):168–173. https://doi.org/10.1016/j.bbrc.2007.11.100
Modak B, Contreras ML, Gonzalez-Nilo F, Torres R (2005) Structure-antioxidant activity relationships of flavonoids isolated from the resinous exudate of Heliotropium sinuatum. Bioorg Med Chem Lett 15(2):309–312. https://doi.org/10.1016/j.bmcl.2004.10.081
Mokbel MS, Suganuma T (2006) Antioxidant and antimicrobial activities of the methanol extracts from pummelo (Citrus grandis Osbeck) fruit albedo tissues. Eur Food Res Technol 224(1):39–47. https://doi.org/10.1007/s00217-006-0286-0
Nakajima A, Aoyama Y, Nguyen TT, Shin EJ, Kim HC, Yamada S, Nakai T, Nagai T, Yokosuka A, Mimaki Y, Ohizumi Y, Yamada K (2013) Nobiletin, a citrus flavonoid, ameliorates cognitive impairment, oxidative burden, and hyperphosphorylation of tau in senescence-accelerated mouse. Behav Brain Res 250:351–360. https://doi.org/10.1016/j.bbr.2013.05.025
Ng TBLF, Wang ZT (2000) Antioxidative activity of natural products from plants. Life Sci 66(8):709–723
Ni J, Guo Y, Chang N, Cheng D, Yan M, Jiang M, Bai G (2019) Effect of N-methyltyramine on the regulation of adrenergic receptors via enzymatic epinephrine synthesis for the treatment of gastrointestinal disorders. Biomed Pharmacother 111:1393–1398. https://doi.org/10.1016/j.biopha.2018.12.145
Njoroge SM, Ukeda H, Kusunose H, Sawamura M (1994) Volatile components of the essential oils from Kabosu, Daidai, and Yuko, Japanese sour Citrus fruits. Flavour Fragr J 9(6):289–297. https://doi.org/10.1002/ffj.2730090603
Nykamp DL, Fackih MN, Compton AL (2004) Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacother 38(5):812–816. https://doi.org/10.1345/aph.1D473
Okamoto T, Kobayashi T, Yoshida S (2007) Synthetic derivatives of osthole for the prevention of hepatitis. Med Chem 3(1):35–44. https://doi.org/10.2174/157340607779317607
Okuyama S, Miyazaki K, Yamada R, Amakura Y, Yoshimura M, Sawamoto A, Nakajima M, Furukawa Y (2017) Permeation of polymethoxyflavones into the mouse brain and their effect on MK-801-induced locomotive hyperactivity. Int J Mol Sci. https://doi.org/10.3390/ijms18030489
Pan X, Li Y, Wu Z, Zhang Q, Zheng Z, Shi X, Qiao Y (2015) A online NIR sensor for the pilot-scale extraction process in Fructus Aurantii coupled with single and ensemble methods. Sensors (Basel) 15(4):8749–8763. https://doi.org/10.3390/s150408749
Park HJ, Kim MJ, Ha E, Chung JH (2008) Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. Phytomedicine 15(1–2):147–151. https://doi.org/10.1016/j.phymed.2007.07.061
Pellati F, Benvenuti S (2007) Chromatographic and electrophoretic methods for the analysis of phenethylamine [corrected] alkaloids in Citrus aurantium. J Chromatogr A 1161(1–2):71–88. https://doi.org/10.1016/j.chroma.2007.05.097
Peng Y, Liu F, Ye J (2006) Quantitative and qualitative analysis of flavonoid markers in Frucus Aurantii of different geographical origin by capillary electrophoresis with electrochemical detection. J Chromatogr B 830(2):224–230. https://doi.org/10.1016/j.jchromb.2005.10.043
Penzak SR, Jann MW, Cold JA, Hon YY, Desai HD, Gurley BJ (2001) Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol 41(10):1059–1063
Pharmacopoeia NCoC (2015) Pharmacopoeia of the People’s Republic of China. Chemical Industry Press, Beijing
Qiu XJ, Huang X, Chen ZQ, Ren P, Huang W, Qin F, Hu SH, Huang J, He J, Liu ZQ, Zhou HH (2011) Pharmacokinetic study of the prokinetic compounds meranzin hydrate and ferulic acid following oral administration of Chaihu-Shugan-San to patients with functional dyspepsia. J Ethnopharmacol 137(1):205–213. https://doi.org/10.1016/j.jep.2011.05.009
Rajadurai M, Prince PSM (2006) Preventive effect of naringin on lipid peroxides and antioxidants in isoproterenol-induced cardiotoxicity in Wistar rats: biochemical and histopathological evidences. Toxicology 228(2–3):259–268. https://doi.org/10.1016/j.tox.2006.09.005
Ratamess NA, Bush JA, Kang J, Kraemer WJ, Stohs SJ, Nocera VG, Leise MD, Diamond KB, Campbell SC, Miller HB, Faigenbaum AD (2016) The effects of supplementation with p-synephrine alone and in combination with caffeine on metabolic, lipolytic, and cardiovascular responses during resistance exercise. J Am Coll Nutr 35(8):657–669. https://doi.org/10.1080/07315724.2016.1150223
Rossato LG, Costa VM, Limberger RP, Bastos Mde L, Remiao F (2011) Synephrine: from trace concentrations to massive consumption in weight-loss. Food Chem Toxicol 49(1):8–16. https://doi.org/10.1016/j.fct.2010.11.007
Rouseff RL (1982) Nomilin, a new bitter component in grapefruit juice. J Agric Food Chem 30(3):504–507. https://doi.org/10.1021/jf00111a022
Santana J, Sharpless KE, Nelson BC (2008) Determination of para-synephrine and meta-synephrine positional isomers in bitter orange-containing dietary supplements by LC/UV and LC/MS/MS. Food Chem 109(3):675–682. https://doi.org/10.1016/j.foodchem.2007.12.076
Sara B (2004) Essential oils: their antibacterial properties and potential applications in foods—a review. Int J Food Microbiol 94(3):223–253. https://doi.org/10.1016/j.ijfoodmicro.2004.03.022
Shakeel UR, Khan R, Bhat KA, Raja AF, Shawl AS, Alam MS (2010) Isolation, characterisation and antibacterial activity studies of coumarins from Rhododendron lepidotum Wall. ex GV Don, Ericaceae. Rev Bras Farmacognosia 20(6):886–890. https://doi.org/10.1590/s0102-695x2010005000037
Shen CY, Jiang JG, Zhu W, Ou-Yang Q (2017) Anti-inflammatory effect of essential oil from Citrus aurantium L. var. amara. Engl J Agric Food Chem 65(39):8586–8594. https://doi.org/10.1021/acs.jafc.7b02586
Shen CY, Lin JJ, Jiang JG, Wang TX, Zhu W (2020) Potential roles of dietary flavonoids from Citrus aurantium L. varV amara Engl. in atherosclerosis development. Food Funct 11(1):561–571. https://doi.org/10.1039/c9fo02336d
Shen CY, Wan L, Wang TX, Jiang JG (2019) Citrus aurantium L. var. amara Engl. inhibited lipid accumulation in 3T3-L1 cells and Caenorhabditis elegans and prevented obesity in high-fat diet-fed mice. Pharmacol Res 147:104347. https://doi.org/10.1016/j.phrs.2019.104347
Shi X, Huang W, Liu Y (2012) Dynamic changes of chemical constituents of Aurantii Fructus and Aurantii Fructus Immaturus at different phenological stages. Lishizhen Med Mater Medica Res 23(1):146–148
Shi S, Yan H, Chen Y, Liu Y, Zhang X, Xie Y, Xu J, Wu L, Chen K, Shen X, Ren P, Huang X (2020) Pharmacokinetic study of precisely representative antidepressant, prokinetic, anti-inflammatory and anti-oxidative compounds from Fructus Aurantii and Magnolia Bark. Chem Biol Interact 315:108851. https://doi.org/10.1016/j.cbi.2019.108851
Shi X (2012) Studies on dynamic changes of chenmical components in fruit from Citrus aurantium L. at different harvest periods, and quality evaluation of Fructus Aurantii Immaturus and Fructus Aurantii. Master, Chengdu University of TCM, Chengdu Sichuan China
Shu Z, Yang Y, Ding Z, Wang W, Zhong R, Xia T, Li W, Kuang H, Wang Y, Sun X (2020) Structural characterization and cardioprotective activity of a novel polysaccharide from Fructus Aurantii. Int J Biol Macromol 144:847–856. https://doi.org/10.1016/j.ijbiomac.2019.09.162
Shu Z, Yang Y, Xing N, Wang Y, Wang Q, Kuang H (2018) Structural characterization and immunomodulatory activity of a pectic polysaccharide (CALB-4) from Fructus Aurantii. Int J Biol Macromol 116:831–839. https://doi.org/10.1016/j.ijbiomac.2018.01.165
Sp N, Kang DY, Joung YH, Park JH, Kim WS, Lee HK, Song KD, Park YM, Yang YM (2017) Nobiletin inhibits angiogenesis by regulating Src/FAK/STAT3-mediated signaling through PXN in ER(+) breast cancer cells. Int J Mol Sci. https://doi.org/10.3390/ijms18050935
Stohs SJ (2017) Safety, efficacy, and mechanistic studies regarding Citrus aurantium (bitter orange) extract and p-synephrine. Phytother Res 31(10):1463–1474. https://doi.org/10.1002/ptr.5879
Stohs SJ, Preuss HG, Shara M (2012) A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine. Int J Med Sci 9(7):527–538. https://doi.org/10.7150/ijms.4446
Stohs SJ, Ray SD (2020) Review of published bitter orange extract and p-synephrine adverse event clinical study case reports. J Diet Suppl 17(3):355–363. https://doi.org/10.1080/19390211.2019.1577936
Stohs SJ, Shara M, Ray SD (2020) p-Synephrine, ephedrine, p-octopamine and m-synephrine: comparative mechanistic, physiological and pharmacological properties. Phytother Res 34(8):1838–1846. https://doi.org/10.1002/ptr.6649
Su M-S, Shyu Y-T, Chien P-J (2008) Antioxidant activities of citrus herbal product extracts. Food Chem 111(4):892–896. https://doi.org/10.1016/j.foodchem.2008.05.002
Su M, Li Y, Li P, Chen H, Yang W (2010) Preliminary study on marmin microbial transformation. In: The 1st Jiangxi provincial science and technology association annual conference jiangxi provincial traditional chinese medicine academic development forum, NanChang JiangXi China, pp 257–260
Sun C, Chen K, Chen Y, Chen Q (2005) Contents and antioxidant capacity of limonin and nomilin in different tissues of citrus fruit of four cultivars during fruit growth and maturation. Food Chem 93(4):599–605. https://doi.org/10.1016/j.foodchem.2004.10.037
Takase H, Yamamoto K, Hirano H, Saito Y, Yamashita A (1994a) Pharmacological profile of gastric mucosal protection by marmin and nobiletin from a traditional herbal medicine, Aurantii Fructus Immaturus. Jpn J Pharmacol 66(1):139–147
Takase H, Yamamoto K, Hirano H, Saito Y, Yamashita A (1994b) Pharmacological profile of gastric mucosal protection by marmin and nobiletin from a traditional herbal medicine, Aurantii Fructus Immaturus. Jpn J Pharmacol 66(1):9
Tan M (1998) 31 cases of gastroptosis treated by Aurantii Fructus China’s. Naturopathy 05:54–55
Tian F, He XF, Sun J, Liu XD, Zhang Y, Cao H, Wu MH, Ma ZG (2020) Simultaneous quantitative analysis of nine constituents in six Chinese medicinal materials from Citrus genus by high-performance liquid chromatography and high-resolution mass spectrometry combined with chemometric methods. J Sep Sci 43(4):736–747. https://doi.org/10.1002/jssc.201901033
Tian Q, Stewart SJ (2003) Mass spectrometry and tandem mass spectrometry of citrus limonoids. Anal Chem 75(20):5451–5460
Ting W, Xin L, Mingsan M (2017) Chemical composition and clinical application of daidaihua. Acta Chin Med 32(2):276–278. https://doi.org/10.16368/j.issn.1674-8999.2017.02.070
Tripoli E, Guardia ML, Giammanco S, Majo DD, Giammanco M (2007) Citrus flavonoids: molecular structure, biological activity and nutritional properties: a review. Food Chem 104(2):466–479. https://doi.org/10.1016/j.foodchem.2006.11.054
Vaiyapuri S, Roweth H, Ali MS, Unsworth AJ, Stainer AR, Flora GD, Crescente M, Jones CI, Moraes LA, Gibbins JM (2015) Pharmacological actions of nobiletin in the modulation of platelet function. Br J Pharmacol 172(16):4133–4145. https://doi.org/10.1111/bph.13191
Viuda-Martos M, Ruiz-Navajas Y, Fernández-López J, Pérez-Álvarez J (2008) Antifungal activity of lemon (Citrus lemon L.), mandarin (Citrus reticulata L.), grapefruit (Citrus paradisi L.) and orange (Citrus sinensis L.) essential oils. Food Control 19(12):1130–1138. https://doi.org/10.1016/j.foodcont.2007.12.003
Wang J (1955) The effect of Aurantii Fructus on raising blood pressure. Jiangxi J Tradit Chin Med 2:41–43
Wang W (2002) Study on the conditioning mechanism of Aurantii Fructus with Platycodonis Radix. Study J Tradit Chin Med 04:466–480
Wang SN (2004) Toxicity and preclinical evaluation of traditional Chinese medicine. Science Press, Beijing
Wang S, Bao YR, Li TJ, Yu T, Chang X, Yang GL, Meng XS (2017) Mechanism of Fructus Aurantii flavonoids promoting gastrointestinal motility: from organic and inorganic endogenous substances combination point of view. Pharmacogn Mag 13(51):372–377. https://doi.org/10.4103/pm.pm_179_16
Wang J, Chen X, Gu X (2010) Study of evaluation on resources and Materia Madica of Fructus Aurantii in Zhejiang Province. J Zhejiang Univ Tradit Chin Med 34(4):603–604
Wang QH, Shu ZP, Xu BQ, Xing N, Jiao WJ, Yang BY, Kuang HX (2014) Structural characterization and antioxidant activities of polysaccharides from Citrus aurantium L. Int J Biol Macromol 67:112–123. https://doi.org/10.1016/j.ijbiomac.2014.03.004
Wang W, Zhao L, Huang H, Yao J, Zhou L, Wang D, Qiu X (2018) Development of an ultra-high performance liquid chromatography method for simultaneous determination of six active compounds in Fructus Aurantii and Rat Plasma and Its application to a comparative pharmacokinetic study in rats administered with different doses. J Anal Methods Chem 2018:7579136. https://doi.org/10.1155/2018/7579136
Wang C, Zhu M, Xia W, Jiang W, Li Y (2012) Meta-analysis of traditional Chinese medicine in treating functional dyspepsia of liver-stomach disharmony syndrome. J Tradit Chin Med 32(4):515–522. https://doi.org/10.1016/S0254-6272(13)60063-1
Wang W, Heideman L, Chung CS, Pelling JC, Koehler KJ, Birt DF (2000) Cell-cycle arrest at G2/M and growth inhibition by Apigenin in human colon carcinoma cell lines. Mol Carcinog 28(2):102–110
Wheaton TA, Stewart I (1969) Biosynthesis of synephrine in citrus. Phytochemistry 8(1):85–92
Whitman SC, Kurowska EM, Manthey JA, Daugherty A (2005) Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis 178(1):25–32. https://doi.org/10.1016/j.atherosclerosis.2004.07.034
Wilkinson GR (2005) Drug metabolism and variability among patients in drug response. N Engl J Med 352(21):2211–2221. https://doi.org/10.1056/NEJMra032424
Wu L, Xu R (2010) Research progress on the relationship between the pharmacological activity and structure-activity of coumarins. Her Med 29(4):498–501
Wu YQ, Zhou CH, Tao J, Li SN (2006) Antagonistic effects of nobiletin, a polymethoxyflavonoid, on eosinophilic airway inflammation of asthmatic rats and relevant mechanisms. Life Sci 78(23):2689–2696. https://doi.org/10.1016/j.lfs.2005.10.029
Xiao J, Chen T, Chen L, Wu J (2009) Comparison of volatile oil’s components between Fructus Auranti Immaturus and Fructus Auranti by GC–MS Analysis. J Fujian Univ TCM 19(4):25–27
Xie Y, Huang X, Hu SY, Qiu XJ, Zhang YJ, Ren P, Wang Y, Ji H, Zhang CH, Xie WB, He J, Xie MZ, Huang HY, Liu ZQ, Zhou HH (2013) Meranzin hydrate exhibits anti-depressive and prokinetic-like effects through regulation of the shared alpha2-adrenoceptor in the brain-gut axis of rats in the forced swimming test. Neuropharmacology 67:318–325. https://doi.org/10.1016/j.neuropharm.2012.10.003
Xie Y, Huang X, Hu SY, Zhang YJ, Wang Y, Qiu XJ, Ren P, Fan R, Zhang CH, Xie WB, Ji H, He J, Chen X, Xie L, Liu ZQ, Zhou HH (2013) The involvement of AMPA-ERK1/2-BDNF pathway in the mechanism of new antidepressant action of prokinetic meranzin hydrate. Amino Acids 44(2):413–422. https://doi.org/10.1007/s00726-012-1347-2
Xie Q, Wang Y, Xu Q, Yan H, Xiao Z, Huang X, Ren P (2019) Effects of synephrine on depression-like behavior and serum metabonomics in CUMS Rat. J Nanjing Univ Tradit Chin Med 35(5):590–595
Xing N, Shu Z, Xu B, Jiao W, Li Z, Wang Q, Kuang H (2015) GC–MS analysis of volatile oil components in Fructus Aurantii from different regions and study of its antitumor activity. Inf Tradit Chin Med 32(5):1–6
Xiong X, Peng W, Chen L, Liu H, Huang W, Yang B, Wang Y, Xing Z, Gan P, Nie K (2015) Traditional Chinese medicine Zhiqiao-Houpu herb-pair induce bidirectional effects on gastric motility in rats. J Ethnopharmacol 175:444–450. https://doi.org/10.1016/j.jep.2015.10.001
Xiong Y, Yang Y, SongJiang FP, Zhao X (2010) Research progress of furan coumarin components and pharmacological effects. Chin Tradit Pat Med 32(10):1764–1770
Xu Y, Feng J, Guo J (2013) Mechanism underlying the antidepressant effect of Fructus Aurantii. Chin J Clin Pharmacol Therap 18(10):1086–1092
Xu G, Feng L, Song P, Xu F, Li A, Wang Y, Shen Y, Wu X, Luo Q, Wu X, Sun Y, Wu X, Xu Q (2016) Isomeranzin suppresses inflammation by inhibiting M1 macrophage polarization through the NF-κB and ERK pathway. Int Immunopharmacol 38:175–185. https://doi.org/10.1016/j.intimp.2016.05.027
Xu S, Xu J, Zhang X, Zhang T, Liu C (2018) Research progress on Citri Reticulatae Pericarpium, Aurantii Fructus Immaturus, and Aurantii Fructus and Q-marker predictive analysis. Chin Tradit Herb Drugs 49(1):35–44
Xue L, Gao L, Qin X, Du G, Zhou Y (2017) A review of recent literature on anti-aging activity of medicinal and edible traditional Chinese herbs. Food Sci 38(15):302–309. https://doi.org/10.7506/spkx1002-6630-201715047
Yabuki Y, Ohizumi Y, Yokosuka A, Mimaki Y, Fukunaga K (2014) Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neuroscience 259:126–141. https://doi.org/10.1016/j.neuroscience.2013.11.051
Yamada Y, Nakatani N, Fuwa H (1987) Epoxyaurapten and marminfrom juice oil in hassaku (Citrus hassaku) and the spasmolytic activity of 7-geranyloxycoumarin-related compounds. Agric Biol Chem 51(4):1105–1110
Yan H, Zuo Y, Zhang Z (2018) Chemical constituents from Citrus aurantium by UHPLC-Q-TOF-MS. J Chin Med Mater 41(10):2343–2348
Yang Y, Ding Z, Zhong R, Xia T, Wang W, Zhao H, Wang Y, Shu Z (2019) Cardioprotective effects of a Fructus Aurantii polysaccharide in isoproterenol-induced myocardial ischemic rats. Int J Biol Macromol. https://doi.org/10.1016/j.ijbiomac.2019.11.063
Yang J, Zheng J, Shen K, Han Y, Gu Y, Zhu Y, Zhou H, Zhao A, Zhao H, Yang J (2003) Clinical study on post-operative metastasis prevention of progressive stage of gastric cancer by Weichang’an. Chin J Integr Tradit West Med 23(8):580–582
Yasuda N, Ishii T, Oyama D, Fukuta T, Agato Y, Sato A, Shimizu K, Asai T, Asakawa T, Kan T, Yamada S, Ohizumi Y, Oku N (2014) Neuroprotective effect of nobiletin on cerebral ischemia-reperfusion injury in transient middle cerebral artery-occluded rats. Brain Res 1559:46–54. https://doi.org/10.1016/j.brainres.2014.02.007
Yi X, Xia F, Chen H, Luo X, Pei K, Huang P, Xiao Y, Yang W (2015) Effect of the flavanones in Fructus Aurantii on small intestinal propulsion function of mice. Lishizhen Med Mater Medica Res 26(2):278–280
Yu X, Sun S, Guo Y, Liu Y, Yang D, Li G, Lu S (2018) Citri Reticulatae Pericarpium (Chenpi): botany, ethnopharmacology, phytochemistry, and pharmacology of a frequently used traditional Chinese medicine. J Ethnopharmacol 220:265–282. https://doi.org/10.1016/j.jep.2018.03.031
Yu J, Wang L, Walzem RL, Miller EG, Pike LM, Patil BS (2005) Antioxidant activity of citrus limonoids, flavonoids, and coumarins. J Agric Food Chem 53(6):2009–2014. https://doi.org/10.1021/jf0484632
Zhang D (2005) New clinical application of Aurantii Fructus. Zhejiang J Integr Tradit Chin West Med 1:57
Zhang Y (2019) Systematic review on study of Jizhi syrup. Asia Pac Tradit Med 15(8):182–184
Zhang B, Cheng RH, Wang GD, Li QS, Fan WX (2003) Clinical observation of 112 cases of postoperative abdominal complications treated by Weichang fuyuan Electuary. Jiangsu J Tradit Chin Med 24(2):30
Zhang X, Han L, Liu J, Xu Q, Guo Y, Zheng W, Wang J, Huang X, Ren P (2018) Pharmacokinetic study of 7 compounds following oral administration of Fructus Aurantii to depressive rats. Front Pharmacol 9:131. https://doi.org/10.3389/fphar.2018.00131
Zhang YJ, Huang W, Huang X, Wang Y, Wang Z, Wang C, Zhong BW, Sheng CX, Wang B, Zhang SF, Su NX, Liu ZQ, Zhou HH, Ren P (2012) Fructus Aurantii induced antidepressant effect via its monoaminergic mechanism and prokinetic action in rat. Phytomedicine 19(12):1101–1107. https://doi.org/10.1016/j.phymed.2012.05.015
Zhang B, Jin J, Jin Z, Wu F (2013) Advances in pharmacological action and clinical application of Aurantii Fructus. Her Med 32(11):1462–1464
Zhang P, Li Y, Tu M, Zhang Y, Chen H, Yang W (2010) The synthesis and biological activity of auraptene and marmin. Lishizhen Med Mater Medica Res 21(8):1851–1853
Zhang JL, Liu MG, Yan DM, Sun XJ, Tu JY, Liu YJ, Li N, Gong QF (2018) Study on acute toxicity and GC-MS chemical constituent analysis of volatile oil of Fructus Aurantii pieces made by methods of Pharmacopoeia and Zhang-bang method. China J Tradit Chin Med Pharm 33(2):689–693
Zhang H, Sun M, Wang L (2009) Advances in research on the chemical constituents and pharmacological effects of Zhishi. J Chin Med Mater 32(11):1787–1790
Zhao T, Hu S, Ma P, Che D, Liu R, Zhang Y, Wang J, Li C, Ding Y, Fu J, An H, Gao Z, Zhang T (2019) Neohesperidin suppresses IgE-mediated anaphylactic reactions and mast cell activation via Lyn-PLC-Ca(2+) pathway. Phytother Res 33(8):2034–2043. https://doi.org/10.1002/ptr.6385
Zhao S, Liu Z, Wang M, He D, Liu L, Shu Y, Song Z, Li H, Liu Y, Lu A (2018) Anti-inflammatory effects of Zhishi and Zhiqiao revealed by network pharmacology integrated with molecular mechanism and metabolomics studies. Phytomedicine 50:61–72. https://doi.org/10.1016/j.phymed.2018.09.184
Zhao J, Wang Y, Weng Q, Jin Y, Zhang W, Peng H, Cai Q, Li B, Yang H, Zhang H, Zhan Z (2020) Herbal Textual Research on Aurantii Fructus Immaturus and Aurantii Fructus in Chinese Classical Prescriptions. Modern Chinese Medicine. http://kns.cnki.net/kcms/detail/11.5442.R.20200306.1001.002.html. Accessed 6 Mar 2020
Zhou DY, Chen DL, Xu Q, Xue XY, Zhang FF, Liang XM (2007) Characterization of polymethoxylated flavones in Fructus aurantii by liquid chromatography with atmospheric pressure chemical ionization combined with tandem mass spectrometry. J Pharm Biomed Anal 43(5):1692–1699. https://doi.org/10.1016/j.jpba.2006.12.032
Zhou L, Cui M, Zhao L, Wang D, Tang T, Wang W, Wang S, Huang H, Qiu X (2018) Potential metabolic drug–drug interaction of Citrus aurantium L. (Rutaceae) evaluating by its effect on 3 CYP450. Front Pharmacol 9:895. https://doi.org/10.3389/fphar.2018.00895
Zhou JY, Ma Y, Liang JL, Xia LL (2015) Guogong Vinum local massage assists in the treatment of scleredema. Glob Tradit Chin Med 8(S2):234
Zhu HQ, Zuo XH, Zhang MY (2020a) Retrospective study of lactulose combined with Simo decoction in the treatment of elderly constipation. Shanxi Med J 49(9):1067–1069
Zhu J, Yuan E, Mou J, Zhong L, Zhang J, Yang M, Liu H (2020b) Analysis of influence of Jiangxi characteristic processing technology on chemical compositions of Aurantii Fructus based on UPLC-Q/TOF-MS. Chin J Exp Tradit Med Formul 26(16):142–153
Zou B, Wei M, Yuan J (2004) Effect of Areca nut on gastrointestinal of normal peptide and its function of improving the gastrointestinal motility. Study J Tradit Chin Med 22(6):1040–1041
Funding
This work was supported by the National Natural Science Foundation of China (No. 81803742).
Author information
Authors and Affiliations
Contributions
GT and JM carried out the collection and analysis of data, design of charts and drafted the manuscript. FQ and FC came up with the idea of review and implemented the revision of the manuscripts. DB and ZZ participated in revision and proof of manuscripts.GT and JM carried out the collection and analysis of data, design of charts and drafted the manuscript. FQ and FC came up with the idea of review and implemented the revision of the manuscripts. DB and ZZ participated in revision and proof of manuscripts.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declared that they have no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Gao, T., Jiang, M., Deng, B. et al. Aurantii Fructus: a systematic review of ethnopharmacology, phytochemistry and pharmacology. Phytochem Rev 20, 909–944 (2021). https://doi.org/10.1007/s11101-020-09725-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11101-020-09725-1