Akhlaghi, M., Shabanian, G., Rafieian-Kopaei, M., Parvin, N., Saadat, M., and Akhlaghi, M. Citrus aurantium blossom and preoperative anxiety. Rev Bras.Anestesiol. ;61(6):702-712. View abstract.
Link to chenlv
Arbo, M. D., Schmitt, G. C., Limberger, M. F., Charao, M. F., Moro, A. M., Ribeiro, G. L., Dallegrave, E., Garcia, S. C., Leal, M. B., and Limberger, R. P. Subchronic toxicity of Citrus aurantium L. (Rutaceae) extract and p-synephrine in mice. Regul.Toxicol.Pharmacol ;54(2):114-117. View abstract.
Bent, S., Padula, A., and Neuhaus, J. Safety and efficacy of citrus aurantium for weight loss. Am.J.Cardiol. 11-15-;94(10):-. View abstract.
Blumenthal, M., Goldberg, A., and Brinckmann, J. Herbal Medicine Expanded Commission E Monographs. ;
Calapai, G., Firenzuoli, F., Saitta, A., Squadrito, F. R., Arlotta, M., Costantino, G., and Inferrera, G. Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat: a preliminary report. Fitoterapia 12-1-;70(6):586-592.
Campbell-Tofte, J. I., Molgaard, P., Josefsen, K., Abdallah, Z., Hansen, S. H., Cornett, C., Mu, H., Richter, E. A., Petersen, H. W., Norregaard, J. C., and Winther, K. Randomized and double-blinded pilot clinical study of the safety and anti-diabetic efficacy of the Rauvolfia-Citrus tea, as used in Nigerian traditional medicine. J Ethnopharmacol. 1-27-;133(2):402-411. View abstract.
Cherniack, E. P. Potential applications for alternative medicine to treat obesity in an aging population. Altern.Med Rev ;13(1):34-42. View abstract.
Colker, C., Kalman, D., and Torina, G. Effects of Citrus aurantium extract, caffeine, and St. John's Wort on body fat loss, lipid levels, and mood states in overweight healthy adults. Curr Ther Res ;60:145-153.
Gougeon, R., Harrigan, K., Tremblay, J. F., Hedrei, P., Lamarche, M., and Morais, J. A. Increase in the thermic effect of food in women by adrenergic amines extracted from citrus aurantium. Obes.Res ;13(7):-. View abstract.
Gray, S. and Woolf, A. D. Citrus aurantium used for weight loss by an adolescent with anorexia nervosa. J Adolesc.Health ;37(5):414-415. View abstract.
Haller, C. A., Duan, M., Jacob, P., III, and Benowitz, N. Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions. Br J Clin Pharmacol ;65(6):833-840. View abstract.
Higgins, J. P., Tuttle, T. D., and Higgins, C. L. Energy beverages: content and safety. Mayo Clin Proc. ;85(11):-. View abstract.
Kaats, G. R., Miller, H., Preuss, H. G., and Stohs, S. J. A 60day double-blind, placebo-controlled safety study involving Citrus aurantium (bitter orange) extract. Food Chem Toxicol. ;55:358-362. View abstract.
Lynch B. Review of the safety of p-synephrine and caffeine. Intertek-Cantox Report, ;1-20.
Preuss, H. G., DiFerdinando, D., Bagchi, M., and Bagchi, D. Citrus aurantium as a thermogenic, weight-reduction replacement for ephedra: an overview. J.Med. ;33(1-4):247-264. View abstract.
Seifert, J. G., Nelson, A., Devonish, J., Burke, E. R., and Stohs, S. J. Effect of acute administration of an herbal preparation on blood pressure and heart rate in humans. Int J Med Sci ;8(3):192-197. View abstract.
Shara M, Stohs SJ. Safety evaluation of Bitter orange extract (p-synephrine) in healthy volunteers. J.Amer.Coll.Nutr. ;30:358.
Stohs, S. J., Preuss, H. G., and Shara, M. 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. View abstract.
Stohs, S. J., Preuss, H. G., Keith, S. C., Keith, P. L., Miller, H., and Kaats, G. R. Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes. Int J Med Sci ;8(4):295-301. View abstract.
Thomas, J. E., Munir, J. A., McIntyre, P. Z., and Ferguson, M. A. STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature. Tex.Heart Inst.J ;36(6):586-590. View abstract.
Wason, S., DiGiacinto, J. L., and Davis, M. W. Effects of grapefruit and Seville orange juices on the pharmacokinetic properties of colchicine in healthy subjects. Clin Ther ;34(10):-. View abstract.
Wu, H., Jing, Z., Tang, X., Wang, X., Zhang, S., Yu, Y., Wang, Z., Cao, H., Huang, L., Yu, Y., and Wang, Y. To compare the efficacy of two kinds of Zhizhu pills in the treatment of functional dyspepsia of spleen-deficiency and qi-stagnation syndrome: a randomized group sequential comparative trial. BMC.Gastroenterol ;11:81. View abstract.
Xu, L., Jiang, J., and Du, F. Z. [Application of dannang recipe no. 2 in the perioperative stage of laparoscopic cholecystectomy]. Zhongguo Zhong.Xi.Yi Jie.He.Za Zhi ;28(12):-. View abstract.
Zhou, L., Hao, R., and Jiang, L. [Clinical study on retarding aging effect of tongbu recipe to traditional Chinese medicine]. Zhongguo Zhong.Xi.Yi.Jie.He.Za Zhi. ;19(4):218-220. View abstract.
Abbaspoor Z, Sharifipour F, Siahposh A, Nazaralivand R, Mohaghegh Z, Faal Siahkal S. Effects of Aromatherapy With Citrus Aurantium Lavender on Sexual Function of Postmenopausal Women: A Randomized Controlled Trial. J Family Reprod Health ;16(2):147-154. View abstract.
Abbaspoor Z, Siahposh A, Javadifar N, Faal Siahkal S, Mohaghegh Z, Sharifipour F. The Effect of Citrus Aurantium Aroma on the Sleep Quality in Postmenopausal Women: A Randomized Controlled Trial. Int J Community Based Nurs Midwifery ;10(2):86-95. View abstract.
Abdelkawy KS, Donia AM, Turner RB, Elbarbry F. Effects of Lemon and Seville Orange Juices on the Pharmacokinetic Properties of Sildenafil in Healthy Subjects. Drugs R D. Sep;16(3):271-278. View abstract.
Allison DB, Cutter G, Poehlman ET, et al. Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain? Int J Obes Relat Metab Disord ;29:443-6. View abstract.
Andrew R, Best SA, Watson DG, et al. Analysis of biogenic amines in plasma of hypertensive patients and a control group. Neurochem Res ;18:-82. View abstract.
Benjamim CJR, Júnior FWS, Porto AA, et al. Bitter Orange (Citrus aurantium L.) Intake Before Submaximal Aerobic Exercise Is Safe for Cardiovascular and Autonomic Systems in Healthy Males: A Randomized Trial. Front Nutr ;9:. View abstract.
Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications, .
Bouchard NC, Howland MA, Greller HA, et al. Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. Mayo Clin Proc ;80:541-5. View abstract.
Buckle J. Use of aromatherapy as a complementary treatment for chronic pain. Altern Ther Health Med ;5:42-51. View abstract.
Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate effects following a single dose of bitter orange. Ann Pharmacother ;40:53-7. View abstract.
Burke J, Seda G, Allen D, Knee TS. A case of severe exercise-induced rhabdomyolysis associated with a weight loss dietary supplement. Mil Med ;172:656-8. View abstract.
Calapai G, Firenzuoli F, Saitta A, et al. Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat: A preliminary report. Fitoterapia ;70:586-92.
Carnat A, Carnat AP, Fraisse D, Lamaison JL. [Standardization of the sour orange flower and leaf]. Ann Pharm Fr ;57:410-4. View abstract.
Colker CM, Kalman DS, Torina GC, et al. Effects of Citrus aurantium extract, caffeine, and St. John's wort on body fat loss, lipid levels, and mood states in overweight healthy adults. Curr Ther Res ;60:145-153.
D'Andrea G, Terrazzino S, Leon A, et al. Elevated levels of circulating trace amines in primary headaches. Neurology ;62:-5. View abstract.
Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. Life Sci ;71:-60. View abstract.
Dragull K, Breksa AP 3rd, Cain B. Synephrine content of juice from Satsuma mandarins (Citrus unshiu Marcovitch). J Agric Food Chem ;56(19):-8. View abstract.
Edwards DJ, Fitzsimmons ME, Schuetz EG, et al. 6',7'-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther ;65:237-44. View abstract.
Electronic Code of Federal Regulations. Title 21. Part 182 -- Substances Generally Recognized As Safe. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=182
Farshbaf-Khalili A, Kamalifard M, Namadian M. Comparison of the effect of lavender and bitter orange on anxiety in postmenopausal women: A triple-blind, randomized, controlled clinical trial. Complement Ther Clin Pract ;31:132-8. View abstract.
Firenzuoli F, Gori L, Galapai C. Adverse reaction to an adrenergic herbal extract (Citrus aurantium). Phytomedicine ;12:247-8. View abstract.
Fugh-Berman A, Myers A. Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: Current status of clinical and basic Research. Exp Biol Med ;229:698-704. View abstract.
Gange CA, Madias C, Felix-Getzik EM, et al. Variant angina associated with bitter orange in a dietary supplement. Mayo Clin Proc ;81:545-8. View abstract.
Gray SG, Clair AA. Influence of aromatherapy on medication administration to residential-care residents with dementia and behavioral challenges. Am J Alzheimers Dis Other Demen ;17(3):169-74. View abstract.
Greenway F, de Jonge-Levitan L, Martin C, et al. Dietary herbal supplements with phenylephrine for weight loss. J Med Food ;9:572-8. View abstract.
Gutiérrez-Hellín J, Ruiz-Moreno C, Del Coso J. Acute p-synephrine ingestion increases whole-body fat oxidation during 1-h of cycling at Fatmax. Eur J Nutr. Nov 5. View abstract.
Gutiérrez-Hellín J, Salinero JJ, Abían-Vicen J, Areces F, Lara B, Gallo C, et al. Acute consumption of p-synephrine does not enhance performance in sprint athletes.J. Appl Physiol Nutr Metab. ;41(1):63-9. doi: 10./apnm--.View abstract.
Haller CA, Benowitz NL, Jacob P 3rd. Hemodynamic effects of ephedra-free weight-loss supplements in humans. Am J Med ;118:998-.. View abstract.
Health Canada. Synephrine, Octopamine and Caffeine Health Risk Assessment (HRA) Report. Approved May 16, . Accessed November 6, . Available at: https://www.nutratechinc.com/advz/Studies/Safety/S1%20Health%20Canada%.pdf.
Heydari N, Abootalebi M, Jamalimoghadam N, Kasraeian M, Emamghoreishi M, Akbarzadeh M. Investigation of the effect of aromatherapy with Citrus aurantium blossom essential oil on premenstrual syndrome in university students: A clinical trial study. Complement Ther Clin Pract. ;32:1-5. View abstract.
Hu JF. [Inhibitory effects of Phyllanthus emblica juice on formation of N-nitrosomorpholine in vitro and N-nitrosoproline in rat and human]. Chung Hua Yu Fang I Hsueh Tsa Chih ;24:132-5. View abstract.
Huang YT, Wang GF, Chen CF, et al. Fructus aurantii reduced portal pressure in portal hypertensive rats. Life Sci ;57:-20. View abstract.
Ishiwa J, Sato T, Mimaki Y, et al. A citrus flavonoid, nobiletin, suppresses production and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts. J Rheumatol ;27:20-5. View abstract.
Jordan S, Murty M, Pilon K. Products containing bitter orange or synephrine: suspected cardiovascular adverse reactions. Canadian Adverse Reaction Newsletter ;14:3-4.
Jung YP, Earnest CP, Koozehchian M, et al. Effects of acute ingestion of a pre-workout dietary supplement with and without synephrine on resting energy expenditure, cognitive function and exercise performance. J Int Soc Sports Nutr. ;14:3. doi: 10./s-016--2.View abstract.
Jung YP, Earnest CP, Koozehchian M, et al. Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males. J Int Soc Sports Nutr. ;3;14:1. doi: 10./s-016--3. View abstract.
Karimzadeh Z, Azizzadeh Forouzi M, Rahiminezhad E, Ahmadinejad M, Dehghan M. The Effects of Lavender and Citrus aurantium on Anxiety and Agitation of the Conscious Patients in Intensive Care Units: A Parallel Randomized Placebo-Controlled Trial. Biomed Res Int ;:. View abstract.
Karimzadeh Z, Azizzadeh Forouzi M, Tajadini H, Ahmadinejad M, Roy C, Dehghan M. Effects of lavender and Citrus aurantium on pain of conscious intensive care unit patients: a parallel randomized placebo-controlled trial. J Integr Med :S-(21)-6. Online ahead of print. View abstract.
Keogh AM, Baron DW. Sympathomimetic abuse and coronary artery spasm. Br Med J ;291:940.
Kim DH, Song MJ, Bae EA, Han MJ. Inhibitory effect of herbal medicines on rotavirus infectivity. Biol Pharm Bull ;23:356-8. View abstract.
Kim KW, Kim HD, Jung JS, et al. Characterization of antidepressant-like effects of p-synephrine stereoisomers. Naunyn Schmiedebergs Arch Pharmacol ;364:21-6. View abstract.
Koncz D, Tóth B, Bahar MA, Roza O, Csupor D. The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis. Nutrients ;14(19):. View abstract.
Liu Y, Santillo MF. Cytochrome P450 2D6 and 3A4 enzyme inhibition by amine stimulants in dietary supplements. Drug Test Anal. ;8(3-4):307-10. View abstract.
Lopez HL, Ziegenfuss TN, Hofheins JE, et al. Eight weeks of supplementation with a multi-ingredient weight loss product enhances body composition, reduces hip and waist girth, and increases energy levels in overweight men and women. J Int Soc Sports Nut ;10(1):22. View abstract.
Malhotra S, Bailey DG, Paine MF, Watkins PB. Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin Pharmacol Ther ;69:14-23. View abstract.
Martin KW, Ernst E. Herbal medicines for treatment of fungal infections: a systematic review of controlled clinical trials. Mycoses ;47:87-92. View abstract.
McLester CN, Bailey P, Bechke EE, Williamson CM, McLester JR, Kliszczewicz B. The Effects of Caffeine and Citrus Aurantium on Performance During Repeated Maximal Anaerobic Exercise Bouts in Habitual Caffeine Users. J Strength Cond Res. Sep 2. View abstract.
If you want to learn more, please visit our website Citrus Aurantium Extract Powder.
Min B, Cios D, Kluger J, White CM. Absence of QTc-interval-prolonging or hemodynamic effects of a single dose of bitter-orange extract in healthy subjects. Pharmacotherapy ;25:-24. View abstract.
Mohammadi F, Moradi M, Niazi A, Jamali J. The Impact of Aromatherapy with Citrus Aurantium Essential Oil on Sleep Quality in Pregnant Women with Sleep Disorders: A Randomized Controlled Clinical Trial. Int J Community Based Nurs Midwifery ;10(3):160-171.View abstract.
Moradi K, Ashtarian H, Danzima NY, et al. Essential oil from Citrus aurantium alleviates anxiety of patients undergoing coronary angiography: a single-blind, randomized controlled trial. Chin J Integr Med ;27(3):177-82. View abstract.
Moslemi F, Alijaniha F, Naseri M, Kazemnejad A, Charkhkar M, Heidari MR. Citrus aurantium Aroma for Anxiety in Patients with Acute Coronary Syndrome: A Double-Blind Placebo-Controlled Trial. J Altern Complement Med. Aug;25(8):833-839. View abstract.
Mwaiko GL. Citrus peel oil extracts as mosquito larvae insecticides. East Afr Med J ;69:223-6. View abstract.
Naganuma M, Hirose S, Nakayama Y, et al. A study of the phototoxicity of lemon oil. Arch Dermatol Res ;278:31-6. . View abstract.
Nasir JM, Durning SJ, Ferguson M, et al. Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine. Mayo Clin Proc ;79:-62.. View abstract.
National Collegiate Athletic Association. NCAA Banned-Drug Classes -. Available at: https://www1.ncaa.org/membership/ed_outreach/health-safety/drug_testing/banned_drug_classes.pdf.
Nykamp DL, Fackih MN, Compton AL. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacother ;38:812-6. View abstract.
Pawar RS, Sagi S, Leontyev D. Analysis of bitter orange dietary supplements for natural and synthetic phenethylamines by LC-MS/MS. Drug Test Anal ;12(9):-51. View abstract.
Pellati F, Benvenuti S, Melegari M, Firenzuoli F. Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC. J Pharm Biomed Anal ;29:-9. . View abstract.
Penzak SR, Acosta EP, Turner M, et al. Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics. J Clin Pharmacol ;42:-70. View abstract.
Penzak SR, Jann MW, Cold JA, et al. Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol ;41:-63. View abstract.
Ramadan W, Mourad B, Ibrahim S, Sonbol F. Oil of bitter orange: new topical antifungal agent. Int J Dermatol ;35:448-9. View abstract.
Ratamess NA, Bush JA, Kang J, et al. The effects of supplementation with P-Synephrine alone and in combination with caffeine on resistance exercise performance. J Int Soc Sports Nutr. ;12:35.View abstract.
Ratamess NA, Bush JA, Stohs SJ, et al. Acute cardiovascular effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine in human subjects: A placebo-controlled, double-blind study. Phytother Res. ;32(1):94-102. View abstract.
Sale C, Harris RC, Delves S, Corbett J. Metabolic and physiologic effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males. Int J Obes (Lond) ;30(5):764-73. View abstract.
Satoh Y, Tashiro S, Satoh M, et al. [Studies on the bioactive constituents of Aurantii Fructus Immaturus]. Yakugaku Zasshi ;116:244-50. View abstract.
Shara M, Stohs SJ, Mukattash TL. Cardiovascular safety of oral p-synephrine (bitter orange) in healthy subjects: a randomized placebo-controlled cross-over clinical trial. Phytother Res. ;30(5):842-7. View abstract.
Shara M, Stohs SJ, Smadi MM. Safety evaluation of p-synephrine following 15 days of oral administration to healthy subjects: A clinical study. Phytother Res. ;32(1):125-131. View abstract.
Smith TB, Staub BA, Natarajan GM, et al. Acute myocardial infarction associated with dietary supplements containing 1,3-dimethylamylamine and Citrus aurantium. Tex Heart Inst J ;41(1):70-2. View abstract.
Song DK, Suh HW, Jung JS, et al. Antidepressant-like effects of p-synephrine in mouse models of immobility tests. Neurosci Lett ;214:107-10. View abstract.
Sultan S, Spector J, Mitchell RM. Ischemic colitis associated with use of a bitter orange-containing dietary weight-loss supplement. Mayo Clin Proc ;81:-1.. View abstract.
Suzuki O, Matsumoto T, Oya M, Katsumata Y. Oxidation of synephrine by type A and type B monoamine oxidase. Experientia ;35:-4. View abstract.
The Federal Institute for Risk Assessment (Bundesinstitut fur Risikobewertung - Germany). Health assessment of sports and weight loss products containing synephrine and caffeine. . BfR Opinion No. 004/.
Uckoo RM, Jayaprakasha GK, Nelson SD, Patil BS. Rapid simultaneous determination of amines and organic acids in citrus using high-performance liquid chromatography. Talanta ;83(3):948-54. View abstract.
Vatsavai LK, Kilari EK. Interaction of p-synephrine on the pharmacodynamic and pharmacokinetics of gliclazide in animal models. J Ayurveda Integr Med ; S-(16)-9. doi: 10./j.jaim..04.010.View abstract.
Vierck JL, Icenoggle DL, Bucci L, Dodson MV. The effects of ergogenic compounds on myogenic satellite cells. Med Sci Sports Exerc ;35:769-76. View abstract.
Visentin V, Morin N, Fontana E, et al. Dual action of octopamine on glucose transport into adipocytes: inhibition via beta3-adrenoceptor activation and stimulation via oxidation by amine oxidases. J Pharmacol Exp Ther ;299:96-104. View abstract.
Vitetta L, Thomsen M, Sali A. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust ;178:411-2.. View abstract.
Zhang L, Xu X, Jiang T, et al. Citrus aurantium Naringenin Prevents Osteosarcoma Progression and Recurrence in the Patients Who Underwent Osteosarcoma Surgery by Improving Antioxidant Capability. Oxid Med Cell Longev. ;:. View abstract.
Zhao XW, Li JX, Zhu ZR, et al. Anti-shock effects of synthetic effective compositions of fructus aurantii immaturus. Experimental study and clinical observation. Chin Med J (Engl) ;102:91-3. View abstract.
Citrus aurantium L. (Rutaceae), commonly known as bitter orange, possesses multiple therapeutic potentials. These biological credentials include anticancer, antianxiety, antiobesity, antibacterial, antioxidant, pesticidal, and antidiabetic activities. The essential oil of C. aurantium was reported to display marked pharmacological effects and great variation in chemical composition depending on growing locations but mostly contained limonene, linalool, and β-myrcene. Phytochemically, C. aurantium is rich in p-synephrine, an alkaloid, and many health-giving secondary metabolites such as flavonoids. Animal studies have demonstrated a low affinity of p-synephrine for adrenergic receptors and an even lower affinity in human models. The present review focuses on the different biological activities of the C. aurantium in animal and human models in the form of extract and its pure secondary metabolites. Finally, it is concluded that both the extract and isolated compounds have no unwanted effects in human at therapeutic doses and, therefore, can confidently be used in various dietary formulations.
In the last years, phytopharmaceuticals have shown an outstanding role in new drug discovery [ 18 20 ]. Both in the crude form as well as pure chemical entities, a large population around the globe are getting therapeutic benefits from them [ 21 23 ]. In this review article, we have aimed to overview the bioactivity studies performed on C. aurantium revealing its therapeutic potential in the light of isolated molecules and/or essential oils.
Citrus aurantium L. (Rutaceae), commonly known as bitter orange, is usually utilized as a flavoring and acidifying agent for food [ 1 ]. Besides the essential oil and its components [ 2 , 3 ], the fruits of C. aurantium are sources of flavonoid-type compounds with diverse biological effects [ 4 6 ]. Additionally, it was reported that flavonoid glycosides were isolated from the plant [ 7 ] and the biogenic amine and flavanone contents have been determined [ 8 , 9 ]. Due to the abundance of health-giving secondary metabolites, C. aurantium is also used for the treatment of several ailments such as anxiety [ 10 ], lung and prostate cancers [ 11 ], and gastrointestinal disorders and obesity [ 2 , 12 ]. Due to the prohibition of Ephedra sinica Stapf. in Farw.-containing weight loss products in the market, C. aurantium has found an important place as a preferable agent to replace ephedra, as it contains p-synephrine, a phenylethanolamine type alkaloid, which is chemically similar to adrenergic agents, as appetite suppressants [ 12 14 ]. Recently, several scientific studies investigating the potential effects of various parts (including flowers, fruits, and essential oils) of C. aurantium have been conducted [ 15 17 ].
Zarrad and coworkers [ 32 ] explored the chemical composition of Tunisian C. aurantium fruits using gas chromatography (GC) and gas chromatography-mass spectroscopy (GC-MS). 25 compounds were identified in 97.696% exploration, but the most prominent one was limonene with 85.52%, followed by linalool and β-myrcene with 3.365% and 1.628%, respectively. The remaining compounds were in traces. Earlier, Villafane et al. [ 33 ] reported the presence of D-limonene and nootkatone in the essential oil of the plant. Similarly, Sanei-Dehkordi et al. [ 34 ] identified 21 compounds in peel essential oil of the plant. Of the total explored 98.62% composition, the quantity of limonene was 94.81% while the LC 50 was 31.20 ppm against Anopheles stephensi. However, the concentration of limonene was only 0.52.5% in C. aurantium from Algeria and linalool and α-terpineol were 18.6% and 15.1%, respectively [ 35 ]. Thus, overall considerable variation was observed in the concentration of these major components in C. aurantium grown in different parts of the world [ 36 41 ]. Carvalho-Freitas and Costa observed strong anxiolytic and sedative-like effects of the essential oil derived from C. aurantium [ 42 ].
Another class of compounds contained in C. aurantium are phenylethylamine alkaloids with p-synephrine being the most abundant. This compound has a hydroxyl group in the para position on the benzene ring and has some structural similarity to ephedrine. The peel of unripe fruits is the part of the plant which has the highest level of p-synephrine [ 31 ].
The second class of secondary metabolites found in C. aurantium are the limonoids ( Scheme 2 ). The latter were considered as oxygenated triterpenoids as they contain relatively high numbers of oxygen atoms (711) in their structures. All components have a furan ring attached to the D-ring at C-17. Limonoids occur both in glucosidic and aglyconic form. Limonoid aglycones are water-insoluble and responsible for a bitter taste of the Citrus fruits, while limonoid glucosides are water-soluble and tasteless [ 28 ]. Among limonoids, the most important one is limonin, known as Citrus constituent since . Limonoid glucosides are more abundant in juices and pulps, such as limonin glucoside, nomilin glucoside, obacunone glucoside, nomilinic acid glucoside, and deacetylnomilinic acid glucoside, because they are water-soluble, while limonoid aglycones such as limonin, nomilin, obacunone, ichangin, and deacetyl nomilin are water-insoluble and are present mainly in seeds and peels [ 29 , 30 ].
In C. aurantium, the flavones may be present also in the methoxylated form, in which all or almost all hydroxyls are capped by methylation, as nobiletin and tangeretin [ 27 ]. Furthermore, the C. aurantium may contain low amounts of flavonols, as kaempferol and quercetin, mainly in glycosidic form.
The flavones in aglycon or/and glycosidic form are the second major group of flavonoids in C. aurantium. The most commonly detected free flavones are apigenin, luteolin, and diosmetin. O-Glycosides and C-glycosides are the two main forms of flavone glycosides, and the most common linked sugar moieties include glucose, rutinose, and neohesperidose [ 26 ].
Flavanones are the main flavonoids contained in C. aurantium [ 25 ]. The most abundant detected free flavanones are hesperetin (4-methoxy-3,5,7-trihydroxyflavanone) and naringenin (4,5,7-trihydroxyflavanone) [ 26 ]. Hesperetin and naringenin present a common skeleton: two hydroxyl group in positions C-5 and C-7, respectively, and they can be found as aglycone and/or as glycosides [ 25 ]. The most widely distributed glycosides of hesperetin are hesperidin and neohesperidin, which are conjugates with rutinose and neohesperidose, respectively, while, for naringenin, the most abundant glycosyl derivatives are naringin (naringenin-7-neohesperidoside) and narirutin (naringenin-7-rutinoside) [ 25 ].
Flavonoids are mainly present in Citrus fruits as glycosyl derivatives. Aglycones are mainly present in specific parts of the fruit as peel and seeds, owing to their lipophilic nature and consequently their low solubility in water [ 21 23 ]. For glycoside forms, O-glycosides, C-glycosides, rutinosides, glucosides, and neohesperidosides are common [ 21 23 ]. The presence of a relatively large number of glycosylated flavonoids in Citrus is a result of many different combinations possible between polyhydroxylated aglycones and a limited number of mono- and disaccharides [ 24 ].
The chemical composition of C. aurantium is responsible for health-promoting effects. The chemical composition includes vitamins, minerals, phenolic compounds, and terpenoids [ 21 23 ]. Among the diverse chemical components in C. aurantium, flavonoids belonging to phenolics have been recognized as important due to their physiological and pharmacological role and their health benefits [ 21 23 ].
The anticancer activity of the plant has been reported in literature [26, 43]. Cytotoxic properties of the polysaccharides obtained from C. aurantium were examined. Cytotoxic activity on human breast cancer cells (MCF-7) and lung cancer cells (HCC827) and immune-enhancement effect were examined. The results indicated that C. aurantium var. amara polysaccharides displayed good immune-enhancement activity by stimulating the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in RAW264.7 cells and by promoting the mRNA expression levels of inducible nitric oxide synthase (iNOS), TNF-α, interleukin-1β (IL-1β), and IL-6. Moreover, phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated c-Jun N-terminal kinase (JNK), phosphorylated p38, and phosphorylated p65 were significantly enhanced in C. aurantium var amara polysaccharides-treated RAW264.7 cells [24, 44]. Isolimonic acid and ichanexic acid from ethyl acetate extract of C. aurantium were isolated by using chromatographic methods. The compounds for their inhibitory action on human colon cancer cells (HT-29) proliferation, apoptosis, and on noncancerous (COS-1 fibroblast) cells were investigated. The compounds displayed an increment in the cell counts in G2/M stage, demonstrating a potential effect in the cell-cycle arrest [25].
Protective activity of the extract obtained from the peels of C. aurantium against apoptosis in cholestatic liver fibrosis-induced mice was investigated. As part of the experiment, cholestatic liver injury was induced by bile duct ligation and the mice were treated with C. aurantium peel extract. According to the histopathological analysis, the administration of C. aurantium peel extract significantly decreased liver fibrosis. Biochemical analysis revealed that the extract reduced the concentrations of alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase, total bilirubin, nitric oxide, and thiobarbituric acid reactive substances (TBARS), suggesting C. aurantium can efficiently regulate bile duct ligation-induced liver injury by displaying antioxidant, anti-inflammatory, and antiapoptotic effects [27].
C. aurantium was shown to possess antimetastasis activities in in vitro assays. A study by Park et al. evaluated the antimetastatic effect of flavonoids, isolated from Korean C. aurantium in mice models. Flavonoids were shown to prevent cancer cell infiltration and localization to the lungs. Moreover, through the regulation of caspase-3 and phospho-p53, the flavonoids induced cancer cell apoptosis. In vitro tests demonstrated that flavonoids inhibited A549 cells metastasis and induced apoptosis and downregulation of the Ddx3x and ANP43B proteins, supporting the use of C. aurantium flavonoids in human lung cancer treatment. According to the bioactivity assays conducted on the major compounds of C. aurantium var. amara, namely, 5-hydroxy-6,7,30,40-tetramethoxyflavone (HTF) and limonexic acid (LA), both compounds showed remarkable antioxidant effects and notable inhibitory action on the B16 and SMCC- cell lines, at a concentration between 6.25 and 50μg/mL and between 12.5 and 200μg/mL, respectively [28]. Figure 1 illustrates the cytotoxic effects and mechanisms of C. aurantium extracts.
Cytotoxic effects and mechanisms of C. aurantium extracts.
Miyazawa et al. [45] isolated three polymethoxy flavonoid-type compounds, namely, tetra-O-methylscutellarein, sinensetin, and nobiletin from C. aurantium. These compounds caused marked downstream regulation of a variety of gene expressions and thus showed strong antimutagenic activity. Wang and coworkers [46] summarized the anticancer effects of polymethoxyflavones with detailed molecular mechanisms. The various amines and flavonoids have been quantitatively analyzed in C. aurantium using liquid chromatography [47, 48]. Hesperidin has been isolated from C. aurantium [49]. It displayed a significant apoptotic effect against liver cell lines, HepG2 cells, by mediating through the upstream regulation of mitogen-activated protein kinase ERK1/2 [50].
The anxiolytic and sedative effects of C. aurantium by in vivo light-dark box and the marble-burying assays were evaluated. C. aurantium essential oil enhanced the period the mice spent in the light chamber, as well as the number of transitions between the two compartments in the light-dark box test [29]. Moreover, single and repeated treatments with the essential oil were reported to suppress marble-burying behavior [10]. The anxiolytic activity of the blossom of C. aurantium was also evaluated clinically on 60 patients undergoing minor surgical operation with no organic pathology. Two hours before the anesthesia induction, two groups consisting of 30 patients were administered at 1mL/kg of either C. aurantium distillate or saline solution. Anxiety was assessed by using the Spielberger state-trait anxiety inventory, the Amsterdamd preoperative anxiety, and information scale. The outcome of this study revealed that C. aurantium could be active by reducing preoperative anxiety before minor operation [30].
In traditional Chinese medicine (TCM), the combination of the aqueous extracts of the fruits of Gardenia jasminoides Ellis, C. aurantium, and the bark of Magnolia officinalis Rehd. et Wils. is called Zhi-Zi-Hou-Po (ZZHPD) and has been used to treat depression-like symptoms. Xing et al. [51] explored in vivo antidepressant activity of ZZHPD in rats, by using coat state test, sucrose preference test, forced swimming test, and open-field test. The effects of ZZHPD on hypothalamic-pituitary-adrenal (HPA) axis were determined by measuring the hormone levels. The results showed that ZZHPD improved depressive behaviors and normalized the adrenocorticotropic hormone (ACTH) and corticosterone levels, by restoring the function of HPA axis, and increasing brain-derived neurotrophic factor expression in hippocampus and promoting hippocampal neurogenesis [51]. ACTH/corticotropinis a peptidic hormone secreted from the anterior pituitary, which regulates glucocorticoid cortisol production from the adrenals [52]. Stress increases ACTH release, which induces the stress hormone cortisol, together they cause numerous diseases [53].
Letie et al. [54] conducted another study in vivo, where rat models were exposed to the essential oil of C. aurantium at 1.0%, 2.5%, and 5.0% concentrations by inhalation, in acrylic boxes before employing elevated plus maze and open-field assays. C. aurantium essential oil increased the time of the animals in the open arms of the elevated plus maze test and the time of active social interaction in the open field [54].
Wolfenbuttel et al. [55] investigated the influence of C. aurantium essential oil on melatonin and corticosterone in mice after inhalation for 30min. Melatonin provides protective effects on neuronal cells and acts as an antidepressant by restoration of corticosterone levels. After treatment, the hormone levels did not present variation, whereas behavioral tests showed that the inhalation of 10% essential oil causes an anxiolytic-like and sedative effect. From these data, Citrus essential oil represents a valuable tool for the treatment of the anxiety disturbs, apparently without interference with melatonin and corticosterone physiological levels [55].
Several reports have been cited in literature regarding the antidiabetic effects of C. aurantium [5658]. An in vivo study was performed to evaluate the antidiabetic effect and to reveal the toxicity profile of the aqueous extract of the fruits of C. aurantium and the leaves of Rauwolfia vomitoria. In this study, NMRI lean mice (6-week-old) and C57BL/6J lean mice (6- or 11-week-old) were used. A single dose, which corresponds to seventy-fold of a human daily dose, was detected to be nontoxic to the animals. A significant weight loss was determined when the dosage, which corresponds to tenfold of a human daily dose, was administered to C57BL/KsBom-db (db/db) genetic diabetic mice for 6 weeks. These mice were maintained on the carbohydrate-deficient diet during the treatment period. The food intake was not significantly different from the control group animals; however, the serum triglyceride levels of the treated animals were significantly higher suggesting the lipid mobilization from internal stores. The fatty acid levels of the eyes of the treated mice remarkably reduced along with stearoyl-CoA desaturase activity [59]. A possible effect of the extract obtained from C. aurantium and p-synephrine on liver metabolism was evaluated. In order to measure catabolic and anabolic pathways, an isolated perfused rat liver was used. Both the extract and the compound were found to enhance glycolysis, glycogenolysis, oxygen uptake, and perfusion pressure. p-Synephrine increased the glucose output at 200μM concentration. C. aurantium extract enhanced gluconeogenesis at low concentrations, however, inhibited at high concentrations. The effects of C. aurantium extract on liver metabolism was found to be similar to those of adrenergic agents, and p-synephrine could be responsible from the activity [14].
Besides its scientifically proven antimicrobial, antioxidant, cytotoxic, anxiolytic, and antidiabetic effects, C. aurantium extract has been commonly utilized for the weight loss and as sports performance enhancer, in dietary supplements [6062]. Therefore, the use of C. aurantium extract and its constituent p-synephrine (C9H13NO2), for the treatment of obesity in 360 subjects, was reviewed. More than 50% of the subjects involved in these clinical studies were overweight, and approximately two-thirds of them consumed caffeine (132528mg/day) and p-synephrine (1053mg/day). Approximately 44% of the subjects used a C. aurantium/p-synephrine product, while the remaining consumed a combination product containing multiple ingredients with p-synephrine. The results showed that C. aurantium extract alone or in combination with other ingredients did not cause significant adverse effects including an increase in heart rate or blood pressure or change in electrocardiographic data, serum chemistry, blood cell counts, or urinalysis. p-Synephrine, alone or in combination products, was demonstrated to enhance metabolic rate and energy expenditure and to promote weight loss when given for six to 12 weeks [63].
The study by Verpeut et al. [64] investigated the effect of the combination of C. aurantium (standardized to 6% p-synephrine) and Rhodiola rosea L. (golden root) (standardized to 3% rosavins and 1% salidroside) on diet-induced obesity in Sprague-Dawley rats. Acute administration of C. aurantium (110mg/kg) or R. rosea (220mg/kg) alone did not decrease food intake in normal weight animals; however, the combination of C. aurantium (5.6mg/kg) and R. rosea (20mg/kg) provided a 10.5% feeding suppression. On the other hand, 10 days of treatment with C. aurantium (5.6mg/kg) or R. rosea (20mg/kg) alone, or in combination, to the animals fed on a high-fat diet (60% fat) during the 13-week period led to a 30% decline in visceral fat weight, compared with other treatments. Coadministration of C. aurantium and R. rosea also resulted in an elevation in hypothalamic norepinephrine and frontal cortex dopamine, indicating the beneficial role of C. aurantium and R. rosea in the treatment of obesity [64]. Figure 2 illustrates the various pharmacological effects of C. aurantium extracts.
Pharmacological effects of C. aurantium extracts.
The cardiovascular toxicity of C. aurantium extracts with different concentrations of protoalkaloid p-synephrine (4 and 6%) was reported by Calapai et al. in in rats. Authors showed an antiobesity effect by the administration of C. aurantium but also possible cardiovascular toxicity. The cardiovascular effects have not been confirmed by studies using much higher doses of p-synephrine [65].
Another study was carried out to evaluate the cardiovascular effects of different doses of C. aurantium and pure p-synephrine in rats. C. aurantium extract and pure p-synephrine enhanced the heart rate and blood pressure. Higher activities were obtained with C. aurantium extract than p-synephrine, suggesting that other compounds in the extract can alter physiological parameters [13]. The effect of p-synephrine on heart rate and blood pressure in female Sprague-Dawley rats was assessed. During 28 days, two types of extracts, one of which contained 6% and other 95% p-synephrine, were administered daily by gavage at 10 or 50mg/kg, doses for a 60kg human equal to 600 and mg/kg. The outcome of the study showed that both p-synephrine and C. aurantium extract resulted in clinically insignificant increases in heart rate and blood pressure at doses many times greater than used in humans. p-Synephrine and bitter orange extract exhibited little or no effect on the cardiovascular effects of caffeine [13].
Safety of p-synephrine was investigated by Ratamess et al. [66] on humans, animals, and in vitro. Authors reported over 30 human studies indicating that the cardiovascular effects of p-synephrine and bitter orange extracts are clinically insignificant. p-Synephrine showed a greater ability to bind adrenergic receptors in rodents than in humans, and the data in literature on its effects on animals cannot be indicative for men at commonly used doses.
This review concluded that C. aurantium extract and p-synephrine are safe for use in dietary supplements and foods at commonly used doses. Also, other authors reported similar conclusions [67, 68]. While p-synephrine alone seems to have low toxicity, when it is formulated in combination with other ingredients such as caffeine (Paullinia cupana, Cola nitida, Cola acuminata, and Camellia sinensis), salicin (Salix sp.), and ephedrine (ma huang, Ephedra sinica, and Ephedra sp.) in weight loss products, the mixture could induce some cardiovascular effects. However, the study did not demonstrate that p-synephrine contributed to cardiovascular effects.
Schmitt et al. [69] reported clear signs of toxicity of this mixture in mice of both sexes as reduction in locomotor activity, ptosis, seizures, salivation, agitation, piloerection, and deaths after acute oral administration of 300, 350, and 400mg/kg total of p-synephrine, ephedrine, salicin, plus caffeine in a 10:4:6:80 w/w ratio.
The volatile oil obtained from the flowers of C. aurantium var. amara, namely, neroli oil, is used to reduce heart rate and palpitations, to encourage sleep, and to soothe the digestive tract. Kang et al. [15] investigated the activity mechanism of neroli in mouse aorta. Neroli was found to exert vasodilator activity in mice precontracted with prostaglandin (PG)-F2α. Nevertheless, the relaxation was reduced in the endothelium-denuded ring or preincubation with the nitric oxide synthase inhibitor by neroli treatment. Moreover, the relaxation induced by neroli was partially reversed by soluble guanylyl cyclase inhibitor. Neroli also inhibited extracellular Ca2+-dependent and depolarization-induced contraction in a dose-dependent manner. Nonselective cation channel blocker, Ni2+, decreased neroli-induced relaxation. On the other hand, a K+ channel blocker, tetraethylammonium chloride, did not alter the relaxation. In order to prevent Ca2+ influx through the smooth muscle voltage-gated Ca2+ channels, verapamil was added. In this case, the ryanodine (a class of intracellular calcium channels) receptor inhibitor reduced neroli-induced relaxation. All these data indicated that neroli-induced relaxation might be partly mediated by the nitric oxide-soluble guanylyl cyclase, and ryanodine receptor signaling pathway [15].
Antimicrobial activity of C. aurantium was investigated by using several in vitro assays [7072]. For instance, Karabıyıklı et al. [1] explored the antimicrobial action of C. aurantium juice against Salmonella enterica Typhimurium and Listeria monocytogenes. For this purpose, both neutralized and unneutralized juice samples with various concentrations were tested for the inoculation of the microorganisms at 4°C and 37°C temperatures, during a period of seven days. The results showed that Salmonella enterica Typhimurium and Listeria monocytogenes not only survived but also grown for two days in neutralized juice at 37°C. On the other hand, on day 7, none of them survived. The results also revealed that L. monocytogenes was less resistant than S. enterica Typhimurium. The low pH of C. aurantium juice was suggested to be responsible for its antimicrobial potential along with the duration of the incubation period as well as the temperature [1]. In another research, the antimicrobial potential of C. aurantium was investigated, and high antimicrobial activity was recorded against Bacillus subtilis and Staphylococcus aureus (among 12 microorganisms tested), with the minimum inhibition concentration (MIC) values of 2.7mg/mL and 4.8mg/mL. Moderate effects were detected against Saccharomyces cerevisiae and Mucor ramannianus with the values of 9.2mg/mL and 5mg/mL, respectively. In the same study, radical scavenging and antibacterial effects of the essential oil obtained from the leaves of C. aurantium were evaluated. Weak antioxidant effect was detected against 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azinobis-3-ethylbenzothiazoline-6-sulphonate (ABTS) radicals [73].
Previous in vitro investigations on the essential oil of C. aurantium peels and its isolated component limonene have demonstrated their pest fumigant activity against Bemisia tabaci (silverleaf whitefly). In 24h exposure, insect mortality between 41.00 and 47.67% was determined at 2.5 and 20.0μL/L air concentrations. In the same study, the authors conducted another assay, investigating the anticholinesterase effect of the oil itself, as well as that of the pure compound. Both exerted anticholinesterase effect with the IC50 values of 2.94mM and 3.54mM, respectively [7476]. Other studies investigated the larvicidal effect of the essential oils of C. aurantium against Anopheles labranchiae. After 24h, the mortality counts were carried out, and LC50 and LC90 values were determined. The outcome of this study demonstrated that the essential oils exerted significant larvicidal potential. C. aurantium essential oil was found to be the most active by the LC50 and LC90 values of 22.64mg/L and 83.77mg/L, respectively [13, 77]. The essential oil extract from the fresh peeled ripe fruit of Citrus aurantium showed also good larvicidal effect against mosquito vector Anopheles stephensi (LC50 values, 31.20ppm) The main constituent of the leaf oil was limonene (94.81).
DPPH, ABTS, and ferric-reducing antioxidant power assays were used for the determination of the antioxidant potential of the macerate of the albedo layers of C. aurantium fruits obtained by protopectinase-SE (produced by Geotrichum klebahnii and hydrolyzed selectively the intercellular protopectin of plant tissues). Moreover, the levels of total phenols, reducing sugars, vitamin C, total flavonones, naringin, and galacturonic acid and total acidity were detected. Antioxidant activity, vitamin C, and total flavonone levels were found to be the highest with the greatest degree of tissue maceration [7881]. In vivo and in vitro antioxidant activities of polysaccharide fractions from C. aurantium were evaluated. The most active fraction was subjected to ion exchange and gel-filtration chromatography to obtain four purified polysaccharides. Upon the evaluation of their antioxidant effect, it was found that C. aurantium can be utilized as an antioxidant in the food and medical industries [82, 83].
In a study by Lagha-Benamrouche et al. [84], the antioxidant potentials of the peels and leaves of seven orange varieties obtained from Algeria were investigated by linoleic acid and β-carotene oxidation assays. The presence of phenolic compounds was also investigated. C. aurantium cv. Bigarade was found to have the highest phenol level. The antioxidant activity assay was in accordance with the phytochemical findings. C. aurantium displayed the highest action on slowing down the rate of linoleic acid and β-carotene oxidation [84, 85]. An antioxidant study was performed on the C. aurantium fruits on different ripening stages. According to the outcome obtained from DPPH free radical-scavenging and β-carotene/linoleic acid systems, the antioxidant activity was found to be varied related to the amount of the phenolic components [86]. Another antioxidant activity study revealed that during dehydration, different air-drying temperature affected the antioxidant effect of the C. aurantium by-products, including peel and pulp remaining after juice extraction [79]. C. aurantium peel and juice were suggested as a new potential source of natural antioxidants; although, they were found to be less effective than butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbic acid, used as antioxidant standards [87, 88]. Anti-inflammatory activity of the flavonoid-type compounds of Korean C. aurantium, namely, nobiletin, naringin, and hesperidin was investigated. Inhibition of proinflammatory mediators by blocking nuclear factor-kappa B (NF-ƘB) and mitogen-activated protein kinase (MAPK) signaling in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages was assessed [89]. The flavonoids were found to have the capacity to suppress the mRNA and protein expression of COX-2 and iNOS, by clarifying their anti-inflammatory action [4]. A polymethoxy flavonoid-rich C. aurantium extract was shown to have a protective effect on alcohol-induced liver injury in an animal study via AMPK and Nrf2-related signal regulation [90].
In order to assess the effect of C. aurantium essential oil and its main compound limonene on gastric mucosa, Moraes et al. [2] conducted a study in vivo. The essential oil and its compound limonene were found to possess protective activity in the gastrointestinal system against lesions, which were induced by ethanol and nonsteroidal anti-inflammatory drugs in rats, at doses of 250mg/kg and 245mg/kg, respectively. The essential oil and limonene increased the production of gastric mucus. The findings revealed that C. aurantium essential oil and its main compound limonene can be used as a promising target for the development of a novel gastroprotective drug [2]. In another study, the gastroprotective effect of β-myrcene, a monoterpene-type compound of C. aurantium, was evaluated. Experimental models of ulcer, induced by ethanol, NSAID stress, Helicobacter pylori, ischemia-reperfusion injury (I/R), and cysteamine (a drug used to treat cystinosis) was used to assess the ameliorative activity. β-Myrcene was administered at dose of 7.5mg/kg. The results showed a potential role for β-myrcene against peptic ulcer disease. β-Myrcene contributed to the maintenance of integrity of the gastric mucosa with a significant decrease of ulcerative lesions, attenuating lipid peroxidative damage and preventing depletion of GSH, GR, and GPx [91].
Polo et al. confirmed the healing properties of C. aurantium essential oil on gastric ulcers after treatment in middle-aged Wistar rats. They showed a significant reduction of the lesion area (76%) within the gastric mucosa that appears regenerated (59%) when compared to the negative control group [92].
On the other hand, Hamdan et al. assessed the effects of hesperidin and neohesperidin, important flavonoid-type components of C. aurantium. For this purpose, indomethacin-induced ulcer models of rats were used. Omeprazole was administered as a reference standard for the comparison. The parameters analyzed in the present study were ulcer index, gastric cyclooxygenase-2 (COX-2) gene expression, TNF-α, MDA, and GSH levels. Histopathalogical analysis was also performed. The findings of the study revealed that hesperidin and neohesperidin notably aggravated indomethacin-induced gastric damage as evidenced by increased ulcer index and histopathological alteration [93]. Recently, hesperidin showed strong inhibition against ovarian cancer cell viability and caused apoptosis mediated through endoplasmic reticulum stress signaling pathways [94]. Hafidh et al. [95] observed the potent anticancer effects of limonene in hepatocellular carcinoma and HepG2, and the cell line caused the modulation of cancer-inducing genes. These data confirmed the antioxidant and prooxidant behavior of flavonoids showing the potential benefits and adverse effects of these opposing events.
If you are looking for more details, kindly visit Rhodiola Crenulata Extract Price.