Bitter Orange is antianxiety, antibacterial, antiemetic, antifungal, antispasmodic, antitussive, carminative, contraceptive, diaphoretic, digestive, sedative, stimulant and orexigenic. Citrus species are rich in vitamin C, flavonoids, acids and volatile oils. They also contain coumarins such as bergapten. The plants also contain umbelliferone, which is antifungal, as well as essential oils that are antifungal and antibacterial. They also contain the pyrone citrantin, which shows antifertility activity and was once used as a component of contraceptives. The fruit peel is bitter, digestive and stomachic. The seed and the pericarp are used in the treatment of anorexia, chest pains, colds, coughs. The immature fruit can be used (called Zhi Shi in China) which has the strongest stronger action and are used in the treatment of dyspepsia, constipation, abdominal distension, stuffy sensation in the chest, prolapse of the uterus, rectum and stomach (1).
In TCM Liquorice is called Zhi Shi 枳实. Zhi Shi is pungent, bitter and sour and enters the Spleen Stomach and Large intestine meridians. In TCM Primary conditions or symptoms for which Zhi Shi may be prescribed by TCM doctors include indigestion, abdominal bloating, constipation, chest pain, chest congestion and prolapse (2).
Bitter orange (Citrus aurantium) fruit contains several adrenergic agonists, primarily p-synephrine, but also octopamine and tyramine, as well as numerous flavonoids (3). P-synephrine has been studied for is weight loss effects. p-Synephrine alone as well as in combination products were shown to increase resting metabolic rate and energy expenditure, and modest increases in weight loss were observed with bitter orange extract/p-synephrine-containing products when given for six to 12 weeks (4).
The antiviral activity of essential oils from bitter orange, Citrus x aurantium L. have been well documented (5). C. aurantium extracts exhibit antibacterial activity against all tested gram-positive (S. aureus, B. subtilis, M. luteus, E. faecalis and S. epidermidis) and gram-negative bacteria (Klebsiella, P. aeruginosa and E. coli) (6).
Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2 in SARS-CoV-2. Additionally the flavonoid hesperidin could act as a high potent inhibitor of SARS-CoV-2 3CLpro inhibitor to inhibit viral replication (7). Antivirals such as Remdesivir, Favipiravir, and Galidesivir target the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. RdRp is crucial for the replication and transcription of this positive-sense single-stranded RNA virus (8). Several flavonoids including naringenin have been shown to inhibit SARS-CoV-2 attachment to ACE2, thus preventing infection, and/or to interact with PLpro/Mpro/RdRp, thus inhibiting viral replication (9).
Naringin is a natural flavanone glycoside that is found in the Chinese herbal medicines and citrus fruits. Naringin and naringenin, are also found in chamomile (Matricaria chamomilla L.) and linden flowers (Tilia Cordata) (10). Naringenin is described a s a possible candidate against SARS-CoV-2 and in the pathogenesis of COVID-19 although no human trials have been undertaken thus far (1). The antiviral potential of naringenin in COVID-19 associated risk factors and its predicted therapeutic targets against SARS-CoV-2 infection have been elucidated. Naringin modulates signalling pathways and interacts with signalling molecules and thus has a wide range of pharmacological activities, including anti-inflammatory, anti-cancer activities, as well as effects on bone regeneration, metabolic syndrome, oxidative stress, genetic damage and central nervous system (CNS) diseases. Information was gathered that showed the extraction of naringin can be improved using several modifications. Whilst no human studies have been undertaken, there has been progress in the development of controlled release formulations of naringin (11).
1. PFAF. Citrus aurantium - L. Devon, UK: Plants For A Future; 2022 [Available from: https://pfaf.org/user/Plant.aspx?LatinName=Citrus+aurantium.
2. Qi M. Zhi Shi Denver, CO USA: Me & Qi 2021 [Available from: https://www.meandqi.com/herb-database/immature-bitter-orange.
3. Bitter Orange. Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US); 2006.
4. Stohs SJ, Preuss HG, 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. 2012;9(7):527-38.
5. Fadilah NQ, Jittmittraphap A, Leaungwutiwong P, Pripdeevech P, Dhanushka D, Mahidol C, et al. Virucidal Activity of Essential Oils From Citrus x aurantium L. Against Influenza A Virus H1N1:Limonene as a Potential Household Disinfectant Against Virus. Natural product communications. 2022;17(1):1934578X211072713.
6. Maksoud S, Abdel-Massih RM, Rajha HN, Louka N, Chemat F, Barba FJ, et al. Citrus aurantium L. Active Constituents, Biological Effects and Extraction Methods. An Updated Review. Molecules (Basel, Switzerland). 2021;26(19).
7. Liu W, Zheng W, Cheng L, Li M, Huang J, Bao S, et al. Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2. Nat Prod Bioprospect. 2022;12(1):4.
8. Naydenova K, Muir KW, Wu L-F, Zhang Z, Coscia F, Peet MJ, et al. Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP. Proceedings of the National Academy of Sciences. 2021;118(7):e2021946118.
9. Agrawal PK, Agrawal C, Blunden G. Naringenin as a Possible Candidate Against SARS-CoV-2 Infection and in the Pathogenesis of COVID-19. Natural product communications. 2021;16(12):1934578X211066723.
10. Gupta V, Mittal P, Bansal P, Khokra S, Kaushik D. Pharmacological Potential of Matricaria recutita-A Review. International Journal of Pharmaceutical Sciences and Drug Research. 2010;2.
11. Chen R, Qi Q-L, Wang M-T, Li Q-Y. Therapeutic potential of naringin: an overview. Pharmaceutical biology. 2016;54(12):3203-10.