Pharmacological, nutraceutical, functional and therapeutic properties of fennel (foeniculum vulgare)

ABSTRACT Fennel (Foeniculum vulgare) is a cuisine spice of the Apiaceae genus extensively cultivated in tropical and temperate regions. Due to its commercial significance and considerable pharmaceutical industry uses, fennel is regarded as one of the world’s most important medicinal plants while being one of the oldest spice plants. The aim of the study is to discuss pharmacological qualities including antibacterial, antidiabetic, anticancer, antihyperlipidemic, antioxidant, anticancer, and other activities. Flavonoids, glycosides, and other phytoconstituents found in fennel are utilized as remedies for many illnesses. Fennel contains phenolic chemicals that are beneficial to human health. From this plant, bioactive substances like trans-anethole, estragole, fenchone, and quercetin have been identified. Several of these chemicals have been linked to potential human body systems. Fennel may be utilized in the creation of many drugs since it has a variety of pharmacological qualities and their bioactive components are crucial to maintaining human health.


Introduction
Since the beginning of time, people have frequently used plants to treat illnesses.Public health frequently makes use of various plant components.Utilizing herbal treatments and natural cures is a good and economical way to heal illnesses [1] .The fact that medicinal herbs have fewer adverse effects than chemical medications make them a good alternative to such treatments today. [2]Plants have always been crucial to the well-being and care of human society.Compared to synthetic medications, medicinal herbs have fewer adverse effects, and since they contain antioxidant capabilities, they lessen the toxicity of other pharmaceuticals. [3]Additionally, the natural, powerful components promote biological harmony and prevent drug buildup in the body.Consequently, a variety of ailments may be treated using medicinal plants.More than 5000 of the 422,000 blooming plants that exist worldwide are utilized medicinally.Fennel (Foeniculum vulgare Mill) is very significant and utilized in the pharmaceutical, food, cosmetic, and healthcare sectors might be mentioned as one of these herbs. [4]ue to its commercial significance and extensive occurrences in dry and semi-arid regions, fennel is considered the oldest spice plant and it is among the most powerful medicinal herbs in the world.Fennel is useful in treating gastrointestinal disorders since it possesses anti-inflammatory, antispasmodic, antibacterial, carminative, diuretic, and analgesic properties.Additionally, it is utilized to treat neurological problems thanks to its anti-ulcer and antioxidant effects as shown in Figure 1. [4]The current study's objective was to evaluate fennel's phytochemical characteristics and therapeutic properties in light of its relevance as a medicinal herb.

Methods
In order to gather the material, the keywords Fennel and Foeniculum vulgare mill, therapeutics, and pharmacology were searched from journals accessible in databases such as ScienceDirect, Scopus, EBSCO, Medline, PubMed, Embase, SID and Iran Medex.Repeated papers were removed and only one retained.

Phytology
Foeniculum vulgare Mill with the English name of Fennel, Fenouil in French, belongs to the Apiaceae family.It is a 1 to 2-meter tall, herbaceous, and fragrant plant that is found throughout Asia, the Mediterranean, and many regions of Europe. [3]A perennial herb known as fennel has grooved stems, intermittent leaves that are combined with dark green, fluffy leaves and sheathed petioles.Its flowers are typically bisexual, irregular, or regular, and have yellow umbrellas that resemble oval beads.Small seeds from fennel have a fragrant scent and pleasant flavor.They are around 8 mm in length and 3 mm in width.Fennel seeds have a long, thin, cylindrical shape, and their sizes fluctuate with plant growth. [5]Figure 2 shows Foeniculum vulgare Mill (a) stem; (b) bulb (c) leaves and flowers; and (d) population of F. vulgare Mill. [6]

Phytochemical composition of fennel
Fennel is utilized in all of its components, notably the seeds, roots, leaves, and fruit, [3] 6.3% of fennel seed is water, 9.5% is protein, 10% is fat, 13.4% is mineral, 18.5% is fiber, and 42.3% is carbs.Its leaves include calcium, potassium, salt, iron, phosphorus, thiamine, riboflavin, niacin, and vitamin C, among other vitamins and minerals. [7]Fruits contain between 10 and 12% oil, which is kept in the cotyledons of seeds.The fennel fruit oil contains 6% petrocylic acid, 22% oleic acid, 14% linoleic acid, and 4% palmitic acid.The fruit's essence content ranges from 4 to 6%, and the combination of elements depends on where the plant was grown. [8]The essence of fennel is what gives it its fragrant quality.The essential oil of fennel contains more than 30 different types of terpene chemicals; the most significant of them are 50 to 80% trans-anethole and 5% limonene.Additionally, this plant includes phenolic substances: tannin, coumarin, hydroxycinnamic acids, flavonoids, and phenolic acids. [9]hytochemicals are chemical compounds produced by plants.Various phytochemicals such as "phenols, alkaloids, terpenoids, flavonoids, glycosides, tannins, and saponins" are tested for in fennel seed methanolic extract."In water and ethanol extracts of F. vulgare seeds, the total phenolic content was calculated as the Gallic acid equivalent (GAE).Phenolic acids include 3-O-Caffeoylquinic acid, 4-O-caffeoylquinic acid, 5-O-caffeoylquinic acid, 1, 3-O-di-caffeoylquinic acid, 1, 4-O-dicaffeoylquinic acid and 1, 5-O-di-caffeoylquinic acid.Its flavonoid contains eriodictyol-7-rutinoside, quercetin-3-rutinoside and rosmarinic acid."Also aqueous extract of fennel fruit includes "quercetin-3-O-galactoside, kaempferol-3-Orutinoside, kaempferol-3-O-glucoside, quercetin-3-O-glucuronide, kampferol-3-O-glucuronide, isoquercetin, and isorhamnetin-3-O-glucoside." [9]epending on the morphological condition and place of origin of the fennel, the relative content of these chemicals varies significantly.The phenolic component present in Fennel helps to lessen the effects of oxidative stress-related disorders such as cancer, inflammation, and cardiovascular diseases.Due to their importance to the general public's health, such phenolic chemicals have drawn a lot of interest from food scientists, dieticians, and users. [10]Ascorbates, polyphenolics, carotenoids, terpenoids, and tocopherols are the major naturally occurring plant-based phytoconstituents.These substances have been examined and used as suitable chemotherapeutic drugs to treat a variety of oxidative stress disorders that cause the accumulation of free radicals. [10]nctional and therapeutic properties of fennel For thousands of years, fennel has been used in traditional medicine to treat a number of diseases and has a long history of use by humans.Fennel was thought to have calming characteristics in the fifth century, and from the ninth through the fourteenth centuries, it was credited with a wide range of medicinal benefits. [11]Fennel seed, according to the Romans, might enhance eyesight.The English thought that the herb may help with digestion and provide comfort from a bloated stomach.Since the 18th century, fennel has been used therapeutically, and several research has been conducted.The various plant components are now utilized to treat a variety of illnesses, including digestive system discomfort.Additionally, it is highly effective in the treatment of kidney stones, bronchitis, diabetes, and persistent cough. [12]Meals with cream use fennel seeds as an ingredient.The plant is used to treat kidney and bladder disorders because of its diuretic properties.It is also used to stop vomiting and ease nausea.The herbs are useful for treating chronic fever as well as obstructions in the hepatic, gastrointestinal, respiratory, and urinary tracts.In addition, they are utilized to treat conditions relating to the eyes, such as cataracts, and the stomach, such as persistent diarrhea, endocrine, reproductive, and respiratory systems.In addition to that, it is also utilized in the treatment of breastfeeding women as a galactagogue agent. [11]armacological and nutraceutical activities of fennel The pharmacological and nutraceutical activities of fennel include the following items. [13]

Antibacterial properties
Due to the presence of substances including linoleic acid, 1, 3-benzenediol, oleic acid, and 2,4-undecaprenyl, Fennel has antibacterial properties and is used to treat a variety of infectious bacterial, fungal, viral, and mycobacterial disorders.Fennel contains 5-hydroxyfuranocoumarin, a key component of the plant's antibacterial action. [13]Fennel's aqueous extract exhibits bactericidal action against "Escherichia coli, Shigella flexneri, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhi and Enterococcus faecali" as shown in Figure 3. [14] It was discovered during a study that this plant extract significantly inhibits the growth of most bacteria, with the exception of Klebsiella pneumoniae and one strain of Pseudomonas aeruginosa.Additionally, this study determined the minimum inhibitory concentrations (MIC) for aqueous and alcoholic extracts of fennel seed, which were in the range of 20-80 mg/ml and 5-15 mg/ml, respectively.A study on the antibacterial effects of fennel extract by Moradi et al. focused on Acinetobacter baumannii strains that cause nosocomial infections. [15]gure 3. Antibacterial activity of fennel seeds extract.

Anti-fungal activity
Fennel extract contains antifungal properties that are effective against a variety of fungi, including dermatophytes, Aspergillus species, and Candida albicans.Aspergillus niger and Fusarium oxysporum, two fungi commonly found in food waste, were significantly resistant to the antifungal effects of some herbs.For these molds, the MIC of fennel extract was 750 and 250 micrograms per milliliter, respectively. [16]According to different research, the phenyl propanoid derivative from fennel stalks exhibits antibacterial characteristics that are effective against the molds Aspergillus niger, Bacillus subtilis, and Cladosporium cladosporioides.Scopoletin, a coumarin derivative, displayed antibacterial effects against the aforementioned microorganisms but was less significant than dillapional. [17]Fennel essence's antifungal effects on Sclerotinia sclerotiorum were studied.Based on the persistence of the microorganisms, the antifungal efficacy of fennel seeds against Sclerotinia sclerotiorum was discovered.
The research found that peritoneal macrophages treated with 10 mg/ml of fennel extract generated much more nitric oxide.Additionally, a surge in reactive oxygen species production was seen when compared to the control group.The treated macrophages showed more potent anti-candidate effects than the control group when given dosages of 10 and 20 mg/ml, according to a lethality experiment.Chemical components of fennel extract called Anethole have the strongest antifungal effects. [18]tioxidant activity Natural antioxidants may be found in abundance in fennel.Because it contains a lot of polyphenols and flavonoids, this plant can prevent the formation of free radicals.This plant included phenolic components that showed antioxidant action, including "caffeoylquinic acid, rosmarinic acid, eriodictyol-7-orutinoside, quercetin 3-O-galactoside, and kaempferol-3-O-glucoside."Additionally, fennel volatile oil has potent antioxidant properties.Plant ethanolic and aqueous extracts in comparison to their essence have less antioxidant activity. [9]The total antioxidant capacity (TAC) and total phenolic component analysis of fennel seed were looked at in a research.TAC was determined for phenolic compounds using the DPPH, H2O2, FRAP, and Folin-Ciocalteu reagents.This study showed that fennel extracts may serve as the primary antioxidant and can stop free radicals.In a different study, the antioxidant activity of fennel seed extracts in both aqueous and ethanolic forms were assessed using a range of antioxidant techniques, including: total antioxidant, free radical scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, and metal chelating activity. [19]Those popular antioxidants including a-tocopherol, butylated hydroxyanisole, and butylated hydroxytoluene were compared to these compounds' antioxidant capabilities.According to the study's findings, fennel seed may be a rich source of natural antioxidants.Furthermore, 100 mg of each of the ethanol and watery extracts of fennel showed 99.1% and 77.5% of antioxidant activity and alpha-tocopherol (36.1%) respectively. [14]

Inflammatory-reduction capacity
Anti-inflammatory action is one of the fennel plant's pharmacological properties.Fennel methanol extract has been proven through research to have anti-inflammatory properties.Fennel fruit extract in methanol, administered orally, has inhibitory effects on type 4 allergic responses and acute and subacute inflammatory disorders.Additionally, it reduced the activity of catalase (CAT) and superoxide dismutase (SOD).HDL cholesterol levels in plasma were also markedly raised.As a marker of lipid peroxidation, it considerably decreased the quantity of malondialdehyde (MDA).These findings show that fennel fruit methanol extract effectively reduces inflammation.Fennel's ability to reduce inflammation was researched by Mostafa et al.The findings demonstrated that fennel seed methanol extract reduces inflammation. [20]Additionally, Choi et al. examined the anti-inflammatory properties of fennel methanol extract.The results showed that both central and peripheral routes were necessary for the fennel methanol extract's anti-inflammatory effects. [21]nti-anxiety activity There have been reports of crude fennel extract having anxiolytic properties.Fennel is often used therapeutically to alleviate problems caused by estrogen insufficiency since it contains phyto estrogens.
Estrogens are hormones that appear to operate through GABA A receptors and are linked to anxiety phenomena.According to study findings, plants that spent more time in the open arm had substantial anxiolytic effects.Tamoxifen and picrotoxin, a GABA receptor antagonist, blocked the anxiolytic effect.As a result, fennel is likely an herbal treatment with calming properties that are mediated by the GABA-ergic system and estrogen receptors. [22]Alvarado-García et al. looked into the fennel's ability to reduce anxiety in mice.It was discovered that the group treated with fennel essence had much lower stress levels than the control group.As a result, it may be claimed that this plant may help with stress and anxiety management. [23]Anka et al. looked into aptitudes of fennel extract to improve rat memory and reduce stress.This study shows that this herb may lessen stress and problems linked to stress by increasing memory, acting as an anti-stress agent, and having antioxidant properties. [24]stro-protective activity The fennel plant has been shown to significantly reduce the risk of digestive disorders.In comparison to the control group, fennel oil emulsions were shown to significantly alleviate colic in 65% of infants.Fennel plant on stomach ulcers in research.The research revealed that the herb protected against stomach ulcers.Additionally, the herb reduced the mucosal lining of the stomach.These effects were connected to its antioxidant capacity. [25]Estrogenic characteristics for a very long time, fennel has been used as an estrogenic substance.This property of fennel increases milk production, reduces menstrual pain, facilitates labor, and magnifies sexual desire.The primary component of the fennel plant with estrogenic effects is called anethole.Research has revealed that anethole polymers are used as active medicinal ingredients. [26]When used to treat primary dysmenorrhea, fennel essence had less negative effects than other treatments.Different dosages of fennel extract greatly reduced the strength of contractions brought on by oxytocin and prostaglandins.Higher dosages increased the weight of the oviduct, endometrium, myometrium, and cervix whereas moderate levels raised the weight of the mammary glands. [27]Bayrami et al. looked at the effect of fennel seed ethanol extract on changes in gonadotropin in mature male rats.The treatment groups' testosterone, FSH, and LH levels were significantly lower than those of the control group.Fennel seed consumption significantly reduces male reproductive activity as evidenced by the quantity of sperm produced, which also causes the epididymis to lose weight and hormone levels to rise. [28]Because of its estrogenic properties, fennel herb has long been used to treat infertile women.Follicle-stimulating hormone levels in serum were shown to be elevated by fennel extract, whereas testosterone and yolk hormone levels were lowered in treatment groups.

Cardiovascular and lipid activity
According to studies on the anti-cholesterol and anti-atherogenic actions of fennel methanol extract, therapy with the substance significantly reduced plasma lipid levels and can be used as a preventive for cardiovascular disease by lowering the deposition of triglycerides in the form of fatty liver and enhances blood flow in coronary arteries by preventing the deposition of lipid in the lumen of coronary arteries by reducing serum and liver lipids. [29]The plant also showed strong antiatherogenic qualities.By reducing plasma and liver fats, it decreased triglycerides in fatty livers and improves blood flow in coronary arteries, limiting the accumulation of fatty deposits in arteries. [30]ue to its hypolipidemic and anti-atherogenic properties, this plant may be utilized to manage cardiovascular diseases Additionally, the extract administered intravenously dramatically lowered blood pressure without altering heart rate or breathing.It appears that adrenergic, muscarinic, ganglion and serotonergic receptors did not modulate the impact of fennel extract on blood pressure. [5]

Diabetic prevention
Research looked into how aqueous extracts from plants in the Apiaceae family, including fennel, affected blood glucose levels and had anti-diabetic effects.The results showed that the extract might be helpful for diabetic patients to regulate blood glucose, and that regular usage could be successful in lowering chronic problems related to diabetes. [31]On rats treated with streptozotocin to induce diabetes, a study was done to assess the impact of fennel on lowering blood sugar.The results show that fennel extract lowers blood sugar levels in diabetic rats, which may be partially attributed to the herb's effects on the oxidation system.As a result, this plant can be used to make anti-diabetic drugs in the pharmaceutical industry.Fennel fruit extract in methanol also reduced blood sugar and cholesterol. [32]Figure 4 shows the effects of fennel on blood glucose.

Anti-cancer activity
TNF-dependent responses are known to have a part in both inflammation and malignancy.It was shown that the anethole in fennel seed suppresses TNF transcription factor NF-activation KBs.The findings suggest that anethole inhibits the cellular responses induced by these cytokines, which may provide some insight into how it prevents cancer.Fennel extracts in ethanol were tested for their ability to induce apoptosis in leukemia by Kaveh et al., the results of this study revealed that the extract significantly induced apoptosis in cancer cells. [33]Another study looked at how fennel methanol extract affected the anticancer and cytotoxic actions in mice that were carrying cancer.This study's findings showed that cancer-bearing mice's liver and tumor tissue had much greater levels of MDA and significantly lower levels of CAT activity and glutathione.However, there was a decrease in the ascites fluid's total protein content.The findings showed that fennel's methanol extract significantly reduced the growth of breast cancer cells (MCF-7) and liver cancer cells (Hepg) via modifying lipid peroxidation, enhancing the antioxidant defense system, and blocking free radicals. [34]

Hepato-protective activity
The fennel herb has a liver-protective function, according to research.In rats with liver damage brought on by carbon tetrachloride, a different investigation looked at how fennel methanol extract affected the antitumor and cytotoxic capabilities in cancer-bearing mice.According to the findings of this study, MDA levels were substantially greater while CAT activity and glutathione levels were noticeably reduced in the liver and tumor tissue of mice with cancer.The ascites fluid's overall protein concentration, on the other hand, decreased.The findings showed that fennel extract in methanol significantly reduced the growth of breast cancer cells (MCF-7) and liver cancer cells (Hepg) via modifying lipid peroxidation, enhancing the antioxidant defense system, and inhibiting free radicals.It is possible to draw the conclusion that fennel may prevent hepatic fibrosis by influencing the control of lipid peroxidation, based on the findings. [5]The outcomes showed that the fennel-treated group had lessened inflammation and lipid breakdown as shown in Figure 5.
According to the findings of this study, fennel may significantly protect hepatocytes from liver injury while also reducing liver inflammation. [35]Another study examined the effects of fennel on hepatic fibrosis as well as the quantity of potassium supplementation.The patient group with fibrosis, liver tissue inflammation and excessive fat breakdown significantly improved after getting fennel treatment.Following fennel medication, potassium levels increased while ascites levels decreased.These findings support the notion that fennel may guard against liver fibrosis. [8]Further research was done on how fennel affected the TNF-cytokine in a model of liver fibrosis.PBMCS reduced inflammation and the amount of TNF-release in the group that received treatment.These findings suggest that fennel may reduce TNF production by single-core cells, reduce inflammation and prevent liver fibrosis. [35,36]Fennel exerts many important biological functions, along with associated action mechanisms as shown in Table 1.

Side effects
[40][41] One of the most significant components in fennel extract is estragole.Use of this substance is prohibited due to reports that it caused malignant tumors to form in animals.Although Estragole has not been proven to be carcinogenic to people, it does induce tumors in rats.Active substances with anti-microbial action are present in both the aqueous and the alcoholic extracts, including coumarin and oleic acid.[13]   Antioxidant activity Presence of antioxidant compounds such as flavonoids and phenols in aqueous and ethanolic extract [9]   Anti-inflammatory activity Through the inhibition of cyclooxygenase and lipoxygenase, methanol extract has preventive benefits against acute and subacute diseases, type 4 allergic responses. [25] Hepato-protective activity reduced levels of proinflammatory cytokines such TNF-and CTGF in fibrosis, as well as AST, ALT, ALP, and bilirubin.[37]   Anti-cancer activity anethole's presence, an inhibitory impact on TNF-activation, antiangiogenic actions, and apoptotic and anticancer effects are examples of active substances. [33] Gastro-protective activity gastrointestinal spasm and chronic colitis therapy, protection against gastric ulcers, and a reduction in the mucosal membrane of the stomach. [26] Estrogenic activity Compounds like anatole influence enhancing milk secretion, which is present, reduce menstruation pain, make childbirth easier, treat primary dysmenorrhea, and minimize infertility.

References
Anti-lipid activity Effects that are hypolipidemic include reduced plasma triglycerides, lower total cholesterol, lower LDL, lower apolipoprotein B, higher HDL, and higher apolipoprotein A-1 with anethole [20]   Cardiovascular activity a cardiovascular workout lower systolic blood pressure, less sodium, potassium, water excretion and fennel extract [5]   Anti-diabetic activity The hypoglycemic impact reduces blood sugar levels, boosts glutamine peroxide activity, and increases liver and muscle glycogen stores.[31]  Fennel has 2090 mg/kg of Anethole in total.Repeated injections of 695 reportedly resulted in moderate liver damage in rats.Thus, it was discovered that Anatole causes minor liver damage at typical therapeutic levels. [6,42]

Conclusion
Various pharmacological effects of fennel extracts, including anti-allergic, analgesic, antiinflammatory, antioxidant, antibacterial, anti-cancer, anti-stress, and cytotoxicity activity, have been demonstrated by studies that are now available.The plant's many chemical components are what provide it medicinal benefits.Phenolic chemicals are regarded as the most significant and active compounds among the numerous substances present in fennel plant essence.The bioactive compounds found in fennel are used in the manufacturing of a variety of drugs and are crucial to maintaining human health.The most well-known and effective research has been done on fennel's antioxidant, antibacterial, and estrogenic properties in numerous animal models.Therefore, it is advised that future studies be done on how this plant can use as medicine to treat different noncommunicable diseases.

Figure 1 .
Figure 1.Health benefits of fennel seeds.

Figure 4 .
Figure 4. Effect of fennel seeds extract on blood glucose level.

Figure 5 .
Figure 5. Positive effect of fennel seeds on fatty liver.

Table 1 .
Functional, nutraceutical, and therapeutic properties of fennel and their associated action mechanisms.