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Chamomile: A Review of Its Traditional Uses, Chemical Constituents, Pharmacological Activities and Quality Control Studies

Matricaria chamomilla L. (MC) and Chamaemelum nobile (L.) All. (CN) are two varieties of Chamomile. These herbs have been used for thousands of years in Greece, Rome and ancient Egypt. Chamomile has been used for the treatment of stomach problems, cramps, dermatitis, and minor infections. The purpose of this study was to introduce the botanical characteristics and geographical distribution, traditional uses, chemical constituents, pharmacological activities, toxicity studies and quality control studies, and lay a theoretical foundation for the rational development and utilization of chamomile. This review powered that chemical constituents include flavonoids, coumarins, volatile oils, terpenes, organic acids, polysaccharides, and others. These compounds possess anticancer, anti-infective, anti-inflammatory, antithrombotic, antioxidant, hypolipidaemic, hypoglycaemic, antihypertensive, antidepressant, neuroprotective activities, among others. Chamomile is a widely used herb in traditional medicine. It brings great economic value due to its numerous pharmacological effects and traditional uses. However, more toxicity tests should be carried out to confirm its safety. There is need for further research to provide concrete scientific evidence and validate its medicinal properties.

1. Introduction

Traditional Chinese medicine (TCM) has been used for a long time in China and recorded for more than 5000 years. Numerous herbs have been used in TCM [ 1 ]. This field is becoming an integral part of various traditional medicine and modern medicine systems globally. In modern medicine, it is primarily used to prevent various diseases. Therefore, TCM is gaining popularity worldwide and supports human health greatly [ 2 ].

Chamomile is an annual or perennial plant belonging to the family Asteraceae. The plant improves the appetite and relieves painful swellings and sweating [ 3 ]. Chamomile is native to temperate regions of Asia and Europe, and cultivated worldwide for its high medicinal, cosmetics and food value [ 4 ]. It has been used for thousands of years in Greece, Rome and ancient Egypt. In China, the detailed use of this plant was first recorded in Uyghur medicine. Veteran doctors of TCM believe that preparations containing chamomile have a calming effect. In addition, the plant is also used in other traditional, homoeopathic and Unani preparations [ 5 , 6 ]. There are two main varieties of chamomile: Matricaria chamomilia L. (MC) and Anthemis nobilis (L.) All. (CN). Matricaria chamomilia L. belongs to the genus Matricaria . It is an annual plant, and the flowering period is from May to July in China. Chamaemelum nobile (L.) All. is a perennial plant of the genus Chamaemelum . The flowering period is from April to May in China [ 7 , 8 ]. Matricaria chamomilia L. is relatively common and has been researched and used widely. At present, 26 countries around the world have included this plant in their pharmacopoeia. Chamomile flower heads are commonly used for medicinal purposes [ 9 ]. Chamomile contains flavonoids, coumarins, volatile oils, terpenes, sterols, organic acids, and polysaccharides, among other compounds. Having a wide array of compounds, chamomile exhibits various pharmacological activities such as anticancer, anti-infective, anti-inflammatory, antioxidant, hypoglycaemic, hypotensive, hypolipidaemic, antiallergic, antidepressant, and neuroprotective effects, and others [ 3 , 4 , 5 , 6 , 7 , 8 ]. In general, this plant has outstanding research value. Still, there are very few reviews of it in the literature. This article provides a comprehensive review of the botanical characteristics and distribution, traditional uses, chemical constituents, pharmacological effects, and quality control methods of chamomile.

Pictures of two species of chamomile from the Global Biodiversity Information Facility “ https://www.gbif.org (accessed on 16 November 2022)” are shown in Figure 1 .

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Two species of Chamomilla: Matricaria chamomilia L. ( a ), Chamaemelum nobile (L.) All. ( b ).

2. Methodology

In this review, the information about the botanical characteristics and geographical distribution, traditional uses, chemical constituents, pharmacological activities, adverse reactions, toxicity studies and quality control studies of chamomile is collected. All information on chamomile and its two species were collected from textbooks, electronic databases and library materials, including PubMed, Web of Science, China National Knowledge Infrastructure, MDPI, Springer, Elsevier, Google Scholar, Yahoo search and Google Scholar. The keywords used to obtain the information. included ‘Yang Gan Jv’, ‘Chamomile’, ‘ Matricaria chamomilia L.’, ‘ Chamaemelum nobile (L.) All.’, ‘botany’, ‘traditional uses’, ‘pharmacological activities’, ‘chemical constituents’, ‘toxicity’, and ‘quality control studies.’ The scientific names and photos of two species of chamomile were confirmed from the World Flora Online database ( www.worldfloraonline.org ). The chemical constituents were verified using PubChem, and the structures were drawn using ChemDraw.

2.1. Botanical Characteristics and Geographical Distribution

Chamomile is an annual or perennial plant native to temperate regions of Asia and Europe. It is widely cultivated worldwide, such as in Germany, Hungary, France, Russia, Brazil and western Xinjiang of China. This plant is native to tropical conditions but it can be cultivated in cold climatic conditions [ 4 ]. The roots are thin, spindle-shaped and grow straight. The stems can grow to 10–80 cm. The leaves are long, narrow and pinnate, with fissures. The head is about 10–30 mm in diameter [ 5 , 10 ]. Matricaria chamomilia L. has small white flowers of the Compositae family and, at their center, a yellow tubular petal is present. Anthemis nobilis (L.) All. contains flowers with double petals, soft stems, and has a green apple fragrance. It is also called “the apple of the ground”. In addition, it is also known as the “Physician of Plants” due to its ability to heal sick plants around it. Although MC and CN are similar in appearance, they have distinct differences. The petals of MC are turned down and have a raised conical center, whereas the center of CN is flat [ 8 ]. Additionally, MC and CN have four and three germination holes in pollen grains, respectively. It is worth noting that CN has a non-glandular hair structure [ 6 , 11 ]. In some areas, such as Europe, Mexico, South America, Russia, the chamomile flower head is the main medicinal part and is used for anti-inflammation and sedation. However, in China, in the majority of cases the whole plant is collected to treat various diseases [ 7 ].

2.2. Traditional Uses

As early as the Eastern Han Dynasty in China, a monograph recorded the use of TCM by human beings to treat sundry diseases, namely “Shennong’s Classic of Materia Medica” (《神农本草经》) [ 12 ]. Several uses of chamomile are reported in the TCM literature, and it is one of the most commonly used herbal medicines to treat stomach problems, cramps, dermatitis, and minor infections [ 13 ]. Chamomile has been used for thousands of years in Greece, Rome, and ancient Egypt. In China, the plant was first recorded in detail in Uyghur medicine. In the “Zhu Medical Canon” (《注医典》), a Uyghur medical work written in the 10th century, chamomile is called “Bamu Nai”. Its taste and fragrance is slightly bitter. The plant nourishes the nerves and the stomach. It improves the appetite and relieves painful swellings and sweating, and is frequently used for chronic headaches, constipation, poor sweating, joint swelling, and urinary system disorders [ 3 , 5 ]. “Chinese Herbs. Uyghur Medicine Volume” (《中华草本.维药卷》) recorded that Chamomile can strengthen the brain and muscles, can be a diuretic and improves e menstrual flow, nourishes the stomach and can be used as an appetizer. It mainly treats symptoms of muscle relaxation, joint swelling and pain, stomach deficiency and anorexia, amenorrhea, and urine retention. “Chinese Ethnic Medicine” (《中国民族药志》) indicates that Chamomile can detoxify, clear heat, stop dysentery, dispel wind, and eliminate paralysis. Meanwhile, the Uyghur folk medicine book “Baidi Yi Medicine Book” (《拜地依药书》) recorded that the plant has a favourable effect on cold headache, black fat and mucous typhoid, and kidney stones [ 6 , 7 ]. It is worth mentioning that 26 countries worldwide have included Chamomile in pharmacopoeia, including German Pharmacopoeia, European Pharmacopoeia, United States Pharmacopeia, British Pharmacopoeia, and more [ 9 ]. It can be used as an ingredient in many traditional medicine preparations, such as Zukamu granules, Fufang Munizi granules, and Strong Madsiri Ayat honey ointment, and is also used in Homeopathy and Unani preparations [ 5 , 7 ]. Furthermore, chamomile is the main active ingredient in many mouthwash preparations [ 14 ]. The oral consumption of this plant relieves pain caused by functional digestive disorders and symptoms of gastrointestinal disorders. Topical application of chamomile essence (as a lotion or powder) can be used to repel mosquitoes, treat skin diseases, wounds, haemorrhoids and inflammation of the eyes, nose, and throat [ 7 , 15 , 16 ]. It has been used in herbal baths for thousands of years, and is commonly consumed as a decoction (in water) in TCM [ 17 ]. According to numerous records, chamomile is one of various TCM bath agents.

In fact, in addition to being used as a medicine, chamomile is also used in cosmetics, food, and more [ 18 , 19 ]. The essential oil in this plant serves as perfume, an in skincare products, massage oil, and toothpaste. [ 20 ]. A small amount of chamomile in bathing water results in emollient and anti-inflammatory effects [ 21 ]. Tea made from dried flowers is reported to induce good sleep, regulate the intestines and sweat, and prevent cold [ 18 ]. Honey chamomile tea brewed with 5 g of Chamomile, two slices of lemon, and one tablespoon of honey has been reported to lower blood pressure, detoxify, and relieve inflammation [ 22 ]. Gould et al. found that chamomile tea could influence hemodynamics in patients with heart disease [ 23 ]. Guo et al. used the essential oil of CN to prepare a clear and transparent flower tea product with a unique flavor [ 24 ]. A medicinal preparation containing chamomile and other herbs produces calming and tranquillizing effects. The traditional uses of chamomile are shown in Table 1 .

Traditional uses of chamomile.

2.3. Chemical Constituents

2.3.1. organic acids.

Organic acids contain carboxylic acid, and sulfonic acid functional groups. A total of 26 organic acids have been isolated from chamomile, among which four acids are primary metabolites and are essential compounds for the growth and development of living organisms [ 33 , 34 , 35 , 36 , 37 , 38 ]. The compounds also have great potential in the treatment of cardiovascular diseases, immune system diseases and cancer [ 39 ]. In addition, the remaining 22 acids are secondary metabolites.

The organic acids from chamomile are shown in Table 2 , and their chemical structures are shown in Figure 2 .

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The chemical structures of organic acid from Chamomile.

Organic acids from Chamomile.

2.3.2. Flavonoids

In general, flavonoids have a core structure of 2-phenyl chromone. A total of fifty flavonoids have been isolated from Chamomile and are its main active components [ 33 , 34 , 35 , 36 ]. They include quercetin, apigenin, luteolin, and rutin. These compounds exhibit antibacterial, antioxidant, anticancer, and other pharmacological effects. Yang et al. reported the presence of apigenin-7-O-β-D-glucoside and luteolin-7-O-β-D-glucose glycosides in an alcohol extract, and these are assumed to be the main bioactive flavonoids of chamomile [ 40 ]. Mire Ayi et al. evaluated the inhibitory effect of a total flavonoid extract on pancreatic lipase using 4-methylumbelliferone oleate (4-MUO) as a substrate [ 34 ]. Therefore, chamomile could be an alternative medicine to prevent and treat obesity. According to reports, apigenin has anti-inflammatory properties. Apigenin reduces inflammation in lipopolysaccharide (LPS)-stimulated BV2 microglia via the Glycogen Synthase Kinase 3β/Nuclear factor E2 related factor 2 (GSK-3β/Nrf2) signaling pathway [ 41 ]. In addition, it affects the levels of interferon-γ and interleukin-10 in lymphocytes [ 42 ].

The flavonoids from Chamomile are shown in Table 3 , and their chemical structures are shown in Figure 3 .

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The chemical structures of flavonoids from Chamomile.

Flavonoids from Chamomile.

2.3.3. Coumarins

The parent nucleus of coumarin is benzopyrone. A total of 10 coumarins, including coumarin, 7-methoxycoumarin, esculetin, skimmin, daphnin, daphnetin, umbelliferone, scopoletin, isoscopoletin, and 3,4-Dihydrocoumarin, have been identified from Chamomile [ 33 , 34 , 38 , 43 ]. Li et al. established a method of simultaneous quantitative analysis for multi-components by single marker (QAMS) to determine the content of 7-methoxycoumarin, which uses an external standard method to determine apigenin, and uses a relative correction factor to determine 7-methoxycoumarin and other components [ 44 ].

The coumarins from chamomile are shown in Table 4 and their chemical structures are shown in Figure 4 .

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The chemical structures of coumarin from Chamomile.

Coumarins from Chamomile.

2.3.4. Volatile Oil

The volatile oil of Chamomile has been prepared using a water distillation method, and its components have been identified using gas chromatography-mass spectrometry (GC-MS). A total of 102 components are reported in the volatile oil [ 33 , 34 , 36 , 37 ]. Volatile components, such as isopentyl isobutyrate, isobutyl isobutyrate, and others, have been reported to exhibit sedative and calming effects [ 45 ].

The chemical constituents of volatile oil from chamomile are shown in Table 5 , and their chemical structures are shown in Figure 5 .

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The chemical structures of volatile oil from Chamomile.

The chemical constituents of volatile oil from Chamomile.

2.3.5. Monoterpenes

Monoterpenes contain two isoprene molecules. Three types of monoterpenes are present in Chamomile. They are (1) chain monoterpenes (e.g., ocimene, geraniol, citronellol) (2) monocyclic monoterpenes (menthol, and others), and (3) bicyclic monoterpenes such as bornanol. A total of 39 monoterpenes have been reported so far [ 33 , 34 , 35 , 36 , 37 , 38 ].

2.3.6. Sesquiterpenes

Sesquiterpenes are polymerized from three molecules of isoprene. A total of 27 sesquiterpenes have been reported in chamomile so far [ 33 , 34 , 35 , 36 , 37 , 38 ]. Among them, α -bisabolol has anti-inflammatory activity, thereby protecting against acute liver injury caused by acetaminophen (APAP) [ 46 ].

2.3.7. Diterpenes and Triterpenes

Diterpenes contain four isoprene units, whereas triterpenes contain six isoprene units. Up to now, two diterpenes (alcohol and phytanetriol) [ 33 , 36 ] and three triterpenes (oleanolic acid, taraxanol, and taraxasterol) have been reported in chamomile [ 7 ].

The terpenes (monoterpenes, sesquiterpenes, diterpenes and triterpenes) from chamomile are shown in Table 6 , and their chemical structures are shown in Figure 6 .

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The chemical structures of terpenes from Chamomile.

Terpenes from chamomile.

2.3.8. Other Phytochemicals

Chamomile contains 1.29–3.25% polysaccharides. Upon hydrolysis they yield 45% D-galacturonic acid, 20.8% D-xylose, 12.2% D-galactose, 10.2% L-arabinose, 5.3% L-rhamnose and 2.3% D-glucose [ 47 ]. A total of 16 sterols (e.g., stigmasterol, taraxasterol) and three guaiacolides (guaianolide, matricin and matricarin) have so far been reported by Zhao [ 7 ] as shown in Table 7 and Figure 7 below.

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The chemical structures of sterols and guaiacolides from Chamomile.

Sterols and guaiacolides from Chamomile.

L(+)-ascorbic acid, adenosine, phenyl propionic acids, benzodiazepines, γ-aminobutyric acid (GABA), choline, bitter substances, gums, amino acids, and (Z,E)-en-yn-dicycloether [ 7 , 33 , 34 ], as well as trace elements, such as Ca, Zn, Fe, Mg, Mn, Na, As, also exists in Chamomile [ 48 , 49 ], also exist in Chamomile.

3. Pharmacological Activities

3.1. anticancer activity.

Glioma is one of the common intracranial malignant tumors with high incidence, rapid growth, high recurrence rate, high mortality and poor prognosis. α-Bisabolol, a fat soluble sesquiterpene compound that is widely found in Chamomile essential oil, has been proven to possess the potential to affect glioma. Yan et al. tested the effect of α-bisabolol on human brain glioblastoma cells (U251 and U87) using the scratch assay. Its effect on migration and invasion was investigated. Protein expression studies have been conducted using Western blot. α-Bisabolol inhibited gliobla stoma cell migration and invasion by down regulating central mucoepidermoid tumor (c-Met) [ 50 ]. α-Bisabolol oxide A and apigenin-7-β-D-glucoside, obtained from chamomile flowers and stems, are reported to inhibit the migration of Caco-2 colon cancer cells and deactivate the vascular epidemal growth factor receptor-2 (VEGFR2) angiogenic enzymes [ 51 ]. Apigenin is a flavonoid component of this plant, which also shows a certain anticancer effect on the liver cancer cells (Hep G2) and leukaemia cells (HL-60) [ 52 ]. Additionally, Srivastava et al. confirmed that apigenin 7-O-glycoside obtained from chamomile extract had a good anticancer effect, but its effect was lower than that of apigenin [ 53 ].

In vitro studies confirmed the antiproliferative effect of this plant on cervical cancer cells (HeLa) [ 54 ]. The anticancer activity is mediated through the Wnt pathway in colon tissue, down-regulating the expression levels of factors such as wingless integration-5A (Wnt5A), β-catenin, transfer cell factor 4 (Tcf4), and up-regulating the expression levels antigen presenting cell (APC) and GSK-3β [ 55 ]. Hydroalcoholic extracts of chamomile (dose-and time-dependent) have been reported to increase apoptosis and necrosis, decrease cell proliferation or migration, colonization, invasion and attachment in Michigan cancer foundation-7 (MCF-7) and MDA-MB-468 cell lines [ 56 ]. Chamomile fermented with Lactobacillus plantarum for 72 h showed selective cytotoxicity on cancer cells compared to normal cells (medical research council cell strain 5 (MRC-5)) [ 57 ].

3.2. Anti-Infective Activity

Chamomile volatile oil has shown an anti-infective effect on the growth of fungi and bacteria [ 58 ]. Furthermore, it effectively reduces the protease in mites and can be used to treat urticaria [ 59 ]. Mean corpsular hemoglobin-ampicillin 1 (MCh-AMP1), a natural peptide from the plant, has broad-spectrum antifungal activity against human pathogenic moulds and yeasts. It kills Candida albicans by increasing cell membrane permeability and inducing reactive oxygen species (ROS) production [ 60 ]. Shikov et al. reported that the minimun inhibitory concentration 90 (MIC90) and MIC50 of chamomile extract against Helicobacter pylori were 125 and 62.5 mg/mL, respectively. In addition, this extract controls the production of urease via modulating the morphology of H. pylori and fermentation capacity [ 61 ]. At present, many mouthwashes and sprays made with chamomile are used for oral bacteriostasis in clinical products, such as the White Gold Medal Compositae essence Product [ 62 ].

3.3. Anti-Inflammatory Activity

The flavonoids in chamomile are reported to be responsible for its anti-inflammatory effects. The possible mechanism involves the suppression of nuclear factor kappa beta (NF-κB)-driven transcription [ 63 ]. Yuan et al. reported the potent anti-inflammatory activity of Chamomile volatile oil in animal models mediated by inhibiting the production of inflammatory mediators (tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β)) [ 64 ]. Because of this activity, chamomile is often used to treat inflammatory diseases such as mammitis, colitis, dermatitis, cystitis, and conjunctivitis [ 12 ]. Chamomile Jinshui, an essential oil mainly composed of Chamomile, can effectively relieve prickly heat in children caused by sweat gathering around sweat glands in summer [ 16 ].

3.4. Antithrombotic Activity

Cardiovascular diseases (CVD) are one of the leading causes of death worldwide. Chamomile extract exhibits antithrombotic activity by prolonging coagulation and hemostasis time [ 65 ]. Luteolin in this plant prevents the development of oxidative stress in adenosine diphosphate (ADP)-induced carotid artery thrombosis in rats [ 66 ]. Bijak et al. reported that polyphenol-polysaccharide conjugate obtained from chamomile exerts an antithrombotic effect by reducing platelet aggregation [ 67 ]. Bas et al. discovered that half-maximal inhibitory concentrations (IC 50 ) of water and butanol extracts on angiotensin-converting enzyme (ACE) were 1.292 mg/mL and 0.353 mg/mL, respectively [ 68 ]. All of the above findings further validate the antithrombotic activity of chamomile.

3.5. Antioxidant Activity

Volatile oil [ 69 ], polysaccharides [ 70 , 71 ] and total flavonoids [ 72 , 73 ] of Chamomile have been confirmed to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl free radicals. The antioxidant effect is dose-dependent [ 74 ]. In addition, chamomile ethanol extract increases the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) and reduces the malondialdehyde (MDA) content in mice [ 75 ]. These findings provide a scientific basis for the antioxidant effect of Chamomile.

3.6. Hypoglycaemic Activity

Chamomile extract reduces fasting blood glucose levels in diabetic mice [ 75 , 76 ] and normal mice and improves glucose tolerance [ 77 ]. In addition, the extract antagonizes the effect of exogenous glucose [ 65 ]. Yang et al. reported the hypoglycaemic effect of total flavonoids in this plant occurs by reducing fibrinogen (FBG), glycated haemoglobin, glucose tolerance and glycated serum protein (GSP) levels in diabetic mice, and promoting glucose tolerance and insulin secretion [ 78 ]. Cemek et al. investigated the hypoglycemic effect of chamomile extract in streptozotocin (STZ)-diabetic rats. The results showed that it protected islet cells and reduced the oxidative stress associated with hyperglycaemia [ 79 ].

3.7. Antihypertensive Activity

Studies have found an antihypertensive activity of chamomile extract in essential hypertensive rats [ 80 ]. At the same time, another study found that chamomile extract did not affect the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in normotensive rats, suggesting it has no toxic side effects in normal blood pressure regulation [ 81 ]. Luo et al. reported that the antihypertensive activity of chamomile extract in N-omega-nitro-L-arginine (L-NNA)-induced hypertensive rats is mediated by reducing angiotension Ⅱ (Ang Ⅱ) content and oxidative stress, and increasing SOD content [ 82 ].

3.8. Hypolipidaemic Activity

Hyperlipidaemia (HLP) refers to a metabolic disorder syndrome in which lipid components in plasma are abnormally dysregulated (increased serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C), with decreased high-density lipoprotein cholesterol (HDL-C)). Chamomile is an effective blood lipid-lowering herb. Lan et al. reported that a chamomile alcohol extract played a role in lowering lipids, reducing TC, TG and LDL-C values and elevating HDL-C values in the blood of experimental hyperlipidemic rats [ 83 ]. A compound in fuzhuan tea, a popular compound tea containing chamomile with a mellow taste and no toxic side effects, can also treat HLP by regulating the above various sterol indicators [ 84 ].

3.9. Antiallergy Activity

As a conventional medicine, chamomile is frequently used to relieve various allergic symptoms. Antiallergic tea, as an example, has positive anti-allergy activity and cosmetology when it is drunk for a long time [ 21 ]. The antiallergic activity of chamomile aqueous extract (1.0 mg/mL) was reported by measuring the β-hexosaminidase (β-Hex) release in rat basophil leukemia (RBL-2H3) cells. This was suggested to inhibit the β-Hex release by 21.42% [ 85 ]. A chamomile methanol extract could restrain compound 48/80-induced allergic reactions. The effect was dose-dependent and mediated via decreased histamine release and NO levels from mast cells [ 86 ].

3.10. Antidepressant Activity

Essential oil aromatherapy is considered an alternative treatment for depression. Chamomile is an excellent reliever when patients with depression have physical and psychological discomfort [ 8 ]. Chamomile tea made from chamomile flower heads can effectively relieve depressive symptoms and the sleep status of postpartum women, which provides a new idea for treatment of depression [ 87 ]. Some pharmacological experiments have suggested the antidepressant activity of Chamomile [ 88 ]. For example, α-pinene contained in this plant elevated protein expression related to oxidative phosphorylation and mRNA expression of parvalbumin in rat brain, as determined by isobaric tag for relative and absolute quantitation (iTRAQ) and polymerase chain reaction (PCR) analysis [ 89 ].

3.11. Organoprotective Effect

Chamomile has protective effects on organs such as the liver, lung, kidney, and stomach, among others.

3.11.1. Hepatoprotective and Pulmoprotective Effect

Chamomile flavonoids ameliorated mouse liver injury by restoring biochemical and molecular parameters in 1,2-Dimethyl hydrazine (DMH)-induced mice [ 90 ]. Zhang et al. ascertained that apigenin in this plant could treat APAP-induced liver injury by activating the adenosine monophosphate-activated protein kinase/GSK-3β (AMPK/GSK-3β) signaling pathway, promoting carnitine palmitoyl transferase 1A (CPT1A) activity and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway [ 91 ]. Additionally, chamomile increases the total antioxidant capacity (TAC) and tissue transglutaminase (tTG) content in liver tissue, protecting against oxidative liver injury from paraquat (PQ) poisoning [ 92 ]. On the other hand, its extract protects oxidative lung damage from PQ poisoning, mainly by improving lipid peroxidation (LPO), SOD, glutathione peroxidase (GPx), and increasing the transporter associated with antigen processing (TAP) in plasma and lung tissue [ 93 ].

3.11.2. Nephroprotective Effect

According to records in the “Baidu Yi Medicine Book”, chamomile is able to resolve the threat posed by kidney stones [ 7 ]. Modern pharmacological studies confirm this plant is an alternative therapy for gastric protection. For example, Salama et al. evaluated the protective effect of chamomile against cisplatin nephrotoxicity by intraperitoneal injection in rats. The study demonstrated that it reduces oxidative stress markers, corrects hypocalcemia caused by cisplatin nephrotoxicity, and inhibits glutamyltransferase activity [ 94 ]. In addition, its extract also inhibits phenomena such as glomerular fibrosis, improves renal tissue structure, and protects against renal tissue damage resulting from hypertension [ 82 ].

3.11.3. Gastroprotective Effect

Chamomile is a promising gastroprotective herb to deal with stomach spasm, flatulence, stomachache, and decreased gastric secretion [ 95 ]. Its extract has shown antiulcer and antioxidant effects in ethanol-induced gastric mucosal injury in rats. Gastroprotective effects are mediated by reducing MDA levels, increasing GSH levels [ 96 ], protecting gastric sulfhydryl groups and the opposing effects of intracellular mediators such as free iron, hydrogen peroxide, and calcium [ 97 ].

3.12. Genitoprotective Effect

Chamomile extract improves reproductive function in polycystic ovary syndrome (PCOS) rats. Chamomile reduced the uterine and insulin resistance index, regulated sex hormones, leptin and blood lipids, and decreased inflammatory cells [ 77 ]. In addition, the interaction of chamomile with the GABA system can regulate luteinizing hormone (LH) secretion and increase dominant follicles for improving reproductive function in rats [ 98 ]. Soltani et al. performed surgical experiments on rats and treated the experimental group with chamomile extract. Histological characterization showed that the extract protected the testicular tissue from torsion/detorsion-induced damage by reducing MDA levels and inhibiting superoxide production [ 99 ]. Afrigan et al. injected formaldehyde and chamomile extract intraperitoneally into male Wistar rats to probe the hormonal status and sperm parameters of testicular tissue. It was found that this extract reduced the adverse effects of formaldehyde on the reproductive system in male rats [ 100 ].

3.13. Neuroprotective Effect

Chamomile has an excellent neuroprotective effect. Its extract restores scopolamine-decreased brain-derived neurotrophic factor (BDNF) expression, increases IL1β, and modulates cholinergic activity in the rat hippocampus [ 101 ]. It has been reported that a chamomile ethanol extract improves formaldehyde-induced memory impairment by reducing cell death and MDA content in the hippocampus, and increasing total antioxidant capacity [ 102 ]. Furthermore, Lim et al. found that apigenin in this plant inhibits H2O2-induced hippocampal cell (HT22) death [ 103 ]. Khan et al. reported the anti-Parkinson activity of chamomile extract by establishing an experimental animal model with chlorpromazine (CPZ). The extract showed vascular proliferation and increased the number of reactive glial cells [ 104 ].

3.14. Analgesic Activity

As early as hundreds of years ago, Chamomile was used as an analgesic remedy to relieve a variety of pains, such as arthralgia, stomach cramps, and neuralgia [ 13 ]. Nowadays, chamomile oil gel has been authenticated as an analgesic by reducing migraine pain without aura [ 105 ]. Saghafi et al. also reported the breast pain-relieving effect of chamomile (treated for 8 weeks) in patients using a visual analogue scale (VAS) and a breast pain scale (BPC) [ 106 ].

3.15. Antidiarrheal and Antispasmodic Activity

Chamomile is widely used in traditional Tunisian medicine and TCM against diarrhea and spasticity. In Germany, the extract of this plant is effective in treating children’s acute diarrhea by reducing symptoms and shortening the duration of disease [ 107 ]. Mehmood et al. reported the antidiarrheal and antispasmodic effects of chamomile using isolated rabbit jejunum. The chamomile extract activates K + channels and reduces Ca 2+ antagonism [ 108 ]. Hichem Sebai reported the beneficial effects of the extract in castor oil-induced diarrhea, which decreased MDA levels and antioxidant enzyme activity [ 109 ]. In addition, apigenin and apiin in Chamomile have a strong antispasmodic effect on smooth muscle [ 38 ].

3.16. Cosmetic Activity

Chamomile is useful in repairing sensitive skin, eliminating acne, and improving skin dehydration. It whitens the skin by inhibiting tyrosinase activity [ 110 ]. Therefore, it can be used as an ingredient in skincare products [ 38 ]. Ointments, creams and lotions containing chamomile active ingredients are used for the treatment of various skin infections and rashes in Europe and other places [ 111 ]. Chamomile Natural Milk Hand Soap, is widely popular for decontamination and sterilization, and can effectively moisturize the skin, enhance elasticity, and calm broken micro-blood vessels [ 112 ].

3.17. Other Activities

Chamomile alleviates muscle atrophy by suppressing muscle ring finger-1 (MuRF1) and increasing mitochondrial transcription factor A (TFAM), MyoD and myogenin-1 genes [ 113 ]. It relieves stiffness and pain in people suffering from knee osteoarthritis [ 114 ]. It also relieves general anxiety [ 115 , 116 ], with efficacy equivalent to conventional anti-anxiety drugs [ 117 ]. Its n-butanol extract showed a beneficial effect in relieving asthma in mice by reducing the eosinophils (EOS) and MDA levels and increasing IL-2, IL-10, IL-12 and SOD levels [ 118 ]. Studies report that Chamomile accelerates the healing of skin wounds by promoting fibroblast proliferation and migration [ 119 ]. Wan et al. indicated that apigenin in this plant inhibits transforming growth factor β1 (TGF-β1)-stimulated cardiac fibroblasts (CFs) differentiation and extracellular matrix (ECM) production by reducing microRNA-155-5p (miR-155-5p) expression, increasing c-Ski expression, and lowering Smad2/3 and p-Smad2/3 expression [ 120 ]. Studies report that chamomile extract abrogates withdrawal behavioural manifestations in morphine-dependent rats [ 121 ].

A summary of various pharmacological activities of Chamomile are shown in Figure 8 .

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Summary of various pharmacological activities of Chamomile.

4. Other Aspects

4.1. adverse reactions.

According to records, the interaction between chamomile and some plants or drugs may cause adverse reactions. In theory, a combination of medicines that affect platelet aggregation may interfere with the effect of coagulation, thus increasing the risk of bleeding. Furthermore, high doses of Chamomile pose a teratogenic risk, affect the menstrual cycle, and cause vomiting [ 122 ]. Although this plant has antiallergic activity, a few studies have reported allergic reactions such as contact dermatitis and hypersensitivity, especially in people who are allergic to pollen or compositae [ 123 , 124 ]. There is a possibility to reduce follicular function and development, leading to premature birth in pregnant women when using chamomile [ 125 , 126 ].

4.2. Toxicity Studies

There have been reports of chamomile as a potential carrier of Clostridium botulinum spores [ 127 ]. Kalantari et al. reported the genotoxicity of Chamomile in mice using ultra-viable micronucleus assay of reticulocytes [ 128 ]. However, Wang et al. reported that the aqueous and alcohol extracts of this plant are safe for mice. It has been reported that the maximum tolerated dose of aqueous and alcohol extracts are 535 and 425 times higher than the usual adult dose in a clinic [ 129 ]. So far, only a few studies have been carried out to evaluate its toxicity, and more studies are required to confirm the safety of consuming chamomile.

4.3. Clinical Preparation

Chamomile has long been known as a medicinal and aromatic plant in Europe, the United States, Japan and other countries. At present, due to its multiple medicinal effects, many chamomile-containing herbal medicinal products have been developed, such as chamomile ointment, cream and lotion [ 111 ]. However, there are relatively few preparations in clinical products. Clinical preparations of this plant are mainly used in clinical research in the form of a mouth rinse [ 130 , 131 ]. For example, the White Gold Medal Compositae essence Gargle, which was listed in Japan in 2002, is able to be applied to oral bacteriostasis, clean care, and relieve oral discomfort [ 62 ]. In addition, three kinds of chamomile preparations can be retrieved from the database of Chinese patent medicine prescriptions “ https://db.yaozh.com/chufang (accessed on 17 November 2022)”, including Fufang Munizi granules, Zukamu capsules and Zukamu granules [ 4 ]. The U.S. National Drug Code also lists more than two hundred kinds of preparations containing this plant, such as Allergies (pellet), SleepCalm (spray), OHM Fever Relief (spray), and Melatonin Pro (tablet) [ 6 ]

4.4. Quality Control Studies

High Performance Liquid Chromatography (HPLC) is a standard method for identifying and quantifying the components in herbs to assess their quality. Furthermore, evaluating chamomile quality is crucial to reproducing its clinical efficacy. You et al. reported the HPLC method for the simultaneous determination of luteolin-7-O-β-D glucoside and apigenin 7-O-β-D glucoside in chamomile extract and displayed the linear range of luteolin-7-O-β-D glucoside and apigenin-7-O-β-D glucoside was 5.11~409.00 and 12.56~1005.00 μg/mL, respectively [ 132 ]. Lan et al. reported the UPLC method to determine the content of apigenin-7-glucoside in chamomile, and the content was found to be 5.2 and 5.8 mg/g, in two batches [ 133 ]. Wu et al. adopted this method to quantify α-bisabolol, and the concentration of α-bisabolol in MC was 0.045 mg/mL, whereas it was not detected in CN [ 134 ]. Gas chromatography also plays a vital role in the quality control of pharmaceuticals. Zhao et al. reported a gas chromatographic method to determine the volatile oil components in this plant. α -Bisabolol, α-bisabolol oxide A and α-bisabolol oxide B were present in volatile oil of MC, whereas CN volatile oil contained only α-bisabolol oxide A. Therefore, the comprehensive quality evaluation of MC and CN could be qualitatively and quantitatively based on the content of bisabolol or the presence or absence of α -bisabolol oxide B [ 95 ].

Total saponins content in Chamomile was determined by utlraviolet (UV) spectrophotometry, and the detected content was 8.02% [ 135 ]. Jing et al. used a flame atomic absorption spectrometric method to measure the content of trace elements (Ca, Zn, Fe, Mg, Mn, and Na). The contents of Ca, Zn, Fe, Mg, Mn and Na were 2.016, 0.032, 0.684, 2.380, 0.044 and 1.235 mg/g, respectively [ 48 ]. In addition, Xin et al. reported the presence of arsenic in this plant using atomic fluorescence spectroscopy [ 49 ]. A thin-layer chromatography method can be used to identify luteolin in chamomile [ 136 ]. QAMS is a research tool for multi-component quality control, which is used to solve the bottleneck problem when the control substance is scarce and expensive in the qualitative evaluation of herbal medicine [ 137 ]. Li et al. utilized QAMS to determine cynaroside, apigenin-7-glucoside, 7-methoxycoumarin, luteolin and apigenin in chamomile. There was no significant difference in the contents calculated using either this method or an external standard method [ 44 ]. Han et al. reported a method in which polyamide was used as a stationary phase and microemulsion as a developing agent to identify above five compounds. This method is better than thin layer chromatography using silica gel [ 138 ].

5. Discussion and Conclusions

A lot of research has been carried out on chamomile in recent years. This article reviews the latest research progress on this plant, including botanical characteristics, traditional uses, chemical constituents, pharmacological effects, and quality evaluation. A total of 301 compounds have been reported in Chamomile, including 26 organic acids, 50 flavonoids, 10 coumarins, 102 volatile oil constituents, 39 monoterpenes, 27 sesquiterpenes, 2 diterpenes, 3 triterpenes, 16 sterols, 6 polysaccharides, 3 guaiacolides, 7 trace elements and 10 other components. Flavonoids represented by apigenin have significant anti-inflammatory effects. Esters in volatile oils have sedative and anxiolytic effects. α-Bisabolol in sesquiterpenes can protect against APAP-induced acute liver injury. Chamomile also plays anticancer, anti-infective, antioxidant, hypoglycaemic, hypotensive, hypolipidaemic, antiallergic, antidepressant, organ protective, genitoprotective, and neuroprotective effects. In addition, chamomile is used as an ingredient in skin whitening products and relieves muscle atrophy, speeds up skin wound healing, and treats asthma. There are many scientific studies on it, but there are still numerous research gaps. For example, more toxicity tests should be carried out to confirm the safe use of chamomile. Its clinical effects depend on chemical composition and the amount of active components. HPLC is an effective analytical method for identifying and quantifying components in herbs. The content of luteolin-7-O-glucoside, apigenin-7-O-glucoside, chlorogenic acid, apigenin, apigenin-7-glucose, α -bisabolol and other substances have been quantified using various HPLC methods. In addition, volatile components such as α -bisabolol and α -bisabolol oxide B have been identified and quantified using gas chromatography. This method is useful to differentiate MC and CN.

In summary, chamomile is a widely used herb in the traditional medicine of Greece, Rome, China, Germany and other countries. It has great economic value due to its numerous pharmacological effects and wide uses. This paper summarizes its various aspects systematically. The information in this review will be a good scholarly resource for its further development and utilization. However, there is a need for further research to provide concrete scientific evidence and validate the medicinal uses of chamomile.

Acknowledgments

We would like to express our gratitude to the Shandong University of Traditional Chinese Medicine, which provided us with precious, ancient books to complete the section “Traditional Uses”.

Abbreviations

Funding statement.

This review received no external funding.

Author Contributions

Y.-L.D., Y.L. and Q.W. collected the literature, drew structures and wrote the manuscript; F.-J.N., K.-W.L., Y.-Y.W. and J.W. checked the tables and figures; C.-Z.Z. and L.-N.G. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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Article Contents

Introduction, chemical constituents, health effects of c. cyminum, health effects of n. sativa, conclusions, cumin ( cuminum cyminum ) and black cumin ( nigella sativa ) seeds: traditional uses, chemical constituents, and nutraceutical effects.

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Krishnapura Srinivasan, Cumin ( Cuminum cyminum ) and black cumin ( Nigella sativa ) seeds: traditional uses, chemical constituents, and nutraceutical effects, Food Quality and Safety , Volume 2, Issue 1, March 2018, Pages 1–16, https://doi.org/10.1093/fqsafe/fyx031

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Although the seeds of cumin ( Cuminum cyminum L.) are widely used as a spice for their distinctive aroma, they are also commonly used in traditional medicine to treat a variety of diseases. The literature presents ample evidence for the biomedical activities of cumin, which have generally been ascribed to its bioactive constituents such as terpenes, phenols, and flavonoids. Those health effects of cumin seeds that are experimentally validated are discussed in this review. Black seeds ( Nigella sativa ), which are totally unrelated to C. cyminum , have nevertheless taken the name ‘Black cumin’ and used in traditional systems of medicine for many disorders. Numerous pre-clinical and clinical trials have investigated its efficacy using the seed oil, essential oil, and its main constituent thymoquinone (TQ). These investigations support its use either independently or as an adjunct along with conventional drugs in respiratory problems, allergic rhinitis, dyspepsia, metabolic syndrome, diabetes mellitus, inflammatory diseases, and different types of human cancer. Multiple studies made in the last decades validate its health beneficial effects particularly in diabetes, dyslipidemia, hypertension, respiratory disorders, inflammatory diseases, and cancer. Nigella sativa seeds also possess immune stimulatory, gastroprotective, hepatoprotective, nephroprotective, and neuroprotective activities. TQ is the most abundant constituent of volatile oil of N. sativa seeds, and most of the medicinal properties of N. sativa are attributed mainly to TQ. All the available evidence suggests that TQ should be developed as a novel drug in clinical trials.

Cumin seeds ( Figure 1 ) are obtained from the herb Cuminum cyminum , native from East Mediterranean to South Asia belonging to the family Apiaceae—a member of the parsley family. Cumin seeds are oblong and yellow–grey. Cumin seeds are liberally used in several cuisines of many different food cultures since ancient times, in both whole and ground forms. In India, cumin seeds have been used for thousands of years as a traditional ingredient of innumerable dishes including kormas and soups and also form an ingredient of several other spice blends. Besides food use, it has also many applications in traditional medicine. In the Ayurvedic system of medicine in India, cumin seeds have immense medicinal value, particularly for digestive disorders. They are used in chronic diarrhoea and dyspepsia ( Table 1 ).

Different varieties of cumin.

Different varieties of cumin.

Differences between seed spices closely related to cumin seeds.

Black seed (also known as black cumin; Nigella sativa ) ( Figure 1 ) is an annual flowering plant belonging to the family Ranunculaceae and is a native of Southern Europe, North Africa, and Southwest Asia. Black cumin is cultivated in the Middle Eastern Mediterranean region, Southern Europe, Northern India, Pakistan, Syria, Turkey, Iran, and Saudi Arabia. Nigella sativa seeds and their oil have a long history of folklore usage in Indian and Arabian civilization as food and medicine ( Yarnell and Abascal, 2011 ). The seeds of N. sativa have a pungent bitter taste and aroma and are used as a spice in Indian and extensively in Middle Eastern cuisines. The dry-roasted nigella seeds flavour curries, vegetables, and pulses. Black seeds are used in food as a flavouring additive in breads and pickles. It is also used as an ingredient of the spice mixture ( panch phoron ) and also independently of many recipes in Bengali cuisine. Cumin was traditionally used as a preservative in mummification in the ancient Egyptian civilization. Black cumin has a long history of use as medicine in the Indian traditional system of medicine like Unani and Ayurveda ( Sharma et al. , 2005 ). The black cumin seeds have traditionally been used in the Southeast Asian and Middle East countries for the treatment of diseases such as asthma, bronchitis, rheumatism, and other inflammatory diseases. Nigella sativa has extensively been used because of its therapeutic potential and possesses a wide spectrum of activities, namely, diuretic, antihypertensive, antidiabetic, anticancer, immune-modulatory, antimicrobial, anthelmintic, analgesic and anti-inflammatory, spasmolytic, bronchodilator, gastroprotective, hepatoprotective, and renal protective properties. Traditionally, seeds of N. sativa are widely used for asthma, diabetes, hypertension, fever, inflammation, bronchitis, dizziness, rheumatism, skin disorders, and gastrointestinal disturbances ( Table 1 ). It is also used as a liver tonic, digestive, antidiarrhoeal, emmenagogue, and to control parasitic infections and boost immune system ( Goreja, 2003 ).

Bunium persicum (occasionally referred to as Cuminum nigrum ; also known as Shahi jeera), belonging to Apiaceae (parsley family), is a smaller variety of cumin with a different flavour, popularly used in North Indian, Pakistani, and Iranian foods ( Figure 1 ). Until now, there is only very little scientific information on this spice.

Cumin seeds are nutritionally rich; they provide high amounts of fat (especially monounsaturated fat), protein, and dietary fibre. Vitamins B and E and several dietary minerals, especially iron, are also considerable in cumin seeds. Cuminaldehyde ( Figure 2 ), cymene, and terpenoids are the major volatile components of cumin ( Bettaieb et al. , 2011 ). Cumin has a distinctive strong flavour. Its warm aroma is due to its essential oil content. Its main constituent of aroma compounds are cuminaldehyde and cuminic alcohol. Other important aroma compounds of roasted cumin are the substituted pyrazines, 2-ethoxy-3-isopropylpyrazine, 2-methoxy-3-sec-butylpyrazine, and 2-methoxy-3-methylpyrazine. Other components include γ-terpinene, safranal, p -cymene, and β-pinene ( Li and Jiang, 2004 ).

Major bioactive compounds of cumin and black seeds.

Major bioactive compounds of cumin and black seeds.

Nigella sativa seeds contain protein (26.7%), fat (28.5%), carbohydrates (24.9%), crude fibre (8.4%), and total ash (4.8%). Nigella sativa seeds also contain a good amount of various vitamins and minerals like Cu, P, Zn, and Fe. Many active compounds have been identified in N. sativa . The most important active compounds of N. sativa are thymoquinone (TQ) (30%–48%) ( Figure 2 ), thymohydroquinone, dithymoquinone (nigellone), p -cymene (7%–15%), carvacrol (6%–12%), 4-terpineol (2%–7%), t -anethole (1%–4%), sesquiterpene longifolene (1%–8%), α-pinene, and thymol. ( Boskabady and Shirmohammadi, 2002 ; Ali and Blunden, 2003 ). Nigella sativa also contains other compounds such as carvone, limonene, citronellol in trace amounts, and two varieties of alkaloids, i.e. isoquinoline alkaloids (e.g. nigellicimine and nigellicimine- N -oxide) and pyrazole alkaloids (e.g. nigellidine and nigellicine). Nigella sativa seeds also contain α-hederin, a water soluble pentacyclic triterpene ( Al-Jassir, 1992 ; Nickavar et al. , 2003 ). The pharmacological properties of N. sativa are mainly attributable to its quinine constituents, TQ being the most abundant. The N. sativa seeds contain fatty oil rich in unsaturated fatty acids, constituting linoleic acid (50%–60%), oleic acid (20%), eicosadienoic acid (3%), and dihomolinoleic acid (10%), and saturated fatty acids (palmitic and stearic acids) constitute up to 30 per cent. α-Sitosterol is the major sterol, accounting for 44%–54% of the total sterols in N. sativa oils, followed by stigmasterol (6.57%–20.9% of total sterols) ( Cheikh-Rouhou et al. , 2008 ; Mehta et al. , 2008 ).

Bitter cumin (Shahi jeera) seeds contain calcium, vitamin A, potassium, sodium, iron, magnesium, and phosphorus. Bitter cumin ( B. persicum ) has 0.5 to 1.6 per cent essential oil, mainly carvone (45%–60%), limonene, and p -cymene. Oleoresin of bitter cumin is brownish to yellowish green. As there is not enough scientific information on the health effects of bitter cumin, this review is limited to C. cyminum (cumin seeds) and N. sativa (black seeds or black cumin)

Although the seeds of cumin ( C. cyminum L.) are widely used as the spice for their distinctive aroma, they are also commonly used in traditional medicine to treat a variety of diseases, including chronic diarrhoea and dyspepsia, acute gastritis, diabetes, and cancer. The literature presents ample evidence for the biological and biomedical activities of cumin, which have generally been ascribed to its bioactive constituents such as terpenes, phenols, and flavonoids ( Mnif and Aifa, 2015 ). Those health effects of cumin seeds that are experimentally validated ( Figure 3 ) are discussed below.

Multiple medicinal properties of Cuminum cyminum (cumin seeds).

Multiple medicinal properties of Cuminum cyminum (cumin seeds).

Digestive stimulant action

In the context of cumin seeds being claimed in home remedies and traditional medicine, to aid digestion, an animal study has examined whether they have any stimulatory effect on the digestive enzymes. The influence of cumin seeds on the digestive enzymes of the rat pancreas and intestinal mucosa has particularly been investigated as a result of both continuous dietary intake and single oral administration ( Platel and Srinivasan, 1996 ; 2000a ) ( Table 2 ). Dietary (1.25%) cumin lowered the activity of pancreatic lipase, whereas the activities of pancreatic trypsin, chymotrypsin, and amylase were significantly enhanced by the same ( Platel and Srinivasan, 2000a ). When given as a single oral dose, cumin exerted a lowering effect on pancreatic lipase, amylase, trypsin, and chymotrypsin. Among the terminal digestive enzymes, a small intestinal maltase activity was significantly higher in animals fed with cumin, whereas lactase and sucrose were unaffected ( Platel and Srinivasan, 1996 ).

Digestive stimulant and antidiabetic effects of Cumin seeds.

Dietary cumin had a significant stimulatory effect on bile flow rate, the extent of increase in bile volume being 25 per cent, whereas its single oral dose did not have any effect on bile secretion rate ( Platel and Srinivasan, 2000b ). Dietary intake of cumin had a profound influence on bile acid output (quantity secreted per unit time), bile acid secretion being as high as 70 per cent over the control. Similar significant increases in bile acid secretion were seen in the case of cumin when administered as a single oral dose. Since bile juice makes a significant contribution to the overall process of digestion and absorption, essentially by supplying bile acids required for micelle formation, it is expected that cumin, which has a digestive stimulant action, could do so by stimulating biliary secretion of bile acids.

Another study has examined whether this digestive stimulant spice cumin also affects the duration of residence of food in the gastrointestinal tract of experimental rats ( Platel and Srinivasan, 2001 ). Cumin produced a significant shortening of the food transit time by 25 per cent. The reduction in food transit time produced by dietary cumin roughly correlates with their beneficial influence either on digestive enzymes or bile secretion.

Antidiabetic effects

The antidiabetic effect of cumin seeds has been reported in human diabetics ( Karnick, 1991 ) ( Table 2 ). In this study, 80 patients with non-insulin dependent diabetes mellitus were orally administered for 24 weeks with an Ayurvedic formulation containing C. cyminum . Fasting and post-prandial blood sugar at 6-week intervals was significantly reduced in all the patients. Dietary cumin seeds were observed to alleviate diabetes-related metabolic abnormalities in STZ-diabetic rats ( Willatgamuwa et al. , 1998 ). An 8-week dietary regimen containing cumin powder (1.25%) was found to be remarkably beneficial, as indicated by a reduction in hyperglycaemia and glucosuria. Hyperlipidemia associated with diabetes mellitus was also effectively countered by dietary cumin in alloxan-diabetic rats ( Dandapani et al ., 2002 ).

Cuminum nigrum seeds or their water or methanol extracts have been observed to be hypoglycemic in alloxan-diabetic rabbits ( Akhtar and Ali, 1985 ). The antihyperglycemic influence of C. nigrum has been attributed to the flavonoid compounds present in these seeds ( Roman-Ramos et al. , 1995 ; Ahmad et al. , 2000 ). Methanolic extract of C. cyminum has been investigated in streptozotocin-diabetic rats on diabetes, oxidative stress, and formation of advanced glycated end products (AGE) in comparison with glibenclamide ( Jagtap and Patil, 2010 ). In vitro studies indicated that cumin inhibited free radicals and AGE formation. The antidiabetic effect of cumin (treated for 4 weeks) was comparable to glibenclamide and even better in controlling oxidative stress and AGE formation, which is implicated in pathogenesis of diabetic microvascular complications. The inhibitory activity of C. cyminum seed–isolated component cuminaldehyde has been evaluated against lens aldose reductase and α-glucosidase isolated from Sprague-Dawley rats and compared with that of quercetin as an aldose reductase inhibitor and acarbose as an α-glucosidase inhibitor ( Lee, 2005 ). Cuminaldehyde was about 1.8 and 1.6 times less in inhibitory activity than acarbose and quercetin, respectively. Nonetheless, cuminaldehyde may be useful for antidiabetic therapeutics.

Anti-inflammatory effects

Cumin essential oil was investigated for the anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the underlying mechanisms ( Wei et al. , 2015 ) ( Table 3 ). Volatile constituents were identified in essential oil using Gas Chromatography - Mass Spectrometry (GC-MS), the most abundant constituent being cuminaldehyde (48.8%). Cumin oil exerted anti-inflammatory effects in LPS-stimulated RAW cells through inhibiting NF-κB and mitogen-activated protein kinases suggesting its potential as an anti-inflammatory agent.

Cardioprotective, anti-inflammatory, and chemopreventive effects of cumin seeds.

Cardio-protective influence through hypolipidemic and hypotensive effects

Cuminum cyminum is traditionally used for the treatment of indigestion and hypertension. The anti-hypertensive potential of aqueous extract of cumin seed and its role in arterial–endothelial nitric oxide synthase expression, inflammation, and oxidative stress have been evaluated in renal hypertensive rats ( Kalaivani et al. , 2013 ) ( Table 3 ). Cumin administered orally (200 mg/kg body) for 9 weeks improved plasma nitric oxide and reduced the systolic blood pressure in hypertensive rats. This was accompanied by the up-regulation of the expression of inducible nitric oxide synthase (iNOS), Bcl-2, TRX1, and TRXR1 and down-regulation of the expression of Bax, TNF-α, and IL-6. These data suggest that cumin seeds augment endothelial functions and ameliorate inflammatory and oxidative stress in hypertensive rats.

Paraoxanase-1 plays a protective role against the oxidative modification of plasma lipoproteins and hydrolyzes lipid peroxides in human atherosclerotic lesions. Flavonoids present in cumin seeds are recognized to have antioxidant activity and improve the antioxidant system. A study demonstrated that cumin extract significantly decreased the level of oxidized Low-density lipoprotein (OxLDL) while increasing the activities of paraoxonase, and arylesterase activities were increased in serum ( Samani and Farrokhi, 2014 ). The effect of cumin added to normal and hypercholesterolemia inducing diet on serum and liver cholesterol levels in rats has been studied ( Sambaiah and Srinivasan, 1991 ). Dietary cumin did not show any cholesterol lowering effect when included in the diet (1.25%) at about 5-fold the normal consumption level.

Chemopreventive effects

Cancer chemopreventive potentials of dietary 2.5 and 5.0 per cent cumin were evaluated against benzo(α)pyrene-induced tumorigenesis in forestomach and 3-methylcholanthrene (MCA)-induced tumorigenesis in uterine cervix in mice ( Gagandeep et al., 2003 ) ( Table 3 ). Cumin produced a significant inhibition of stomach tumour. The effect on carcinogen/xenobiotic metabolizing phase I and phase II enzymes, antioxidant enzymes, and lipid peroxidation in the liver was also examined. Cytochrome P 450 and cytochrome b 5 were significantly augmented by dietary cumin. The phase II enzyme glutathione-S-transferase (GST) was increased by cumin, whereas the specific activities of superoxide dismutase (SOD) and catalase were significantly elevated. Lipid peroxidation was inhibited by cumin, suggesting that the cancer chemopreventive potential of cumin could be attributed to its ability to modulate carcinogen metabolism.

The effect of cumin ( C. cyminum ; dietary 1.25% for 32 weeks) was studied on colon cancer induced in rats by 1,2-dimethylhydrazine (DMH) s.c. 20 mg/kg of body weight (15 doses, at weekly intervals) ( Nalini et al. , 2006 ). Results showed that cumin suppresses colon carcinogenesis in the presence of the procarcinogen DMH. The excretion of fecal bile acids and neutral sterols was significantly increased in cumin+DMH-administered rats. Cholesterol and 3-hydroxy-3-methylglutaryl-CoA reductase activity were decreased in cumin+DMH-treated rats. Spent cumin generated from Ayurvedic industry was evaluated for its nutraceutical potential in terms of antioxidant (in terms of scavenging 2,2-Diphenyl-1-picryl-hydrazyl-hydrate [DPPH] radical), antidiabetic (in terms of better α-amylase inhibition and glucose uptake activity in L6 cells), and anticancer properties (in terms of arresting the cell cycle and inducing apoptosis in HT29 colon cancer cells) and compared with that of the raw cumin ( Arun et al. , 2016 ). The results suggested that nutraceutical food formulation made out of spent cumin could play a major role in the prevention or management of degenerative diseases.

Miscellaneous nutraceutical effects

Cumin seeds are traditionally used for the treatment of diarrhoea. The aqueous extract of cumin seeds (100, 250, and 500 mg/kg) has been examined against diarrhoea in albino rats induced with castor oil ( Sahoo et al. , 2014 ). The extract showed significant inhibition in the frequency of diarrhoea, delaying the defecation time, secretion of intestinal fluid, and intestinal propulsion in a dose-dependent manner. Fibrillation of α-synuclein (α-SN) is a critical process in the pathophysiology of several neurodegenerative diseases, especially Parkinson’s disease. A study on the inhibitory effects of C. cyminum essential oil on the fibrillation of α-SN indicated that the small abundant natural compound, cuminaldehyde can modulate α-SN fibrillation, suggesting that such natural active aldehyde could have potential therapeutic applications ( Morshedi et al. , 2015 ).

Black cumin ( N. sativa ) has been in use in traditional systems of medicine for various medical disorders. Nigella sativa is used in Moroccan folk medicine for the treatment of diabetes mellitus. Many pre-clinical and clinical trials have investigated its efficacy, using the seed oil, essential oil, and its isolated main constituent TQ ( Ali and Blunden, 2003 ). These investigations provide preliminary support for its use in asthma, allergic rhinitis, and atopic dermatitis ( Yarnell and Abascal, 2011 ). Black cumin might help in dyspepsia, respiratory problems, diabetes mellitus, and metabolic syndrome ( Yarnell and Abascal, 2011 ). A meta-analysis of clinical trials suggests that N. sativa has a short-term benefit in lowering systolic and diastolic blood pressure, and its various extracts can reduce triglycerides, LDL, and total cholesterol ( Sahebkar et al., 2016a ; 2016b ). Several studies made in the last decades validate its health beneficial effects particularly in diabetes, dyslipidemia, hypertension, and obesity. A systematic review of all human trials has revealed that N. sativa supplementation might be effective in glycemic control in humans ( Mohtashami and Entezari, 2016 ).

Nigella sativa seeds are traditionally used in the management of diabetes mellitus in indigenous systems of medicine and folk remedies. Defatted extract of N. sativa seed is reported to increase glucose-induced insulin release from isolated rat pancreatic islets in vitro ( Rchid et al. , 2004 ) ( Table 4 ). The effect of N. sativa extracts (defatted fractions either containing acidic and neutral compounds or containing basic compounds) have been investigated on insulin secretion in vitro in rat pancreatic islets in the presence of glucose (8.3 mmol/l). Results showed that the antidiabetic properties of N. sativa seeds may partially be mediated by the stimulation of insulin release, especially by the basic subfraction of the seed. The possible insulinotropic property of N. sativa oil has also been studied in STZ plus nicotinamide (NA) induced diabetes mellitus in hamsters. Nigella sativa oil treatment for four weeks decreased blood glucose and increased serum insulin ( Fararh et al. , 2002 ). Immunohistochemical staining revealed the presence of insulin in the pancreas from N. sativa oil-treated group, suggesting that the hypoglycemic effect results, at least partly, from a stimulatory effect on β-cell function.

Antidiabetic effects of black cumin ( Nigella sativa ) seeds.

The oil of N. sativa significantly lowered blood glucose in STZ-diabetic rats after 2, 4, and 6 weeks ( El-Dakhakhny et al. , 2002 ). A study of the effect of N. sativa oil on insulin secretion from isolated rat pancreatic islets in the presence of glucose indicated that its hypoglycemic effect might be mediated by extra-pancreatic actions rather than by stimulation of insulin release. The hypoglycemic effect of N. sativa oil (400 mg/kg by p.o.) is partly due to decreased hepatic gluconeogenesis ( Fararh et al. , 2004 ). Indazole-type alkaloid 17-O-(β-D-glucopyranosyl)-4-O-methyl nigellidine present in the defatted extract of N. sativa seeds increased glucose consumption by hepatocytes (HepG2 cells) in vitro through activation of AMP-activated protein kinase (AMPK) ( Yuan et al. , 2014 ).

Nigella sativa extract given orally for 2 months decreased lipid peroxidation and increased antioxidant defence system and also prevented the lipid peroxidation-induced liver damage in diabetic rabbits ( Meral et al. , 2001 ). Daily oral administration of ethanol extract of N. sativa seeds (300 mg/kg) to STZ-diabetic rats for 30 days reduced the elevated levels of blood glucose, lipids, plasma insulin, and improved altered levels of lipid peroxidation products and antioxidant enzymes in liver and kidney ( Kaleem et al. , 2006 ). This suggested that in addition to antidiabetic activity, N. sativa seeds may control diabetic complications through antioxidant effects. Treatment of N. sativa oil (0.2 ml/kg, i.p.) for 30 days decreased the elevation in serum glucose and restored lowered serum insulin with partial regeneration or proliferation of pancreatic β-cells in STZ-diabetic rats ( Kanter et al. , 2003 ). The possible protective effects of N. sativa (0.2 ml/kg, i.p.) against β-cell damage from STZ-diabetes in rats have been evidenced by the observed decrease in lipid peroxidation and serum nitric oxide and increase in the activities of antioxidant enzymes in the pancreas ( Kanter et al. , 2004 ). Increased staining for insulin and preservation of β-cell numbers were evident in N. sativa– treated diabetic rats. This suggests that N. sativa treatment exerts a protective effect on diabetes by decreasing oxidative stress and preserving pancreatic β-cell integrity.

Nigella sativa oil administration (daily) to STZ-induced diabetic rats maintained on a high-fat diet significantly induced the gene expression of insulin receptor ( Balbaa et al. , 2016 ). Nigella sativa oil upregulated the expression of IGF-1 and phosphoinositide-3 kinase, whereas the expression of ADAM-17 was downregulated. Also, the N. sativa oil significantly reduced blood glucose level, individual lipid profile, oxidative stress markers, serum insulin or insulin receptor ratio, and the TNF-α, confirming that N. sativa oil has an antidiabetic activity. Thus, the daily N. sativa oil treatment improves insulin-induced signalling.

Hyperglycaemia is an important risk factor for the development and progression of the macrovascular and microvascular complications that occur in diabetes. The expression of apoptotic markers in the medial aortic layer of diabetic rats and the effects of N. sativa seed oil on the expression of these markers have been investigated ( Cüce et al ., 2015 ). It is understood that N. sativa seed oil is effective against diabetes and merits further treatment strategies for preventing apoptosis in vascular structures.

Treatment of streptozotocin-diabetic rats with N. sativa extract, N. sativa oil, and TQ, significantly decreased the diabetes-induced lipid peroxides and hyperglycemia, and significantly increased serum insulin and SOD activity in tissues. Nigella sativa oil and TQ have therapeutic potential and are protective against STZ-diabetes by decreasing oxidative stress, thus preserving pancreatic β-cell integrity, leading to increased insulin levels ( Abdelmeguid et al. , 2010 ). The protective effects of N. sativa oil on insulin sensitivity and ultrastructural changes of pancreatic β-cells in STZ-induced diabetic rats are reported ( Kanter et al. , 2009 ). It is evident that N. sativa treatment exerts a protective effect on diabetes by decreasing morphological changes and preserving the pancreatic β-cell integrity ( Kanter et al. , 2009 ). The anti-hyperglycemic potential of TQ and the effect on the activities of key enzymes of carbohydrate metabolism in STZ-NA–induced diabetic rats have been evaluated ( Pari and Sankaranarayanan, 2009 ). Oral administration of TQ (20, 40, and 80 mg/kg body weight for 45 days) dose-dependently improved the glycemic status in STZ/NA-induced diabetic rats. The levels of insulin and haemoglobin increased along with a decrease in glucose and HbA1c levels. The altered activities of carbohydrate-metabolizing enzymes were also restored ( Pari and Sankaranarayanan, 2009 ).

In a clinical study, the adjuvant effect of N. sativa oil on various clinical and biochemical parameters of the insulin resistance syndrome in patients with diabetes and dyslipidemia has been evidenced ( Najmi et al. , 2008 ). Nigella sativa accentuates glucose-induced secretion of insulin besides negatively affecting glucose absorption. Hence, it is of immense therapeutic benefit in diabetic individuals ( Kapoor, 2009 ). The effect of N. sativa seeds used as an adjuvant therapy in addition to the anti-diabetic medications on the glycemic control of patients with type 2 diabetes mellitus was investigated ( Bamosa et al. , 2010 ). Nigella sativa at a dose of 2 g/day caused significant reductions in fasting blood glucose, 2-hour post-prandially, and glycosylated haemoglobin. The results indicate that a dose of 2 g/day of N. sativa could serve as a useful adjuvant to oral hypoglycemic drugs in patients with type 2 diabetes mellitus.

Ameliorative effects of N. sativa on dyslipidemia

Dyslipidemia is an established risk factor for ischemic heart disease. Nigella sativa has been used for the treatment and prevention of hyperlipidemia ( Asgary et al. , 2015 ). Different preparations of N. sativa including seed powder (100 mg–20 g daily), seed oil (20–800 mg daily), TQ (3.5–20 mg daily), and methanolic extract reduced plasma levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In clinical trials, N. sativa was found to be effective when added as an adjunct to conventional hypolipidemic and antidiabetic medications. Inhibition of dietary cholesterol absorption, decreased hepatic cholesterol synthesis, and up-regulation of LDL receptors contribute to lipid-lowering effects of N. sativa . Overall, the evidence from an experimental and a clinical study suggests that N. sativa seeds are promising natural therapy for patients with dyslipidemia.

Anti-inflammatory property and analgesic activity

The antinociceptive and anti-inflammatory effects of TQ ( Table 6 ), supporting the common perception of N. Sativa as a potent analgesic and anti-inflammatory agent, have been recently reviewed ( Amin and Hosseinzadeh, 2016 ). Many protective properties are attributed to radical scavenging activity as well as an interaction with molecular targets involved in inflammation (proinflammatory enzymes and cytokines). Further investigations are needed to understand the precise mechanisms responsible for the antinociceptive and anti-inflammatory effects of its active constituents.

Anti-inflammatory/analgesic effects and immunomodulatory property of black cumin ( Nigella sativa ) seeds.

Development of solid tumour malignancies is closely associated with inflammation. The steam-distilled essential oil of N. sativa , which mainly contains p -cymene (37.3%) and TQ (13.7%), investigated for its analgesic and antiinflammatory properties in rats was found to produce a significant analgesic effect on acetic acid-induced writhing, formalin, and light tail flick tests ( Hajhashemi et al. , 2004 ). Intraperitoneal injection of 100, 200, and 400 µl/kg significantly inhibited carrageenan-induced paw oedema. Mechanism(s) other than opioid receptors are believed to be involved in this analgesic effect of the Nigella essential oil. Its administration showed anti-inflammatory activity probably attributable to TQ, one of the major components of black cumin. The anti-inflammatory effect of TQ on LPS-stimulated BV-2 murine microglia cells has been reported, wherein TQ was effective in reducing nitrate with parallel decline of iNOS protein expression evidenced ( Taka et al. , 2015 ). TQ also reduced LPS-mediated elevation in gene expression of Cxcl10 and some of other cytokines. The anti-inflammatory properties of TQ in LPS-activated microglial cells suggested the applicability of TQ in delaying the onset of inflammation-mediated neurodegenerative disorders.

The aqueous extract of N. sativa has been found to possess anti-inflammatory and analgesic activities in animal models. Although osteoporosis is linked to oxidative stress and inflammation, the anti-osteoporotic effects of N. sativa and TQ are evidenced by observing the inhibition of inflammatory cytokines (interleukin (IL)-1 and 6) and the transcription factor (NFκB). Both N. sativa and TQ have shown potential as an anti-osteoporotic agent ( Shuid et al. , 2012 ). TQ induced apoptosis and inhibited proliferation in pancreatic ductal adenocarcinoma (PDA) cells. This anti-inflammatory potential involved an effect on the expression of different proinflammatory cytokines and chemokines. TQ dose-dependently reduced PDA cell synthesis of MCP-1, TNF-α, IL-1β, and Cox-2. TQ as an inhibitor of proinflammatory pathways provides an effective strategy that combines anti-inflammatory and proapoptotic modes of action ( Chehl et al. , 2009 ). A clinical trial was conducted to investigate the anti-inflammatory effects of N. sativa in patients with allergic rhinitis symptoms. The anti-allergic effects of N. sativa components could be attributed to allergic rhinitis ( Nikakhlagh et al. , 2011 ). The anti-arthritic activity of orally administered TQ (5 mg/kg body once daily for 21 days) in collagen-induced arthritic Wistar rats was evidenced with significantly reduced proinflammatory mediators [IL-1β, IL-6, TNF-α, IFN-γ, and PGE 2 ] and increased IL-10 ( Umar et al. , 2012 ).

Immunomodulatory action

The immunomodulatory properties of N. sativa and its major active ingredient, TQ in terms of their experimentally documented ability to modulate cellular and humoral adaptive immune responses ( Table 6 ) have comprehensively been reviewed ( Majdalawieh and Fayyad, 2015 ). The molecular and cellular mechanisms underlying such immunomodulatory effects of N. sativa and TQ are highlighted, and the signal transduction pathways implicated in the immunoregulatory functions are suggested. Experimental evidence suggests that N. sativa extracts and TQ can therapeutically be employed in the regulation of immune reactions in infectious and non-infectious conditions such as allergy, autoimmunity, and cancer.

The potential immunomodulatory effects of aqueous extract of N. sativa investigated in BALB/c mice and C57/BL6 primary cells with respect to splenocyte proliferation, macrophage function, and anti-tumor activity demonstrated that N. sativa significantly enhances splenocyte proliferation in a dose-responsive manner ( Ghonime et al. , 2011 ). Aqueous extract of N. sativa significantly suppressed the secretion of key proinflammatory mediators (IL-6, TNF-α, and NO) by primary macrophages indicating anti-inflammatory effects in vitro . Nigella sativa methanolic extract treatment (intraperitoneal) enhanced the total white blood cells count and increased spleen weight in BALB/c mice, suggesting the immunomodulatory activity of N. sativa seeds ( Ghonime et al. , 2011 ). Treatment with N. sativa oil significantly decreased the antibody production in response to typhoid vaccination (antigen typhoid TH) in a Long-Evans rat model. These results indicated that the N. sativa seeds could be considered as a potential immunosuppressive cytotoxic agent ( Torres et al. , 2010 ). Co-administration of N. sativa (2.5%) with oxytetracycline completely blocked the leukocyte and lymphocyte decreasing effects elicited by oxytetracycline and produced immunostimulant effects in pigeons indicating an immune-protective effect ( Abel-Salam, 2012 ). Nigella sativa oil is also shown to have a promising radioprotective action against immunosuppressive and oxidative effects of γ-radiation in rats ( Assayed, 2010 ). Nigella sativa seed extract significantly improved symptoms and immune parameters in murine ovalbumin-induced allergic diarrhoea in mice ( Duncker et al. , 2012 ).

Antioxidant and antimicrobial activity

An evaluation of the essential oil of N. sativa seeds, for antioxidants, showed that TQ and other components (carvacrol, t -anethole, and 4-terpineol) have a radical scavenging property. These constituents and the essential oil showed variable antioxidant activity when tested in the diphenylpicrylhydrazyl assay; they also effectively scavenged OH radical in the assay for non-enzymatic lipid peroxidation.

TQ has been shown to suppress the ferric nitrilotriacetate-induced oxidative stress in Wistar rats ( Khan and Sultana, 2005 ). Dietary N. sativa seeds inhibited the oxidative stress caused by oxidized corn oil in rats ( Al-Othman et al. , 2006 ). Dietary N. sativa (10%) neutralized the oxidative stress induced by hepatocarcinogens such as dibutylamine and sodium nitrate in albino rats by normalizing glutathione and nitric oxide levels ( Gendy et al. , 2007 ). The N. sativa seed oil and TQ (intraperitoneal) are shown to have protective effects on lipid peroxidation process during ischemia-reperfusion injury in rat hippocampus ( Hosseinzadeh et al. , 2007 ). Treating broiler chicks with N. sativa seed for 6 weeks reduced the oxidative stress in the liver by increasing the activities of myeloperoxidase, glutathione-S-transferase, CAT, adenosine deaminase, and by decreasing hepatic lipid peroxidation ( Sogut et al. , 2008 ). The TQ pre-treatment countered the increased level of lipid peroxidation and augmented the antioxidant enzyme activities in the erythrocyte during 1,2-dimethylhydrazine-induced colon carcinogenesis in Wistar rats ( Harzallah et al. , 2012 ).

The bioactive compounds of N. sativa essential oil identified using GC and GC-MS included p -cymene, TQ, α-thujene, longifolene, β-pinene, α-pinene, and carvacrol. Nigella sativa essential oil exhibited different biological activities including antifungal, antibacterial, and antioxidant potentials. Nigella sativa essential oil completely inhibited different Gram-negative and Gram-positive bacteria ( Morsi, 2000 ). Nigella sativa oil also exhibited stronger radical scavenging activity against DPPḢ radical in comparison with synthetic antioxidants.

Anti-cancer properties

The anti-cancer effect of N. sativa has extensively been studied in different in vitro and in vivo models ( Table 5 ). Nigella sativa is able to exert antioxidant, anti-mutagenic, cytotoxic, pro-apoptotic, anti-proliferative, and anti-metastatic effects in various primary cancer cells and cancer cell lines ( Majdalawieh and Fayyad, 2016 ). The available studies strongly suggest that N. sativa could serve as an effective agent to control tumour initiation, growth, and metastasis independently or in combination with conventional chemotherapeutic drugs.

Anti-cancer effects of black cumin ( Nigella sativa ) seeds.

Nigella sativa extract ameliorated the benz(α-)pyrene-induced carcinogenesis in the forestomach in mice ( Aruna and Sivaramakrishnan, 1990 ). This is partly attributed to the ability to influence phase II enzymes. Orally administered N. sativa oil (14 weeks) interfered with the induction of aberrant crypt foci (ACF) by 1,2-dimethylhydrazine, putative preneoplastic lesions for colon cancer in rats ( Salim and Fukushima, 2003 ). This inhibition may be associated, in part, with the suppression of cell proliferation in the colonic mucosa. Nigella sativa aqueous suspension significantly prevented gastric ulcer formation experimentally induced by necrotizing agents and also significantly ameliorated the severity of ulcer and gastric acid secretion in pylorus-ligated Shay rats ( Al Mofleh et al., 2008 ).

The chemopreventive potential of N. sativa oil on tumour formation has been revealed in a study using a rat multiorgan carcinogenesis model induced by five different carcinogens ( Salim, 2010 ). Post-initiation administration of 1000 or 4000 ppm N. sativa volatile oil in the diet for 30 weeks significantly reduced colon tumour sizes, incidences, and multiplicities. Nigella sativa volatile oil also significantly decreased the incidences and multiplicities of tumours in the lungs and alimentary canal (particularly the oesophagus and forestomach). Thus, N. sativa exerts potential inhibitory effects on tumour development in multiple organ sites ( Salim, 2010 ). Nigella sativa oil (orally administered for 3 days) decreased the proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in the blood of rats with experimental colitis induced with trinitrobenzene sulfonic acid ( Isik et al. , 2011 ). Nigella sativa oil, by preventing inflammatory status in the blood, partly protected colonic tissue against experimental ulcerative colitis. Oral TQ (1–10 mg/kg) or N. sativa oil (thrice in a week for 4 months) exerted a protective effect against breast cancer in female rats induced by 7,12-dimethylbenz[α-]anthracene as revealed by tumour markers, histopathological alterations, and the regulation of several genes (Brca1, Brca2, Id-1, and P53 mutation) related to breast cancer ( Linjawi et al. , 2015 ).

Acute lymphoblastic leukaemia (ALL) is a common childhood malignancy and is conventionally treated with methotrexate which also produces hepatotoxicity. The therapeutic value of N. sativa oil in methotrexate-induced hepatotoxicity has been assessed in 40 Egyptian children with ALL under methotrexate therapy ( Hagag et al. , 2015 ). Nigella sativa oil (80 mg/kg/day for 1 week) produced significant differences in remission, relapse, death, and disease-free survival. Nigella sativa seeds decreased methotrexate hepatotoxicity and improved survival. This report is suggestive of its application as an adjuvant drug in patients under methotrexate therapy.

Nigella sativa seed oil and TQ have been understood to exert antioxidant and chemopreventive properties ( Allahghadri et al. , 2010 ). TQ could suppress tumour cell proliferation in the case of breast adenocarcinoma, pancreatic carcinoma, colorectal carcinoma, osteosarcoma, ovarian carcinoma, and myeloblastic leukaemia ( Allahghadri et al. , 2010 ). The cancer chemopreventive ability of TQ has been explained by its ability to modulate cell division in cancer cells, involving downregulation of Bcl-xL, cyclin D1, and VEGF ( Aggarwal et al. , 2008 ). TQ is reported to be effective in inhibiting human umbilical vein EC migration and invasion, suggesting its role in angiogenesis ( Gali-Muhtasib et al. , 2006 ). TQ is shown to prevent tumour angiogenesis in a xenograft human prostate cancer (PC-3) model ( Yi et al. , 2008 ). Nigella sativa , its oil, and TQ are effective against cancer in the blood system, lung, kidney, liver, prostate, breast, cervix, and skin. Some studies attribute the anti-cancer effect of TQ to its role as an antioxidant, ability to improve body’s immune system, and ability to induce apoptosis and control Akt pathway ( Khan et al. , 2011 ).

The cytotoxic effects of N. sativa seed extract as an adjuvant therapy to doxorubicin on human MCF-7 breast cancer cells are reported. Nigella sativa lipid extract was found to be cytotoxic to MCF-7 cells with LC 50 of 2.7 mg/ml, whereas its aqueous extract exhibited cytotoxicity at about 50 mg/ml ( Mahmoud and Torchilin, 2012 ). TQ was found to be cytotoxic to human cervical squamous carcinoma cells (SiHa) with IC 50 values of 10.7 µg/ml as determined by MTT assay, whereas it was less cytotoxic towards the normal cells. Cell cycle analysis indicated induction of apoptosis by the compound and elimination of SiHa cells via apoptosis with down-regulation of the Bcl-2 protein ( Ng et al. , 2011 ). An investigation of the anti-tumour and anti-angiogenic effects of TQ on osteosarcoma in vitro and in vivo showed that TQ induced higher growth inhibition and apoptosis in the human osteosarcoma cell line SaOS-2. TQ significantly blocked human umbilical vein endothelial cell tube formation in a dose-dependent manner. The anti-tumour and anti-angiogenic activity of TQ in osteosarcoma is possibly mediated by inhibition of NF-κB and downstream effector molecules ( Peng et al. , 2013 ).

TQ exerted a strong anti-proliferative effect in breast cancer cells via its potential effect on the PPAR-γ activation pathway, and in combination with doxorubicin and 5-fluorouracil, TQ’s cytotoxicity was found to be increased. Migration and invasion of MDA-MB-231 cells were also reduced by TQ, which was found to increase PPAR-γ activity and down-regulate the expression of Bcl-2, Bcl-xL, and survivin in breast cancer cells ( Woo et al. , 2011 ). An investigation of the effect of TQ on pancreatic cancer cells and on MUC4 expression revealed down-regulated MUC4 expression and induced apoptosis in pancreatic cancer cells. The decrease in MUC4 expression was accompanied by increased apoptosis, decreased motility, and decreased migration of pancreatic cancer cells ( Torres et al. , 2010 ).

The administration of N. sativa reduced the carcinogenic effects of DMBA in mammary carcinoma which indicated its protective role in mammary carcinoma ( Shafi et al. , 2008 ). TQ dose-dependently suppressed the migration and invasion of Panc-1 cells. TQ also significantly down-regulated NF-kB and MMP-9 in Panc-1 cells. Administration of TQ significantly reduced tumour metastasis. Furthermore, the expression of NF-kB and MMP-9 protein in tumour tissues was down-regulated after treatment with TQ, thus exerting anti-metastatic activity on pancreatic cancer both in vitro and in vivo ( Wu et al. , 2011 ). The chemo-sensitizing effect of TQ and 5-fluorouracil (5-FU) on gastric cancer cells both in vitro and in vivo is reported ( Lei et al. , 2012 ). Pre-treatment with TQ significantly increased the apoptotic effects induced by 5-FU in gastric cancer cell lines in vitro . The combined treatment of TQ with 5-FU was more effective in anti-tumour action than either of them individually in a xeno-graft tumour mouse model. The TQ/5-FU-combined treatment induces apoptosis by enhancing the activation of both caspase-3 and caspase-9 in gastric cancer cells ( Lei et al. , 2012 ).

In summary, N. sativa oil and TQ are found to inhibit experimental carcinogenesis in different animal models. It has been shown to arrest the growth of various cancer cells in culture as well as xenograft tumours in vivo . The mode of anticancer effects of TQ includes inhibition of carcinogen-metabolizing enzyme activity and oxidative damage to cellular macromolecules, amelioration of inflammation, inhibition of cell cycle and apoptosis in tumour cells, inhibition of tumour angiogenesis, and suppression of migration, invasion, and metastasis of cancer cells. TQ improves anti-cancer effects when combined with conventionally used chemotherapeutic agents. At the molecular level, TQ targets intracellular signalling pathways, particularly a variety of kinases and transcription factors, which are activated during tumourigenesis.

Gastroprotective effect

Nigella sativa oil and its constituents are proved to exert gastroprotective effect ( Table 7 ); some of the potential mechanisms exhibited by N. sativa in preventing or curing gastric ulcers are reviewed recently ( Khan et al. , 2016 ). The mechanism of gastroprotective effect of TQ has been assessed in rats injected with TQ (10 and 20 mg/kg) and subsequently subjected to ischemia or reperfusion insult. TQ restored the altered acid secretion, gastric mucosal content, lipid peroxide, and the activity of myeloperoxidase, reduced glutathione, and total nitric oxide along with ulcer index, the efficacy being comparable with that of the reference drug omeprazole. TQ exerted gastroprotection via inhibiting proton pump, acid secretion and neutrophil infiltration, while enhancing mucin secretion, and nitric oxide production, in addition to the antioxidant influences ( Magdy et al. , 2012 ).

Gastroprotectove, hepatoprotective, nephroprotective, and pulmonary-protective effects of black cumin ( Nigella sativa ) seeds.

The anti-ulcer potential of N. sativa aqueous suspension on gastric ulcers experimentally induced with various noxious chemicals (indomethacin, 80% ethanol, and 0.2 M NaOH) in Wistar rats was examined ( Al Mofleh et al. , 2008 ). Nigella sativa significantly prevented gastric ulcer formation induced by necrotizing agents by significantly replenishing the depleted gastric wall mucus content and gastric mucosal non-protein sulfhydryl concentration. The anti-ulcer effect of N. sativa was exerted through its antioxidant and anti-secretory activities ( Al Mofleh et al. , 2008 ). Both N. sativa (2.5 and 5.0 ml/kg, p.o.) and TQ (5, 20, 50, and 100 mg/kg, p.o.) were found to possess gastro-protective activity against gastric mucosal injury induced by ischemia or reperfusion in Wistar rats ( El-Abhar et al. , 2003 ). Lipid peroxidation and lactate dehydrogenase, elevated by the ischemia or reperfusion insult and decreased glutathione and activity of SOD accompanied by an increased formation of gastric lesions, were countered by N. sativa or TQ treatment, indicating their gastroprotective effect, probably by conservation of the gastric mucosal redox state.

Nigella sativa and TQ are reported to protect gastric mucosa against the ulcerating effect of alcohol on hypothyroidal rats and mitigate most of the biochemical adverse effects on gastric mucosa, viz., increase in lipid peroxidation and reduced gastric glutathione content, and enzyme activities of gastric SOD and GST ( Khaled, 2009 ). The beneficial effect of N. sativa oil (2 ml/kg daily, i.p.) in rats with necrotizing enterocolitis (NEC) was studied in newborn Sprague-Dawley rats ( Tayman et al. , 2012 ). Histopathologic and apoptosis evaluation indicated that the bowel damage was less severe in the N. sativa oil–treated group. Nigella sativa oil had a beneficial preserving effect on tissue antioxidant enzymes, whereas lipid peroxide levels were significantly lower than those in the NEC control group. In a mouse model of inflammatory bowel disease (C57BL/6 murine colitis induced with dextran sodium sulfate), treatment with TQ (5, 10, or 25 mg/kg) ameliorated colonic inflammation ( Lei et al. , 2012 ). The treatment of mice with TQ prevented and reduced the occurrence of diarrhoea and body weight loss, associated with amelioration of colitis-related damage. Also, there was a significant reduction in colonic myeloperoxidase activity and malondialdehyde levels and an increase in glutathione levels ( Lei et al. , 2012 ).

Nephroprotective effect

The nephroprotective effect of N. sativa oil is observed in gentamicin-induced nephrotoxicity in rabbits ( Saleem et al. , 2012 ) ( Table 7 ). Vitamin C and N. sativa oil when given as combination showed a synergistic nephroprotective effect ( Saleem et al. , 2012 ). Oral treatment of N. sativa oil (0.5, 1.0, or 2.0 ml/kg/day for 10 days) produced a dose-dependent amelioration of gentamycin-induced nephrotoxicity in rats as assessed by the biochemical and histological indices of nephrotoxicity ( Ali, 2004 ). The protective effect of N. sativa oil on methotrexate-induced nephrotoxicity has been reported in albino rats which is medicated through restoring the antioxidant status ( Abul-Nasr et al. , 2001 ; Yaman and Balikci, 2010 ). The protective effects of N. sativa oil in the prevention of chronic cyclosporine A-induced nephrotoxicity in rats were evidenced by attenuation of the oxidative stress ( Uz et al. , 2008 ). TQ supplementation prevented the development of gentamycin-induced degenerative changes in kidney tissues and cisplatin-induced renal injury in rats as indicated by lipid peroxides and renal organic anion and cation transporters ( Sayed-Ahmed and Nagi, 2007 ; Ulu et al. , 2012 ). Nigella sativa significantly prevented renal ischemia- or reperfusion-induced functional and histological injuries in Wistar rats ( Mousavi, 2015 ). Nigella sativa showed protective effects against ischemia-perfusion damage on kidney tissue based on the total antioxidant capacity, oxidative status index, and activities of catalase and myeloperoxidase in the kidney tissue ( Yildiz et al. , 2010 ).

Hepatoprotective effect

It is reported that N. sativa (i.p. 0.2 ml/kg) relieves the deleterious effects of ischemia-reperfusion injury on liver in rats, as indicated by titers of marker enzymes, total antioxidant capacity, total oxidative status, and myeloperoxidase in the liver tissue ( Yildiz et al. , 2008 ) ( Table 7 ). The protective effect of TQ on the Cd ++ -induced hepatotoxicity in mice, particularly the perturbation of non-enzymatic and enzymatic antioxidants, has been reported ( Zafeer et al. , 2012 ). Pre-treatment with TQ (10 µmol/l) showed a significant protection as indicated by an attenuation of protein oxidation and recovery of the depleted antioxidants, suggesting that TQ exerts modulatory influence on the antioxidant defence system when subjected to toxic insult.

Pulmonary-protective activity and anti-asthmatic effects

Nigella sativa has been investigated for the possible beneficial effects on experimental lung injury in rats after pulmonary aspiration ( Kanter, 2009 ) ( Table 7 ) and found that N. sativa treatment inhibits the inflammatory pulmonary responses. Nigella sativa therapy resulted in a significant reduction in the activity of iNOS and an increase in surfactant protein D in the lung tissue of different pulmonary aspiration models. It is concluded that N. sativa treatment might be beneficial in lung injury that merits potential clinical use. The ameliorative effect of N. sativa oil in rats with hyperoxia-induced lung injury has also been reported ( Tayman et al. , 2012 ).

The prophylactic effect of an extract of N. sativa (15 ml/kg of 0.1 g% boiled extract for 3 months) has been examined in asthmatic adults. All asthma symptoms, the frequency of symptoms, chest wheezing, and pulmonary function tests (PFT values) were significantly improved as a result of N. sativa treatment, generally suggesting a prophylactic effect on asthma disease ( Boskabady et al. , 2007 ). TQ potently and dose-dependently inhibited the formation of leukotrienes—supposedly important mediators in asthma and inflammatory processes, in human blood cells ( Mansour and Tornhamre, 2004 ).

During the last three decades, several in vitro and in vivo animal studies have ascertained the pharmacological properties of N. sativa , including its antioxidant, antibacterial, anti-proliferative, proapoptotic, anti-inflammatory, and antiepileptic properties, and its beneficial effect in conditions of atherogenesis, endothelial dysfunction, glucose dyshomeostasis, and disrupted lipid metabolism. Nigella sativa and its constituents are found to have antioxidant, antidiabetic, anti-inflammatory, and anti-tumour properties as well as therapeutic effects on metabolic syndrome, and gastrointestinal, neuronal, cardiovascular, and respiratory disorders in clinical trials ( Gholamnezhad et al. , 2016 ). Experimental and clinical studies have evidenced therapeutic effects of N. sativa seed extracts, oil, and TQ on different disorders. Standard clinical trials are however needed for N. sativa supplementation for its promotion as an adjuvant therapy.

Long-term administration of N. sativa increased brain serotonin levels and improved learning ability and memory in rats ( Perveen et al. , 2008 ). Chronic administration of N. sativa decreased serotonin turnover and produced anxiolytic effects in rats. Tryptophan concentration in brain and plasma also increased significantly following repeated oral administration of N. sativa oil, suggesting that this oil is useful for the treatment of anxiety ( Perveen et al. , 2009 ). Anti-anxiety-like effects of TQ (20 mg/kg) was observed in mice, which involved modulation of GABA and NO levels. The anxiolytic effect was accompanied by a significant decrease in plasma nitrite and countering of decreased γ-aminobutyric acid content in the brain ( Gilhotra and Dhingra, 2011 ). The neuroprotective effects of the aqueous extract of N. sativa have been recorded during cerebral ischemia in rats; this could be resulting from its free radical scavenging, antioxidant (elevation in reduced glutathione, SOD, and catalase (CAT) activities), and anti-inflammatory properties ( Akhtar et al. , 2012 ).

The incidence of kidney stone may increase the vulnerability of patients to renal failure. Nigella sativa and its main bioactive component—TQ showed positive effects on the prevention or dissolution of kidney stones and renal failure. This involves antioxidative, anti-inflammatory, and immunomodulatory effects. Thus, N. sativa and its components are beneficial in the prevention and curing of nephrolithiasis and renal damages ( Hayatdavoudi et al. , 2016 ).

A number of therapeutic influences of N. sativa and TQ have been scientifically investigated. This includes antidiabetic, anti-allergic, anti-microbial, immune-modulatory, anti-inflammatory, and anti-tumour effects ( Figure 4 ). Nigella sativa and TQ also possess gastro-protective, hepatoprotective, nephroprotective, and neuroprotective activities. The scientific studies conducted so far have confirmed the pharmacological potential of N. sativa seeds, its oil, extracts, and its active principles, particularly TQ. TQ is the most abundant constituent of the volatile oil of N. sativa seeds, and most of the medicinal properties of N. sativa are attributable mainly to TQ. All the available evidence suggests that TQ should be developed as a drug or adjuvant in clinical trials. Nigella sativa seeds, its oil, and constituents like TQ could be used in suitable combinations with conventional therapeutic agents for maximizing the effectiveness in the treatment of many infectious diseases and also to circumvent the drug resistance problem. Further investigations are recommended to explore the specific cellular and molecular targets of various constituents of N. sativa , particularly TQ.

Multiple medicinal properties of Nigella sativa (black cumin seeds).

Multiple medicinal properties of Nigella sativa (black cumin seeds).

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International Journal of Phytomedicine and Phytotherapy

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  • Published: 12 December 2018

The phytochemistry and medicinal value of Psidium guajava (guava)

  • Sumra Naseer 1 ,
  • Shabbir Hussain   ORCID: orcid.org/0000-0002-6979-5687 1 ,
  • Naureen Naeem 2 ,
  • Muhammad Pervaiz 3 &
  • Madiha Rahman 4  

Clinical Phytoscience volume  4 , Article number:  32 ( 2018 ) Cite this article

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Psidium guajava (guava) is well known tropic tree which is abundantly grown for fruit. Many countries have a long history of using guava for medicinal purposes. This plant finds applications for the treatment of diarrhea, dysentery, gastroenteritis, hypertension, diabetes, caries and pain relief and for improvement in locomotors coordination. Its leaf’s extract is being used as a medicine in cough, diarrhea, and oral ulcers and in some swollen gums wound. Its fruit is rich in vitamins A, C, iron, phosphorus and calcium and minerals. It contains high content of organic and inorganic compounds like secondary metabolites e.g. antioxidants, polyphenols, antiviral compounds, anti-inflammatory compounds. The phenolic compounds in guava help to cure cancerous cells and prevent skin aging before time. The presence of terpenes, caryophyllene oxide and p -selinene produces relaxation effects. Guava leaves contain many compounds which act as fungistatic and bacteriostatic agents. Guava has a high content of important antioxidants and has radio-protective ability. Quercetin is considered as most active antioxidant in the guava leaves and is responsible for its spasmolytic activity. Its ethyl acetate extract can stop the germ infection and thymus production. Guava possesses anti-viral, anti-inflammatory, anti-plaque and anti-mutagenic activities. Guava extract shows antinociceptive activity and is also effective in liver damage inflammation and serum production. Ethanolic extract of guava can increase the sperm quality as well as quantity and can be used for the treatment of infertile males.

Psidium guajava (common name-guava) is well known tropic tree which is abundantly grown for fruit. It belongs to phylum Magnoliophyta, class Magnoliopsida and Myrtaceae family [ 1 ]. It has about 133 genera and more than 3,800 species. Psidium guajava and it’s all parts have an old history of medicinal value [ 2 ]. The plant is well known by a common name “Guava” in English, guayabo in Spanish, goyaveandgoyavier in French, guyabaorgoeajaab in Dutch, goiaba and goaibeira in Portuguese and jambubatu in Malaya. Pichi, posh and enandi are the names commonly used in Mexico and America [ 3 ]. Guava plant grows widely in the tropic areas because it is a plant that can be grown on a big range of soils [ 4 ]. In Mexico guava is one of very important crop which is cultivated over 36,447 acres and production is about 192,850 tons. According to records the first money-making guava planting was reputable around 1912 in Florida at Palma Sola [ 3 ].

Psidium guajava is an evergreen shrub like tree which reaches to the height of 6 to 25 ft’s. Figure  1 displays various parts of the plant i.e., leaves, flowers, fruit, seeds and bark.

figure 1

Various parts of guava ( a ) Leaves ( b ) Flowers ( c ) Fruit ( d ) Seeds in the fruit ( e ) Bark

The plant has a wide spreading network of branches. Mostly its branches are curved which display opposite leaves with the small petioles of about 3 to 16 cm. The leaves are wide and clear green in color and have clear and prominent veins [ 5 , 6 ]. The plant produces white flowers with incurved petals having a nice fragrant. Flowers have four to six petals and yellow colored anthers and pollination occurs by the insects. Guava fruit ranges from small to medium sized with 3 to 6 cm length. It has pear like shape and yellow color in ripen condition [ 7 ]. It has a musky special odor when ripened which is strong but pleasant [ 3 ]. Its pulp is slightly darker in color which contains slightly yellowish seeds. The size of seeds is very small and they are easily chewable. They are arranged in regular patterns; their number ranges from 112 to 535 [ 3 , 8 ]. The guava bark is thin and has green colored spots. It is very easy to remove it in long straps. It has a huge content of antimicrobial and antibacterial compounds [ 9 ]. Ethanolic extracts of stem have a high anti-diabetic activity [ 10 , 11 ]. Guava contains a large number of antioxidants and phytochemicals including essential oils, polysaccharides, minerals, vitamins, enzymes, and triterpenoid acid alkaloids, steroids, glycosides, tannins, flavonoids and saponins [ 12 ]. Guava contains a higher content of vitamin C and vitamin A. Guava is also a very good source of the pectin which is an important dietary fiber. It has high content of flavonoids [ 7 ], fructose sugar [ 13 ] and carotenoids [ 14 ]. Keeping in view the historical background, important ingredients and common uses of Psidium guajava (guava), current studies focus on the phytochemistry and medicinal value of this useful plant.

Chemical composition of guava

The guava fruit contains vitamin A, C, iron, phosphorus and calcium. It has more vitamin C than the orange. The fruit contains saponin, oleanolic acid, lyxopyranoside, arabopyranoside, guaijavarin, quercetin and flavonoids [ 5 , 7 , 15 ]. Ascorbic acid and citric acid are the major ingredients of guava that play important role in anti-mutagenic activity [ 16 ]. The chemical structures of quercetin and ascorbic acid have been shown in Fig.  2 .

figure 2

a Chemical structure of quercetin (b) Chemical structure ofascorbic acid

The skin of fruit contains ascorbic acid in very high amount; however, it may be destroyed by heat. The strong pleasant smell of fruit is credited to the carbonyl compounds [ 15 ]. Guava fruit contains terpenes, caryophyllene oxide and p-selinene in large quantity which produce relaxation effects [ 17 ]. The flavonoid content is higher in the methanolic extract of the guava [ 18 ]. There are 41 hydrocarbons 25 esters, 13 alcohols and 9 aromatic compounds in guava [ 19 ]. Titratable acidity and the total soluble solids are present in fruit [ 20 ]. Guajadial is also present in guava [ 21 ].

Essential oil is present in leaves which contain α-pinene, limonene, β-pinene, isopropyl alcohol, menthol, terpenyl acetate, caryophyllene, longicyclene and β-bisabolene. Oleanolic acid is also found in the guava leaves [ 22 ]. Leaves have high content of limonene about 42.1% and caryophyllene about 21.3% [ 23 ]. Leaves of guava have a lot of volatile compounds [ 24 , 25 ].

The bark includes 12–30% of tannin and one source declares that it includes tannin 27.4%, or polyphenols, resin and the crystals of calcium oxalate. Tannin is also present in roots. Leukocyanidins, gallic acid and sterols are also present in roots. Carbohydrates with salts are present in abundance. Tannic acid is also its part.

Medicinal importance of guava

Psidium guajava L. is consumed not only as food but also as folk medicine in subtropical areas all over the world due to its pharmacologic activities [ 26 ]. Medicinal plants find a very important place in medical systems almost in the entire world. These observations are reflected from traditional knowledge. It is well known that guava is frequently employed in numerous parts of the world for the cure of a lot of sickness like diarrhea reducing fever, dysentery, gastroenteritis, hypertension, diabetes, caries, pain relief and wounds. The countries which have a long history of using medicinal plants are also using guava at big level like Mexico, Africa, Asia and Central America. With its medicinal uses it is also used as food and in the preparation of food products. It is also used in house construction and toys making. Guava contains high content of organic and inorganic compounds like secondary metabolites e.g. antioxidant, polyphenols, antiviral compounds and anti-inflammatory compounds. Guava has a lot of compounds which have anti cancerous activities. It has a higher number of vitamins and minerals. Phenolic compounds like flavonoids also find an important place in the guava. Lycopene and flavonoids are important antioxidants. They help in the cure of cancerous cells and help to prevent skin aging before time [ 27 ]. Guava can affect the myocardium inotropism [ 28 ]. Guava skin extract can control level of diabetes after 21 days treatment [ 29 ].

Antimicrobial activity

Guava has a high antimicrobial activity. Guava leaf’s extract doses can reduce the amount of cough due to its anti-cough activity. Aqueous, chloroform and methanol extract of leaves can reduce the growth of different bacteria. Due to its anti-cough activity it is recommended in the condition of cough [ 30 ].

Guava leaves have high antibacterial activity in extracts that can inhibit the growth of S. aureus . Plant leaf and bark methanolic extracts of P. guajava have high antimicrobial activity. These extracts can inhibit the Bacillus and Salmonella bacteria [ 31 ]. Methanolic extract of guava contains a remarkable antimicrobial activity. Species of Bacillus and Salmonella bacteria can be controlled by these extracts. It also has anti-plaque activity due to the presence of active flavonoids compounds [ 32 ].

The flavonoid compounds and their derivatives can be isolated from the guava. These compounds can inhibit the growth of different bacteria in different dilutions. Terpinene and pinene are present into the aqueous extract of plant’s leaves which shows antimicrobial activity. Due to bacteriostatic effects on pathogenic bacteria it is also used as medicine in cough, diarrhea, oral ulcers and in some swollen gums wound [ 1 , 33 ].

Aqueous and ethanol extracts show low antimicrobial activity or minimum inhibitory concentration (MIC) whenever methanol extract shows high MIC. Due to it high activity methanolic extract is most effective. This extract also displays anti hemolytic potential as it shows activity against hemolysis [ 34 ]. The antibacterial activity of guava is high against gram positive bacteria and moderate against the gram negative bacterial strains [ 35 ]. In 2012 it was reported that guava leaves have many compounds which act as fungistatic and bacteriostatic agents. They can stop the growth of a lot of bacteria and act as anti-viral agents. They can control the viral infections like influenza virus. They can hold and occupy the viral resistance. The actual reason of guava anti-viral activity is protein degradation ability of the guava extract [ 36 ]. Essential oil of guava also has activity against the Salmonella and S. aureus [ 37 ]. Guava also possesses anticancer and antioxidant activities. There are a lot of compounds like Gallic acid, galangin, kaempferol, homogentisic acid and cyanidin 3-glucoside which are found in peels, seeds and pulp of guava. But it is surprising that the amount of these compounds is high in seeds and skin as compared to the pulp. Due to the presence of these compounds guava’s food importance becomes high [ 38 ]. It is very clear that aqueous and methanol extract of the guava leaves inhibit the growth of bacteria and can produce a remarkable zone of inhibition. The extracts in methanol and water show maximum MIC whenever ethanol extract shows minimum anti-fungal activity. Conclusively leaves, seeds, skin and pulp of guava have a remarkable anti-microbial activity [ 39 ].

The antimicrobial activities of alcohol fruit extracts from guava ( Psidium guajava ) were compared to those of pineapple ( Ananas comosus) and apple ( Malus pumila ). Eight bacterial strains including Pseudomonas aeruginosa, Klebsiella, Enterococcus faecalis, Shigella flexineri, Enterobacter cloacae, Enterotoxigenic E.coli (ETEC), Enteroaggregative E.coli (EAEC) and Staphylococcus aureus were used for antimicrobial evaluations. The fresh fruits of the above mentioned plants were purchased from the market; then they were cut into small cubes and finally dried over 4–5 days in sun to a crisp. The pieces were blended to the fine powder; finally methanol extracts were obtained by passing 75 g of each powder through a Soxhlet apparatus having 250 ml of 99% methanol. The same process was performed with 250 ml of ethanol to produce a methanolic crude extract. The sample extracts were evaluated using agar well diffusion method. Norfloxacin and water were used as positive and as negative controls, respectively. The extracts caused the inhibition of microbes; the zones of inhibition were measured and an activity index was calculated from the mean zone sizes. It was concluded that all the fruits possess some antimicrobial potential; the highest activity index (2.6) was observed from pineapple extracts against EAEC . The pineapple fruit displayed strong potential against all the bacteria. The guava extracts possessed the antimicrobial potential against all the microbes with the exception of ETEC . The methanolic and ethanolic extracts of apple were found active only against EAEC And Staph. Aureus . The methanolic extracts of guava and apple were found active as compared to the ethanolic extracts while the ethanolic extracts of pineapple showed slightly larger inhibition zones. The results of this investigation show great promise for potential antimicrobial drugs [ 40 ].

The antimicrobial potential of guava can be compared to that of similar commonly used fruit like pomegranate which have been found to possess high antimicrobial properties [ 41 ]. The antimicrobial activity of various extracts prepared from pomegranate fruit peels were evaluated using both in-vitro agar diffusion and in-situ methods against some food-borne pathogens. It was found that 80% methanolic extract of peels was a potent inhibitor for Yersinia enterocolitica, Listeria monocytogenes, Staphyllococcusaureus and Escherichia coli . And the presence of active inhibitors in peels including phenolics and flavonoids were revealed by phytochemical analysis as potent constituents. The study suggested that the various extract of pomegranate can successfully control various kinds of human pathogenic bacteria [ 42 ].

There is a growing trend to use the medicinal plants as the natural resources in order to develop new drugs. The natural products are applied to treat various viral, fungal and bacterial diseases. The genus citrus is well known for its pharmaceutical importance. The peel extracts of Dargiling Orange (C8), South African Malta (C5), Kagja Lemon (C2), Batabi Lemon (C4), Elachi Lemon (C3), Kagja Lemon (C2) and Kagji Lemon (C1) show excellent antimicrobial potential against various bacterial strains e.g., B. cereus , S. aureus etc [ 43 ]. The antimicrobial activities of peels extract of two Citrus fruits viz., Citrus aurantium and Citrus sinensis were evaluated. The peels of the fruits were separated, shade dried, powdered and extracted using methanol; finally the peel extracts were subjected to test their antifungal and antibacterial activities by poisoned food technique and agar well diffusion assay, respectively. The extracts were found effective against the tested fungal and bacterial strains. It was concluded that the peel extracts of selected citrus fruits can be used to control anthracnose of chilli caused by C. capsici and against infectious agents [ 44 ]. Eating fruits is very important to reduce the pressure of antibiotics; the fruits are also relatively cheaper and readily available and could greatly help the people [ 40 ].

Antidiarrheal activity

Diarrhea is one of most common and well recognized health problem and a global issue. It is very common even in developed countries. It is estimated that about 2.2 million people die annually by diarrhea; most of them, are children or infants [ 45 ].

Guava leaves have quercetin-3-arabinoside and quercetin which can be isolated from leaves. Its leaves contain a compound which has morphine like action. It controls the muscular tone. Quercetin repressed intestinal contraction encouraged by enhanced absorption of calcium. Quercetin has a strong effect on ileum. It is thought that quercetin in guava leaf are responsible for its spasmolytic activity. Guava has high cytotoxicity [ 46 ]. Guava can be used to treat the diarrhea caused by the E. coli or S. aureus toxins [ 47 ]. Ethanolic and aqueous extracts of Psidium guajava at a concentration of 80 g/ml in an organ bath, display more than 70% embarrassment of acetylcholine and/or KCl solution-induced reduction of isolated guinea- pig ileum. The rates of impulsion in the small intestine into male Sprague Dawley rats as it means of evaluate anti-diarrhoeal activity of the aqueous extracts of leaf of Psidium guajava using morphine like the standard drug for reference was measured [ 48 ]. Locomotor coordination can be improved by the ethyl acetate extract of guava fruit [ 49 ].

Ojewole 2008 examined anti-diarrheal activity of guava leaves extract in water provoked diarrhea in the rodents. This extract produces important protection to rats and the mice in opposition to castor oiled induced diarrhea. It inhibits the intestinal transit in rats. The activity of this extract is dose dependent. Atropine dose have significant anti motility effect due to which castor oil-induced diarrhea is inhibited. Loperamide dose significantly delays the onset of the castor oil-induced diarrhea. By comparison of animals it was noticed that intestinal fluid secretion is reduced significantly. Guava extract have anti diarrhoeal activity and it can be used for the treatment and prevention of diarrhaea [ 50 ]. Guava have significant antidiabetic and antidiarrhoeal activities in ethanolic extracts [ 51 , 52 ].

Anti-inflammatory activity

Extract of guava in ethyl acetate can stop the germ infection and thymus production. It can act as anti-viral agent. It can enhance the mRNA expression. Guava can alter the heme oxygenase-1 protein’s work. And due to this reason, it can be used as anti-inflammatory agent for skin. Extract of guava in ethanol inhibit the lipopolysaccharide from manufacturing of nitric oxide. It suppresses the expression of E2. In this way it works as anti-inflammatory agent [ 53 ].

Extract in ethyl acetate has the ability to minimize the antigen. It can stop the release of the β-hexosaminidase with histamine into RBL-2H3 cells. Due to this reason the appearance of TNF-α and IL-4 mRNA stops. In this way the antigen inhibits and IκB-α become spoil. Benzophenone and flavonoids are important compounds found in guava. These compounds are responsible for the histamine inhibition and nitric acid production [ 54 ].

Guava extract also show anti-nociceptive activity. It happened by acetic acid production. Phenol is an important compound which is present in guava and dependable for the anti-allergic and anti-inflammatory activity [ 55 ]. The dose of guava extracts are effective in liver damage inflammation and serum production [ 56 ].

Antioxidant activity

Antioxidants are molecules which retard the oxidation process. The oxidation reactions may produce free radicals which damage the cells by starting various chain reactions. Free radicals which damage the cells cause cancer and many other diseases. Antioxidants terminate the free radicals and stop the chain reactions. Examples of antioxidants include beta-carotene, lycopene, vitamins C, E, and A and other substances. Oxidative reaction is one of most important destructive reaction. Free radical’s damage is responsible for a lot of disorders in human like nervous disorders, inflammation, debates and viral infections. When drugs are metabolized in body the free radicals are produced. Sometimes the environmental changes and hormones become the reason of free radical production. These free radicals are responsible for all the oxidation reactions [ 57 ].

Guava contains high amount of antioxidants and anti-providing nutrients which are essential not only for life but also help to control the free radical activities. It also have a variety of phytochemicals which are beneficial for human health like diabetes, obesity and high blood pressure. There are two common methods by which antioxidants neutralize free radicals that is DPPH and FRAP assay. Extracts of guava in water and organic solvents have a large quantity of antioxidants which can stop the oxidation reaction. The concentration of these compounds become high with the increase in concentration [ 58 ]. Pink guava also has a high antioxidant activity [ 59 ].

Guava is highly rich in antioxidants which are helpful in decreasing the incidences of degenerative diseases such as brain dysfunction, inflammation, heart disease, cancer, arteriosclerosis and arthritis [ 60 ]. In fruits, the most abundant oxidants are polyphenols and ascorbic acid. The polyphenols are mostly flavonoids and are mainly present in glycoside and ester forms [ 61 ]. The free elagic acid and glycosides of apigenin and myricetin and are found to be present in guava [ 62 ].

Guava extracts in organic solvent influence the sperm production. It can increase the sperm concentration due to the presence of antioxidants. Ethanolic extract can increase the sperm quality and quantity. So, it can be used for the treatment of infertile males. Leaves of guava also have high content of antioxidants which can be separated in extracts. Ascorbic acid an important antioxidant, is present in leaves in excess [ 58 , 63 ]. Guava has a high content of protocatechuic acid, quercetin, ferulic acid, ascorbic acid, quercetin, gallic acid and caffeic acid which are important antioxidants. Some studies says that guava has radio-protective ability with antioxidant activity [ 4 , 58 ].

DPPH method shows that the guava has remarkable antioxidantcontents and these antioxidants dose not damage the human neutrophils. Extracts in different solvents shows that antioxidant activity of guava depends upon phenolic compounds rather than flavonoids. Methanol and aqueous extraction shows maximum activity [ 64 , 65 , 66 ]. Ethanolic extract of guava shows low activity in all antioxidant assays like DPPH and FRAP assay [ 67 ]. Due to antioxidant activity of guava it can control the diabetes. It shows a significant diabetic control in mice [ 68 ].

Quercetin, quercetin-3-O-glucopyranoside and morin can be isolated from leaves. These compounds show the anti-oxidant activity. Quercetin has free radical balancing activity. Its reducing power is much higher than all other compounds. It is considered as most active and strong antioxidant in the leaves of guava [ 69 , 70 ].

A comparison was made between the antioxidant properties of convection oven-dried and fresh guavas. Convection oven-drying was resulted to retain most of the total phenolic contents (TPC), ascorbic acid equivalent antioxidant capacity (AEAC) and ferric reducing power (FRP) assay of guava. However, the drying resulted in a significant decrease of AEAC, TPC and FRP [ 71 ].

The antioxidant contents and activities of two different varieties of guava fruit were assessed; the results were based on the ability to scavenge DPPH of the fruit extracts in 50% ethanol, to bind to Fe(II) ion and to reduce Fe(III) to Fe(II). The results were compared with similar analyses of several other local fruits like orange, water apple, sugar apple, star fruit, dragon fruit and banana. It was found that the guava fruit is relatively rich in antioxidants. It demonstrates higher primary antioxidant potential as compared to the other fruits e.g. orange, however it displays lower secondary antioxidant potential. When guava fruit is stored at at 4 °C then increase in ascorbic acid content has been observed. The total phenol and ascorbic acid contents are higher in non-peeled fruit as compared to the peeled fruit. The banana was suggested as a powerful secondary antioxidant, however, it is weaker than orange as a primary antioxidant [ 72 ].

The antioxidative potential of guava extracts has rendered a new therapeutic path against the various complications and diseases. Further investigations are required in this regard to find the actual mechanism involved in antioxidant and other pharmacological activities of guava [ 73 ].

Conclusions

Psidium guajava (guava) is well known tropic tree grown in tropic areas for fruit. It is found to be effective in diarrhea, dysentery, gastroenteritis, hypertension, diabetes, caries, pain relief, cough, oral ulcers and to improve locomotors coordination and liver damage inflammation. Its skin contains a lot of phytochemicals in intuits fruit which is rich in vitamins (A & C), iron, phosphorus and calcium and minerals. The phenolic compounds in guava help to cure cancerous cells and prevent skin aging before time. The leaves contain many fungistatic and bacteriostatic agents and important oxidants. Its ethyl acetate extract contains quercetinwhich can stop the germ infection and thymus production. Guava possesses anti-viral, anti-inflammatory, anti-plaque, antinociceptive activity and anti-mutagenic activities. Due to these biological activities it is can be quite helpful for the preventions and treatments of diseases. Ethanolic extract of guava can increase the sperm quality and quantity and can be used for the treatment of infertile males.

Abbreviations

Escherichia coli

Interleukin 4

Potassium chloride

Messenger RNA

Rat Basophilic Leukemia cells

Staphylococcus aureus

Tumor necrosis factor

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The links for guava fruit (i), leaves (ii), flowers (iii) and stem (iv) of Fig.  1 are given below:

(i) https://www.indiamart.com/proddetail/jumbo-guava-17296565155.html , https://homeguides.sfgate.com/long-guava-tree-full-grown-86015.html

(ii) https://www.stylecraze.com/articles/how-are-guava-leaves-beneficial-for-your-hair/#gref

(iii) http://www.plantsrescue.com/tag/common-guava/

(iv) http://www.cocobolotreefarm.com/plants/guava-chinese

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Naseer, S., Hussain, S., Naeem, N. et al. The phytochemistry and medicinal value of Psidium guajava (guava). Clin Phytosci 4 , 32 (2018). https://doi.org/10.1186/s40816-018-0093-8

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El Hellani, Brinkman advocate for watchdog tobacco surveillance

In The New England Journal of Medicine, researchers call for maximizing public health gains 

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A new perspective piece from researchers at the College of Public Health and Ohio State’s  Center for Tobacco Research calls on researchers and policymakers to anticipate how the tobacco industry may use loopholes to skirt new rules being considered by the Food and Drug Administration (FDA) to reduce harm caused by cigarette smoking.

The paper, which appears in the  New England Journal of Medicine , was coauthored by CPH Assistant Professor  Ahmad El Hellani and Research Professor  Marielle Brinkman in collaboration with  Theodore Wagener , director of the Center for Tobacco Research and co-leader of the Cancer Control Program at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

The tobacco industry has manipulated the design and composition of cigarettes for decades, the authors say, by increasing nicotine content, incorporating chemical additives, and reengineering filters to deliver nicotine at levels that encourage and sustain addiction among consumers. The FDA is considering limiting nicotine levels in cigarettes, which could substantially reduce rates of disease and premature deaths. The authors warn the industry might chemically and physically modify cigarettes in ways that would void the public health benefit of a future FDA nicotine standard for cigarettes.

“Implementing a nicotine product standard for cigarettes has the potential to support the tobacco ‘endgame’ by helping to curb cigarette smoking, which has been the leading cause of preventable death in the United States for decades,” the authors write. “To ensure that its potential is realized, we believe researchers and health officials should anticipate, examine, and prevent the use of possible tactics by the tobacco industry that would threaten the public health benefits of such a standard.”

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