A review on the traditional uses, phytochemistry, and pharmacological activities of clove basil (Ocimum gratissimum L.)

In traditional medicine, Ocimum gratissimum (clove basil) is used in the treatment of various diseases such as diabetes, cancer, inflammation, anaemia, diarrhoea, pains, and fungal and bacterial infections. The present study reviewed the phytochemicals, essential oils, and pharmacological activities of O. gratissimum. The bioactive compounds extracted from O. gratissimum include phytochemicals (oleanolic acid, caffeic acid, ellagic acid, epicatechin, sinapic acid, rosmarinic acid, chlorogenic acid, luteolin, apigenin, nepetoidin, xanthomicrol, nevadensin, salvigenin, gallic acid, catechin, quercetin, rutin, and kaempfero) and essential oils (camphene, β-caryophyllene, α- and β-pinene, α-humulene, sabinene, β-myrcene, limonene, 1,8-cineole, trans-β-ocimene, linalool, α- and δ-terpineol, eugenol, α-copaene, β-elemene, p-cymene, thymol, and carvacrol). Various in vivo and in vitro studies have shown that O. gratissimum and its bioactive constituents possess pharmacological properties such as antioxidant, anti-inflammatory, anticancer, hepatoprotective, antidiabetic, antihypertensive, antidiarrhoeal, and antimicrobial properties. This review demonstrated that O. gratissimum has a strong preventive and therapeutic effect against several diseases. The effectiveness of O. gratissimum to ameliorate various diseases may be attributed to its antimicrobial and antioxidant properties as well as its capacity to improve the antioxidant systems. However, despite the widespread pharmacological activities of O. gratissimum, further experiments in human clinical trial studies are needed to establish effective and safe doses for the treatment of various diseases.


Introduction
The use of medicinal plants in traditional and complementary medicine for the treatment, management, or prevention of various diseases is as old as the origin of mankind (Yuan et al., 2016;Ekweogu et al., 2019). It has been estimated that approximately 80% of the world's population depends mainly on ethnomedicine or herbal medicine for the treatment of numerous diseases worldwide (Joshi, 2013;Pant, 2014). Interestingly, the increasing preference for the use of herbal medicines over conventional medicines may be attributed to the efficacies of the active ingredients present in herbal medicine to serve as natural healing agents as well as their availability, accessibility, affordability, and acclaimed less or non-toxic effects (Ikpeazu et al., 2018;Ijioma et al., 2021).
Furthermore, over the last decade, medicinal plants and their bioactive compounds have attracted the attention of several researchers because of their usefulness in the management and prevention of life-threatening and chronic diseases (Sofowora et al., 2013;WHO, 2019) such as cancer, diabetes, stroke, and arthritis (Bernell and Howard, 2016), as an alternative therapy for the treatment of psychiatric disorders (Venuprasad et al., 2014), and in meeting the health requirements of the elderly (WHO, 2019). Currently, these medicinal plants have not only been employed in the treatment of numerous ailments, but also serve as a source of novel drugs for use in traditional or orthodox medicine. Drugs such as quinine, digoxin, aspirin, and morphine were produced from medicinal plants such as Cinchona officinalis, Digitalis purpurea, Saix alba, and Papaver somniferum, respectively (Mbanaso et al., 2020).
Ocimum gratissimum L., popularly known as scent leaf, is one of the discovered medicinal plants with the potential to serve as an alternative therapy for the treatment of various ailments or as a source of a new drug. It is a widespread and commercially viable perennial herbaceous plant with a very strong aromatic smell. It belongs to the family of Lamiaceae and is found in Africa, Asia, and South America (Tanko et al., 2008;Akara et al., 2021). It is used as a natural flavouring agent, condiment, or vegetable in the preparation of fish, meat, soup, and stew. It is also used in traditional medicine for the treatment of several ailments such as cough, pneumonia, fever, inflammation, anaemia, diarrhoea, pains, and fungal and bacterial infections (Akara et al., 2021).
Scientific reports have shown that O. gratissimum has a wide range of bioactive compounds such as flavonoids and polyphenols (Venuprasad et al., 2014;Irondi et al., 2016) and essential oils with several beneficial effects (Benitez et al., 2009;Melo et al., 2019), as shown in Tables 1 and  2.
This study aims to provide comprehensive and up-to-date information on the medicinal uses, bioactive phytochemicals or essential oils, and the pharmacological activities of O. gratissimum. This paper also provides useful information on the beneficial effects of O. gratissimum and identifies gaps in current knowledge that can encourage further investigation into the effectiveness and commercialization of O. gratissimum in the treatment of various human diseases.

Methods used to obtain the materials for the review
In this study, only peer-reviewed journals and papers published in English were used. All the relevant materials were collected from only four online databases, namely PubMed (https://pubmed.ncbi.nlm.nih .gov/), Springer (https://www.springer.com/gp), Wiley (https://www. wiley.com/en-us), and Sciencedirect (https://www.sciencedi rect.com/). The key search terms or words were Ocimum gratissimum or scent leaf alone or in combination with botanical description, taxonomy, ethnopharmacological uses, phytochemistry, essential oil, pharmacological activities, antioxidant activity, anxiolytic activity, antinociceptive activity, neuroprotective activity, anti-bacterial activity, anti-fungal activity, anti-viral activity, anti-protozoal activity, antianaemic activity, wound healing properties, and analgesic activity.

Botanical description
Ocimum gratissimum is an aromatic herbaceous plant also known as basil, basil-clove, or alfavaca. It belongs to the Lamiaceae family (genus Ocimum and species gratissimum) (Nweze and Eze, 2009). It is about 1-3 cm tall, has an erect stem, and is branched, round-quadrangular, and woody at the base, with opposite, slender, and marginalized leaves.

Taxonomy
Plants of the Lamiaceae family are mostly classified as spices, herbs, and other aromatic variations. The Lamiaceae family comprises 236 genera and 7200 species of vines, shrubs, and trees found all over the globe. The genus Ocimum comprises about 60 species, most of which are found in Africa (Tanko et al., 2008). Ocimum gratissimum can be found in many forms and oftentimes classified into different species and subspecies.

Traditional uses
Ocimum gratissimum has been described as a plant easily available to communities and commonly utilized for the treatment of a plethora of diseases in numerous ethnopharmacological surveys (Ajayi et al., 2017a, b,c). This perennial and odoriferous plant is now found in all continents and possesses generally acknowledged medicinal properties. Its medicinal potential in Africa is incredibly vast and varies by country (Kpoviessi et al., 2014). Its infusions are regarded as tonic and pectoral in Cameroon, and the juice of its sheets is used to treat giddiness, headaches, cold, and cough. In Côte d'Ivoire, several formulations of this plant are used to treat ear infections, dermatoses, and ophthalmias (Kpoviessi et al., 2014). In Nigeria, it is recommended for diarrhoea therapy (Kpoviessi et al., 2014), while Sofowora (1970) recommended it for respiratory ailments and for use as an anthelminthic. It was also used to treat headaches, fevers, and ophthalmic and skin problems, as well as pneumonitis. In Togo, the plant's infusion is used to relieve cough (antitussive). The fresh juice from its leaves has antidiarrheic and antidysentric properties; and its aqueous maceration is used to treat haematuria and purulent urethritis (Kpoviessi et al., 2014). In Benin Republic, the aqueous maceration of its pulp or aerial portions is used to treat dystopias, pelvic aches, colic, candidoses, digestive dysmenorrhoea, emesis, haemorrhoid (pile), and diarrhoea. Its stem decoction is used to treat hepatitis, cough, asthma, and wound infections (Chah et al., 2006;Kpoviessi et al., 2014). The juice from its leaves is used to treat angina, cephalgias, headaches, fever, and malnutrition. Its inflorescences are utilized as aromatizers in a variety of meals.
Previous studies have shown that this type of basil has anaesthetic, anti-stress, anti-inflammatory, anthelminthic, antidiarrhoeal (Offiah and Chikwendu, 1999), antipyretic, anti-mutagenic, anti-ulcerative, gastroprotective, hepatoprotective, sedative, and fungicidal properties, validating its widespread medical use (Priyanka et al., 2018;Martins et al., 2021). O. gratissimum is antiseptic and has found widespread applications in the preparation of toothpaste and mouthwash and in topical therapies (Pessoa et al., 2002). It is an excellent wash for sore throat and tonsillitis. It is also used as an expectorant and as a cough suppressant. The plant extract is used to treat gastrointestinal helminths in both animals and humans (Chitwood, 2002). Reports on O. gratissimum revealed that the plant extract may be used as a medicinal resource for people living with the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) (Priyanka et al., 2018). It is used as a febrifuge and as a component in several malarial treatments in West Africa (Chah et al., 2006). Crushed leaves of the plant are used to cure conjunctivitis, while the oil extracted from the leaves is considered highly antimicrobial and has been used in wound dressing, the preparation of mouthwash, and the prevent postnatal sepsis (Chah et al., 2006). Furthermore, fresh aerial portions are consumed directly as vegetables in traditional soups, while dried and powdered aerial parts are utilized in a variety of traditional dishes (Kpoviessi et al., 2014).

Antioxidant activity
The antioxidant and anti-inflammatory properties of Ocimum gratissimum have been ascribed to its therapeutic benefits (Olamilosoye et al., 2019;Oyem et al., 2021). Its leaf extracts have been shown to contain antioxidant vitamins such as alpha-tocopherol and ascorbic acid (Olamilosoye et al., 2019). Previous research has shown that flavonoids and phenols protect against oxidative stress-induced cellular damage. Flavonoids and phenols exert anti-inflammatory and anti-oxidative effects through a variety of mechanisms, such as scavenging or quenching free radicals, chelating metal ions, or blocking enzyme systems that generate free radicals Olamilosoye et al., (2019). The presence of saponins, terpenoids, glycosides, and alkaloids in the aqueous extract of O. gratissimum may further contribute to its anti-inflammatory and anti-oxidative activities (Olamilosoye et al., 2019;Oyem et al., 2021). Joshi (2013) investigated the antioxidant activities of O. gratissimum and eugenol essential oils utilizing 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2 0 -azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) test models. The DPPH and ABTS models had substantial IC 50 values of 23.66 and 23.91, respectively, indicating that the essential oils of O. gratissimum may have antioxidant properties. The authors also revealed that the oils of O. gratissimum had higher antioxidant properties than pure eugenol (Joshi, 2013). Venuprasad et al. (2014) investigated the antioxidant activity of the leaf extract using a variety of in vitro free radical scavenging tests. The DPPH, iron chelating, ABTS, NO, and hydroxyl radical scavenging capabilities were tested, and the IC 50 values were 470, 17.4, 133, 83, and 260 g/mL, respectively. The analytical results revealed that O. gratissimum may have free radical scavenging properties. Shittu et al. (2016) investigated the effects of the aqueous leaf extract of O. gratissimum on haematological and oxidative stress markers in alloxan-induced diabetic rats. The results showed that diabetic rats fed with the aqueous extract of O. gratissimum had a considerable decline in fasting blood glucose levels compared with untreated diabetic rats. There was a reversal of weight loss found in the rats tested. The authors also reported a decreased level in malondialdehyde (MDA) concentration and this marker increases during lipid peroxidation (Shittu et al., 2016) (Table 3).

Anxiolytic activity
Anxiety is a mental disorder marked by a person's unpleasant conduct and inner turmoil that affects people of all ages, from children to the elderly. Benzodiazepines and other allopathic medicines that nonselectively target gamma-aminobutyric acid (GABA) receptors are commonly used to treat anxiety (Rudolph and Knoflach, 2011). Okoli et al. (2010) reported that 200 and 400 mg/kg of methanol or petroleum ether extract increased the latency of tonic and tonic-clonic seizures and death. They also offered 50% protection in treated mice against seizure-induced mortality. Several studies have shown a link between antioxidant activity and anti-anxiety action (Hovatta et al., 2010). Several gene products play an important role in anxiety, with glyoxalase-1 and glutathione-1 being the major proteins whose activities affect anxiety (Hovatta et al., 2005). Venuprasad et al. (2014) emphasized O. gratissimum's protective effect against DNA, protein, and lipid peroxidation. Pre-treatment with the leaf extract of the plant resulted in 44.8% protection from H 2 O 2 -induced DNA damage in SH-SY5Y human neuronal cells, 80% protection from AAPH-induced BSA oxidation, and lipid peroxidation inhibition at an IC 50 value of 735 g/mL. As observed from the open field and elevated plus maze tests, the plant had a substantial anxiolytic effect on the test mice at a dosage of 400 mg/kg body weight (Venuprasad et al., 2014).

Antinociceptive activity
In traditional medicine, O. gratissimum is used to treat painful conditions. In classic pain models, the antinociceptive effects of O. gratissimum essential oil and two of its active components (eugenol and myrcene) were investigated (hot plate test and formalin test) on neurogenic and inflammatory pain in murine pain models (Paula-Freire et al., 2013). In the first and second stages of the formalin test, the essential oil of O. gratissimum at a dose of 40 mg/kg, as well as its active components, eugenol and myrcene, at a dose of 10 mg/kg, successfully reduced pain in animals. These findings support the work of other authors on the antinociceptive action of the essential oil of O. gratissimum (Paula-Freire et al., 2013). Rabelo et al. (2003) showed that 30, 100 and 300 mg/kg of O. gratissimum essential oil inhibited writhing and inflammation in male Swiss mice. The report of Tanko et al. (2008) showed a significant antinociceptive effect of O. gratissimum at 1264.9 mg/kg body weight in the acetic-acid-induced abdominal constriction test and hot plate technique in rats, and this supports its traditional use in pain management.

Neuroprotective activity
Supplements of O. gratissimum leaf extract promote brain performance. Ajayi et al. (2018) reported the use of O. gratissimum at body weights of 25, 50, and 100 mg/kg in the treatment of behavioural impairment and depressive-like behaviour in mice using the open field test (OFT) and the forced swim test (FST). Bora et al. (2011) revealed that the neuroprotective ability of the extract of O. gratissimum in cerebral ischaemia is mediated by its antioxidant properties as observed during pre-treatment in Wistar rats with middle cerebral artery occlusion for 24 h followed by 24-hour reperfusion, as shown in Table 3.

Antimicrobial activity
A couple of studies have confirmed the antimicrobial activities of Ocimum gratissimum (Ilori et al., 1996;Nweze and Eze, 2009;Prakash et al., 2011;Melo et al., 2019). Prakash et al. (2011) described Ocimum gratissimum essential oil as a plant-based preservative and suggests its use as a nontoxic antibacterial and anti-aflatoxigenic agent against fungal and aflatoxin contamination of spices and as a shelf-life enhancer due to its antioxidant activity. Chimnoi et al. (2018) showed that 0.015-8.00 mg/ml essential oil extract of O. gratissimum leaf caused rapid inhibition of Escherichia coli and S. typhimurium. As reported by Talabi and Makanjuola et al. (2017), the aqueous extract of O. gratissimum strongly inhibited Pseudomonas aeruginosa and moderately inhibited Staphylococcus aureus, but the aqueous ethanolic leaf powder extract demonstrated a broader range of antimicrobial activities with significant inhibitory properties against E. coli, Bacillus cereus, P. aeruginosa, and S. aureus (Talabi and Makanjuola, 2017). Joshi (2013) used the tube-dilution method to test the antibacterial activity of O. gratissimum essential oils and its primary ingredient, eugenol, revealed strong antibacterial activity against Klebsiella pneumoniae, Serratia marcescens. and E. coli. Matias et al. (2011) reported that 2.5-0.0012 mg/ml aminoglycosides and 8-512 μg/ml methanol or hexane extracts of O. gratissimum synergistically inhibited E. coli and S. aureus.
Many studies have reported the antifungal activities of O. gratissimum Mohr et al., 2017). Lemos et al. (2005) showed that chloroformic fraction inhibited 23 isolates (92 %) of C. neoformans at a  Arrested sperm maturation with empty spermatozoa in lumen, and decreased sperm count Impairs sperm production in diabetic-induced rats   (Nakamura et al., 2004). According to Silva et al. (2005), the leaf extract of the plant contains bioactive components that are effective in vitro against dermatophytes. These findings further support O. gratissimum's antifungal activity. Nakamura et al. (1999) conducted an experimental examination of the antibacterial activity of O. gratissimum essential oil on various bacterial species. The essential oil of O. gratissimum extract suppressed the growth of S. aureus at 0.75 μg/mL concentration. Minimal inhibitory concentrations (MICs) ranged from 3 to 12 μg/mL for Shigella flexineri, Salmonella enteritidis, E. coli, Klebsiella species, and Proteus mirabilis. Eugenol was discovered as the primary component responsible for the antibacterial action of O. gratissimum essential oil. As a result, the plant has the potential to be used therapeutically in the prevention and treatment of bacterial infections (Nakamura et al., 1999). Melo et al. (2019) investigated the antibacterial activity of O. gratissimum essential oil extract against multidrug-resistant bacteria in planktonic and biofilm forms, such as isolates of S. aureus and E. coli. The antibacterial activity of the essential oil extract was determined by disk diffusion, while the checkerboard assay was used to assess the microdilution (MIC/MBC), growth curve under sub-MIC exposure, and combinatorial activity with ciprofloxacin and oxacillin. S. aureus and E. coli had much lower biofilm biomass and cell viability. These findings support the use of O. gratissimum essential oil extract as a natural option for treating infections caused by multidrug-resistant bacterial strains (Melo et al., 2019). Aneke et al. (2019) reported that except for Penicillium species, two primary dermatomycotic agents isolated from animals exhibited considerable activity at 128 μg/mL concentration of ethanolic leaf extract of O. gratissimum, namely Microsporum species and Trichophyton species. They showed a considerable degree of susceptibility at 128 μg/mL concentration. These findings imply that ethanolic extracts of O. gratissimum contain active components with antifungal action against these fungal pathogens. As a result, it has the potential to be employed therapeutically in the treatment of dermatomycoses (Aneke et al., 2019) (Table 3).

Anti-protozoal activity
The essential oils and ethanolic crude extract of O. gratissimum leaves and stems were evaluated in vitro against Trypanosoma brucei and Plasmodium falciparum in pre-and full flowering phases. The best growth inhibition of Trypanosoma brucei was observed, suggesting its antiprotozoal activities (Kpoviessi et al., 2014). In an in vitro and in vivo study reported by Adamu et al. (2009), the survival time of the parasite (Trypanosoma brucei) was dependent on the concentration of the extract, with lower (25 and 12.5 mg/ml) concentrations lasting longer than higher (100, 75, and 50 mg/mL) concentrations. Tchoumbougnang et al. (2005) conducted a study on the suppressive impact of O. gratissimum essential oil extract on Plasmodium berghei development in vivo in an animal model. According to the findings of their investigation, the extracted essential oil of O. gratissimum shows considerable antimalarial activity in test mice after a four-day suppressive in vivo assessment. The plant's essential oil extract showed highest effectiveness at dosages of 200, 300, and 500 mg/kg, with parasitaemia suppression percentages of 62.1 %, 81.7 %, and 86.6 %, respectively. Based on the findings of this investigation, the essential oil extract of O. gratissimum might be therapeutically effective in the treatment and control of malaria (Tchoumbougnang et al., 2005) (Table 3).

Anti-anaemic activity
Several studies have suggested that O. gratissismum leaf extract has the ability to abate toxicities induced on haematological indices of Wistar rats. For example, Akara et al. (2021) reported that O. gratissimum leaf extract at the dose of 400 mg/kg body weight ameliorates phenylhydrazine-induced anaemia in rats. Extracts of O. gratissimum were identified to have haematological effects on the body as they led to an increase in the red blood cells, packed cell volume, haemoglobin, and platelet and neutrophil counts. A decrease in the platelet count was observed when 500 mg/kg of the extract alongside feed pellets were used (Ofem et al., 2012). Akara et al. (2021) contended that the iron and vitamins present in the aqueous extract of O. gratissimum may be responsible for the haematopoietic characteristics found in their investigation (Table 3).

Bio-pesticide
Essential oils from Ocimum gratissimum at a concentration of 1 μL/mL showed repellence and a toxic fumigation effect when used on Tuta absoluta (Essoung et al., 2020). The adult form of Tribolium castaneum is susceptible to the cinnamic acid esters isolated from O. gratissimum at 26.92 mg/mL concentration (Buxton et al., 2020). Nguemtchouin et al. (2013) revealed that a mortality rate of 100-95% was observed with the combination of modified montmerillonite clay and O. gratissimum essential oil, which declined after 30 days as it had lost its insecticidal function by 60% and persisted for around 7-80 days. Chang et al. (2021) reported that 100 μg/mL O. gratissimum restored cell activity and protected against ultraviolet C-induced inhibition of cell proliferation and migration of skin cells, and therefore can serve as a potent natural wound care agent. Orafidiya et al. (2006) state that the formulation containing 2% O. gratissimum and honey as a surfactant had an antibacterial effect on S. aureus. It indicated that the net electrical charge on the surfactant with which it is produced influences the antibacterial activity of ocimum oil. The remarkable antibacterial action of the 2% ocimum oil in honey formulation, together with the documented wound healing characteristic of honey, suggests that the 2% ocimum oil in honey formulation might be useful as a topical antiseptic agent for wounds (Orafidiya et al., 2006).

Enzyme-inhibitory activity
The leaf extract of O. gratissimum inhibited pancreatic lipase and angiotensin 1-converting enzyme significantly, with IC 50 values of 20.69 g/mL and 29.44 g/mL, respectively. As a result, the leafy parts of O. gratissimum can be used as functional foods in a therapeutic approach for the control of obesity and obesity-related hypertension (Irondi et al., 2016). Ojo et al. (2019) investigated the inhibitory effect of an aqueous extract (1:10 w/v) of O. gratissimum leaves on some vital enzymes associated with erectile dysfunction, such as phosphodiesterase-5 (PDE-5), arginase, angiotensin 1-converting enzyme (ACE), and acetylcholinesterase (AChe), in penile and testicular tissues of study rats. The results of the study revealed that the extract has inhibitory effects on enzyme activities linked with erectile function, as well as free radical scavenging capacities, and these activities are linked with the plant's phenolic and flavonoid components (Ojo et al., 2019) (Table 3). Aziba et al. (1999) studied the pharmacological activity of O. gratissimum aqueous extracts in isolated rabbit jejunum, as well as their analgesic qualities in mice. Following administration of the extract, the spontaneous pendular movement of the rabbit jejunum was inhibited in a dose-dependent manner. The analgesic investigation also indicated an extended reaction time of 85% throughout a 20-minute observation period with no evident signs of toxicity. Their findings suggested that the aqueous extract of O. gratissimum has analgesic and spasmolytic properties (Aziba et al., 1999). Ajayi et al. (2017b) reported that O. gratissimum exhibited the potential to reduce pain perception in analgesic experiments, as observed when all the constituents of O. gratissimum were administered to mice.

Larvicidal activity
O. gratissimum substantially reduced the mortality of Anopheles gambiae larvae at all doses of the extract tested on the organisms in an O.C. Ugbogu et al. Heliyon 7 (2021) e08404 experiment conducted by Ileke and Adesina (2019). It had a remarkable effectiveness against the pre-adult stages and adults of Anopheles gambiae, leading to 90% pupae death at a concentration of 0.5% (Ileke and Adesina, 2019). Following exposure of newly emerging adult beetles (Callosobruchus maculatus) at a dose of 25 mL/vial during a fumigation operation, essential oils produced by steam distillation from O. gratissimum caused 80% death. It also had a substantial influence on the egg hatch rate, lowering it to roughly 15% at a concentration of 30 mL for the extract. Thus, the essential oil of O. gratissimum may have anti-larval characteristics that might be useful in pest management (Keita et al., 2001). Harikarnpakdee and Chuchote (2018) reported that O. gratissimum has the potential to enhance the control of dengue fever. They investigated the oviposition deterrent activity of the essential oil of O. gratissimum and O. gratissimum alginate beads against Aedes aegypti (Ae. aegypti) mosquitoes. The study's findings revealed that the beads offered substantially longer oviposition deterrent efficacy against gravid Aedes aegypti, but free O. gratissimum oil only did so for a shorter amount of time. The results suggest a less expensive method of managing dengue disease (Harikarnpakdee and Chuchote, 2018).

Leishmanicidal activity
Ueda- Nakamura et al. (2006) found that the eugenol-rich essential oil of O. gratissimum had increasing inhibitory actions against Leishmania amazonensis growth at extract concentrations ranging from 100 to 1000 Ag/mL. At inhibitory concentrations (IC 50 ) of 135 and 100 Ag/ml for promastigotes and amastigotes, respectively, there were significant mitochondrial alterations in essential oil-treated promastigotes and amastigotes. Both promastigotes and amastigotes have a minimum inhibitory concentration of 150 Ag/ml. Their research revealed that the essential oil had no cytotoxic effects on mammalian cells. This underlines the potential effectiveness of the essential oil of O. gratissimum against protozoas and as a novel therapeutic source of antileishmanial drugs (Ueda-Nakamura et al., 2006). Pessoa et al. (2002) conducted a research to assess the ovicidal efficacy of O. gratissimum essential oil and its major component, eugenol, against Haemonchus contortus, a gastrointestinal parasite found in small ruminants. During the egg hatch test, H. contortus eggs were also retrieved from the faeces of goats that had been experimentally infected with the test organism. The essential oil and eugenol, on the other hand, revealed a maximum eclodibility suppression of the organism's growth at 0.5% concentration. These findings suggest that the use of the essential oil of O. gratissimum might be a useful method to manage gastrointestinal helmintosis in small ruminants (Pessoa et al., 2002).

Cytotoxic activity
The cytotoxic impact of methanolic extract O. gratissimum (ME-Og) was studied in murine peritoneal macrophages at doses ranging from 0.1 to 100 g/ml using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) technique. The findings indicated that O. gratissimum plant extracts have a considerable modulatory influence on nicotine-induced free radical production, lipid-protein damage, and antioxidant status in peritoneal macrophages. Following a 12-hour treatment of murine peritoneal macrophages in culture medium with hazardous 10 mM nicotine, it was observed that ME-Og exerted a protective effect against nicotine toxicity. In rats treated with the extract, the impact of the poisonous substance was significantly decreased and the negative effects were significantly reduced. Therefore, the results confirm the modulatory effect of O. gratissimum on hazardous chemicals such as nicotine (Mahapatra et al., 2009). Chiu et al. (2012) found that O. gratissimum aqueous extract (OGAE) protected the liver against CCl 4 -induced damage in rats utilized as a model of chronic hepatic damage. An increase in the blood catalase activity of CCl 4 -administered rats treated with the aqueous plant extract was observed, which was much higher than that of the control rats treated with saline solution. In a study comparing those given OGAE to those given saline or CCl 4 , it was observed that the livers of the CCl 4 -administered rats given the plant extract showed a significant decrease in stress proteins such as heat shock protein (HSP70) and inducible nitric oxide synthase (iNOS). A significant reduction in the ratio of MMP-9/MMP-2, phosphorylated ERK (p-ERK), and NF-kB (p-P65) was observed, suggesting the possible protective effect of OGAE against CCl 4 -induced toxicity in rats (Chiu et al., 2012).
The aqueous extract of O. gratissimum exhibited ameliorative activities, which enabled it to provide protective benefits against acetic acidinduced colitis in male rats when administered at doses ranging from 200 to 400 mg/kg/day for 20 consecutive days (Olamilosoye et al., 2019). Similarly, it ameliorated the haematological parameters and significantly reduced the activities of MPO, SOD, and NO and increased the GSH levels in colitis rats (Olamilosoye et al., 2019). O. gratissimum ameliorated the cytotoxic effects of H 2 O 2 -induced apoptosis by modulating the apoptotic pathway at concentrations ranging from 150 to 200 μg/mL (Chao et al., 2017) (Table 3).

Anti-infertility effect
When administered, Ocimum gratissimum was observed to have an effect on penile and testicular tissues present in rats in the treatment of erectile dysfunction (Ojo et al., 2019). Joseph et al. (2019) reported that methanolic and oil extracts of O. gratissimum leaves, when administered at two dosages of 250 and 500 mg for 14 and 28 days, had no negative effect on the reproductive capabilities of the male rats. Ajayi et al. (2011) discovered that O. gratissimum given to mice at different concentrations might protect the liver by controlling the increase in catabolic enzyme levels induced by CCl 4 damage in liver cells. Chiu et al. (2014) opined that 0-40 mg/kg O. gratissimum extracts reduced liver damage, steatosis, and fibrosis and increased catalase and anti-oxidative enzymes. Huang et al. (2020) revealed that in hepatocarcinomal cell (HCC) following treatment with O. gratissimum at concentrations more than 20 mg/mL, an increase in p/ERK1/2 levels was observed, indicating that it has an effect on the survival signalling of the liver cancer cells. The flavonoid-rich ethyl acetate fraction of O. gratissimum was discovered to exhibit hepatoprotective properties, indicating that it may be useful in slowing down the LPS-mediated sickness process in mice with LPS-induced sickness behaviour (Ajayi et al., 2019). Fandohan et al. (2008) reported that the administration of O. gratissimum oil at the dose of 1000 mg/kg did not produce any hepatotoxic effects on the rat's liver, as shown in Table 3. Ogundipe et al. (2017) showed that 100, 200, and 400 mg/kg/day of O. gratissimum leaf could be employed in the management of gentamicin-induced kidney injury. Treatment with O. gratissimum aqueous leaf extract, on the other hand, induced a reduction in creatinine, urea, HCO 3 , K þ , Cl À , and Na þ , suggesting that O. gratissimum leaf extract may have renoprotective properties (Akara et al., 2021).

Anti-diarrhoeal activity
Offiah and Chikwendu (1999) investigated the anti-diarrhoeal effects of an aqueous extract of O. gratissimum leaves. They were able to demonstrate the anti-diarrhoeal efficacy of the extract on castor oil-induced diarrhoea in rats, as evidenced by a substantial decrease in the amount of wet faeces in rats treated with the extract. The aqueous leaf O.C. Ugbogu et al. Heliyon 7 (2021) e08404 extract of the plant reduced diarrhoea and the propulsive movement of intestinal contents. It also had no direct effect on guinea pig harvested ileum, but it greatly reduced the ileum's responsiveness to acetylcholine, nicotine, and histamine, resulting in lower contractile activity induced by these drugs. Further phytochemical assessments revealed that the plant's principal constituents include tannins, steroids, triterpenoid, and carbohydrates. These findings suggest that the aqueous extract of O. gratissimum leaves may include pharmacologically active ingredients with antidiarrhoeal effects defined primarily by inhibitory activity on intestinal motility, perhaps via muscarinic receptor inhibition (Offiah and Chikwendu, 1999), as shown in Table 3.

Anti-diabetic activity
Studies on the hypoglycaemic activities of O. gratissimum have been reported by various researchers using animal models (Egesie et al., 2006;Shittu et al., 2019). In mice, co-administration of the O. gratissimum leaf extract after oral administration of starch and glucose demonstrated that the extract inhibited the increase in postprandial blood glucose levels (Shimada et al., 2019). Their findings suggested that the inhibitory effect on sodium-dependent glucose transporter (SGLT1) could be one of the underlying mechanisms of the anti-hyperglycaemic effect of the leaf extract of O. gratissimum (Shimada et al., 2019). Aguiyi et al. (2000) observed a significant reduction in plasma glucose levels when O. gratissimum was administered at 400 mg/kg body weight. The research carried out by Casanova et al. (2014) showed the hypoglycaemic activity of O. gratissimum against streptozotocin-induced diabetes in rats. They contended that the chicoric acid, a major phenolic constituent, may be responsible for this activity. However, further characterization of the plant's bioactive components is recommended to determine other bioactive components that may exhibit these pharmacological activities. Other studies reported by Antora and Salleh (2017) showed that extracts of O. gratissimum when used on streptozotocin-induced diabetic rats at 500 mg/kg was found to be 81% effective. Okon and Umoren (2017) contended that the hypoglycaemic efficacy of O. gratissimum was higher than that of insulin in streptozotocin-induced diabetic rats at 208 mg/kg (Table 3).

Anti-inflammatory activity
The plant has been reported to exhibit anti-inflammatory activities (Ajayi et al., 2017a,b,c;Alabi et al., 2018). For example, Ajayi et al. (2017a) suggested that O. gratissimum extract when used to treat rats induced with carrageenan was able to reduce inflammations at 50,100, and 200 mg/kg body weight. The extract at 100 mg/kg body weight had a significant effect on rats by inhibiting carrageenan-induced paw oedema, suggesting its therapeutic use in the treatment of inflammations (Ajayi et al., 2019). In the study conducted by Alabi et al. (2018), O. gratissimum was found to have anti-inflammatory effects on dextran sodium sulphate (DSS) induced colitis in rats at doses of 100-800 mg/kg where signs of repair were evident. The extract was found to be useful in the treatment of eosinophilic airway inflammation in male AJ mice induced by Blomia tropicalsis. In a murine model, doses of 25, 50, and 100 mg/kg of methanolic extract of the plant were found to be effective in alleviating respiratory allergy   (Table 3).

Anticancer activity
Anticancer activities from plant bioactive components have been documented (Sun et al., 2002;Surh, 2003;Ohiagu et al., 2021). Lin et al. (2014) investigated the anticancer efficacy of an aqueous extract of O. gratissimum due to its antioxidant capabilities after treating human osteosarcoma cells with the extract, adding to the expanding body of research on the plant and its involvement in cancer treatments. Cell viability experiments demonstrated that the activity of the aqueous extract of O. gratissimum affected the viability of U2-OS and HOS cells considerably and dose dependently. It is characterized by an increase in cell shrinkage, sub-G1 fragmentation, and caspase 3 activations (Lin et al., 2014). Treatment with O. gratissimum at 200 mg/kg caused tumour growth decrease through modulation of the ERK signalling pathway and aerobic glycolysis, and increasing cell apoptosis in mice induced with mahlavu cells (Huang et al., 2020). Nangia-Makker et al. (2013) showed that 12.5-300 μg/mL extract of O. gratissimum decreased basement membrane disintegration, angiogenesis, and matrix metalloproteinases (MMP-2 and MMP-9) activities. This subsequently resulted in the inhibition of tumour growth and breast cancer cells. When human breast cancer cells were treated with both O. basillium and O. gratissimum, it was observed that O. gratissimum had a lower cystotic and apoptotic impact on the MCF-7 human breast cancer cell line through activation of the mTOR/Akt/AMPK signalling pathway (Torres et al., 2018). Ekunwe and his co-researchers reported that partially purified O. gratissimum fractions (Ekunwe et al., 2010) or aqueous or organic solvent-soluble extracts of O. gratissimum  inhibited the proliferation of several cancer cell lines, especially prostate adenocarcinoma (PC-3) cells (Table 3). Mahapatra et al. (2011) investigated the immunological functions and immunological responses in nicotine-induced (10 mM) macrophages as well as the immunomodulatory activity of O. gratissimum extract. Nicotine-induced NO production and iNOS II expression were considerably reduced after the administration of a 10 μg/mL aqueous extract of the plant. The aqueous extract of the plant had protective effects on murine peritoneal macrophages by downregulating Th1 cytokines in nicotine-treated macrophages while simultaneously activating Th2 responses (Mahapatra et al., 2011).

Conclusion and future perspectives
In conclusion, O. gratissimum has remarkable dietary and pharmaceutical applications, which make it an excellent functional ingredient for use in the treatment of a plethora of health abnormalities. Currently, various researchers are conducting in-depth studies on the useful components of this health-promoting plant. Because O. gratissimum is an excellent source of vital phytochemicals, nutrients, and essential oils, bioactive isolates with a higher biological value of this plant could be a better replacement for traditional medicine in the treatment of microbial infections, cough, cancer, diarrhoea, anaemia, and inflammatory diseases. Apart from its bioactive potential, O. gratissimum is an excellent source of micronutrients. The reported pharmacological/clinical activities exhibited by O. gratissimum are not limited to its antioxidant properties and ability to suppress inflammatory biomarkers. The presence of bioactive substances demonstrates the variations in this plant's components. These differences arise as a result of variations in topography, meteorological conditions, yield, preparation process, and many other factors. Therefore, there is a need to investigate the phytochemical properties of O. gratissimum, which may be utilized to enhance the health benefits (animal and human nutrition), as well as the environment, by using its isolated chemicals in natural weed and pest control management. Therefore, further research in human clinical trials is recommended to effectively confirm the safe concentration of the extract required to manage health deviations. Apart from these benefits, O. gratissimum has been effective against diabetes, anemia, infertility, diarrhoea, and inflammatory disorders. Hence, further studies are required to determine the specific mechanism by which O. gratissimum protects against various diseases, which can be used to design and create effective therapies for these disorders in the future. The studies included in this review collectively suggest that this plant has several healing properties. Owing to its multidirectional activities, O. gratissimum has been regarded as an important medicine for a variety of diseases.

Author contribution statement
All authors listed have significantly contributed to the development and the writing of this article.

Funding statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability statement
Data included in article/supplementary material/referenced in article.