INTRODUCTION
Traditionally, numerous plant species have been extensively used to treat various ailments by ethnic people throughout the world. In general, plants contain a wide variety of biologically active components, including phenolic acids, flavonoids, alkaloids, terpenoids, phytosterols, saponins, tannins, and lignins (Clardy and Walsh, 2004; Goyal et al., 2012; Shanmugam et al., 2021). The genus Callistemon (Myrtaceae) contains about 50 species with immense medicinal importance. Callistemon species are mainly found in the eastern and southeastern regions of Australia (Sharma et al., 2021). The general characteristics of this genus are lanceolate leaves, flower spikes like bottlebrushes, and red stamens (Gad et al., 2019). Previous studies reported the isolation and identification of different chemical groups from Callistemon species, including polyphenols and terpenoids (Shehabeldine et al., 2020). The leaves of this plant possess a pleasant fragrance due to the presence of essential oil. Different species of Callistemon are cultivated for the purposes of essential oils, farm trees, land reclamation, and ornamental horticulture besides other applications (Lopez-Mejía et al., 2021; Zubair et al., 2013).
Callistemon lanceolatus (Sm.) Sweet is a medium-sized tree, native to Australia, and is widely found in subtropical and tropical zones. This plant is commonly known as lemon bottlebrush due to its cylindrical brush-like red flowers (Singh et al., 2020). It is also widely cultivated as an ornamental plant throughout the world. Aerial parts of C. lanceolatus are known to possess various biological activities, including antimicrobial (Nazreen et al., 2020), antioxidant, antidiabetic (Ahmad et al., 2018; Kumar et al., 2011a), anti-inflammatory (Kumar et al., 2011b), and antiproliferative (Park et al., 2018) activities. In particular, essential oils from the leaves of C. lanceolatus have antimicrobial and anti-inflammatory properties (Shukla et al., 2012; Sudhakar et al., 2004). This plant is a versatile source of bioactive components. The leaves have been used as the best tea substitute owing to their refreshing flavor. In Egypt, essential oil from this plant is used to treat cough and bronchitis in addition to insecticidal properties (Das and Singh, 2012; Shinde et al., 2012).
Based on the highly acclaimed biological properties of C. lanceolatus, this review aimed to summarize the chemical composition and biological properties of crude extracts and isolated compounds from C. lanceolatus (Table 1).
METHODOLOGY
Published articles in connection with C. lanceolatus were retrieved from PubMed, Science Direct, Taylor and Francis, BMC, Wiley Online Library, Springer Link, ACS, Google Scholar, and other literature databases. In addition, some articles were found by tracking citations from other publications. The search keywords used were C. lanceolatus and lemon bottlebrush. The collection of literature was restricted to publications in English language. The search was carried out until August 2021. Chemical names were authenticated from PubChem website and chemical structures were made using ChemDraw Ultra 12.0. In this review, we briefly discussed recent scientific findings regarding the biological activities of C. lanceolatus and suggested some fields where further study is required.
Chemical Compositions of C. Lanseolatus
Phytochemicals are very important in pharmaceutical and medicinal fields owing to their biological properties. Numerous methods have been employed to isolate and characterize chemical components from different parts of C. lanceolatus (Fig. 1A and B). Sitosterol, erythrodiol, betulin, betulinic acid, ursolic acid, and 2-hydroxyursolic acid were isolated from this plant by Varma and Parthasarathy (1975). Phloroglucinol derivatives from the leaves of C. lanceolatus were identified by Lounasmaa et al. (1977). Rattanaburi et al. (2013) isolated callistenones A–E (acylphloroglucinols) from C. lanceolatus leaves.
The flavones are an important class of flavonoids, which can act as strong antioxidants. 3-Methyltetradec-2-en-7-ol, 5-hydroxy-7,4?-dimethoxy-6,8-dimethylflavone, and 5-hydroxy-7,4?-dimethoxy-6-methylflavone were characterized from the leaves of C. lanceolatus (Huq and Misra, 1997) and 5,7-dihydroxy-6,8-dimethyl-4?-methoxy flavone and 8-(2-hydroxypropan-2-yl)-5-hydroxy-7-methoxy-6-methyl-4?-methoxy flavone from the aerial parts of C. lanceolatus (Nazreen et al., 2012). In addition, 8-(1″-hydroxyisopranyl)-5,6-dihydroxy-7,4?-dimethoxy flavone, 2,3,4-trihydroxyphenethyl tetracontanoate, and 2,3,4-trihydroxyphenethyl tetracontanoate-4-β-xylopyranoside were isolated (Nazreen et al., 2019). In the aerial parts of C. lanceolatus, 4?,5-dihydroxy-6,8-dimethyl-7-methoxyflavanone, eucalyptin, 8-demethyleucalyptin, sideroxylin, syzalterin, and quercetin were also isolated (Park et al., 2010; 2018).
In the flowers and leaves of C. lanceolatus, Marzouk (2008) employed HPLC-ESI/MS followed by one- and two-dimensional nuclear magnetic resonance for characterizing quercetin 3-O-β-D-glucuronopyranoside n-butyl ester and n-butylgallate 4-O-(2?,6′-di-O-galloyl)-β-D-glucopyranoside from the aqueous methanol extracts. The leaves of C. lanceolatus also contain flavonol glycosides such as kaempferol 3-O-beta-D-galacturonopyranoside and quercetin 3-O-(2″-O-galloyl)-beta-D-glucoronopyranoside, in addition to 18 known polyphenols (phenolic acids, flavonoids, and 3 tannins) (Mahmoud et al., 2002).
Jeong et al. (2009) isolated triterpenoids such as 30-hydroxyalphitolic acid, alphitolic acid, lupenol, 3-acetoxy-olean-18-en-28-oic acid, betulinic acid, ursolic acid, betulinic acid 3-O-caffeate, morolic acid 3-O-caffeate, and ursolic acid 3-O-caffeate from C. lanceolatus. 2-Amino-2-ethylpropane-1,3-diyl dioleate and ursolic acid 3-O-acetate were identified from the ethanol extract of C. lanceolatus stems (Kim et al., 2012). Ahmad et al. (2018) reported the presence of 4-fluoro-2-trifluoromethylbenzoic acid, neopentyl ester, fumaric acid, di(pent-4-en-2-yl) ester, 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one, and 2-furancarboxaldehyde,5-(hydroxymethyl). 1-Triacosanol, n-eicosanyl palmitate, n-heptadecanyl arachidate, n-tricosanyl palmitate, 4-hydroxyphenethyl carbocerate, 4-hydroxyphenethyl gheddate, urs-12-en-3alpha-acetoxy-18beta-H-28-oic acid, and stigmast-5-en-3beta-ol-3beta-D-glucuronopyranoside were also identified from C. lanceolatus (Nazreen et al., 2020). Two neolignans such as callislignan A and B along with a lignan, C-methyl-flavonoids, and pentacyclic triterpenoid esters were identified from C. lanceolatus leaves (Rattanaburi et al., 2012).
The aerial parts also contain an appreciable amount of essential oils. Misra et al. (1997) investigated the essential oil composition of the leaves, flowers, and fruits of C. lanceolatus. The authors reported that 1,8-cineole and α-pinene were major components in the leaves. The flower contained a higher amount of β-pinene and 1,8-cineole, whereas l,8-cineole and α-terpineol were the major components in fruits. In the essential oils of C. lanceolatus leaves, the most abundant components were 1,8-cineole and α-pinene, followed by α-phellandrene, limonene, and α-terpineol (Sharma et al., 2006).
Biological Activities of C. Lanceolatus
The biological activities of crude extracts and compounds isolated from C. lanceolatus are presented in Table 1.
Antimicrobial activity
New eco-friendly approaches are required to prevent the growth of microbial pathogens in food products due to the adverse effects of synthetic preservatives. In recent times, numerous researchers evaluated the possible utilization of plant natural products as effective preservatives. Pandey et al. (1982) screened the inhibitory activity of 20 plant species from 12 families against Fusarium oxysporum and the authors found that only C. lanceolatus leaves exhibited absolute toxicity. The methanol extract from the leaves of C. lanceolatus exhibited maximum inhibitory activity against Staphylococcus aureus and minimum inhibitory activity against Candida albicans (Paluri et al., 2012). Kavitha and Satish (2013) investigated the antibacterial effect of different extracts (petroleum ether, chloroform, ethyl acetate, and methanol) of C. lanceolatus leaves against various human and plant pathogenic bacteria. The minimum inhibitory concentration (MIC) of different extracts ranged between 0.156 and 5 mg/ml.
Nim and Arora (2018) found that ethyl acetate extract from the leaves of C. lanceolatus exhibited strong inhibitory activity against different microbial pathogens with the zone of inhibition ranging from 15 to 27 mm. Among various pathogens, the ethyl acetate extracts effectively control the growth of S. aureus and Klebsiella pneumonia. Maximum antimicrobial activity was observed for cardiac glycosides and phytosterols. The partially purified components showed the maximum inhibitory effect against methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis, and S. aureus. The ethyl acetate extract and partially purified constituents indicated a lower MIC (0.5–7 μg/ml). The methanol extract of C. lanceolatus showed appreciable antibacterial activity against S. aureus and S. epidermidis (Srishti et al., 2017).
 | Table 1. Biological activities of extracts and isolated compounds from C. lanceolatus. [Click here to view] |
The essential oil of C. lanceolatus also showed a potent anticandidal activity (Dutta et al., 2007). Shukla et al. (2012) studied the antifungal activity of essential oil and its major component, 1,8-cineole, against fungal pathogens isolated from chickpea. The essential oil and 1,8-cineole exhibited significant antifungal activity against all the tested fungal isolates. Furthermore, the essential oil and 1,8-cineole strongly inhibited the production of aflatoxin B1 by the isolate of Aspergillus flavus with lower fungistatic concentration. Kavitha and Satish (2014) evaluated the antibacterial activity of different solvent extracts from the seed of C. lanceolatus against 11 uropathogenic bacteria. Different extracts showed least to moderate inhibitory activity against these uropathogenic bacteria. The aqueous extract of C. lanceolatus seeds revealed a broad-spectrum antimicrobial activity against different microbial pathogens with MIC values ranging from 1 to 5 mg/ml (Arora et al., 2016).
The isolated compounds, callislignan (A and B) as well as callistenones (A–C), showed antibacterial activity against S. aureus and MRSA (Rattanaburi et al., 2012; 2013). Urs-12-en-3alpha-acetoxy-18beta-H-28-oic acid isolated from C. lanceolatus effectively inhibited the growth of Escherichia coli with the MIC value of 32 mg/ml (Nazreen et al., 2020). A recent study indicated that C. lanceolatus essential oil-loaded chitosan nanoparticles exhibited a strong inhibitory effect on aflatoxin B1 production by A. flavus when compared to C. lanceolatus essential oil alone (Singh et al., 2020).
 | Figure 1(A and B). The chemical structure of some important compounds isolated from C. lanceolatus. [Click here to view] |
Antioxidant activity
Antioxidant substances such as phenolic acids, flavonoids, and tannins possess various biological properties, including anti-inflammatory, anticancer, and antidiabetic effects due to their antioxidant potential. Kumar et al. (2011a) studied the antioxidant potential of methanol extracts of C. lanceolatus and found that the extract showed antioxidant effect by scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH), superoxide, nitric oxide, and hydroxyl radicals. Methanol extracts from the leaves of C. lanceolatus revealed a considerable DPPH radical scavenging activity with an IC50 value of 155 μg/ml in addition to protecting ability against pBR322 plasmid DNA (Kumar et al., 2015). The ethyl acetate and methanol extracts from the leaves of C. lanceolatus showed a potent antioxidant activity under various in vitro assays such as DPPH, superoxide, hydrogen peroxide, nitric oxide radical scavenging assays, and reducing power assay (Ahmad et al., 2018). The methanol extract from the stem of C. lanceolatus also showed potent antioxidant activity in terms of antioxidant assays such as ion chelating, free radical scavenging, and reducing power (Kumar et al., 2020). Furthermore, the fatty acid esters from C. lanceolatus such as 4-hydroxyphenethyl carbocerate and 4-hydroxyphenethyl gheddate DPPH radical scavenging activity (Nazreen et al., 2020).
Antidiabetic activity
Diabetes mellitus is one of the important metabolic diseases and is a major health concern today around the world due to increased mortality. Nowadays, medicinal plants play a major role in replacing synthetic antidiabetic drugs due to unavoidable side effects. In streptozotocin-induced diabetic rats, 8-(1″-hydroxyisopranyl)-5,6-dihydroxy-7,4?-dimethoxy flavone isolated from the chloroform fraction of the ethanol extract of C. lanceolatus aerial parts significantly reduced the blood glucose level. The isolated compound also exhibited a moderate PPAR-γ transactivation activity in vitro (Nazreen et al., 2019). Nazreen et al. (2012) reported that 5,7-dihydroxy-6,8-dimethyl-4?-methoxy flavone and 8-(2-hydroxypropan-2-yl)-5-hydroxy-7-methoxy-6-methyl-4′-methoxy flavone isolated from C. lanceolatus aerial parts effectively reduced the blood glucose level in streptozotocin-induced diabetic rats.
Kumar et al. (2011a) studied the antidiabetic potential of methanol extract from the leaves of C. lanceolatus in streptozotocin-induced diabetic rats. Oral administration of the methanol extract for 21 days markedly decreased the level of blood glucose level in glucose-loaded as well as streptozotocin-induced diabetic rats. When compared with the diabetic control group, there were decreases in blood glucose, serum cholesterol, and triglycerides levels and increases in the levels of high-density lipoprotein (HDL) cholesterol and serum insulin in the methanol extract-treated group. Oral administration of ethyl acetate fraction from the methanol extract of C. lanceolatus leaves markedly decreased the level of blood glucose and improved the functions of kidney and liver functions in alloxan-diabetic rats. Furthermore, the ethyl acetate fraction enhanced body weight, liver, and renal profiles in addition to total lipid levels (Kumar et al., 2011b). Recently, Kumar et al. (2020) investigated the antidiabetic potential of methanol extract from the stem of C. lanceolatus methanolic in alloxan-induced diabetic rats. The authors reported that the methanol extract-treated group for 28 days significantly reduced blood glucose level and serum markers accompanied by improving body weight and HDL level in alloxan-induced diabetic rats.
Anti-inflammatory activity
Uncontrolled production of inflammatory mediators is the major cause of various diseases, including allergies, cardiovascular dysfunctions, diabetes, cancer, and immune-mediated disorders. Extracts and secondary metabolites from plants have been increasingly used for the treatment of inflammatory-mediated diseases (Ghasemian et al., 2016). Sudhakar et al. (2004) studied the antinociceptive and anti-inflammatory activities of essential oil from C. lanceolatus leaves under in vivo animal models. Oral administration of C. lanceolatus essential oil showed antinociceptive activity in terms of a tail flick latent test in rats, hot plate reaction time, analgesymeter-induced mechanical pain, and acetic acid-induced writhing in mice. C. lanceolatus essential oil also decreased paw edema volume in the carrageenan-induced paw edema in rats. In a carrageenan-induced paw edema rat model, oral administration of the methanol extract of C. lanceolatus leaves showed appreciable anti-inflammatory activity at the concentration of 200 and 400 mg/kg bw (Kumar et al., 2011c). Another study revealed that betulinic acid 3-O-caffeate 7 moderately inhibited the production of nitric oxide in lipopolysaccharide- induced RAW264.7 cells with the IC50 value of 15.4 μM (Jeong et al., 2009).
Antiproliferative activity
The continuing search for novel and effective drugs from medicinal plants is a promising strategy for the prevention of cancer. The ethyl acetate and methanol extracts of C. lanceolatus leaves showed a potent antiproliferative effect against liver cancer cells HepG2 cells by reducing the cell growth, reactive oxygen species generation, and cell migration as well as inhibiting the metastatic activity. Furthermore, pretreated HepG2 cells with both extracts significantly suppressed signal transducer and activator of transcription 3 expression and upregulated p53 and inhibited cdk2 and cyclin A activities (Ahmad et al., 2018). The ethyl acetate extract and partially purified constituents from the leaves of C. lanceolatus showed promising antiproliferative activity against HeLa cell lines (Nim and Arora, 2018). A C-methylated flavone, sideroxylin, isolated from C. lanceolatus effectively decreased the proliferation of cells and increased apoptosis in ovarian cancer cells such as ES2 and OV90 cells by inducing mitochondrial dysfunction and activating phosphoinositide 3-kinase and mitogen-activated protein kinase signal transduction (Park et al., 2018).
Insecticidal activity
In Asia and Africa, Callosobruchus chinensis L. (Pulse beetle) is the most devastating insect pest in the stored pulses. The essential oil of C. lanceolatus and its major component, 1,8-cineole, registered 100% and 74.7% repellency of pulse beetle, respectively, in a Y-shaped olfactometer at the concentration of 150 μl. The essential oil and 1,8-cineole afforded 100% insect mortality at the concentration of 0.1 μl/ml. At the concentration of 0.1 μl/ml, the essential oil was found to be the most effective fumigant in terms of oviposition deterrent (96.03%) and antifeedant activity (100%). Furthermore, C. lanceolatus essential oil exhibited promising safety profiles when recorded on mice with the LD50 of 14,626.3 μl/kg (Shukla et al., 2011).
El-Ansary et al. (2001) demonstrated that the dry powdered C. lanceolatus exhibited molluscicidal activity against Biomphalaria alexandrina. The extract of C. lanceolatus showed antithrombin activity (80%) based on a chromogenic bioassay (Chistokhodova et al., 2002). The extracts from the leaves of Vinca rosea and C. lanceolatus alone and their mixtures effectively reduced the growth, increased larval toxicity, and inhibited normal adult emergence of Helicoverpa armigera (Halder et al., 2009).
Miscellaneous activities
A study reported that the methanol extract of C. lanceolatus leaves exhibited protective activity against carbon tetrachloride (CCl4)-induced hepatic damage in rats by attenuating the increased serum level of enzymes (Jain et al., 2000). The ethanol extract from the leaves of C. lanceolatus (100 and 200 mg/kg bw) showed protective activity in doxorubicin-induced cardiomyopathy in rats (Firoz et al., 2011).
The essential oil of C. lanceolatus exhibited 100% toxicity against the test dermatophyte, Trichophyton tonsurans (Anita and Misra, 2012). A study indicated that the essential oil of C. lanceolatus showed an inhibitory effect on seed germination and seedling growth of Echinochloa crus-galli (L.) Beauv. at a concentration of 25 μl/plate (Bunkoed et al., 2017).
A higher amount of beta-amyloid (Aβ) production and its aggregation play a major role in Alzheimer?s disease. Hence, reducing the accumulation of Aβ neuronal cells could provide an appropriate way of prevention of Alzheimer?s disease. A flavanone, 4′,5-dihydroxy-6,8-dimethyl-7-methoxyflavanone isolated from C. lanceolatus aerial parts showed a potent neuroprotective effect against beta-amyloid (Aβ)-induced toxicity in PC12 cells (ED50 value: −6.7 μM). This compound significantly decreased Aβ-induced apoptotic cell death by decreasing the activation of caspase-3 and increasing the ratio of Bcl-2/ Bax (Park et al., 2010).
Nanoparticle Synthesis
In recent years, the biosynthesis of nanoparticles has gained considerable attention because of its eco-friendly approach, biocompatibility, extended half-life of drugs, cost-effectiveness, and no toxicity. Ravichandran et al. (2016) used the aqueous extract obtained from the leaves of C. lanceolatus to synthesis silver oxide nanoparticles. The biosynthesized silver oxide nanoparticles exhibited significant antioxidant activity in a concentration dependent-manner under various in vitro chemical assays and time-dependent cytotoxic activity against brine shrimp nauplii. C. lanceolatus was utilized to synthesis gold nanoparticles (Kowsalya et al., 2021).
CONCLUSION AND FUTURE PERSPECTIVES
The leaves of C. lanceolatus contain various compounds, including flavones, acylphloroglucinols, C-methyl-flavonoids, and most importantly essential oils. According to previous reports, crude extracts and isolated compounds from C. lanceolatus showed significant antimicrobial, antioxidant, antidiabetic, anti-inflammatory, and insecticidal activities. In particular, the essential oil and its major component, 1,8-cineole, exhibited remarkable antimicrobial activity with special reference to an inhibitory effect on aflatoxin production. The leaves of C. lanceolatus may be a potential candidate for the development of antimicrobial and antidiabetic agents. However, further studies are warranted in relation to mechanisms of antimicrobial and antidiabetic properties, toxicity profiles, and other animal model investigations. This review will provide a scientific basis for future studies in connection with the isolation of biologically active components from C. lanceolatus for the development of novel drugs.
AUTHOR CONTRIBUTIONS
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.
FUNDING
There is no funding to report.
CONFLICTS OF INTEREST
The authors report no financial or any other conflicts of interest in this work.
ETHICAL APPROVALS
This study does not involve experiments on animals or human subjects.
PUBLISHER’S NOTE
This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.
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