Introduction

The genus Cinnamomum belongs to the plant family of Lauraceae. It comprises about 250 species, which are distributed in tropical and subtropical Asia, Australia, Pacific islands [1]. The inner bark of the Cinnamomum trees is known as cinnamon [1]. Commercial cinnamons are obtained from various Cinnamomum species, such as Ceylon cinnamon and Cassia cinnamon. The Ceylon cinnamon usually refers to the dried bark of C. verum Berchthold and Presl. (synC. zeylanicum), and it is indigenous to Sri Lanka and southern India [1]. Cassia cinnamons are differ from Ceylon cinnamon, which are usually known as Chinese cassia (C. cassia (L.) Berchthold and Presl.), Saigon cassia (C. loureiroi Nees, Vietnamese cinnamon), and Indonesian cassia (C. burmannii) [1]. The species of Cinnamomum are cultivated as landscape plants and sidewalk trees, and used in traditional medicine, timber, as well as edible fruits. Importantly, cinnamon is commonly used as a spice in food to give aroma taste and flavor, and to act as a preservative [1]. Other folk uses of cinnamon include applying its essential oil as a fragrance in cosmetics, perfumes, and cigarettes [1].

Although people used cinnamon for quite a long time, however, the hepatotoxic compound, coumarin is found in cinnamon in various amounts [2]. Coumarin is a natural flavoring molecule used as an ingredient in foods, alcoholic beverages, tobaccos, toothpastes, and detergents. In this connection, it is interesting to note that the coumarin contents of Cassia cinnamons are generally higher (~40‒12180 mg/kg), than that of Ceylon cinnamon (~0−486 mg/kg) [3,4]. However, the use of coumarin as a food flavoring agent is prohibited in the 1950s due to its hepatotoxicity. In this connection, it is necessary to found the alternative source for the safer cinnamons with low coumarin content, which can be beneficial to the global spice market.

Cinnamomum osmophloeum Kanehira is a native tree species in Taiwan, commonly known as pseudo cinnamomum or indigenous cinnamon [5]. Eight of 14Cinnamomum species in Taiwan are endemic, including C. osmophloeum [5]. It is a small evergreen tree that grows in the mountainous area of Po-Li, Taiwan [6]. The plant C. osmophloeum grows to 12 m in height and about 40 cm in diameter, and normally inhabits in Taiwan’s natural hardwood forests at elevations between 400 and 1500 m [6]. The leaves of C. osmophloeum are traditionally used in Taiwanese folk medicines as an antibacterial, antifungal, antitermite, antidiabetic, antihyperuricemia, antiinflammatory, and antioxidant agent [5]. Additionally, C. osmophloeum leaves are used in food, flavoring agent, spices, beverages, medical products, and perfumes. The leaves of C. osmophloeum has nine chemotypes with various secondary metabolite profiles, which are discussed later of this review. It is interesting to note that the leaf essential oil of C. osmophloeum is similar to those of commercial C. cassia bark essential oil [2]. However, the Cassia cinnamon bark samples contain higher level of coumarin, whereas the C. osmophloeum leaf samples comparatively contains the lower levels of coumarin [2]. Taste-wise, C. osmophloeum leaves are milder than ceylon cinnamon, and less heavy on the spicy notes with wafts of vanilla. The plant C. osmophloeum is cultivated in the large areas in Taiwan. A recent review reported that the potential use of C. osmophloeum in the alleviation of oral mucositis [7]. However, the chemical structures of the compounds and their complete pharmacological activities are not fully displayed. Therefore, the present review reported the phytochemical constituents and their potential pharmacological activities, analyses methods, as well as other economic benefits of C. osmophloeum.

Literature Methodology

Relevant information about C. osmophloeum is obtained from ancient books, records, doctoral and

master's theses, and scientific search engines including, PubMed, SciFinder, Web of Science, Science Direct, Google Scholar, and so on. The literature search is carried out to gather all relevant information about the traditional uses, phytochemicals and pharmacological activities, and underlying mechanism of action, toxicological and safety considerations of C. osmophloeum. All chemical structures were drawn using ChemDraw 17.0 software.

Specific Identification of C. osmophloeum

Many Cinnamomum plants are morphologically similar [1]. The hepatotoxic adulterant Cinnamomum

species, such as C. burmannii, C. loureiroi, andC. cassia, are easily confused with that of non-hepatotoxicC. osmophloeum. Therefore, specific differentiation of C. osmophloeum is critical to avoid toxic issues associated with fraudulent adulteration. In this connection, it is reported that the genetic variation and taxonomic relationship of C. osmophloeum, C. macrostemon and C. insulari [8]. The linalool synthase (LIS) genes are isolated from different provenances of C. osmophloeum [9], and the cinnamaldehyde is increased in 4-coumarate: coenzyme A ligase 1 and 4 (Co4CL1 and Co4CL4 ), and cinnamoyl-CoA reductase (CoCCR) transgenic plants [10]. Further, the Cinnamomum species, C. burmannii (Nees & T. Nees) Blume, and C. insularimontanum Hayata are morphologically similar with C. osmophloeum [11,12]. However, the leaves of C. burmannii and C. insularimontanum contains lower amount of cinnamaldehyde as compared with the leaves of C. osmophloeum [12]. Therefore, quantitative determination of cinnamaldehyde is an optional method for the identification of C. osmophloeum from C. burmannii and C. insularimontanum [12]. On the other hand, a novel method using leaf images and deep convolutional neural networks (CNN), is reported for the distinction of C. burmannii, C. insularimontanum and C. osmophloeum [12]. To continue, a novel DNA sequence comparisons of internal transcribed spacer 2 (ITS2) method is also reported for the identification of gene resources, genetic diversity, and nucleotide sequence polymorphisms for 73 geographical strains of C. osmophloeum [13]. Recently, Yang et al., developed a polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) method for rapid identification C. osmophloeum from adulterant Cinnamomum species by DNA polymorphism analysis [14].

Chemical Constituents of C. osmophloeum

Essential oil components

Essential oils (EOs) are colorless volatile liquids with a characteristic feature of strong odor. Hence, they are widely used in aromatherapy and cosmetics industry [15]. The EOs comprising the aromatic and volatile compounds naturally present in all parts of the plants including seeds, flowers, peel, stem, bark and whole plants [15]. EOs are freely soluble in various solvents such as alcohol, ether, and fixed oils, but insoluble in water [15]. In general, EOs display similar chemical composition and biological activities when obtained from a single plant species grown under similar climate, edaphic conditions and common harvest season. However, the quality and quantity of EOs are vary depends on plant organ, age of trees, chemotypes, growing season, methods of preparation, soil type and climatic conditions [15]. The GC and GC/MS analyses methods are widely used to identify the leaf EO components of C. osmophloeum. The chemical components of leaf EOs are different from various C. osmophloeum clones found in different regions in Taiwan [16-20]. It is interesting to note that the chemical constituents of C. osmophloeum leaf EOs are similar to those of C. cassia bark oil with cinnamaldehyde as the major component [21]. C. cassia bark oil has commercial value, and generally used in food and beverages.

Hu et al., (1985) [22], established an indigenous cinnamon clonal orchard with cuttings of trees from 13 natural populations from central, eastern and southern regions of Taiwan, and analyzed the composition of the EOs ofC. osmophloeum leaves [22]. They found that C. osmophloeum leaves from certain provenances contain cinnamaldehyde as the major constituent, whereas linalool is a major compound in some other provenances. Based on the abundances of each individual constituent, it is classified the C. osmophloeum leaf EOs into nine types: cassia type, cinnamaldehyde type, coumarin type, linalool type, eugenol type, camphor type, 4-terpineol type, linalool/terpineol type, and mixed type [22]. The GC/MS analysis of volatile oil obtained from the steam distillation of C. osmophloeum leaves, resulted in the identification of EOs components, such as α-pinene (EO14), camphene ( EO15), benzaldehyde (EO1), etc. (Figure 1, Table, 1) [22]. Fang et al., (1989) [24] reported that the quantitative analysis of EO components from the bark and leaves ofC. osmophloeum (Table 1) [24]. They identified that the component, trans-cinnamaldehyde (EO6), as a major constituents in the EO of the both the bark and leaves (~85%) [24]. Furthermore, the five years old plantation trees gives the EOs with an yield of 0.88%, and 0.16% from the leaves and bark, respectively [24]. It is reported that EOs of clones A and B are different, where A belongs to the mixed type, whereas B belongs to the cinnamaldehyde type [25,26]. Further, Cheng et al., (2004) [19] classified the C. osmophloeum leaf EOs of eight provenances into five chemotypes namely, cinnamaldehyde type, linalool type, camphor type, cinnamaldehyde/cinnamyl acetate type, and mixed type [19]. To continue, based on the abundance the leaf EOs are classified into six chemotypes namely, cinnamaldehyde type, cinnamaldehyde/cinnamyl acetate type, cinnamyl acetate type, linalool type, camphor type, and mixed type [27,28]. It is identified that the EOs and key constituents from the leaves of two C. osmophloeum clones are belongs to two different chemotypes, which are classified as the cinnamaldehyde type and camphor type [29]. Cheng et al. (2012) [30], reported that the content of linalool (EO12) varied from 28.8 to 35.1 mg/g, in the EOs of C. osmophloeum ct. linalool leaves collected from various plants and seasons [30]. Lee et al., identified the chemotype of majorC. osmophloeum leaf EOs are linalool type (40.24%), followed bytrans-cinnamyl acetate (EO10, 11.71%), camphor (EO38, 9.38%), cinnamaldehyde ( EO6, 6.87%), etc. (Figure 1, Table 1) [31]. This chemotype, contains relatively small amount of cinnamaldehyde as compared with linalool (6.87% vs 40.24%) [31]. To continue, C. osmophloeum leaf EOs are obtained by hydrodistillation, and the GC-MS analysis indicates that the trans-cinnamaldehyde (70.20%) as a the major one, while the caryophyllene oxide (EO11, 0.08%) is the least abundant [32]. These above previous reports indicates that the leaf EOs of C. osmophloeum contains numerous volatile compounds, including monoterpenes, sesquiterpenes, and their oxygenated derivatives and, alcohols, phenols, aldehydes, ketones, esters, acids, and other miscellaneous compounds (Figure 1, Table 1). It is also observed that the major components of C. osmophloeum leaf EOs are, trans-cinnamaldehyde, cinnamyl acetate, linalool and eugenol (Table 1).

On the other hand, EOs from the twigs of C. osmophloeum constituents various components including trans-cinnamaldehyde (EO6) (Table 1) [41]. The thermal stability results of C. osmophloeum leaf EOs indicated that trans -cinnamaldehyde content in eugenol-free EO is affected by high temperatures, however, the stability of EO improved by adding appropriate amounts of eugenol [33]. The identified chemical structures of the EOs from the C. osmophloeum are presented as in Figure 1, and the components names are listed in Table 1.

Figure 1: Chemical structures of essential oil components from C. osmophloeum.

Table 1: The essential oil components of C. osmophloeum

Cinnamon (C. cassia) is a common spice with sweet, spicy, and special flavor. It has been widely used in bakeries, drinks, desserts, and cuisines. The main constituent of essential oil from cinnamon bark is transcinnamaldehyde (EO06). The leaf EOs of indigenous cinnamon (C. osmophloeum) contains higher amount of EO06 as compared with Cinnamon (C. cassia) [2]. In particular, the C. osmophloeum leaf EOs contains ~80% (w/w) of trans-cinnamaldehyde (EO06), and these values ranged from 769 to 809 g/kg of EOs, which correspond to about 8.9−26.1 g/kg of sample [2]. Additionally, the cinnamaldehyde content of the cinnamon bark EOs is ~325 g/kg, which is much lower than the cinnamaldehyde contents of the C. osmophloeum leaf EOs (769 to 809 g/kg). Therefore, C. osmophloeum leaves can be considered a good quality and has a potential cinnamon substitute source to replace commercial bark cinnamons [2]. Further, a recent report indicates that the relative content of transcinnamaldehyde in the leaves of C. osmophloeum ct. cinnamaldehyde has the seasonal variation, which is relatively lower (32.2%) in the month of May as compared with the rest of the months (>76.3%) [42]. On the other hand, the leaf EOs of C. osmophloeum contains comparatively lower level of coumarin (0.29−13.99 mg/kg), as compared with the EOs of Cassia cinnamon (26.8−97.4 mg/kg) [2]. Therefore, it is reasonable to suggest that the C. osmophloeum as a safer spice substitute for C. cassia.

Other (Non-essential oil) metabolites of C. osmophloeum

Flavonoids are a class of secondary metabolites that consist of more than 7000 structures with fifteen carbon atoms. This class of compound have a wide-range of bioactive properties, including antioxidant, protective against inflammatory processes, hypertension, arthritis and AIDS, and so on. The flavonoid glycosides compounds, kaempferitrin (F1) and kaempferol-7-O-α-rhamnoside (F10) along with coumarin, fumaric acid are reported from the leaves of C. osmophloeum (Figure 2, Table 2) [43]. Chemical examination of the 80% methanolic extract from C. osmophloeum leaves, resulted in the isolation of highly sweet constituent, trans-cinnamaldehyde (in 1.03% yield, w/w) [23]. Phytochemical investigation on the n-butanol fraction of methanol extract from C. osmophloeum leaves, resulted in the isolation of four kaempferol glycosides (F1 ‒ F4), including a novel one, kaempferol 3-O-β -Dglucopyranosyl-(1→4)-α-L-rhamnopyranosyl-7-O-α-L-rhamnopyranoside ( F2) (Figure 2, Table 2) [44]. It is interesting to mention that the compound kaempferitrin (F1) is obtained in an appreciable quantity of 0.2428% (w/w) from the leaves ofC. osmophloeum [44]. The hot water extract of leaves ofC. osmophloeum resulted in the identification of F1 and F3 [37]. The ethanolic extract of twigs from C. osmophloeum led to the isolation of kaempferol glycosides, F1 ‒ F3, and F5 ‒ F10 (Figure 2, Table 2) [45]. Chemical examination of water extract of C. osmophloeum leaves resulted in the isolation of kaempferol glycosides F1 and F10 (Figure 2, Table 2) [46]. To continue, chemical investigations of the CHCl ₃- and n-BuOH-soluble layer of the methanolic extract of the stems of C. osmophloeum resulted in the isolation of flavonoids, lignans, and benzenoids (Figure 2, Table 2) [47].

Figure 2: Chemical structures of non-essential oil metabolites from C. osmophloeum

On the other hand, lignans are an important part of the secondary metabolites of Cinnamomum species, which have high content and abundant structural types. The phytochemical investigations of the ethanol extracts of C. osmophloeum heartwood and roots, resulted in the isolation of various lignans including three novel structurally related lignan esters, one secolignan ester (L3) and two cyclolignan (or aryltetralin lignan) esters (L4 andL5) (Figure 2, Table 2) [48]. Chemical examination of then-butanol soluble fraction of 70% acetone extract from C. osmophloeum twig extracts, resulted in the isolation and structure identification of proanthocyanidins, cinnamtannin B1 ( A1) and parameritannin A1 (A2) (Figure 2, Table 2) [49]. Recently, a novel cyclopropanoid, 4(2-(benzo[d][1,3]dioxol-5-yl)cyclopropoxy)-2,6-dimethoxyphenol ( B5) is reported from the stems of C. osmophloeum (Figure 2, Table 2) [50].

Table 2: The reported non-essential oil metabolites of C. osmophloeum

Pharmacological Activities of C. osmophloeum Extracts and Compounds

Pharmacological potential of essential oils (EOs)/components

Most of the chemical components in EOs of C. osmophloeum are low-molecular weight compounds, which can easily diffuse across cell membranes to induce biological reactions [7]. A couple of studies have proposed cinnamaldehyde to be a major functional compound for the antidiabetic activity of cinnamon [1]. The antibacterial activities of the EOs from leaves of two C. osmophloeum clones (A and B) were examined against nine strains of bacteria. The results showed that the MICs (minimum inhibitory concentrations) of the B leaf oil were 500 µg/ml against both Klebsiella pneumoniae and Salmonella sp. and 250 µg/ml against the other 7 strains of bacteria (Table 3) [25]. The MICs of cinnamaldehyde against the Escherichia coli,Pseudomonas aeruginosa, Enterococcus faecalis,Staphylococcus aureus, S. epidermidis, MRSA,K. pneumoniae, Salmonella sp., and Vibrio parahemolyticus are 500, 1000, 250, 250, 250, 250, 1000, 500, and 250 µg/ml, respectively (Table 3) [25]. The compound transcinnamaldehyde showed potent inhibitory activity against Jurkat (IC₅₀=0.057µM) and U937 (IC₅₀=0.076µM) cell viability, without affecting the viability of primary purified T cells and macrophages (Table 3) [51]. The leaf EOs from various geographical provenances showed potential antifungal effect against tree pathogensRhizoctonia solani, Collectotrichum gloeosporioides, Ganoderma australe and Fusarium solani [36], and inhibit the expression of pro-IL-1β, IL-1β and IL-6 in endotoxin-induced J774A.1 macrophages [39]. The leaf EOs of 92 cutting clones from a clonal orchard of C. osmophloeum showed antioxidant activity [38]. The EOs of C. osmophloeum leaves showed potential xanthine oxidase (XOD) inhibition and anti-hyperuricemia effect in mice [37], and the major component in it EO06 showed inhibitory effect in controlling the red imported fire ant [34]. The mosquito larvicidal activity of leaf EOs and their constituents from six chemotypes of C. osmophloeum is examined against the three mosquito species, and the results demonstrated that the cinnamaldehyde type and cinnamaldehyde/cinnamyl acetate type showed superior inhibitory effect against Aedes albopictus larvae [35]. The compounds, trans-cinnamaldehyde, Τ-cadinol, and α-cadinol are the major components of leaf EOs to the observed anti-inflammatory activity of C. osmophloeum in the endotoxin-treated RAW 264.7 macrophages [52]. The leaf EO components showed in vivo hepatoprotective effects through reduction in serum levels of AST, ALT, TNF-α, and IL-6, as well as hepatic inflammation and, necrotic and apoptotic tissue injury in lipopolysaccharide/Dgalactosamine (LPS/D-GalN)-treated mice [53]. The compound trans-cinnamaldehyde (EO6, 1 mg/kg) showed in vivo cytokine modulatory effects through increased serum concentrations of IL‐2, IL‐4 and IL‐10, but not IFN‐γ in ovalbumin (OVA)‐primed balb/c mice [54]. The EOs fromC. osmophloeum leaves exert in vivo antioxidant [29], and in vivo anti-diabetic effect through improved insulin secretion [31]. The linalool chemotype leaf EOs from C. osmophloeum showed, in vivo protective effect in the endotoxin-induced systemic inflammatory response through suppression of the TLR4 and NLRP3 signaling pathways [55]. The leaf EOs (13 mg/kg body weight) of C. osmophloeum reduced the endotoxin-induced systemic inflammation through the inhibition of the expression of molecules in both TLR4 and NLRP3 signaling pathways [40]. Additionally, it is confirmed that both cinnamaldehyde (EO06) and linalool (EO12) are the responsible active compounds for the observed biological activity [40]. The thermos-stability of cinnamaldehyde-chemotype C. osmophloeum leaf EOs is stabilized by microencapsulation with β-cyclodextrin, and the microencapsulated oil showed superior xanthine oxidase inhibitory activity [56]. The C. osmophloeum ct. linalool leaf oil showed in vivo antidepressant and motor coordination activities in a rodent animal model [57]. Additionally, the thermal degradation of linalool-chemotype C. osmophloeum leaf EOs is stabilized by its microencapsulation with β-cyclodextrin [58]. On the other hand, twigs EOs and its major constituents from the twigs of C. osmophloeum showed anti-inflammatory activity through reduced nitric oxide (NO) and prostaglandin E2 (PGE2) production in activated RAW 264.7 macrophages [41]. The reported pharmacological activities of C. osmophloeum EOs and their major constituents are presented as in Table 3.

Table 3: The biological activities of C. osmophloeum essential oil / components.

Pharmacological activities of C. osmophloeum crude extracts

Studies are reported that C. osmophloeum crude extracts showed various pharmacological activities such as antioxidant, anti-inflammatory, anti-tyrosinase, anti-obesity, and anti-diabetic, and wound-healing effects. Diabetes mellitus (DM) is a chronic disease that affects about 7% of the world's people and it is expected to increase by 5.5% in 2025 [69]. DM type 2 (T2DM) accounts for 85–90% of all diagnosed diabetic patients with high medical and social costs [69]. Cinnamon also has a long history of therapeutic use for various health problems including diabetes [1]. However, it was not until the past decade that the possible antidiabetic role of cinnamon in humans and in experimental animals has been investigated scientifically [1]. The results of the antidiabetic effect of cinnamon are inconsistent [1]. Although several clinical studies and a few meta-analyses have confirmed the usefulness of cinnamon as an antidiabetic agent, the results of other clinical studies and meta-analysis have shown cinnamon to be ineffective in oral glucose tolerance, insulin sensitivity, fasting blood glucose, glycated hemoglobin, lipid profile, or peripheral insulin levels in type 2 diabetes patients [1].

Rao et al., (2007) [70] reported that the chloroform and methanol extracts of C. osmophloeum bark showed anti-inflammatory and anti-cancer properties through the reduced inflammatory mediators (NO, TNF-α and IL12) production in activated macrophages, and tumor cells proliferation, respectively [70]. Oral administration of C. osmophloeum leaves hot‐water extracts, reduced the total cholesterol (TC), triglyceride (TG) and low‐density lipoprotein (LDL‐C) levels in hyperlipidemic hamsters [71]. The phenolic content of C. osmophloeum water extracts is 160.9 mg/g, which showed a potential antioxidant activity with an IC₅₀ values of 10.3 and 16.9 μg/mL, for DPPH and superoxide radical scavenging assays, respectively (Table 4) [46]. The ethanolic extract of C. osmophloeum leaves, dose-dependently (10, 25, 50, 100, and 200

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