Beneficial Biological Activities of Cinnamomum osmophloeum and Its Potential Use in the Alleviation of Oral Mucositis: A Systematic Review

The aim of this review was to provide an updated overview of studies on the medical-biological activities of Cinnamomum osmophloeum (C. osmophloeum) in vitro and in vivo and the potential therapeutic use of natural agents prepared from this plant for the alleviation of oral mucositis (OM). Reported articles were collected using web search engine tools. The systematic review was organized according to the preferred reporting items for reviews and meta-analyses (PRISMA) statement. Additional sources were identified through cross-referencing to identify the potential use of C. osmophloeum in the alleviation of OM. The results disclosed that C. osmophloeum is comprised of bioactive ingredients that could act diversely as a reagent in anti-inflammation, antibacterial, antioxidant, anti-hyperglycemic, antidyslipidemia, anti-cancer, renal disease therapy and anti-hyperuricemia capacities. Recent studies revealed that the overall effects on anti-inflammation, wound repair, and the antibacterial and antioxidant activities of its constituents would act as a potential remedy for oral mucositis. Up-to-date in vitro and in vivo studies on the medical-biological activities of C. osmophloeum suggested that C. osmophloeum and its constituents could be promising remedies as adjuvants in OM therapy and warrant further investigation.


No Chemical Compositions References
Cinnamaldehyde type
Other constituents such as Kaempferol glycosides were associated with nitric oxide inhibitory activities [28]. In certain studies, linalool extracted from C. osmophloeum exhibited a protective effect on the pancreas by ameliorating pancreatic levels of interleukin (IL)-1β and nitric oxide [3], which play an important role in the prevention of LPS-induced inflammation in vivo [40].
C. osmophloeum has been used as a tyrosinase suppressor, which exhibited a substantial effect on wound repair. This phenomenon occurred through the inhibition of tyrosinase activity and reduced melanin content. Lee et al. carried out an animal experiment and explored the role of C. osmophloeum in wound repair and as an anti-oxidative agent. They evaluated a wound size assay, which revealed a decrease in the wound area by day 5 [20].
In light of the specific activities of the constituents of C. osmophloeum, it is noteworthy to mention that one specific and major constituent (flavanol glycosides) with outstanding properties was involved in inhibiting the production of NO and cytokines (TNF-a and IL-12), from LPS/IFNc-activated macrophages (inhibition of inflammatory activities) [25]. An additional study revealed the in vitro inhibitory effect of IL-1â and IL-6 production resulting from the 21 constituents of C. osmophloeum (cell-mediated immune response) observed [24]. Anti-inflammatory activity studies of C. osmophloeum have also been applied systemically in specific disease treatment [3,22,27,40]. Numerous mechanisms of inhibiting inflammation, including the compositional contents, mechanisms, anatomical parts, and promising investigations, have also been reported elsewhere [22][23][24][25][26]28,40,45].

Antimicrobial Activities
The literature survey indicated that several pathogenic bacteria, including Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Salmonella sp., and Vibrio parahaemolyticus have been used to investigate the antibacterial activity of C. osmophloeum [30]. For constituents of C. osmophloeum, the order of antibacterial activities was in the following sequence: cinnamaldehyde > cinnamic acid > cinnamyl alcohol > cinnamyl acetate. Cinnamaldehyde has been used as a bactericidal agent of Legionella pneumophila in vitro [31]. Two investigations confirmed that C. osmophloeum possesses antibacterial activities in both Gram-negative and Gram-positive bacteria [31,32]. Hence, further study should be carried out to examine animals infected by a specific group or both Gram-negative and Gram-positive bacteria.

Antioxidant Activities
As one of the biomaterials commonly used for traditional medical therapy, C. osmophloeum has been reported to be antioxidative, and its properties encompassing other medical-biological effects have been assessed systematically and independently by researchers worldwide [18,20,[35][36][37]41].
DPPH and NBT Assays reported the antioxidant activities of kaempferol-7-O-rhamnoside [35]. The content had an excellent inhibitory effect on rat aldose reductase [51]. The flavonoid glycoside was proven to be the key antioxidant in a C. osmophloeum twig ethanolic extract [35]. These activities are associated with beneficial health effects. Therefore, cinnamomum has been widely used for its medicinal purpose and in nutritional food [52].

Antidyslipidemic Activities
The activity of C. osmophloeum in lowering the cholesterol level was investigated by Lin et al. They showed that both Kaempferol and kaempferitrin from C. osmophloeum have antidyslipidemic activity [38]. Furthermore, the S-(þ)-linalool in C. osmophloeum was also reported to have hypolipidemic activity by inhibiting the accumulation of body fat through downregulating adipocyte differentiation [39]. Two in vivo studies disclosed encouraging results demonstrating that S-(þ)-linalool was effective at cutting lipid accumulation. They also showed that low-density lipoprotein (LDL) was significantly decreased compared to high-density lipoprotein (HDL) [38,39].

Anti-Hyperglycemic Activities
Diabetes mellitus (DM) has become a serious medical problem. Numerous studies have been conducted by adapting natural materials as DM therapy. Among these bio-resource candidates, C. osmophloeum is one of the promising candidates. Proanthocyanidin and tannin from C. osmophloeum may possess anti-hyperglycemic activity [21]. CoTE (C. osmophloeum twig extracts) showed protein tyrosine phosphatase 1B inhibitory (PTP1B) activity to improve the insulin or leptin resistance [18]. Linalool, the constituent of the essential oil of C. Osmophloeum, might ameliorate the pancreatic values of thiobarbituric acid reactive substances. The activities of superoxide dismutase and glutathione reductase ameliorated pancreatic levels of IL-1β and NO in vivo in streptozotocin-diabetes mellitus (STZ-DM)) animals [3]. It was reported that a higher degree of polymerization of proanthocyanidins correlates with the inhibitory activity of α-glucosidase and α-amylase [21]. The studies explored leaves and twigs with different contents for decreasing the blood glucose level and treating diabetes mellitus. The results indicated that the leaves were more effective than the twigs, which contained less linalool. Moreover, in a practical sense, the leaves were much easier to preserve than twigs.

Effects on the Cardiovascular System
Cinnamaldehyde was shown to be one of the protective ingredients for cerebral microvascular endothelial cells in mice induced by aortic banding (AB) by reducing IL-1β-induced cyclooxygenase-2 (COX-2) activity [53]. In addition, the protective role of cinnamaldehyde in cardiac hypertrophy induced by AB was related to its regulatory effect on the ERK1/2 signaling pathway [7]. The effect on the cardiovascular system was related to the anti-inflammatory mechanism [7,53]. The authors introduced cinnamaldehyde as a major compound extracted from C. osmophloeum and it was bought from Sigma-Aldrich (USA). It was discussed that Cinnamomum cassia (C. cassia) would be a potential drug for cardiovascular disease [7]. Unreliable cinnamon species (C. cassia or C. osmophloeum) used in the report would be a critical issue to clarify because the authors may have been inconsistent in discussing the species of cinnamon.

Effect on Renal Disease and Anti-Hyperuricemia
It was reported that cinnamaldehyde in C. osmophloeum successfully inhibited the high glucose-induced hypertrophy of renal interstitial fibroblasts, as indicated by the decreased cell size; the falling cellular hypertrophy index; and the descending protein levels of collagen IV, fibronectin, and α-smooth muscle actin [4]. In order to decrease the level of uricemia, several in vivo study reports confirmed the proposed mechanisms [2,5]. The cinnamaldehyde type of C. osmophloeum leaf oil demonstrated anti-hyperuricemia effects through its xanthine oxidase inhibitory activity. Xanthine oxidase can catalyze the oxidation of hypoxanthine/xanthine to produce uric acid. Gout and hyperuricemia are caused by an excessive accumulation of uric acid [2,19].

Anti-Tumor and Anti-Cancer Activity
Trans-cinnamaldehyde, a bioactive content of C. osmophloeum, showed an inhibition of tumor growth [46,54,55]. It could stimulate Ca 2+ entry with subsequent cell membrane scrambling and cell shrinkage, hallmarks of eryptosis, and the suicidal death of erythrocytes [46]. Trans-cinnamaldehyde exposure induced cell death via caspase-dependent and -independent pathways resulting from the depletion or induction of ROS [54]. Lignan ester, one of the C. osmophloeum constituents, was shown to be a possible anticancer compound (liver and oral cancer). The cytotoxicity had a significant effect on human liver cancer (HepG2 and Hep3B) and oral cancer (Ca9-22) cells [42].

Potential Use of C. osmophloeum for the Treatment of Oral Mucositis (OM)
The current protocols of medicine for chemotherapy are associated with oral mucositis. Cytarabine, high-dose 5-fluororacil, alkylating agents, and platinum-based compounds are highly associated with the incidence of oral mucositis. Actinomycin D, amsacrin, bleomycin, busulfan, capecitabine, carboplatin, chlorambucil, cisplatin, cytarabine, docetaxel, doxorubicin, etoposide, floxuridine, ifofsamide, irinotecan, leucovorin, methotrexate, mitoxantron, oxaliplatin, paclitaxel, plicamycin, tioguanin, vinblastine, vincristine, vindecine, and vinorelbine (the protocol can be combined) are the medicines used for chemotherapy and are reported to lead to the development of oral mucositis [56,57]. In order to prevent oral mucositis, the Multinational Association of Supportive Care in Cancer (MASCC) and International Society of Oral Oncology (ISOO) help clinics by comprising Clinical Practice Guidelines for Oral Mucositis [58]. The recommendations are comprised of basic oral care, growth factors and cytokines, anti-inflammatory agents, laser and other light therapy, cryotherapy, and natural and miscellaneous agents (Table 3). Köstler et al. provided several experimental approaches to treat oral mucositis; they included locally applied non-pharmacological methods, anti-inflammatory and mucosa protectant agents, cytokines, granulocyte colony-stimulating factor (G-CSF, filgrastim) and granulocyte-macrophage colony-stimulating factor (GM-CSF, molgramostim), antiseptic agents, corticosteroids, mouth-coating agents, and dexpanthenol [57]. The study of C. osmophloeum and/or its constituents in OM are limited. In one study, the effect of cinnamaldehyde on oral mucositis and an evaluation of the salivary total antioxidant capacity of gamma-irradiated rats were carried out. The saliva samples were taken from the rats in triplicate [59]. In order to evaluate the consequences and severity of mucositis, the conditions of the oral cavity were assessed by using Parkin's clinical scale, where 0 represents normal mucosa, 0.5 indicates normally pink mucosa, 1 stands for minor red mucosa, 2 is severe red mucosa, 3 is local desquamation, 4 describes exudation and crust around less than half of the lip area, and 5 characterizes exudation and crust for more than half of the lip area [60]. The authors concluded that the clinical effects in the intervention group seemed to be due to the antioxidant, antibacterial, and anti-inflammatory effects of cinnamaldehyde. It is noteworthy to mention that through anti-inflammation and antioxidant mechanisms, cinnamaldehyde would delay the onset of oral mucositis. Moreover, alteration in the oral microflora of existing bacteria in the fourth phase (ulceration phase) could exacerbate the severity of mucositis, whereas cinnamaldehyde alleviated oral mucositis via its antibacterial properties [59]. A recent investigation reported the effect of cinnamon bark fractions (an essential oil and an aqueous extract) on Candida albicans growth inhibition (growth, biofilm formation, and adherence properties) and oral epithelial cells (barrier integrity and inflammatory response) [61]. The anti-adherence and anti-inflammatory properties of proanthocyanidins, a family of polyphenols containing flavan-3-ol oligomers and polymers, are used to treat oral infections [61,62]. The two pro-inflammatory cytokines, IL-6 and IL-8, which serve as important cytokines in the development of oral mucositis, were reduced by an aqueous extract enriched with proanthocyanidins of the cinnamon fraction. This shows that the cinnamon presented in the study may be a promising agent in the alleviation of oral mucositis [61].
Flavanoid-rich fractions containing kaempferitin in Bauhinia forficata leaves have been investigated and shown to be effective ingredients for preventing the intestinal toxic effects of irinotecan chemotherapy. It was stated that kaempferitin, as one of the major active contents of C. osmophloeum, has been tested to prevent or reduce the severity of intestinal mucositis [26,90]. The chemotherapy drug 5-Fluororacil possesses side effects (i.e., induces mucositis manifestations in oral and gastrointestinal after chemotherapy). Chimonatus Nitens var. salicifolius aqueous extract contains three flavonoid contents: quercetin, kaempferol, and rutin, which might have an anti-inflammatory effect on gastrointestinal mucositis [91]. Kaempferol, cinamic acid, and nine other constituents obtained in mucoadhesive propolis agent have been proven to be effective in reducing radiation-induced oral mucositis. A clinical study of 24 patients revealed that mucositis only developed in two patients and each developed grade 1 mucositis and grade 2 mucositis, respectively; however, in the remaining 20 patients, mucositis did not develop [92].

Wild chamomile (Matricaria recutita L.)
Anti-inflammatory, anti-bacterial, and anti-fungal Mazokopakis et al. (2003) [65] According to antibacterial mechanisms, several studies demonstrated bacterial changes due to radiotherapy and/or chemotherapy [85]. The bacteria were Gemella haemolysans, Streptococcus mitis [86], Escherichia coli, Pseudomonas aeruginosa, Enterobacter sp., Klebsiella pneumonia [87], Staphylococcus aureus, Staphylococcus epidermidis, Parvimonasmicra, Fusobacterium nucleatum, Treponema denticola, C. glabrata, C. kefyr [88], and Porphyromonas gingivalis [89]. Among these bacteria, C. osmophloeum has been confirmed to possess the antibacterial properties of Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis (Figure 3) [32]. Flavanoid-rich fractions containing kaempferitin in Bauhinia forficata leaves have been investigated and shown to be effective ingredients for preventing the intestinal toxic effects of irinotecan chemotherapy. It was stated that kaempferitin, as one of the major active contents of C. osmophloeum, has been tested to prevent or reduce the severity of intestinal mucositis [26,90]. The chemotherapy drug 5-Fluororacil possesses side effects (i.e., induces mucositis manifestations in oral and gastrointestinal after chemotherapy  Previous studies investigated the potential of C. osmophloeum to reduce oral mucositis. Nonetheless, C. osmopohloeum, which is a species of cinnamon, faces challenges in its use as an oral treatment. In addition, this review has several limitations. First, there are limited data on the medical-biological effects of C. osmophloeum and its potential use in oral mucositis therapy. Secondly, the reported events related to oral stomatitis allergy induced by cinnamon should be a concern [93][94][95]. In summary, C. osmophloeum and its constituent are anticipated to be effective and efficient in reducing the severity of OM by preventing secondary bacterial infection through their bactericidal activity, preventing the development of the second phase of OM (the primary damage response) or interrupting the third phase in which pro-inflammatory cytokines could enhance and accelerate the process of wound healing ( Figure 4). three flavonoid contents: quercetin, kaempferol, and rutin, which might have an anti-inflammatory effect on gastrointestinal mucositis [91]. Kaempferol, cinamic acid, and nine other constituents obtained in mucoadhesive propolis agent have been proven to be effective in reducing radiationinduced oral mucositis. A clinical study of 24 patients revealed that mucositis only developed in two patients and each developed grade 1 mucositis and grade 2 mucositis, respectively; however, in the remaining 20 patients, mucositis did not develop [92]. Previous studies investigated the potential of C. osmophloeum to reduce oral mucositis. Nonetheless, C. osmopohloeum, which is a species of cinnamon, faces challenges in its use as an oral treatment. In addition, this review has several limitations. First, there are limited data on the medicalbiological effects of C. osmophloeum and its potential use in oral mucositis therapy. Secondly, the reported events related to oral stomatitis allergy induced by cinnamon should be a concern [93][94][95].
In summary, C. osmophloeum and its constituent are anticipated to be effective and efficient in reducing the severity of OM by preventing secondary bacterial infection through their bactericidal activity, preventing the development of the second phase of OM (the primary damage response) or interrupting the third phase in which pro-inflammatory cytokines could enhance and accelerate the process of wound healing (Figure 4). osmophloeum ameliorated oxidative stress and pro-inflammation through its constituents. Several studies have investigated the anti-inflammation, antibacterial, and antioxidant activities. The review of medical-biological activities showed that C. osmophloeum and its constituents inhibit the proinflammatory response. C. osmophloeum potentially prevents the second phase of oral mucositis (the primary damage response) or may intercept in the third phase, with pro-inflammatory cytokines providing a positive reaction to enhance and accelerate the process of wound healing. C. osmophloeum was also confirmed to be bactericidal and inhibit bacteria which can reduce the severity of oral mucositis or secondary bacterial infection.

Conclusions
In conclusion, in vitro and animal studies have revealed the various medical-biological activities of C. osmophloeum encompassing anti-inflammatory, antibacterial, antioxidant, anti-tumor and anticancer, anti-hyperglycemic, anti-hyperuricemia, and antidyslipidemic activities and the effect on the cardiovascular system that have been used for renal disease therapy. Various chemical contents . Proposed potential use of C. osmophloeum in the alleviation of oral mucositis (OM). C. osmophloeum ameliorated oxidative stress and pro-inflammation through its constituents. Several studies have investigated the anti-inflammation, antibacterial, and antioxidant activities. The review of medical-biological activities showed that C. osmophloeum and its constituents inhibit the pro-inflammatory response. C. osmophloeum potentially prevents the second phase of oral mucositis (the primary damage response) or may intercept in the third phase, with pro-inflammatory cytokines providing a positive reaction to enhance and accelerate the process of wound healing. C. osmophloeum was also confirmed to be bactericidal and inhibit bacteria which can reduce the severity of oral mucositis or secondary bacterial infection.

Conclusions
In conclusion, in vitro and animal studies have revealed the various medical-biological activities of C. osmophloeum encompassing anti-inflammatory, antibacterial, antioxidant, anti-tumor and anti-cancer, anti-hyperglycemic, anti-hyperuricemia, and antidyslipidemic activities and the effect on the cardiovascular system that have been used for renal disease therapy. Various chemical contents identified in C. osmophloeum contribute to its valuable medical bioactivities. Several medical-biological activities are attributed to the active ingredients of C. osmophloeum for OM therapy. The key to OM alleviation could be the anti-inflammatory effect of C. osmophloeum, as the activation of several transcription factors might release the inflammatory reaction in the second phase of OM. The antibacterial and antioxidant properties of CO might also alleviate OM. These effects might occur during the first phase of OM, preventing the generation of reactive oxygen species, or in the fourth phase, inhibiting colonized bacteria. It was suggested that bacterial cell wall products could be prevented from entering the oral submucosa.