Cinnamomum cassia Presl: A Review of Its Traditional Uses, Phytochemistry, Pharmacology and Toxicology

Cinnamomum cassia Presl is a tropical aromatic evergreen tree of the Lauraceae family, commonly used in traditional Chinese medicine. It is also a traditional spice, widely used around the world. This paper summarizes the achievements of modern research on C. cassia, including the traditional uses, phytochemistry, pharmacology and toxicology. In addition, this review also discusses some significant issues and the potential direction of future C. cassia research. More than 160 chemicals have been separated and identified from C. cassia. The main constituents of C. cassia are terpenoids, phenylpropanoids, glycosides, etc. Modern studies have confirmed that C. cassia has a wide range of pharmacological effects, including antitumour, anti-inflammatory and analgesic, anti-diabetic and anti-obesity, antibacterial and antiviral, cardiovascular protective, cytoprotective, neuroprotective, immunoregulatory effects, anti-tyrosinase activity and other effects. However, the modern studies of C. cassia are still not complete and more in-depth investigations need to be conducted in alimentotherapy, health product, toxicity and side effects, and more bioactive components and potential pharmacological effects need to be explored in the future.


Introduction
Cinnamomum cassia Presl is an aromatic tree species belonging to the Lauraceae family. From the bark of its young branches, cinnamon is obtained, which is widely used all around the world for its fragrance and spicy flavor ( Figure 1). It can be used not only as a daily condiment, but also as a raw material for medical products, and has high economic value. Cinnamomum cassia Presl is distributed in China, India, Vietnam, Indonesia and other countries; In China, the producing areas are mainly concentrated in Guangxi, Guangdong, Fujian and Hainan provinces. Cinnamomi cortex is the bark of C. cassia, which is often used as a seasoning and spices in the West. For instance, in America, Cinnamomi cortex is used as a food supplements, as a coumarin source of [1]. In Asia, Cinnamomi cortex is usually used as a drug. Cinnamomi cortex is a common traditional Chinese medicine in China. Since 1963, Cinnamomi cortex has been listed in the Pharmacopoeia of the People s Republic of China (CH.P), and there are more than 500 formulas containing Cinnamomi cortex used to treat various diseases, such as cardiovascular disease, chronic gastrointestinal disease, gynecological disorders and inflammatory disease [2][3][4]. Currently, a lot of studies have been done on the pharmacological and phytochemical of C. cassia, and more than 160 chemicals have been separated and identified from C. cassia. More and more studies have confirmed that C. cassia has a wide range of pharmacological effects, including antitumour, anti-inflammatory and analgesic, anti-diabetic and anti-obesity, antibacterial and antiviral, of pharmacological effects, including antitumour, anti-inflammatory and analgesic, anti-diabetic and anti-obesity, antibacterial and antiviral, cardiovascular protective, cytoprotective, neuroprotective, immunoregulatory effects, anti-tyrosinase activity and other effects [3,4]. So far, the CH.P still recognizes Cinnamomi cortex as a common traditional Chinese medicine, and the content of cinnamaldehyde is used as an evaluation index for evaluating the quality of Cinnamomi cortex.

Traditional Usages
As a traditional Chinese medicine Cinnamomum cassia Presl has a wide range of pharmacological activities and a long history of use as a drug. The earliest medicinal history of this plant was recorded in the Shennong Bencao Jing, which is the earliest and most important encyclopaedia of traditional Chinese medicine in the Eastern Han Dynasty . In this classic, C. cassia was used for treating arthritis. In Mingyi Bielu, the function of C. cassia was analgesic. In Yaoxing Lun, which is another known traditional Chinese medicine classic, C. cassia was used for treating bellyaches and dysmenorrhea. In addition, C. cassia was also recorded in other famous traditional Chinese medicine books, such as Tangye Bencao, Bencao Gangmu, Bencao Jingshu, Bencao Huiyan, etc. Nowadays, C. cassia has become a common traditional Chinese medicine for treating nephropathy, dysmenorrhea, menoxenia and diabetes [5,6]. In order to be applied to clinic better, various dosage forms, such as pills, capsules, granules, oral liquid and so on, have been developed (Table 1).

Traditional Usages
As a traditional Chinese medicine Cinnamomum cassia Presl has a wide range of pharmacological activities and a long history of use as a drug. The earliest medicinal history of this plant was recorded in the Shennong Bencao Jing, which is the earliest and most important encyclopaedia of traditional Chinese medicine in the Eastern Han Dynasty . In this classic, C. cassia was used for treating arthritis. In Mingyi Bielu, the function of C. cassia was analgesic. In Yaoxing Lun, which is another known traditional Chinese medicine classic, C. cassia was used for treating bellyaches and dysmenorrhea. In addition, C. cassia was also recorded in other famous traditional Chinese medicine books, such as Tangye Bencao, Bencao Gangmu, Bencao Jingshu, Bencao Huiyan, etc. Nowadays, C. cassia has become a common traditional Chinese medicine for treating nephropathy, dysmenorrhea, menoxenia and diabetes [5,6]. In order to be applied to clinic better, various dosage forms, such as pills, capsules, granules, oral liquid and so on, have been developed (Table 1).

Prescription Name Main Component Traditional and Clinical Uses Reference
Zi Shen Pills Anemarrhenae Rhizoma, Phellodendri Chinensis Cortex, Cinnamomi Cortex Treating dysuria due to accumulation heat in bladder [7] Curing stomachache, poor appetite and dyspepsia due to asthenia cold of spleen and stomach [17] Li

Phytochemistry
There have been a lot of studies about the phytochemistry of C. cassia, and more than 160 components have been separated and identified from the plant. Among them, terpenoids are the most abundant phytochemicals in C. cassia, and phenylpropanoids are the bioactive components, among which cinnamaldehyde is considered as the representative component of this plant, and the indicator component stipulated in the CH.P. In addtion to the chemical components found in the bark, the chemical components of other parts of C. cassia, including leaves and twigs, were also reported. The identified compounds are listed in this section and the corresponding structures are also comprehensively presented (

Terpenoids
Terpenoids are the main compounds in essential oil of C. cassia (EOC). Plant essential oils have a lot of important biological functions and physiological activities. Essential oils with strong antibacterial, antiviral, antitumor and anti-inflammatory effects are the main characteristic components of the Lauraceae [52][53][54]. The terpenoids in EOC are monoterpenes, diterpenes and sesquiterpenes.

Terpenoids
Terpenoids are the main compounds in essential oil of C. cassia (EOC). Plant essential oils have a lot of important biological functions and physiological activities. Essential oils with strong antibacterial, antiviral, antitumor and anti-inflammatory effects are the main characteristic components of the Lauraceae [52][53][54]. The terpenoids in EOC are monoterpenes, diterpenes and sesquiterpenes.

Lignans
In recent years, lignanoids have been found in C. cassia, and 26 lignanoids have been isolated from it, which are shown in Figure 7. In 2016, cinncassin E (105) was found from the bark of C. cassia and its nitric oxide inhibitory activity has been demonstrated. Meanwhile, the lignanoids isolated from the twigs of C. cassia include cinncassin D (106), picrasmalignan A (107)

Other Compounds
In addition to these major compounds mentioned above, some other chemical compounds are found from C. cassia, including benzyl benzoate (140), 2-hydroxybenzaldehyde (141), 3-

Other Compounds
In addition to these major compounds mentioned above, some other chemical compounds are found from C. cassia, including benzyl benzoate (140), 2-hydroxybenzaldehyde (141), 3-

Anti-Tumor Effects
Histone deacetylases (HDACs) are enzymes which play a special role in tissue development and homeostasis. HDACs are divided into four categories: Class I (HDAC1, 2, 3 and 8); II (HDAC4, 5, 6, 7, 9 and 10); and IV (HDAC11) [55]. Recent studies have shown that HDACs are associated with tumor, cardiovascular, autoimmune and neurodegenerative diseases, and HDAC8 plays an important role in the physiological process of these diseases [56]. Gene knockout of HDAC8 can change the growth of cancer cells, cause cell cycle arrest and differentiation of neuroblastoma cells [57]. Trichostatin A (TSA) is a famous antitumor drug and HDAC inhibitor. In 2017, it was found that the bioactive compounds of water extracts of C. cassia (WEC, including cinnamic acid, cinnamaldehyde, and cinnamyl alcohol) bind to the active sites of the HDAC8 enzyme like TSA, and the molecular descriptors of C. cassia compounds and the binding interactions and energies were similar to those of TSA. Moreover the bioactive components of C. cassia were easier to synthesize. These studies showed that C. cassia is a potential antitumor drug [58]. C. cassia components have been extensively studied in lung cancer, breast cancer, oral cancer, cervical cancer, head and neck squamous cell carcinoma.
In 2013, Kin et al. found that procyanidin C1, isolated from the bark of C. cassia, could inhibit TGF-β-induced epithelial-to-mesenchymal transition (EMT) and cell metastasis in A549 lung cancer cells in a dose-dependent manner [51]. Later, in 2017, it was reported that ethanol extracts of C. cassia

Anti-Tumor Effects
Histone deacetylases (HDACs) are enzymes which play a special role in tissue development and homeostasis. HDACs are divided into four categories: Class I (HDAC1, 2, 3 and 8); II (HDAC4, 5, 6, 7, 9 and 10); and IV (HDAC11) [55]. Recent studies have shown that HDACs are associated with tumor, cardiovascular, autoimmune and neurodegenerative diseases, and HDAC8 plays an important role in the physiological process of these diseases [56]. Gene knockout of HDAC8 can change the growth of cancer cells, cause cell cycle arrest and differentiation of neuroblastoma cells [57]. Trichostatin A (TSA) is a famous antitumor drug and HDAC inhibitor. In 2017, it was found that the bioactive compounds of water extracts of C. cassia (WEC, including cinnamic acid, cinnamaldehyde, and cinnamyl alcohol) bind to the active sites of the HDAC8 enzyme like TSA, and the molecular descriptors of C. cassia compounds and the binding interactions and energies were similar to those of TSA. Moreover the bioactive components of C. cassia were easier to synthesize. These studies showed that C. cassia is a potential antitumor drug [58]. C. cassia components have been extensively studied in lung cancer, breast cancer, oral cancer, cervical cancer, head and neck squamous cell carcinoma.
In 2013, Kin et al. found that procyanidin C1, isolated from the bark of C. cassia, could inhibit TGF-β-induced epithelial-to-mesenchymal transition (EMT) and cell metastasis in A549 lung cancer cells in a dose-dependent manner [51]. Later, in 2017, it was reported that ethanol extracts of C. cassia (EEC) possess antimetastatic activity against A549 and H1299 cells by inhibiting TGF-b1-induced EMT and suppressing A549 tumor growth in vivo [62]. In 2018, Wu et al. reported that EEC can inhibit the metastasis of A549 and H1299 tumor cells by repressing u-PA/MMP-2 via FAK to ERK1/2 pathways, and there was no cytotoxicity at the highest concentration of 60 µg/mL [63]. Furthermore, Lee et al. found that water extracts of twigs of C. cassia (WETC) could inhibit the growth of the lung cancer cell lines A549, H1299 and LLC by inhibiting the activity of pyruvate dehydrogenase kinase (PDHK) [64].
In 2016, Chang et al. reported that EOC and cinnamaldehyde could significantly suppress the activity of HSC 3 cells and promote their apoptosis, with half maximal inhibitory concentration (IC 50 ) values of 13.7 and 10 µg/mL [65]. Later, in 2018, it was reported that ethanol extracts of twigs of C. cassia (EETC) can induce oral cancer cell death and inhibit nude mice tumor growth by activating caspase-3 and reducing Bcl-2 to induce apoptosis [66].
Additionally, an investigation in 2015 indicated that EOTC can significantly inhibit the growth of different cell lines (FaDu, Detroit-562, SCC-25) of head and neck squamous cell carcinoma (HNSCC) by inhibiting the active site of EGFR-TK, and also significantly inhibit the tumor growth in a Hep-2 cell xenotransplantation model [53].
In 2016, Lan et al. demonstrated that EOTC (15, 30 and 60 mg/kg) can significantly reduce the amount of writhing induced by oxytocin and acetic acid, inhibit the Complete Freund's adjuvant (CFA) and formalin-induced paw flinching and licking, in addition, EOTC also inhibited carrageenan-induced mechanical hyperalgesia and paw edema via inhibiting the levels of TNF-α, IL-1β, NO and PGE2, and depressed the expressions of iNOS and COX-2 in paw skin tissue of mice [52]. In addition, EAEBC was reported to be inhibitory to the production of NO in LPS-induced BV-2 microglial cells [46].
Additionally, C. cassia was confirmed to inhibit some other kinds of painful diseases. Oxaliplatin, a chemotherapeutic drug, can induce cold and mechanical hypersensitivity, but there is still a lack of effective treatments for neuropathic pain without side effects, it has been found that C. cassia has an effective analgesic effect on neuropathic pain induced by oxaliplatin [73]. In 2016, Kim et al. reported that WEBC (100,200 and 400 mg/kg) have a potent anti-allodynic effect via inhibiting the activation of astrocytes and microglia and decreasing the expression of IL-1β and TNF in the spinal cord after injection with oxaliplatin [74]. Later, In 2019, cinnamic acid (10, 20 and 40 mg/kg), a major compound of C. cassia, was reported to provide relief against oxaliplatin-induced neuropathic pain through inhibiting spinal pain transmission [75].

Anti-diabetic and Anti-obesity Effects
In 2006, Kwon et al. found that the WEBC (100, 250 and 500 mg/kg) can completely prevent streptozotocin (STZ)-induced diabetes in mice via inhibiting the expression of iNOS and the activation of NF-κB, Moreover, WEBC (0.125, 0.25, 0.5 and 1.0 mg/mL) decreased the production NO and the expression of iNOS mRNA induced by IL-1 β and TNF-γ, which can completely protect rat insulinoma RINm5F cells against IL-1 β and TNF-γ-induced cytotoxicity [3]. In 2013, Jang et al. found that the polyphenols of C. cassia (10 and 50 mg/kg) exhibited strong hypoglycemic activity in STZ-induced diabetes mice [76]. A report in 2014 demonstrated that acetone extract of barks of C. cassia (AEBC) showed great potential of decreasing the plasma glucose level via inhibiting rat α-glucosidase, maltase and sucrase activity (IC 50 = 0.474, 0.38 and 0.10 mg/mL) [77]. Later, Krishna et al. reported that decoumarinated extracts of C. cassia (200 mg/kg) can significantly alter the level of blood glucose, serum insulin, lipid distribution and liver antioxidant enzymes in STZ induced diabetic rats [78].
In addition to its hypoglycemic effect, cinnamon can also alleviate some complications of diabetes. In 2013, Luo et al. found that EEBC (10 µM) resisted the growth of high-glucose-induced mesangial cells via depressing the expression of IL-6, collagen IV and fibronectin [47]. Moreover, Yan et al. revealed that EEBC (10, 30 and 50 µg/mL) restrained the expression of fibronectin, MCP-1 and IL-6 in highglucose-stimulated mesangial cells [37]. In 2018, the extracts of barks of C. cassia (EBC) was reported to reduce the levels of MDA and NO, increase glutathione peroxidase (GPx) and glutathione (GSH), and down-regulate iNOS in thoracic aorta to prevent chronic complications of experimentally induced type II diabetes [79]. Furthermore, C. cassia silver nanoparticles (CcAgNPS) (5, 10 and 200 mg/kg) showed remarkable mitigation of severe distortion of the glomerular network, had a regenerative potential in diabetes-induced kidney damage [80].
In 2016, Lee et al. reported that the extracts of C. cassia (EC) (50, 100 and 200 µg/mL) boosted lipid storage in white adipocytes and increase the fatty acid oxidation capacity throughout the initiation stage of differentiation, which can prevent obesity-induced type II diabetes [81]. In vivo, WEBC (100, 300 mg/kg) significantly decreased serum levels of glucose, insulin, total cholesterol and ALT, suppressed lipid accumulation in liver, prevented oral glucose tolerance and insulin resistance in obese mice. In vitro, WEBC (0.1 and 0.2 mg/mL) increased ATP levels by increasing the mRNA expressions of mitochondrial biogenesis-related factors in C2C12 myoblast [82].

Antibacterial and Antiviral Effects
The abuse of antibiotics has led to the emergence of drug-resistant bacteria. Plant essential oils have a wide range of bacteriostatic effects and are rarely suffer from resistance issues.  [87]. In vitro, the EOC exhibited strong inhibition against Staphylococcus aureus with MIC values of 500 µL/L, and it had no inductive effect on the acquisition of stress tolerance in S. aureus [88]. Using the agar disc diffusion assay, the antibacterial activity of EOBC on Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa was evaluated, and the MIC values were 4.88, 4.88, and 19.53 µg/mL [89].
Molecular diversity in plants has helped humans discover many effective drugs, such as quinine in Cinchona succirubra and artemisinin in Artemisia annua, leading to a shift in anti-malaria research focus. In 2016, CcAgNPS was demonstrated that inhibited H7N3 influenza A virus in Vero cells with MIC values of 125 µg/mL, and it was found that had no-toxicity to Vero cells at the concentration of 500 µg/mL [90].

Cardiovascular Protective Effects
In 2015, Kwon et al. found that WEBC (10, 30 and 50 µg/mL) inhibited the proliferation of VSMCs via arresting G 0 /G 1 and down-regulating the expression of cell cycle positive regulatory proteins (p21 and p27), which can improve cardiovascular disease caused by proliferation of vascular smooth muscle cells [91]. Later, WEC (0-100 µg/mL) was demonstrated to inhibit the phosphorylation of ERK, p38 and vascular endothelial growth factor (VEGF) R2, the activation of MMP and VEGF-induced proliferation, migration, invasion, tube formation in cultured human umbilical vein endothelial cells (HUVECs) [92]. Furthermore, in vivo, Wei et al. revealed that WEBC (750 mg/kg) significantly decreased the serum levels of TG, TC, LDL and BNP shortened the intervals of QRS and P-R, increased the Ca 2+ Mg 2+ -ATP enzyme activity and the contents of PCr, ATP and ADP in STZ-induced myocardial injury diabetic rats [93].

Neuroprotective Effects
Recently, investigations into the neuroprotective effects of C. cassia such as anti-anxiety, cognitive improvement and anti-depressant have been conducted. In 2007, an experimental study on anti-anxiety effects showed that EEBC significantly increased the percentage of entries into and the time spent in the open arms in the elevated plus maze (EPM) test via regulating the 5-hydroxytryptamine1A (5-HT 1A ) and γ-aminobutyric acid (GABA)-ergic system [96]. Further, Jung et al. reported that the anxiolytic-like effects of EEBC (100, 750 mg/mL) were mediated by region-specific changes of 5-HT 1A receptors in the dorsal raphe nucleus [97].
In 2011, the WEC was evaluated for cognitive improvement in vitro and in vivo. The results showed that WEC (1, 10 and 100 µg/mL) markedly inhibited the formation of toxic Ab oligomers and prevented the toxicity of Ab on neuronal PC12 cells with the MIC value of 0.7 µg/mL. In AD fly model, WEC (0.75 mg/mL) extend their life, recovered their locomotion defects and totally eliminated tetrameric species of β-amyloid polypeptide (Aβ) in their brain. Moreover, WEC (100 µg/mL) marked decreased 56 kDa Aβ oligomers, reduced plaques and improved the cognitive functions in AD transgenic mice model [98]. Later, In 2017, it was reported that total flavonoids of Cinnamomi Cortex (20-100 µg/mL) enhanced viability of PC12 cell and activity of SOD, alleviated the DNA damage, decreased the expression levels of the Bax/Bcl-2 rate, cl Caspase-9 and the content of MDA in 6-hydroxydopamine injured PC-12 cell [99]. In 2016, the EC was evaluated for anti-depressant in vivo. The results showed that EC (25 and 50 mg/kg) significantly decreased the immobility time in TST (tail suspension test) and increased the 5-HTP-induced head twitches via rising the levels of serotonin [100].

Immunoregulation Effects
In 2014, Zeng et al. studied the immunoregulation effect of EEBC, the results showed that EEBC (100 µg/mL) inhibited 78.5% of T cell proliferation induced by concanavalin A (ConA), moreover, cinncassiol G and cinnacasol (50 and 100 µM), two new phytocompounds from Cinnamomi Cortex, significantly inhibited T cell proliferation induced by ConA and B cell proliferation induced by LPS in a dose dependent manner, and had no cytotoxicity in mice lymphocytes [39]. In addition, it is reported that phenolic glycosides of Cinnamomi Cortex (12.5-200 µM) inhibited T cell proliferation induced by ConA [48]. Furthermore, In 2017, cinnacasside F (400 µM), a new glycosides from Cinnamomi Cortex, inhibited 36.1% T cell proliferation and 20.3% B cell proliferation [45].

Other Pharmacological Effects
Apart from the pharmacological effects displayed above, C. cassia also possesses some other activities. In 2012, cinnamaldehyde, 2-methoxycinnamaldehyde, 2-hydroxycinnamaldehyde, cinnamic acid and coniferaldehyde and O-coumaric acid isolated from extracts of twigs of C. cassia (ETC) showed significantly inhibitory action on xanthine (IC 50 = 7.8-36.3 µg/mL) [42]. In 2014, the effect of methanol extracts of C. cassia (MEC) on arginase and sexual function were evaluated in vitro and in vivo. The results showed that MEC (0.1, 1, 10, and 100 µg/mL) inhibited arginase activity with an IC 50 of 61.72 ± 2.20 µg/mL in rat corpus cavernosum smooth muscle (CCSM). In addition, MEC (100 mg/kg) increased smooth muscle level, decreased collagen level in rat penile tissue and increased sexual function of young male rats [102]. Moreover, In 2017, it is reported that methanol extracts of barks of C. cassia (MEBC) (50, 100 and 150 mg/kg) aided in the recovery of the antioxidant system as well as protective role in histological damages and some haematological parameters in the rat liver treated with titanium dioxide nanoparticles (TiO 2 NPS) or titanium dioxide bulk salt (TiO 2 bulk salt) via increasing the serum level of CAT, decreasing the levels of SOD, lipid peroxidation, alanine aminotransaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) [103]. Later, the effect of EOTC on uterine contraction was evaluated in vitro and in vivo. The results showed that EOTC (25, 50 and 100 µg/mL) inhibited spontaneous uterus contractions in a dose-dependent manner via inhibiting the level of Ca 2+ in Myometrial cells (IC 50 = 361.3 µg/mL). In addition, EOTC (15, 30 and 60 mg/kg) reduced oxytocin (OT)-induced writhing responses via decreasing the level of PGF 2α , COX-2 and phosphorylation of myosin light chain 20 (P-MLC 20) [104].
Visceral leishmaniasis (VL) or kala-azar is the fatal form of leishmaniasis caused by Leishmania donovani, outbreaks in the tropics and subtropics, producing physical and reproductive disabilities and causing an immense death toll of 20,000-40,000 each year, which have made a great impact on society [105]. Despite decades of research, there is no available commercial vaccine against VL and chemotherapy is failing owing to emerging resistance and adverse side effects [106]. In 2019, Afrin et al. found that EBC showed great anti-promastigote activity through inducing apoptosis in vitro with IC 50 values of 33.66 ± 3.25 µg/mL. In addition, EBC (50 and 100 mg/kg) showed significant protection against L. donovani infected mice and hamsters, the in vivo protection achieved was 80.91% (liver) and 82.92% (spleen) in mice and 75.61% (liver) and 78.93% (spleen) in hamsters. The results showed that Cinnamomi Cortex had direct antileishmanial activity and non-toxicity in vitro and in vivo [107].

Summary of Pharmacologic Effects
In conclusion, C. cassia has a wide range of pharmacological effects including anti-tumor effects, anti-inflammatory and analgesic effects, anti-diabetic and anti-obesity effects, antibacterial and antiviral effects, cardiovascular protective effects, cytoprotective effects, neuroprotective effects, immunoregulation effects and anti-tyrosinase activity (Table 3). Modern pharmaceutical research mainly focuses on extracts and chemical components, which indicated the prospects of C. cassia in the treatment of such diseases.

Toxicity
C. cassia, as a common flavor and medicinal material, has little toxicity, and there are few reports about the toxicity and clinical adverse reactions of C. cassia. In 2002, it was reported that a 47 yearold male patient had swelling and itching in both hands and face after touching steamed Cinnamomi cortex for 1 h, while the other two people in the same group were normal. After disengagement, 10% calcium gluconate 10 mL and 50% glucose 20 mL was given via intravenous injection for 3 days, and the swelling gradually subsided [108]. In 2005, it is reported for the first time that the use of C. cassia essential oil mud bath could cause extensive eczematous and bullous dermatitis [109]. Later, in a randomized controlled trial of C. cassia hemoglobin A1C reduction in patients with type 2 diabetes, the treatment group received two C. cassia capsules (500 mg each) per day for 90 days, and one of the subjects developed a rash, which subsided after discontinuation, but no further adverse reactions were observed [110]. In 2018, a 13-week repeat-dose oral toxicity study revealed that body weights of rats were normal, the weight of kidney/live and the level of total cholesterol were increased after receiving WEBC at up to 2000 mg/kg, but it was not mutagenic or clastogenic [111]. Later, a 8-week repeat-dose oral toxicity study revealed that renal function showed a significant increase, kidney and liver histology showed distortions in hepatocytes and sinusoidal linings with infiltrations, degenerative changes in glomerular and Bowman's capsules with fibrillary mesangial interstitium after receiving CcAgNPs at up to 200 mg/kg [112]. In summary, C. cassia essential oil may cause skin irritation and its extract may possess potential nephrotoxicity and hepatotoxicity at dose higher than its recommended daily safe dose.

Conclusions and Future Perspectives
In conclusion, the traditional usages, phytochemistry, pharmacological activity and toxicity of C. cassia have been summarized in the present review. Modern studies have confirmed that C. cassia has a wide range of pharmacological activities, including anti-tumor effects, anti-inflammatory and analgesic effects, anti-diabetic and anti-obesity effects, antibacterial and antiviral effects, for which it has been used in the clinic in many countries. Moreover, C. cassia has the same origin as a medicine and food which is often used as a condiment in our daily life. Nevertheless, there is still a lack of sufficient research about the alimentotherapy, health products, toxicity and side effects of C. cassia. Therefore, more investigations need to be done in C. cassia in the future.
Firstly, there is a lack of systematic toxicity and side effects studies of the extracts or compounds isolated from C. cassia. Essential oils are the main constituents of C. cassia, which has been reported to irritate the skin and possibly cause allergies, and the antibacterial effect of essential oil is applied in food and cosmetics. In addition, as a plant with the same origin as medicine and food, people will also eat C. cassia for a long time, therefore, in-depth investigations on its toxicity and side effects are a guarantee for the safe use of this plant. Secondly, with the attention humans attach to health preservation, alimentotherapy and health care products are being more and more widely used, thus, there is great space for the development of valuable C. cassia health products. Thirdly, for traditional medicinal uses, the bark and twigs of C. cassia are important components of traditional Chinese medicine formula, such as Guifu-lizhong pills [113], Guizhi-shaoyao-zhimu decoction [114], thus current pharmacological activity studies of C. cassia have mainly focused on its barks and twigs, and there are few investigations on the leaves, fruits and other parts of C. cassia. Thus the study on other parts of C. cassia may be helpful to the development of alternative medicines and new drugs. Fourthly, the bark is an important part of the tree body, which can maintain the temperature, prevent diseases and pests, its main function is to transport nutrients for the tree body. The barks of C. cassia are officially recognized as Rou-Gui in the CH.P (2015 Edition), but many other Cinnamomum species such as Cinnamomum zeylanicum and Cinnamomum burmannii Blume, are used as C. cassia alternatives in many countries. Therefore, the plant morphology, chemical compositions and pharmacological activities should be used to differentiate the different varieties, and it is important to safeguard the efficacy of C. cassia to ensure its suitability and security for clinical use. Fifthly, the C. cassia was traditionally used in the treatment of dyspepsia, gastrointestinal diseases, irregular menstruation and arthritis, etc., but not all of these uses had been confirmed by modern preliminary studies. The discovery of artemisinin was based on a classical Chinese medical monograph, therefore the traditional uses in classical monographs should be reasonably developed, and more potential pharmacological activity of C. cassia might be explored in the future.
Funding: This research received no external funding.