A review: the botany, ethnopharmacology, phytochemistry, pharmacology of Cinnamomi cortex

Cinnamomi Cortex (CC) is the dried bark of Cinnamomum cassia (L.) J. Presl. Modern pharmacological research shows that CC can be used to treat diabetes, breast cancer, leukemia and other diseases. It has been used for more than 2000 years in China, mainly distributed in Guangxi, Guangdong, Yunnan and Fujian. In this paper, the botany, ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics and other aspects of CC are summarized. We hope to provide convenience for the further exploration and development of CC. There are more than 300 components isolated from CC including essential oils, polyphenols, diterpenes and sesquiterpenes, flavonoids, polysaccharides and others. Pharmacological studies show that CC has a wide range of pharmacological activities such as anti-inflammatory, antibacterial, antioxidant, antitumor, improving glucose and lipid metabolism, neuroprotection and so on. It shows that CC has great potential to develop into a cheap, low-toxicity and highly-efficient natural therapeutic drug. However, there is still a long way to go for research of CC, although great progress has been made. For instance, clinical practices for CC recorded in traditional medicine books need to be paid more attention. Present achievements are still not enough to clearly explain the mechanism for some diseases. New skeletons and new drugs will be required to be discovered, so that the potential of CC can be brought into full play.


Introduction
The dried bark of Cinnamomum cassia (L.) J. Presl (CCP), CC is used as a food spice or medicine. CC has been cultivated and used worldwide for thousands of years. In China, people call it rougui. In India, CC is called tejpat, and it is consumed as a spice. The earliest record of rougui can be traced to Sheng Nong's herbal classic . It is also listed as a top-grade herb in ancient medical volumes. The Chinese Pharmacopoeia mentions that CC is sweet and pungent in avor; hot in property. It affects the kidney, spleen, heart, and liver meridians, where it has the functions of eliminating cold and relieving pain, promoting blood circulation and raising body temperature. Clinically, CC is used as a remedy to treat impotence, arthritis, dizziness, vomiting, fever, diarrhea, abdominal pain, cardiopathy, prostatitis, dysmenorrhea, and amenorrhea. 1 CC is produced in Guangdong and Guangxi provinces. Phytochemical studies showed that its constituents include essential oil, 2 polyphenols, 3 diterpenes, 4 avonoids, 5 polysaccharides, 6 and other compounds. Pharmacological studies showed that CC's effects include anti-inammatory, 7 antibacterial, 8 antioxidant, 8 and antitumor 9 properties; it also improves glucose and lipid metabolism, 10 mediates neuroprotection, 11 and performs other functions. It is irregular pieces, thin and dry, with no yellow-brown lines between the inner and outer layers, with the light aroma and more mucus It tastes slightly pungent and sweet, with the warm nature. And it has the effect of dispelling wind and cold, warming the baby and relieving pain 99 Yin Xiang Cinnamomum tamala (Ham.) Nees et Eberm.
Bark is mostly semi-cylindrical, with dark brown outer skin and gray-white pattern, dark brown inner surface and yellow-brown lines between them, contains a lot of mucus, and has a faint scent like camphor It enters liver and spleen meridians, tastes pungent and sweet, with the warm nature. And it has the effect of warming and dredging meridians, activating qi and relieving pain 99 Chai Gui Lindera obtusiloba Bl.
Its outer surface is reddish brown, with occasional gray spots, and its inner surface is reddish brown and smooth. It is easy to break, slightly fragrant, light in taste, and the water extract has more mucus It tastes pungent, with the warm nature. And it has the effect of promoting blood circulation for removing blood stasis and detumescence 98 San Ya Wu Yao

Machilus pauhoi Kanehira
The outer surface is brown and smooth, the inner surface is brown, which is not easy to break, slightly fragrant, slightly bitter and astringent, and the chewing viscosity is large. Aer soaking in water, there is a lot of mucus on the inner surface As an ornamental plant, it is generally not used for medicinal purposes CC has visible white markings and thin longitudinal stripes. The inner surface is dark reddish-brown and uneven. It is easy to break and difficult to cut. Sand lines are in the middle. Slices appear semi-aky and uneven. The outer layer is yellow-brown, rough, and granular. The inner layer is reddish-brown and oily with a faint, aromatic scent. The taste is sweet and spicy. 15 The brous cells in the powder of CC are long spindle-shaped, with concave-convex edges. The cell wall is thick and shows a ligni-cation reaction. The oily cell wall is thin and spherical. The cork cell wall is thick and polygonal. Starch granules are ne and oval. 16 As a deep-rooted tree species, CCP grows in warm, humid, and sunny environments and is strongly shade-tolerant. It does not tolerate frost and snow, drought, stagnant water, or severe cold. It grows well in loose and fertile sandy soil that is welldrained, acidic, and rich in organic matter, including sand dunes or sloping mountains. 17 It primarily grows in Guangdong, Guangxi, Fujian, Taiwan, and Yunnan in China and is also found in India, Laos, Vietnam, and Indonesia. Generally, the harvest time of CC is spring and autumn. People rst draw a line on the tree surface, then peel off bark from the trees individually. The bark is cut into strips, putting it under the laundry basket to braise it. 18 CC is preferred when it is exquisite, thick and heavy, unbroken, sufficiently oily, intensely fragrant, sweet and slightly pungent, with less chewing residue.
Unfortunately, herbal markets are currently full of CC imitations. 19 It is not uncommon that businesses use other bark that has a similar appearance to CC to sell at a low price; this practice is detrimental to evaluations of quality and clinical efficacy and may even cause medical accidents. For these reasons, standardizing the quality of CC is critical. We consulted the literature and summarized the plants that are confused with CC in terms of morphological characteristics and medicinal characteristics (Table 1).

Traditional uses
CC has been used in China for thousands of years and recorded in many Chinese medicine books. It warms the spleen and stomach, promoting blood circulation. The recommended dosage is 1-5 g. Individuals with bleeding tendency or pregnant women should use it with caution. CC cannot be used with halloysitum rubrum. The adsorption effect of halloysitum rubrum inuences the dissolution of the essential oil, reducing or weakening the sedative and analgesic effects of CC. 20 There are some records in the classic literature.
De Pei Ben Cao of the Qing Dynasty recorded that sputum-producing cough and pharyngeal pain, insufficient qi and blood and excessive internal heat, pregnancy, and postpartum blood heat, were four prohibitions for CC using.
Tang Ben Cao of the Tang Dynasty wrote that CCP had two or three layers of bark, with three lines in the leaves, and the texture was as thin as bamboo. The skin of the large branches and twigs was full of laurel; however, the skin of the large branches cannot be rewound. Its taste is very mild, so it is not used as medicine. The appearance of its bark and leaves were recorded.
For Yu Qiu Yao Jie of Qing Dynasty, CC is the bark herb, which is generally considered to treat supercial lesions. However, later studies found that it can also treat liver and kidney diseases deeply.
The medicine books of Bie Lu of the Han Dynasty pointed that CC is used for angina pectoris, warming tendons, dredging veins, relieving vexation, sweating, headache, waist pain, relieving salivation and curing cough. It warms the middle, beneting the liver and lungs. It also causes abortion, strengthens the joints, passes the blood vessels, and complements insufficiency. It illustrated the broad clinical application of CC, in which the effect of blood circulation will lead to abortion. However, doctor Pang An Shi in Song Dynasty said that frying would not damage the fetus, indicating the importance of processing herbs.
Yi Yu Lu records a particular treating case for eye inammation with swelling and paining. Patient is anorexia with the spleen deciency. His liver was hyperstimulation, but his spleen was fatigue. Treating the liver only with suppressive medicine will make his spleen more fatigued, while treating the spleen only with warm medicine will make the liver more stimulating. Surprisingly, adding CC into the mild medicine can both inhibit the liver and benet the spleen. It successfully treats two symptoms with one herb.

Compound compatibility and their uses
CC plays an essential therapeutic role in combination with other drugs. There are lots of compound preparations in classical Chinese medical monographs. These prescriptions comply with the theory of "Jun Chen Zuo Shi." 21 The "Jun" drugs can treat major diseases, the "Chen" drugs can enhance the efficacy of the monarch drugs, the "Zun" drugs can eliminate the toxic and side effects of herbs, and the "Shi" drugs can promote the absorption of drugs in the body. 96 The efficacy of prescriptions was not only exerted by a single way, but through multi-channel, multi-target synergy or antagonism to achieve the ultimate therapeutic goals. 148 The herb pairs can keep the health of the human body through the synergistic effect of herbs and have reputed effectiveness and a relative absence of side effects. By comparison, chemotherapeutic drugs are targeted and quickly, but they could produce many side effects, such as myelosuppression, decreased immune function, organ damage, hair loss and so on. 149 In clinic practice, CC can be used by combining with other herbs.
CC combined with Coptidis rhizoma can treat insomnia caused by disorder of physiological coordination between heart and kidney.
CC is compatible with Caryophylli os. Piperis Longi fructus protects the spleen and relieves cold and diarrhea. It is also suitable for the auxiliary treatment of diarrhea and abdominal pain in children. The commonly used formulations of CC include the Shiliuwei Dongqing pill, Fugui Gutong tablet, and Tianhe zhuifeng plaster. There are also Huixiang Juhe pill and      Anmo Ruan ointment, used to promote blood circulation, reduce swelling, and relieve pain, hernia, and testicular swelling and pain. Others promote digestion, remove phlegm, break nodules, strengthen the body, and be used for dyspepsia, gastric distention and stomach and liver discomfort caused by sudden phlegm disease and epigastric pain. The dosage forms include decoction, tablet, capsule, granule, pill, plaster, powder, ointment, and others. Common compatibilities and clinical applications of CC from the Chinese pharmacopeia or classic Chinese medicine books are summarized in Table 2. CC of the same origin can be a medicine or food and is popular in all walks of life in China. CC is oen added to foods and cakes in the food processing industry and drinks as avoring agents and preservatives. The famous condiment "Thirteen Fragrances" contains CC. CC is also used in cosmetics, perfumes, and tobacco. There are health drinks such as CC wine and tea. CC has also been used in toothpaste and chewing gum because of its bactericidal effects.

Phytochemistry
CC contains various chemical components, including essential oil, diterpenes, sesquiterpenes, avonoids, polyphenols, polysaccharides, and other components. In this section, the chemical constituents of CC are summarized.

Essential oil
Essential oil is the main volatile component in CC, which is a mixture with an aromatic scent. It is insoluble in water and can be extracted from plants by steam distillation. The Chinese Pharmacopoeia (2020 edition) stipulates that essential oil content should not be less than 1.2% (mL g À1 ). We searched the literature on CC from 1987 to 2021 and found that the most oen mentioned components are essential oil. Therefore, we summarized the essential oil constituents in Table 3. Structures of components are shown in Fig. 2. To date, more than 200 essential oil components have been isolated and identied. Various parts of CC contain essential oil; however, the content differs substantially. 22 Cinnamaldehyde is abundant, with a relative percentage of 76-86%. 23 Tao et al. extracted 47 essential oils from the dried bark and branch bark of the CCP, which were as old as ten years, using supercritical CO 2 extraction. The relative content of cinnamaldehyde was 90.74%. 24 Huang et al. separated 60 components from dried bark and branch bark of CCP of various ages using gas chromatographytandem mass spectrometry (GC-MS); 53 components were identied, including myrcene, trans-anethole, hexadecanoic acid, and others. 25 Fenchone and a-bergamotene were rst identied in CC by Bao et al. 26 Chen et al. isolated 22 chemical constituents from an ethanolic extract of CC, and 4-hydroxymellein was isolated for the rst time. 27 Dong et al. identied 35 essential oil compounds from CC using GC-MS, and 21 substances were isolated for the rst time. 28 Song et al. extracted 54 and 56 aroma components from Ceylon cinnamon bark oil and Chinese cinnamon bark oil, respectively, using gas chromatography-time-of-ight mass spectrometry. There were some differences in the composition and content of aroma components between them. 29 In summary, there are substantial differences in the composition of essential oil compounds in different parts of CCP. This section summarizes the components isolated from CC to provide scientic evidence for Chinese medicine theory, stating that CC is hot and Cinnamomi ramulus is warm.
Modern pharmacological research showed that essential oil has analgesic, spasmolytic, and antipyretic effects; it also lowers blood pressure, has antibacterial properties, increases leukocyte counts, combats tumors and ulcers, strengthens yang, among other effects. 30 The differences in essential oil components and contents may be caused by different habitats, different parts, and different harvest years and extraction methods. Therefore, it is essential to establish unied quality evaluation standards to conduct in-depth compound studies of CC.

Flavonoids
CC also contains avonoids. Flavonoids are compounds with a 2-phenylchromone as the mother nucleus and C6-C3-C6 as the basic carbon skeleton. They can detoxify, antibacterial and anti-inammatory, also possess antitumor activity and improve immunity. Mei 39 We summarize the avonoids in Table 5 and the structures of components in Fig. 4.
Wei et al. extracted avonoids from CCP leaf by the water diffusion method and determined the content of total  Cinncassiol Cinncassiol avonoids. The extraction rate was 0.39%, and it strongly inhibited Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. 40 Zou et al. extracted avonoids from CC by the ultrasonic extraction method. The content of total avonoids in stems, leaves, and fruits in the samples were 2.4177, 0.9097, and 0.1759 g L À1 , respectively. 41 Kun et al. optimized the extraction conditions of total avonoids and found that the extraction rates of total avonoids from CC and residue by ethanol extraction were 16.10% and 3.80%, respectively. The results were higher than those of water extraction and ultrasonicassisted extraction. 42 Lin et al. determined the best extraction process of CC avonoids: the ratio of material to liquid was 1 : 10 (g mL À1 ), the extraction time was 1.5 h, and the extraction temperature was 80 C. 43

Polysaccharides
Studies showed that polysaccharides in CC have antibacterial and antioxidant effects. A neutral polysaccharide (cinnaman AX) was isolated from the dried bark of CCP by Kanari M et al. It was composed of L-arabinose and D-xylose in a molar ratio of 4 : 3, and its molecular weight was determined to be 10 6 . 46 Liu et al. compared CC and Cinnamomi Ramulus's chemical constituents and found that they all contained polysaccharides. 47 Qin et al. optimized the extraction process of total polysaccharides in CC and obtained the best extraction process: the ratio of solid to liquid was 1 : 20, the extraction time was 3 h, ethanol concentration was 80%, and the extraction temperature was 80 C. 48 Wei et al. extracted polysaccharides from Cinnamomum cassia leaf by the water diffusion method; the amount of polysaccharide was 40.879 mg mL À1 , and the extraction rate was 0.818%. 40 Li et al. used GC-MS to analyze polysaccharide content in CC and isolated the following six compounds: galactose, D-xylose, D-glucofuranose, D-arabinose, D-ribose, and a-D-glucopyranose. The proportion of D-glucofuranose was the largest, accounting for 38.64%. 49 The structures of polysaccharides are shown in Fig. 6.

Others
The ingredients in Chinese herbal medicines are complex. In addition to the ingredients summarized above, there are components with low content and some trace elements that have been. Using inductively coupled plasma mass spectrometry/inductively coupled plasma-atomic emission spectrometry (ICP-MS/ICP-AES), Chen investigated trace elements from CC, including Li, Be, Tl, Mo, Pb, Cd, Sr, V, Cr, Cu, Ni, Co, Na, B, Mg, Al, P, Ca, Ti, Zn, Ba, Mn, Fe, K. Of these, the content of Ca accounted for the highest, and Be was the lowest. 50 CC tastes sweet and pungent. This may be related to trace elements. The correlations further study. In this paper, the chemical constituents of CC were summarized, providing a scientic basis for studying the relationship between the biogenic pathway, traditional efficacy, modern pharmacological effects, and chemical constituents. This work creates a basis for synthesizing lead compounds, developing new drugs for clinical use, and expanding their commercialization. Nevertheless, many components in CC have not been identied, and this fact is an obstacle to its qualitative and quantitative analysis. Moreover, the research on these components focuses on an essential oil, and there are relatively few reports on polyphenols, avonoids, and terpenoids. It is hoped that future works will concentrate on these compounds.

Analytical method and quality control
There are several components in CC; therefore, there is substantial demand for a rst-rate analytical method. With the development of science, technology, and instruments, analytical methods are also improving. The methods reported in previous studies include gas chromatography, liquid chromatography, GC-MS, high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), second-derivative differential pulse polarography, ultraviolet spectrophotometry, and others. The trend is towards increasingly fast, inexpensive instruments that are environmentally friendly. HPLC is the most commonly used method. The Chinese Pharmacopoeia (2020 edition) suggests TLC and HPLC for the qualitative and quantitative analysis of indicator cinnamaldehydes, respectively. Most of these methods are rapid, sensitive, accurate, simple to operate, and have a wide application range. Their disadvantages include complex pre-treatments, expensive instruments, high costs of organic solvents, time-consuming procedures, and resources that pollute the environment. In the future, we believe that technological advances will yield cheaper, more sensitive, and environmentally friendly instruments. Jin et al. suggested that the quality standard of CC should be as follows: moisture content 4.98-6.47%, total ash content not higher than 6.10%, acid-insoluble ash not higher than 3.84%, water-soluble leachates by cold soaking and hot soaking not less than 0.51% and 3.41% (respectively), and alcohol-soluble extracts by cold soaking and hot soaking, not less than 1.08% and 3.11, respectively. The essential oil content shall not be less than 3.44%, and the cinnamaldehyde content determined by HPLC should not be less than 0.25%. 51 Li et al. established a method for simultaneous determination of coumarin, cinnamic acid, and cinnamaldehyde in CCP leaves using HPLC. 52 Ma et al. determined the contents of cinnamaldehyde and cinnamic acid in CC from 16 areas by using HPLC and found that the contents of cinnamaldehyde and cinnamic acid in CC from Vietnam were the highest. 53 Yuan et al. determined the contents of seven phenylpropanoids in CC and Cinnamomi ramulus using HPLC. They found that the content ratios of (cinnamyl alcohol + cinnamic acid)/cinnamaldehyde were 0.0121-0.0467 and 0.0598-0.182, respectively, which could be used to distinguish CC (<0.05) from Cinnamomi ramulus (>0.05). 54 3   Cinnacasolide A Stem bark of CCP 122 57 Cinnacasolide B Stem bark of CCP 122 58 Cinnacasolide C Stem bark of CCP 122 59 Secoisolariciresinol Stem bark of CCP 125 60 5,5-Dimethoxysecoisolariciresinol Stem bark of CCP 125 Most reports consider the content of chemical components as the basis for the quality evaluation of CC, while pharmacological activity as a quality evaluation method is rarely reported. More quality control methods based on the activity should be established.

Pharmacology
CC is a traditional Chinese medicine with many activities, including anti-inammation, antibacterial, anti-oxidation, antitumor, and others. Various experts and scholars have conrmed these. The pharmacological effects of CC are summarized in Table 7.

Anti-inammatory effects
CC can be used to treat diseases caused by inammatory factors. Viral myocarditis is frequently seen in the clinic. It is caused by the heart being infected by viruses, resulting in localized or diffuse myocarditis. CC is a highly effective treatment for viral myocarditis. Ding et al. investigated the pharmacological mechanisms of essential oils on coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC) in mice. They found that the mortality of mice treated with essential oil or cinnamaldehyde (CA) was signicantly lower, and the median survival time was prolonged. The expression of inducible nitric oxide synthase, tumor necrosis factor (TNF-a), nuclear transcription factor kappa B (NF-kB), P65, and Toll-like receptor 4 protein in myocardium decreased signicantly (P < 0.05). There was no statistical difference between the two treatment groups (P > 0.05). Experiments conrmed that the mechanism of essential oil in treating VMC might be related to CA, which selectively inhibits TLR4-NF-kB signaling in vivo. This study provides a scientic basis for clinical treatment in VMC using essential oil. 55 However, the experiment only investigated a single dose of essential oil and cinnamaldehyde at 30 mg kg À1 and lacked analysis of maximum and minimum effective doses. In addition, only cinnamaldehyde was selected as the indicator control, and there was no positive control group, compromising the validity of the ndings. The components in CC are complex, and the anti-inammatory effects of other components should be further studied.
Hu et al. studied the anti-inammatory effect of cinnamaldehyde on xylene-induced auricle swelling in mice. The results showed that middle and high doses of cinnamaldehyde signicantly inhibited auricle swelling of mice, suggesting that it inhibits acute inammation. The effect was signicantly better than that of aspirin and low-dose cinnamaldehyde (P < 0.05). 56 However, this study only investigated an animal model in vitro and lacked analyses at the cellular and clinical practice levels. Meanwhile, detail anti-inammatory mechanisms and targeted pathways need to be explored further in this study.
Ren et al. evaluated the anti-inammatory activity of CC-Portulaca oleracea on an ulcerative colitis (UC) model in mice induced by 3% dextran sodium sulfate. The authors found that ulcers of the colon mucosa in mice in the administration group were somewhat repaired. Unlike the model group, the content of serum anti-inammatory factor interleukin (IL)-10 increased signicantly (P < 0.01), and the content of pro-inammatory factor TNF-a decreased signicantly (P < 0.01), suggesting that the combination of the herb pair inhibited UC activity. This experiment provides a new basis for the treatment of UC. 57 Unfortunately, the method was tested only at the animal level. Its therapeutic mechanism at the cellular and molecular levels should be studied in the future. The specic active compounds that mediate the anti-inammatory role should also be studied to provide a basis for developing effective and safe drugs with few side effects.
Kwon et al. found that the anti-inammatory mechanisms of CC extract in a 2,4,6-trinitrobenzenesulfonic acid-induced colitis mice model were related to regulatory dendritic cells (RDCs). RDCs produced low levels of the pro-inammatory cytokines IL-1b, interferon-gamma, and TNF-a, and high levels of the immunoregulatory cytokine IL-10 aer medication. Treatment was also associated with the inhibition of cyclooxygenase-2. 58 However, this experiment was conned to cellular and protein related to anti-inammation and did not fully explore the mechanistic pathways. There are many components in CC extract; the components with the primary anti-inammatory effect and the structural material bases of this effect need to be studied.
Hagenlocher et al. analyzed the effect of cinnamaldehyde, the active ingredient of CC, on the activation of mast cells. They found that cinnamaldehyde reduced the release of b-hexosaminidase in human-intensive mast cells (hiMC) and RBL-2H3 cells. Expression of LTC4, CXCL8, CCL2, CCL3, and CCL4 was signicantly inhibited in hiMC by cinnamaldehyde. The phosphorylation of extracellular signal-regulated kinase and phospholipase g1 was inhibited. The outcomes were similar to CC extract, suggesting that cinnamaldehyde is the active component mediating CC's anti-inammatory and anti-allergic properties. 59 However, this experiment did not study the relationship between the chemical structure of cinnamaldehyde and its pharmacological activity. The bioavailability, activity at the cellular level, and whether its mechanism proceeds successfully should be further study subjects.

Anti-bacterial effects
Cheng et al. studied the antibacterial effect of cinnamaldehyde and tested its antibacterial effect on three pathogenic bacteria that cause mastitis in dairy cows using the double dilution method. They found that the minimum inhibitory concentration (MIC) of cinnamaldehyde against E coli, standard E. coli, S. aureus, standard S. aureus, and Streptococcus in vitro was 6.4 mmol L À1 , 3.2 mmol L À1 , 3.2 mmol L À1 , 1.6 mmol L À1 , and 1.6 mmol L À1 , respectively. The minimum bactericidal concentrations (MBCs) were 25.6 mmol L À1 , 12.8 mmol L À1 , 25.6 mmol L À1 , 12.8 mmol L À1 , and 12.8 mmol L À1 , respectively. 60 These ndings suggested that cinnamaldehyde is a potential clinical treatment for bovine mastitis; furthermore, according to the standard of bacterial drug resistance (MBC $ 32 MIC), there was no drug resistance. Nevertheless, the investigators only compared the inhibitory effects of cinnamaldehyde on several bacteria, and the mechanism of the inhibition was not studied; furthermore, the reasons for the differences in inhibition rates among the three bacteria were not explored. There were differences between the bacteriostatic effect in vitro and in vivo (in cows). We suggest conducting experiments in animals and measuring the production of drugresistant bacteria.
Xu et al. found that essential oil signicantly inhibited Penicillium and Aspergillus niger, common pathogens in winter jujube, with MICs of 0.313 mmol L À1 and 0.156 mmol L À1 , respectively. These ndings suggest that the oil is a suitable inhibitor of winter jujube storage mold. 61 Gu et al. studied the antibacterial activity of CC essential oil against six bacteria, including Staphylococcus cremoris, Bacillus subtilis, E. coli, Aspergillus niger, Penicillium sp. and Saccharomyces cerevisiae. They found that essential oil potently inhibited bacteria, mold, and yeast, in the following order mold > yeast > bacteria. The bacteriostatic effect was affected by pH, with the optimal range of pH 3-7. The bacteriostatic effect decreased with increasing pH. 62 The antibacterial mechanism in vivo was not studied, and there was no MIC or positive control. Therefore, the reliability of these results is in doubt.
Liang et al. measured the inhibitory effect of CC essential oil on the growth of intestinal bacteria in rats and found that most of the intestinal bacteria were inhibited; however, the growth of lactic acid bacteria was not affected, suggesting that essential oil had a greater regulatory effect on intestinal ora. 63 An indepth study on the morphological structure of lactobacillus may reveal the mechanism of drug resistance. This experiment had no positive control group, although there was a blank control.
Huang et al. studied the changes of antibacterial effect when the essential oil was emulsied. They found that the antibacterial effect of the emulsion on E. coli was the same as that of the aqueous solution group; however, its antibacterial effect on S. aureus and Candida albicans was weakened, possibly related to the different structures and morphologies among Gramnegative bacteria, Gram-positive bacteria and fungi. 64 Nevertheless, there was no investigation of the mechanism of bacteriostasis. There was no positive control group and no measurement of the maximum bacteriostatic concentration.   Li et al. measured the killing activity of different solvent extracts of CC against Dermatophagoides farinae and found that CC's petroleum ether and ethyl acetate extracts had good killing activity against the organism. The lethal dose 50s (LD 50 s) were 4.64 mg cm À2 and 1.44 mg cm À2 , respectively, in a concentrationand time-dependent manner. When the dosages reached 6.09 mg cm À2 and 9.75 mg cm À2 , the acaricidal rate was 100% aer 24 h, while methanol extracts had no acaricidal activity. 65 Chen et al. found that the alcoholic extracts of CC and aniseed had sound inhibitory effects on E. coli, B. subtilis, and Patchouli. CC had a more substantial bacteriostatic effect more than aniseed fruit and leaf (p < 0.05). This study suggested that the inhibitory Adrenal regeneration hypertensive rat model

In vivo
Cinnamomi cortex can signicantly reduce blood pressure (p < 0.001) and urinary aldosterone excretion (p < 0.001), and signicantly increase the content of enkephalin in striatum and hypothalamus (p < 0.001) 90 effect of CC on B. subtilis was better than that of the preservative chrysa, suggesting that CC has the potential to be utilized as a preservative. 66 However, the authors did not study the bactericidal chemical constituents that dominated the role of CC. Moreover, the pharmacological mechanism of inhibiting CC remained at the experimental phenomenon level. Future research should explore the drug targets and mechanisms. Guo et al. compared the bacteriostatic effects of cinnamaldehyde, cinnamic acid, and ethyl cinnamate. They found that the cinnamaldehyde has the best bacteriostatic effect, even better than traditional fungicide carbendazim, with the potential to be used as a pollution-free bactericide. 67

Antioxidant effects
Chen et al. found that three cinnamon tannin samples had strong scavenging ability on hydroxyl radical and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical in a concentration-dependent manner. When the concentrations of ethyl acetate extract, resin purication, and crude extract were 0.04 mg mL À1 , the clearance rates of DPPH radical were 90.98%, 90.48%, and 89.38%, respectively. These rates were higher than the clearance rates of ascorbic acid at the same concentration of 50.2%. For hydroxyl radical, the maximum clearance rates of the three samples were all over 65% and increased in a dose-dependent manner in the range of 0.1-0.6 mg mL À1 . CC tannin can be developed as a natural antioxidant in the future. This study had profound and extensive signicance. 68 Nevertheless, a limitation of the study was that it only included in vitro experiments; the bioavailability and antioxidant capacity of tannins in humans are not clear. Studying only the scavenging capacity of hydroxyl and DPPH radicals cannot reect the total antioxidant capacity of tannins.
Li et al. analyzed the total antioxidant properties of CC essential oil and found that essential oil was weaker in antioxidant capacity, inhibition of lipid peroxidation in linoleic acid, and scavenging DPPH radical hydroxytoluene (BHT) and propyl gallate (PG). In terms of scavenging hydroxyl radical, the essential oil group was the strongest, followed by BHT, and PG was the weakest. The essential oil was more potent than PG at 1.0 mg mL À1 . 69 The authors concluded that CC essential oil was superior to synthetic antioxidants in some aspects and might be a candidate for use in the food industry. Nevertheless, it remained unclear whether the antioxidant activity of essential oils was the result of a component or a combination of several components; therefore, it is necessary to screen them in detail. There is also a problem about whether its antioxidant performance changes in vivo. The relationship between its basic structure and pharmacological activity is also worth studying.
Flavonoids from CC have good antioxidant effects. Zeng et al. studied the pharmacological action and mechanism of CC avonoids on a Parkinson's disease model established by 6hydroxydopamine (6-OHDA)-induced injury to PC12 cells. The cell survival rate and superoxide dismutase activity were signicantly increased (P < 0.05). The apoptosis rate, DNA damage, Bax/Bcl-2 ratio, caspase-9 expression, and malondialdehyde content was signicantly lower; these effects were dose-dependent. These ndings suggest that total avonoids of CC protect mitochondria by inhibiting oxidative stress, thereby reducing the damage of 6-OHDA to PC12 cells. 70 However, the study was conducted only at the cellular level. Medications are affected by several factors aer entering the body. Therefore, it is best to test animal models and verify the clinical level results to develop safe and effective medications from natural antioxidants.

Anti-tumor effects
Tumors are characterized by mutated cells growing irregularly and rapidly due to gene mutations or DNA replication errors. Tumors can be divided into benign and malignant classes. Malignant tumors can be further divided into carcinoma and sarcoma according to the site of origin. Cancer is one of the three diseases with the largest death in the world. Chemotherapy is the primary treatment; however, these treatments are expensive and carry substantial side effects. CC invigorates qi and keeps the individual healthy, improving immunity and resistance to cancers.
Qian et al. studied the antitumor effect of the rougui (CC)-Huanglian (Rhizoma coptidis)-Dahuang (Radix et Rhizoma Rhei) herb pair on a nude mice liver cancer model induced by injection of human liver cancer cells. The tumor weights in the compound and berberine-emodin-cinnamaldehyde groups were lower than the model group, suggesting that both inhibited tumor proliferation, possibly by improving qi and blood and improving quality of life. 71 Although some achievements were made in this experiment, there was no comparison with current anticancer drugs; therefore, the anticancer effect is unclear and should be evaluated. Although the study showed that the compound and groups inhibited tumor proliferation, the maximum safe doses were not determined. Finally, the mechanism of action was not explored.
Song et al. added cinnamaldehyde to the lung cancer cell line A549 and studied its inhibitory effect on cell growth. They found that the cells generated vacuoles, swelling, and shedding aer treatment, suggesting that cinnamaldehyde had good antitumor activity and inhibited the proliferation of lung cancer cells in a dose-dependent manner, with an IC 50 of 0.36 mg mL À1 . 72 Seo et al. screened for anticancer effects in herbs with matrix metalloprotease-9 inhibitory activity from 87 herbal extracts and found that the inhibitory activity of cinnamyl butanol extract at the concentration of 100 mg mL À1 was over 90%. 76 Li et al. studied the antitumor effect of cinnamaldehyde in a Balb/c null female nude mice melanoma model and found that the melanoma tumor volume and the number of new blood vessels in the cinnamaldehyde treatment group were signicantly lower. Expression of vascular endothelial growth factor and hypoxia-inducible factor was inhibited, suggesting possible anti-melanoma mechanisms. 73 However, there were no positive controls, and the antitumor mechanism of cinnamaldehyde was not studied in depth. Although two tumor-related factors were conrmed, the inhibition mechanism remains unclear. The lowest effective and safe dose of cinnamaldehyde should also be investigated to provide the basis for rational treatment.
Zhou et al. studied the effect of cinnamaldehyde on the invasion ability of human melanoma cell line A375 in vitro and found that cinnamaldehyde inhibited the migration and invasion of A375 cells in a dose-dependent manner. The mechanism of action may be inhibition of NF-kB activation. 74 Wang et al. studied the pharmacological effects of cinnamic acid on a differentiation model of osteosarcoma MG-63 cells in vitro and found that the ratio of G0/G1 cells in the cinnamic acid group was signicantly greater. The morphology and ultrastructure of MG-63 cells returned to normal. The expression of osteoblast differentiation markers I collagen, osteomucin, and osteocalcin increased, and calcium deposition and formation of typical bone joints accelerated, suggesting that cinnamic acid inhibited the proliferation of MG-63 cells and induced them to differentiate into osteoblasts. 75 However, these experiments were conned to a cultured cell model, and the pharmacological mechanism obtained from these experiments was unclear. The optimal antitumor dose was not determined. The inhibitory process of cinnamaldehyde or cinnamic acid on tumors is complex, involving many enzymes, protein factors, and pathways. The mechanisms obtained in mentioned experiments did not explain the entire antitumor process. Future work might exploit network pharmacology to predict mechanisms of action and verify them to improve the antitumor effect of CC.

Improvement of glucose and lipid metabolism
Diabetes is characterized by high blood sugar levels caused by insufficient insulin secretion or insulin resistance (types 1 and 2, respectively). Type 2 is more common and is the result of genetic and environmental factors. If diabetes is not controlled in a timely fashion, it causes kidney, nerve, eye, foot, heart, and brain complications. In short, diabetes is among the major diseases endangering human health worldwide. Its incidence increases yearly. At present, western medicine is the primary method of treatment; nevertheless, exacerbations are common. CC has a mild and lasting hypoglycemic effect, attracting substantial attention in China and abroad.
Xiang et al. studied the hypoglycemic effects of CC powder and water extracts on 3T3-L1 adipocytes and diabetic mice and found that CC coarse powder did not affect 3T3-L1 adipocytes. The water extract of CC promoted fat droplet growth at 750 mg mL À1 and inhibited the proliferation of 3T3-L1 adipocytes at 156-1250 mg mL À1 . The inhibitory mechanism at 1250 mg mL À1 might involve regulation of peroxisome proliferator activated receptor g (PPAR-g) and cyclic adenosine monophosphateresponse element binding protein genes. The water extracts of CC at 300 mg kg À1 and 150 mg kg À1 improved blood sugar levels in mice, with insulin-like effects at 2.5 mg mL À1 and 5 mg mL À1 . This experiment preliminarily suggested that CC water extract may treat diabetes. 77 Xu et al. established a diabetic rat model by injecting streptozotocin and feeding a high-calorie diet. Aer two weeks of treatment with CC, liver, and muscle glycogen levels in the CCtreated group were signicantly higher than the model group. These ndings suggest that CC increases glycogen storage in the liver and muscle of rats, improving the utilization of glucose in peripheral tissues and reversing insulin resistance in type 2 diabetic rats. 78 However, the study used only a single dose and lacked an analysis of a detailed mechanism.
Zheng et al. studied the biological mechanisms of CC polyphenol on lipid metabolism of HpeG2 cells at the molecular level and found that CC polyphenol reduced the level of triglycerides and downregulated sterol regulatory elementbinding protein-1 (SREBP-1), a key transcription factor in the de novo synthesis of fatty acids; it also caused a signicant reduction in mRNA expression of downstream target genes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). Aer the NAD-dependent deacetylase sirtuin-1 (SIRT1) gene became silent, the downstream pathway proteins AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), and phosphorylation levels decreased signicantly. The mRNA expressions of SREBP-1, FAS, and SCD1 were signicantly increased, suggesting that CC decreased lipid deposition in hepatocytes by inhibiting lipid de novo synthesis through the SIRT1-AMPK-ACC pathway. 79 However, this method was not veried in clinical experiments or animal models, and there was no positive control group. Polyphenol is not the main component of CC; therefore, the mechanism by which CC polyphenol improves fat deposition in liver cells remains unclear.
Sung et al. found that the water extract of CC signicantly decreased blood sugar levels in a type II diabetic mice model (C57BIKsj db/db) in a dose-dependent manner at 50-200 mg kg À1 . This extract signicantly increased serum insulin and high-density lipoprotein levels aer 6 weeks of treatment, suggesting that the hypoglycemic effect of CC might be mediated by improving insulin sensitivity and reducing the absorption of carbohydrates in the small intestine. 80 However, only the water extract of CC was studied without determining which components played a major role. The mechanism of CC's reversal of insulin resistance was not elaborated in depth.
Lu et al. found that CC polyphenol signicantly reduced blood sugar levels in insulin-resistant diabetic mice but had no effect on weight. At the cellular level, the authors found that CC polyphenol did not inhibit cell growth at 1-15 mg mL À1 . At 15 mg mL À1 , CC polyphenol signicantly increased glucokinase activity in insulin-resistant HepG2 cells. At 10 and 15 mg mL À1 , CC polyphenol inhibited the activity of phosphoenolpyruvate carboxykinase (PEPCK). CC polyphenol inhibited the mRNA expression of recombinant glucose transporter 2 and PEPCK, the key rate-limiting enzyme in the gluconeogenesis metabolic pathway and glucose-6-phosphatase. In short, CC reversed insulin resistance by reducing the production of endogenous glucose in cells and promoting the utilization of glucose in cells. 81 However, this experiment did not explain how CC polyphenol reversed insulin resistance, nor were there clinical experiments.
Yu et al. studied the hypoglycemic effect of CC polysaccharide extract on alloxan-induced diabetic mice and found no signicant difference in body weight or organ coefficient between CC polysaccharide-treated and normal mice. This nding suggests that CC possesses a signicant hypoglycemic effect. 82 However, the polysaccharide extract in this experimental method was impure, affecting the accuracy of the dosage. The study was only conducted using a single dose, and there was no study of safe dose or maximum therapeutic dose.

Neuroprotective effects
Frydman-Marom et al. studied the therapeutic effect of CC extract on Alzheimer's disease (AD) drosophila and AD transgenic mice. They found that the life of AD drosophila was prolonged, exercise ability was restored, and the toxic Ab oligomer in the drosophila brain was eliminated. Aer taking the CC extract, AD transgenic mice showed reduced 56 kDa Ab oligomers and plaques and improved cognitive activity. The results suggest that CC extract prevents the toxic effects on PC12 cells by inhibiting the formation of toxic Ab oligomers. CC might be developed into a medication that is easy to administer and can prevent and treat Alzheimer's disease. 83 Jana et al. demonstrated for the rst time the mechanism by which the CC metabolite sodium benzoate treats neurodegenerative diseases. Via the PKA-CREB pathway, sodium benzoate increased levels of brain-derived neurotrophic factor and neurotrophin-3 in the central nervous system of mice in a dose-dependent manner. These ndings suggest that CC might be used as the main or auxiliary therapy for neurodegenerative diseases. 84 Panickar et al. found that procyanidin type-a trimer (trimer 1), cinnamaldehyde, and coumarin isolated from CC aqueous extract blocked increases in glial cell swelling induced by glucose and oxygen deprivation. Trimer 1 inhibited oxygen-free radical content and calcium movement to reduce nerve cell swelling in ischemic injury. It also prevented the decline in glutamate uptake to reduce glutamate excitotoxicity. The authors concluded that CC could treat ischemic injury and other neurological diseases. 85

Other effects
Du et al. found that cinnamaldehyde signicantly increased bone mineral density (BMD), trabecular number, trabecular thickness, and trabecular area of osteoporosis rats induced by ovariectomy, and reduce trabecular separation, serum TNF-a, and interleukin-6 (IL-6) levels. 86 However, this method was not veried in patients. Gou et al. found that the preservative effect of CC essential oil on Dangshan pears was highest at 60 mL L À1 when combined with 1% chitosan and 1% CaCl 2 . 87 Zhou et al. found that six compounds extracted from ethanol extract of Cinnamomum cassia leaves boosted ConA-induced proliferation of mouse T lymphocytes by 78%. Two compounds promoted the proliferation of lymphocytes when the concentration was lower than 25 mM and inhibited the proliferation of lymphocytes when the concentration was 100 mM, suggesting that CC leaves were immunomodulatory. 88 Chen et al. found that CC extract had a 72% inhibition rate on ADP-induced platelet aggregation in rats and prevented arterial thrombosis. Intravenous injection of CC signicantly increased blood ow in coronary and brain arteries, possibly related to myocardial inhibition. Peripheral circulation experiments showed that CC directly dilated peripheral blood vessels. 89 Kuang et al. found that CC signicantly reduced blood pressure, urinary aldosterone excretion, and signicantly increased enkephalin content in the striatum and hypothalamus, suggesting that CC modulates renal vascular hypertension. 90 CC treats digestive tract ulcers, tranquilizes, relieves spasms, relieves fever, expels insects, relieves cough, eliminates phlegm, relieves asthma, treats senile nocturia, resists prostatic hyperplasia, has a hypnotizing effect.
relate to the compatibility of components in the prescription. 93 Su et al. studied the pharmacokinetics of cinnamaldehyde in rats with deciency heat, cold deciency, and normal, and found that the cold deciency group absorbed less cinnamaldehyde, distributed less cinnamic acid in vivo, stayed for a shorter time, and eliminated faster. This may be related to the change of metabolic enzyme activity. The specic mechanism of the pharmacokinetic difference requires further study. 94

Conclusion and discussion
CC is an excellent natural herbal resource with characteristics that are not shared with other traditional Chinese medicines and can be used as medicine and food. This paper comprehensively illustrated the characteristics of CC in botany, traditional applications, and pharmacokinetics. It is valuable that the structure of more than 300 components isolated from CC has been summarized on paper. The investigations of anti-inammatory, anti-oxidation, antitumor, antibacterial, hypoglycemic, neuroprotective, and other aspects of CC are also exemplied in the pharmacological section. Such in-depth and comprehensive summaries have never been reported in previous literature. Nevertheless, despite the many successes, we found there are yet many shortcomings in the study of CC.
First, limited to the current instruments and analytical methods, many components have not been discovered in CC that may be the keys to its efficacy. We recommend further research on the active components. Their development and utilization of CC should be carried out in the future. At present, most studies concern the components of CC. To better use CC resources, we suggest that more analysis on twigs, leaves, and fruits be done to widen the development of multi-active drugs.
Second, CC has a wide range of pharmacological effects. Essential oils have anti-inammatory, antioxidative, antibacterial, and antitumor effects. Flavonoids compounds of CC exhibit good antioxidant potential. Phenolic compounds improve glucose and lipid metabolism. However, the specic mechanism of CC in humans has not been uniformly demonstrated. There are several opinions regarding the targets and pathway of drug action, and there is no consensus. It is hoped that future investigators will systematically study the specic mechanisms of various pharmacological effects of CC to improve its theoretical basis. The active compounds that can be developed and related to drug efficacy primarily concerned essential oil components, while there is less research on avonoids and polyphenols. We suggest that more attention should be paid to avonoids and polyphenols in the future.
Third, CC resources are abundant in China; however, there was no comprehensive resource investigation or analysis of CCP species for a long time. People randomly denominated CC according to its origin and color, causing confusion in the system and hindering the screening and development of excellent CCP strains. Therefore, checking and standardizing the species and strains of CCP is the fundamental premise for preserving and utilizing germplasm resources, and it is also an essential basis for screening excellent strains and genetic breeding of CCP in the future.
Fourth, herbal processing technology has a long history in China. These technologies enhance the efficacy and purify and detoxify herbs. However, at present, the processing of CC is based on simple mashing, and no other processing methods have been reported. Therefore, it is critical to study the processed products of CC.
Fih, according to the 2020 edition of the Pharmacopoeia, cinnamaldehyde is the active marker of CC. However, it is unwise to cover all herbal medicine with only one marker. Future research should focus on phytochemistry, using new instruments and technologies to identify new biochemical markers and study the relationship between material infrastructure and pharmacological effects. Doing so will provide a scientic basis for future clinical development of targeted preparations.
Finally, there is little research on traditional applications. China has accumulated experience with clinical uses of CC for thousands of years. CC should be widely used currently. However, the modern pharmacological uses of CC are far less abundant than those of traditional uses. Most people only use it as a spice, possibly due to insufficient popularization of Chinese medicine knowledge. We believe more people should pay attention to cosmetic, antioxidative, antitumor effects, weight loss, and hypoglycemic effects. In short, many critical traditional applications have been neglected. To better utilize CC resources, we should conduct a comprehensive study on its application to benet humanity. This paper reviewed CC from botany, ethnopharmacology, phytochemistry, and pharmacology, hoping to provide a basis for future research and promote active lead compounds and innovative drugs. With the development of science and technology and the deepening of research, investigators will have a more thorough understanding of CC, and CC preparations will spread out from the Chinese market and be accepted by the entire world.

Conflicts of interest
The authors declare no conict of interest.