Camellia nitidissima Chi (C. nitidissima) is a precious plant species with high ornamental value because of its canary yellow flowers (1,2). Wild C. nitidissima is predominately distributed in the mountains of Southwest China (particularly in Guangxi Zhuang autonomous region) and North Vietnam (3,4). C. nitidissima has been introduced and cultivated in Japan, Australia, North America, and several provinces in China (5). Guangxi is the main planting area of C. nitidissima in China and the acreage reaches over 2,000 hectares. The annual productions of C. nitidissima fresh leaves and flowers in Guangxi are ~15,000 and ~225 tons, respectively. The economic value of the C. nitidissima industry exceeds 2 billion RMB per year, making it one of the pillar industries in Guangxi (source from the forestry bureau of Fangchenggang City, Guangxi, China).
C. nitidissima was first discovered by the Chinese botanist Jinglie Zuo in Fangchenggang City (Guangxi, China) in 1933, initially named as Theopsis chrysantha Hu by the Chinese botanist Jingwen Qi in 1948 (5), and later revised as Camellia nitidissima Chi in Flora Reipublicae Popularis Sinicae (6). The plant belongs to Theaceae Camellia section Chrysantha Chang, genetically close to Camellia sinensis, Camellia semiserrata, and Camellia oleifera.
Although botanically classified in the last century, C. nitidissima has a long history of use in traditional medicine. It is recorded in Ben Cao Gang Mu, a sixteenth-century Chinese encyclopedia of medical matter and natural history. It exhibits activities in detoxifying, promoting diuresis, and reducing puffiness. It also helps in the treatment of dysentery and pharyngitis. Besides its medical use, C. nitidissima is utilized in daily life for beverages. Freeze-dried C. nitidissima flowers are the most common product of C. nitidissima in the commercial market (Figure 1A). C. nitidissima leaves (Figure 1B) are less popular, which are mainly consumed by ethnic minorities in Guangxi to prepare decoctions for the nourishment. In 2010, C. nitidissima was approved as a new resource food by the Ministry of Health of China, providing a bright future for its applications in medicinal food and dietary supplements.
Phytochemical studies have shown that C. nitidissima contains a variety of active ingredients, such as phenolic compounds, saponins, polysaccharides, volatiles, mineral elements, and amino acids (7). Biological studies have demonstrated that C. nitidissima exhibits antioxidant and anticancer activities in vitro and in vivo (7). In addition, C. nitidissima exhibits lipid-lowering and immunomodulatory activities in animal models (8). In the past decade, several novel compounds in C. nitidissima have been identified and proved to be bioactive (7). In the review, research progresses on the constituents and health-beneficial properties of C. nitidissima in recent years are summarized. It is hoped that the review will cause more readers’ interest in C. nitidissima and inspire them to think about the future prospects of C. nitidissima. It is also hoped that the review will help scientists find out the promising directions for further researches and applications of C. nitidissima.
We present the following article in accordance with the Narrative Review reporting checklist (available at https://lcm.amegroups.com/article/view/10.21037/lcm-22-9/rc).
The references in this review are mainly collected from published books and the scientific literature databases including Web of science, PubMed, and China National Knowledge Infrastructure (CNKI), with a timeframe from January 1986 to March 2022, containing English and Chinese references. The search was conducted between January 3, 2022 to March 8, 2022. Search terms included “Camellia nitidissima” and its Chinese characters “金花茶”. The detailed search strategy is listed in Table 1.
|Date of search||January 3, 2022–March 8, 2022|
|Databases and other sources searched||Databases: Web of science, PubMed, and China National Knowledge Infrastructure (CNKI) Published books|
|Search terms used||Search terms: Camellia nitidissima (for English databases, including Web of science and PubMed), 金花茶 (for the Chinese database CNKI)|
|Timeframe||From January 1986 to March 2022|
|Inclusion and exclusion criteria||Inclusion and exclusion criteria: (I) articles in English and Chinese languages; (II) article types were research articles and reviews|
|Selection process||Hanyu Zheng and Ying Gao conducted the selection together and consensus was obtained after a discussion among all authors|
Main chemical constituents of C. nitidissima
Nowadays, it is generally accepted that herbs play an important role in the prevention and treatment of diseases by virtue of its functional ingredients. There are many studies describing the chemical constituents in C. nitidissima flowers and leaves (1,2,8). Comparatively, less is known about the chemical constituents in other parts of C. nitidissima. Though different in contents, the classes of compounds found in flowers and leaves are similar, including phenolic compounds, saponins, polysaccharides, and other substances.
Phenolic compounds are a diverse group of bioactive secondary metabolites characterized by their structures having at least one phenol unit. Flavonoids, phenolic acids, and lignans are important phenolic compounds in C. nitidissima.
Flavonoids are low-molecular-weight polyphenolic substances characterized by the flavan nucleus. Many flavonoids are with physiological functions such as antioxidant, antiviral, anti-inflammatory, hypotensive, and lipid-lowering activity (9). Flavonoids are classified into 12 major subclasses, six of which, namely flavonols, flavones, flavan-3-ols, anthocyanidins, flavanones, and isoflavones, are widely distributed in the diet.
The flavonoid content of C. nitidissima is not the highest among members in Theaceae Camellia section Chrysantha Chang (10,11). In C. nitidissima, more flavonoids are accumulated in flowers rather than leaves. A research showed that the flavonoid content of C. nitidissima flowers reached 8.5%, which was 37 times to that of leaves. The flavonoid content of C. nitidissima flowers varies in different stages, decreased in the order of semi-open stage > fish-mouth stage ≈ blooming stage > withering stage ≈ budding stage (12). The flavonoid content of C. nitidissima leaves decreases as the leaves grow. Compared with young leaves, about 69% and 77% of flavonoids were lost in one-year-old leaves and two-year-old leaves, respectively (13). C. nitidissima contains more water-soluble flavonoids than alcohol-soluble flavonoids. Tang (11) found that the flavonoid content of C. nitidissima water extract was much higher than that of C. nitidissima alcohol extract. At present, quite a number of flavonoids in C. nitidissima have been identified.
Flavones are a class of flavonoids based on the backbone of 2-phenylchromen-4-one and flavonols are a class of flavonoids that have the 3-hydroxyflavone backbone. Kaempferol, quercetin, apigenin, and their glycosides are main flavones and flavonols in C. nitidissima. Aromadendrin, dihydroquercetin, dihydrokaempferol, and isorhamnetin glucosides are also detected (2,14,15). Glucose and rhamnose are the two most common sugars to form glycosides in C. nitidissima. Peng et al. (16) used repeated silica gel column chromatography, Sephadex LH-20 column chromatography, ODS column chromatography, repeated recrystallization and other strategies to separate and purify the chemical components of C. nitidissima. Seven of the thirteen obtained compounds belonged to flavones and flavonols, including quercetin, quercetin-7-O-β-D-glucopyranoside, quercetin-3-O-β-D-glucopyranoside, rutin, vitexin, kaempferol, and kaempferol-3-O-β-D-glucopyranoside. In addition to usual monoglycosides, several diglycosides and triglycosides are identified. Some glycosides are modified with the acetyl moiety and/or coumaroyl moiety. For example, Yang et al. (17,18) isolated two acetyl flavonol glycosides from C. nitidissima flowers, namely kaempferol 3-O-[2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl-(1/3)-2,4-di-O-acetyl-α-L-rhamnopyranosyl-(1/6)]-β-D-glucopyranoside and kaempferol 3-O-[2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl-(1/3)-4-O-acetyl-α-L-rhamnopyranosyl-(1/6)]-β-glucopyranoside, which showed remarkable inhibitory effects on the advanced glycation end-products (AGEs) formation. To be mentioned, a glycoside dimer called kaempferol-3-O-glycosyl-4'-kaempferol-3-O-glycoside was identified in C. nitidissima flowers, which was rare in other plants.
Flavan-3-ols are derivatives of flavans that possess a 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton. Epicatechin and catechin, two flavan-3-ols distributed in many plants, are found in C. nitidissima. Gallocatechin gallate, epigallocatechin (EGC), epicatechin gallate (ECG), catechin gallate, epigallocatechin gallate, and gallocatechin, which are unusual in plants out of the Theaceae family, are detected in C. nitidissima flowers (19). Among these catechins, the abundance of epicatechin is the highest in flowers, followed by EGC and ECG. The contents of catechins in different parts of flowers are not the same. Stamens and petals contain less catechins than sepals. In leaves, catechin and epicatechin are also detected (20). However, the contents of catechins and epicatechins in leaves are much lower than that in flowers. Old leaves accumulate more catechins than young leaves (21). Besides catechin monomers, procyanidins, which refer to the polymers of catechins, exist in C. nitidissima as well. So far, procyanidin dimers, trimers, tetramers, and pentamers have been identified in C. nitidissima flowers (22). Yang (23) identified a unique procyanidin tetramer in C. nitidissima flowers, which was catechin-4→8-catechin-4→8-catechin-3→7-catechin, and named it nitidissimol A.
Anthocyanins are water-soluble vacuolar pigments which are responsible for the vivid colors in plant tissues. Compared with C. nitidissima flowers, more anthocyanins are in leaves. Young leaves have more anthocyanins than old leaves. Li et al. (21) identified two anthocyanins in C. nitidissima, which were pelargonium-3-O-glucoside and cyanidin-3-O-glucoside. The former one existed in both flowers and leaves of C. nitidissima. The latter one was only detected in leaves and was considered to contribute to the purple color of new leaves.
Phenolic acids are phenols that contain a carboxylic acid. Gallic acid, chlorogenic acid, salicylic acid, and protocatechuic acid, which are common phenolic acids in plants, are found in the flowers of C. nitidissima (23). Ellagic acid is a phenolic acid with outstanding antioxidant and anti-proliferative properties. Multiple ellagic acid derivatives are identified in the leaves of C. nitidissima. Yu (24) demonstrated the presence of ellagic acid and four ellagic acid derivatives, including 3'-methy-4'-glucoside-ellagic acid, okicamelliaside, 3'-methyellagic acid, and 3,4-O,O-methylidyne-ellagic acid, in the leaves of C. nitidissima. Mo et al. (25) identified five ellagic acid derivatives in the leaves of C. nitidissima, which were 3,4-methylenedioxy-3'-O-methyl-4'-O-(6'-O-acetyl-glucoside) ellagic acid, okicamelliaside, 3,4-O,O-methylidyne-ellagic acid, ellagic acid-4-O-β-D-glucopyranoside, and 3,4-methylenedioxy-3'-O-methyl-4'-O-glucoside ellagic acid. Among these compounds, okicamelliaside is the relatively abundant one, whose content ranges from 0.51% to 1.33% (26). Notably, little study on the ellagic acid derivatives in C. nitidissima flowers was found.
Lignans are known to be minor constituents of many plants, often recognized as phytoestrogens. Lignans are derived from phenylanaline, consisting of two phenol units linked by four carbons. Lignans can polymerize to lignin to building the plant cell wall. Lignans often occur in the glycosidic form. They can be metabolized by intestinal bacteria to form mammalian lignans, which have cytostatic activity (27). Zhang et al. (28) isolated and purified lignans from C. nitidissima flowers using silica gel, Sephadex LH-20 gel, C18 reversed silica gel, and semi-preparative high performance liquid chromatography (HPLC). Eight lignans were identified, which were eudesmin, (+)-diasyringaresinol, (+)-isoeucommin A, pinoresinol 4-O-glucoside, 7S, 8R, 8'R-(-)-lariciresinol-4'-O-D-glucopyranoside, (+)-isolariciresinol 9-O-β-D-glucopyranoside, (+)-isolariciresinol 9'-O-β-D-glucopyranoside, and 3', 4-O-dimethylcedrusin. All of them have been reported to possess bioactivity.
|Classes/compound No.||Compound names||References|
|7||Kaempferol 3-O-glucosyl-4'-kaempferol 3-O-glycoside||(23)|
|53||3,4-Methylenedioxy-3'-O-methyl-4'-O-(6'-O-acetyl-glucoside) ellagic acid||(25)|
|55||3,4-Methylenedioxy-3'-O-methyl-4'-O-glucoside ellagic acid||(25)|
|60||7S, 8R, 8'R-(-)-lariciresinol-4'-O-D-glucopyranoside||(28)|
Saponins are plant-derived organic chemicals that have a foamy quality when agitated in water. Booming evidences indicate that various saponins have biological activity, such as anti-cancer, lipid-lowering, and anti-bacteria (29). Saponins are characterized by their structure containing a steroid or triterpene aglycone and one or more sugar moieties. Steroidal saponins almost exclusively occur in monocotyle-donous angiosperms, while triterpenoid saponins more frequently occur in dicotyledonous angiosperms (30).
Saponins are observed in different organs of C. nitidissima and the saponin contents were flowers > fruit shells > leaves > buds (31). Saponins in C. nitidissima mainly belong to ursane-type tetracyclic triterpenoids, lupane-type pentacyclic triterpenes, and oleanolane-type pentacyclic triterpenes. Su et al. (32) isolated three ginsenosides from C. nitidissima leaves, which were ginsenoside Rg1, ginsenoside F1, and ginsenoside F5. Wei et al. (33) demonstrated the presence of ilexside II in the water extract of C. nitidissima leaves. Mo (34) identified a new dammarane-type saponin from C. nitidissima, i.e. (3β,6α,12β)-3,6,12-trihydroxydammar-24-en-20-yl-2-O-β-D-glucopyranosyl-(2→1)-O-β-D-glucopyranosyl-(2→1)-O-α-L-rhamnopyranoside, and proved its anti-tumor activity. Yang (23) identified an oleanolane-type triterpene from C. nitidissima flowers, i.e., 3-O-β-D-galactopyranosyl-(1→2)-β-D-glucuronopyranosyl-21β,22α-di-O-angeloyl barringtogenol C. Qi (14) identified four saponins from C. nitidissima leaves, i.e., 3β-acetoxy-20-lupanol, 3β,6α,13β-trihydroxyolean-7-one, 22α-angeloyl-A1-barrigenol, and rubiprasin.
Polysaccharides are a group of biomolecules that are essential to all living organisms and are structurally composed of aldoses or ketoses linked by glycosidic bonds (35). They are widely distributed in plants, animals, algae, and microorganisms. Polysaccharides have a variety of biological activities, such as antioxidant, anti-hyperglycemia, anti-hyperlipidemia, anti-inflammation, anti-cancer, and immune enhancement (36).
Niu et al. (37) measured the polysaccharide content in the flowers, leaves, buds, and fruit shells of C. nitidissima, which were 32.88, 29.48, 35.89, and 30.02 g/kg, respectively. Tian (38) analyzed the sugar compositions of C. nitidissima polysaccharides, indicating that the C. nitidissima polysaccharides were composed of glucose, galactose, arabinose, mannose, rhamnose, and xylose. The former four monosaccharides were main components, accounting for 31%, 27%, 21%, and 13%, respectively. Some C. nitidissima polysaccharides not only contain monosaccharides, but also combine with galacturonic acid (39). Gong et al. (40) obtained three C. nitidissima polysaccharides, i.e., TPS1, TPS2, and TPS3, using water extraction, alcohol precipitation, and DEAE cellulose anion exchange chromatography. TPS1 is composed of glucose, galactose, and arabinose. TPS2 and TPS3 are composed of rhamnose, galacturonic acid, galactose, and arabinose. TPS3 contained more galacturonic acid than TPS2. Among them, the antioxidant activity of TPS3 was the best. It implies that polysaccharides with higher content of galacturonic acid tend to possess higher antioxidant capacity. One of the mechanisms is that galacturonic acid has electron-withdrawing groups, such as carboxyl and hydroxyl groups, which provide more hydrogen ions to neutralize free radicals (41).
Tian et al. (42) isolated six polysaccharides from C. nitidissima, three of which belonged to neutral polysaccharides and three of which belonged to pectins. Structural analysis suggested that the three pectins were probably composed of a hairy region which had a backbone of alternating galacturonic acid and α-L-rhamnosyl residues and a smooth region which had a backbone of galacturonic acid residues (42). Lin et al. (43) analyzed the structure of a C. nitidissima polysaccharide, and the results suggested that the polysaccharide was composed of a smooth region with highly methyl esterified galacturonic acid residues and three hairy regions with different chemical structures. Due to these structural characteristics, it is no wonder that several C. nitidissima polysaccharides are digestion-resistant. Gong et al. (44) investigated the digestibility of three polysaccharides and found none of them were digestible. However, all of them showed prebiotic activity. They promoted the proliferations of Lactobacillus and Bifidobacterium, and increased the production of short-chain fatty acids.
C. nitidissima contains multiple mineral elements, such as Ca, Mg, Na, K, P, Cu, Fe, Zn, B, Mn, Ni, and Mo. Some trace elements, such as Se, Sr, Cr, Ge, Co, Ga, and V, are also detected.
C. nitidissima are abundant in free amino acids. Zhao et al. (45) found that there were 16 types of amino acids in C. nitidissima leaves, including 7 essential amino acids. The content of free amino acids was 6% in old leaves and 5.37% in young leaves. Essential amino acids accounted for about 42% of total free amino acids in C. nitidissima leaves. The content and composition of free amino acids in C. nitidissima flowers are not quite the same as that in C. nitidissima leaves. Huang et al. (46) revealed that 17 types of amino acids were observed in C. nitidissima flowers. The content of free amino acids in C. nitidissima flowers ranged from was 4.32% to 5.46%, reaching the top at the fish-mouth stage. Essential amino acids accounted for 38% of total free amino acids in C. nitidissima flowers.
Volatiles are components which contribute to the aroma. Some volatiles also act as bioactive compounds, playing roles in anti-bacteria, anti-virus, anti-depression, and so on. Though almost odorless, 45 volatiles were identified in C. nitidissima flowers (47). Elaidic acid, palmitic acid, and stearic acid accounted for over 30% of total volatiles. (E,E)-2,4-heptadienal, (E,E)-2,4-decadienal, and geranyl acetone, each possessed over 1.7% of total volatiles. Huang et al. (48) identified 37 volatiles in C. nitidissima leaves. Benzoic acid-2-hydroxy-methyl ester was the major volatile, accounting for 26.91% of total volatiles. Benzyl alcohol, cis-octahydropentalene, cis-linaloloxide, phenylethyl alcohol, and 2,6-dimethyl-3,7-octadiene-2,6-diol were relatively abundant in C. nitidissima leaves.
Phytosterols are a family of molecules related to cholesterols and serve as structural components of biological membranes of plants. α-spinasterol, α-spinasteryl-β-D-glucopyranoside, β-sitosterol, and stigmasta-7,22-diene-3-O-[α-L-arabinopyranosyl(1→2)]-β-D-galactopyranoside are observed in C. nitidissima (14,23).
Main bioactivity of C. nitidissima
Although C. nitidissima has been traditionally used as an herbal medicine and regarded as health-beneficial, scientific researches on the bioactivity of C. nitidissima have been merely conducted in recent two decades. Evidences indicate that C. nitidissima is potent in antioxidant, anti-cancer, anti-hyperglycemia, and anti-hyperlipidemia (7). Particularly, it works excellent in anti-allergy and anti-depression (7). In next subsections, the main bioactivity (Figure 3) and possible underlying mechanisms are introduced.
At present, there are many studies on the antioxidant activity of C. nitidissima. Wei et al. (49) proved that the ethanol extract of C. nitidissima leaves had hydroxyl radical (·OH) scavenging, superoxide anion radical (O2·−) scavenging, 2,2-diphenyl-1-picrylhydrazyl radical (DPPH·) scavenging activity and reducing power. Qin et al. (50) found that the water extract of C. nitidissima leaves dose-dependently scavenged ·OH and O2·−. At the concentration of 1.25 mg/mL, O2·− was completely scavenged. Yang et al. (18) found that the n-butanol extract of C. nitidissima flowers had a strong inhibitory effect on AGEs. Wen et al. (51) used 95% ethanol to extract the leaves, stamens, buds and petals of C. nitidissima. All the above parts had antioxidant activity, and the buds had the strongest antioxidant activity while the leaves had the weakest.
Phenolic compounds are vital for the antioxidant activity of C. nitidissima. The C. nitidissima flavonoids showed good antioxidant activity with an IC50 of 0.070 mg/mL for the scavenging of DPPH· and an IC50 of 0.679 mg/mL for the scavenging of ·OH (52). Song et al. (15) analyzed the total phenolic content and antioxidant capacity of six types of C. nitidissima leaves by HPLC and liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS), and concluded that the antioxidant capacity was correlated with the total phenolic content. Kaempferol derivatives and quercetin derivatives, well-known for their antioxidant activity, were abundant in C. nitidissima and possibly contributed to the superior antioxidant activity of C. nitidissima. Song et al. (15) found that the dichloromethane and ethyl acetate fractions of C. nitidissima were similarly effective in inhibiting the formation of AGEs in the bovine serum albumin (BSA)-glucose reaction system, while the ethyl acetate fraction was more effective in inhibiting the formation of AGEs in the BSA-methylglyoxal reaction system. Mono- and di-methylglyoxal quercetin adducts were detected in the reaction systems, suggesting that quercetin derivatives inhibited the formation of AGEs by scavenging methylglyoxal. Catechins inhibited the formation of AGEs using the same strategy, i.e., by reacting with methylglyoxal to form adducts (23).
Saponins also play a role in the antioxidant activity of C. nitidissima. Ning et al. (53) used XAD16 macroporous adsorbent resin to isolate and purify C. nitidissima saponins. The crude saponin extract effectively scavenged a variety of free radicals and even worked better than Vitamin C in scavenging ·OH and H2O2. Su et al. proved that ginsenoside F1, which was extracted from C. nitidissima leaves, protected HepG2 cells from H2O2-induced oxidative damage by increasing the superoxide dismutase (SOD) activity (54,55). The results provided a scientific basis for the effectiveness of C. nitidissima on antioxidation in cells.
Polysaccharides from C. nitidissima show antioxidant activity as well. Song et al. (56) isolated three polysaccharides with the β-pyranose configuration from C. nitidissima leaves and demonstrated that the antioxidant activity of neutral polysaccharide was weaker than that of the two acidic polysaccharides, implying the polarity affected the antioxidant activity of polysaccharides. He (41) proved that C. nitidissima polysaccharides with higher content of glucuronic acid exhibited stronger antioxidant activity, which fitted the theory.
Multiple researches have proved that C. nitidissima exhibits its anticancer activity not only by preventing the initiation and promotion of cancer, but also the progression of cancer.
C. nitidissima has the potential to be a chemoprevention agent. Daily consumption of diet containing 5% C. nitidissima leaves or 5% C. nitidissima leave extract significantly decreased diethylnitrosamine-induced precancerous lesion of liver in rats (57). Daily intra-gastric administration of C. nitidissima leave extract for 73 weeks effectively reduced the incidence of aflatoxin B1-induced hepatocellular carcinoma and delayed aflatoxin B1-induced hyperplasia in rats (58). The underlying mechanisms included the inhibition of C. nitidissima leave extract on cytochrome P450 enzyme 3A4 (CYP3A4) and glutathione S-transferase π (GST-π), two enzymes mediating the metabolism of aflatoxin B1, as well as the down-regulation of the aflatoxin B1-induced expression of signal transducer and activator of transcription 3 (STAT3), a transcriptional factor well-validated to promote tumorigenesis. Moreover, Sai (59) found that the intra-gastric administration of C. nitidissima flower extract for 16 weeks reduced the incidence of lung tumors by about 13% in an uratan-treated mouse model. The catalase and SOD activity were increased while the malondialdehyde level was decreased in the C. nitidissima flower extract group. The interleukin-2 and tumor necrosis factor α levels were also increased. It suggested that C. nitidissima flower extract exerted the chemopreventive activity via enhancing the antioxidant and immunomodulatory activity of mice.
In addition to preventing cancer, C. nitidissima directly inhibits cancer via affecting the proliferation, apoptosis, cell cycle, and migration of cancer cells.
C. nitidissima reduces the proliferation of various cancer cells in vitro, for example, gastric carcinoma MGC-803 cells (60), esophageal squamous carcinoma Eca-109 cells (61), leukemia U937 cells (62), cervical carcinoma Hela cells (63) and prostate cancer PC-3 cells (64). The effective parts of C. nitidissima include flowers, leaves, and seeds. Yu et al. (65) showed that the alcoholic extracts of C. nitidissima flowers, seeds, and leaves inhibited the proliferation of U937 cells, and the first two extracts also dose-dependently inhibited human colon cancer HCT116 cells.
C. nitidissima extracts promote the apoptosis of cancer cells. Zhao (63) found that C. nitidissima flower extract time-dependently and dose-dependently triggered the apoptosis of Hela cells. Sai (59) demonstrated that the C. nitidissima flower extract upregulated the expression of Bax, a pro-apoptotic protein in the Bcl-2 family, led to the depolarization of the mitochondrial membrane potential, initiated the mitochondrial apoptotic pathway, and eventually caused the intrinsic apoptosis of lung carcinoma A549 cells.
In some cases, C. nitidissima extracts induce cell cycle arrest of cancer cells. Li (60) proved that C. nitidissima flower extract dose-dependently halted MGC-803 cells at the S and G2 cell cycle phases. Shen (66) demonstrated that C. nitidissima ethanol extract blocked the cell cycle of nasopharyngeal carcinoma CNE-2 cells at the G1 phase, induced apoptosis by activating Caspase-3, and down-regulated the expression of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3, two molecules which were associated with the migration of CNE-2 cells.
At present, most researches on the anticancer property of C. nitidissima are carried out using crude extracts. Only a few studies pinpoint the anticancer components of C. nitidissima. Learning from current studies, saponins may be key anticancer components in C. nitidissima. Mo (34) proved that a dammarane-type saponin from C. nitidissima effectively inhibited the growth of Bel-7402 and SMMC-7721 cells in vitro. Jing et al. (8) verified that 3β,6α,13β-trihydroxyolean-7-one, which was a saponin extracted from C. nitidissima, showed potential cytotoxic activity against SGC7901 cells in vitro. 22α-Angeloyl-A1-barrigenol, another saponin from C. nitidissima, significantly inhibited A549 cells, human gastric carcinoma HGC-27 cells, human breast cancer MDA-MB-435 cells, and human colorectal cancer SW620 cells (8).
Although C. nitidissima has toxicity to cancer cells, it does not hurt normal cells. Li (67) found that C. nitidissima flowers extract had no toxic side effects on human normal liver HL-7702 cells. Sai (59) demonstrated that C. nitidissima extract had no subchronic toxicity in mice. The above results reveal that C. nitidissima is highly selective and effective in inhibiting cancer cells, meanwhile it has low toxicity to normal cells and causes little side effects. It suggests that this plant has a great potential as an anticancer drug candidate.
Hypoglycemic and hypolipidemic activity
Overnutrition is a form of malnutrition in which the intake of nutrients is oversupplied (68). It adversely affects health, causing symptoms like hypoglycemia and hypolipidemia. It may further increase the risks of chronic metabolic diseases, such as diabetes and atherosclerosis.
C. nitidissima leave extracts have excellent hypoglycemic activity. C. nitidissima leave n-butanol and ethyl acetate extracts increased the glucose consumption of insulin-resistant HepG2 cells and decreased the fasting blood glucose and postprandial blood glucose levels in type 2 diabetic mice (69). In another type 2 diabetic mouse model, intra-gastric administration of C. nitidissima leave extract for 28 days increased the insulin level, attenuated pancreatic injury, and promoted the accumulation of hepatic glycogen (70). Feng et al. investigated the effect of C. nitidissima leave extract capsules on lowering blood glucose in diabetic patients. The results supported that C. nitidissima leave extract capsules were effective for the adjuvant therapy of diabetes (71).
C. nitidissima flower extracts display hypolipidemic activity. C. nitidissima flower extract significantly decreased oleic acid-induced lipid accumulation in HepG2 cells by inhibiting the mRNA expression of lipogenesis-related fatty acid synthase, 3-hydroxy-3-methyl glutaryl coenzyme A reductase, and glycerol-3-phosphate acyltransferase genes. It significantly reduced the total triglycerides, total cholesterols, and low-density lipoprotein cholesterols, while increased the high-density lipoprotein cholesterols in serum of hyperlipidemic mice (72). Phenolic compounds may play an important role in it. Zhang (9) observed that C. nitidissima flower flavonoid extract decreased food intake by upregulating the secretion of glucagon-like peptide-1, a hormone negatively regulating the appetite. It inhibited the activity of α-amylase, α-glucosidase, pancreatic lipase, and cholesterol esterase, and decreased the solubility of cholesterol micelles, thus interfering the digestion and absorption of carbohydrates and lipids. In high-fat-diet-induced rats, it reduced lipogenesis, promoted lipolysis and lipid oxidation, attenuated triglycerides and cholesterol accumulation in serum and liver, and alleviated hepatic lipotoxicity. It improved impaired glucose tolerance and restored insulin sensitivity. Additionally, it alleviated high-fat diet-induced dysbiosis.
Allergy is a number of conditions caused by hypersensitivity of the immune system. Type I hypersensitivity, known as the immediate-type reaction, can be triggered by pollen, foods, drugs, and insect stings. It involves immunoglobulin E (IgE)-mediated release of antibodies against the antigen, degranulation of mast cell, and release of inflammatory factors (e.g., histamine), resulting in symptoms like itch, edema, and pain (73).
C. nitidissima leave water extract and C. nitidissima fruit peel ethyl acetate extract effectively alleviated ovalbumin and Al(OH)3 mixture-induced type I allergy in mice (74). The serum IgE and leukotriene levels were reduced, the number of eosinophils in blood and bronchoalveolar lavage fluid were decreased, and the inflammation in lung was attenuated.
Okicamelliaside, an ellagic acid derivative which exists in Camellia japonica and C. nitidissima leaves, is considered to be the major anti-allergic agent in C. nitidissima. It was 12,000 times more potent than ketotifen fumarate, an antihistamine drug, in inhibiting the degranulation of RBL-2H3 cells (75). It significantly inhibited the vascular hyperpermeability in a passive cutaneous anaphylaxis mouse model. Further study indicated that okicamelliaside inhibited antigen-IgE-FcεRI-induced activation of the Lyn-Syk-LAT-PLCγ-1 pathway, blocked the release of Ca2+, decreased the expression of proinflammatory cytokines (e.g., interleukin-4 and interleukin-13), cytokine-producing signaling factors, and prostaglandin-endoperoxidase 2, resulting in the suppression of allergic inflammation.
Kaempferol 3-O-β-D-glucosyl(1→3) [α-L-rhamnosyl(1→6)]-(2-O-E-p-coumaroyl-β-D-glucoside), a flavonol glucoside obtained from C. nitidissima water extract, is another promising anti-allergic agent in C. nitidissima. It significantly inhibited lipoxygenase activity and leukotriene production in vitro (76).
Depression is a common but serious mood disorder. It causes a persistent feeling of sadness and loss of interest. Nowadays, the stress of life increases. Along with it, is the increasing incidence of depression. Current clinical antidepressant drugs are chemical synthetic drugs, which shows several side effects. Therefore, novel antidepressant drugs with less toxic side effects have come into the limelight.
C. nitidissima contains a variety of natural active ingredients with antidepressant effects, such as quercetin (77), kaempferol (78) and ginsenoside Rg1 (79). C. nitidissima extract significantly decreased corticosterone-induced apoptosis of differentiated PC12 neuronal cells by increasing the expression of brain-derived neurotrophic factor (BDNF) via the protein kinase A-cAMP-response element binding protein signaling pathway (80). It indicated that C. nitidissima extract was capable of protecting neurons. In a chronic unpredictable mild stress rat model, C. nitidissima extract alleviated the decrease of body weight and loss of interest in sucrose. Immunohistochemistry staining and Hematoxylin and Eosin staining confirmed that C. nitidissima extract attenuated the hippocampus injury by increasing the expression of BDNF. Serum corticosterone and adrenocorticotropic hormone, which were increased under depression, was decreased. At the same time, serum SOD and glutathione peroxidase activity were increased while serum malondialdehyde levels were decreased, implying C. nitidissima extract attenuated depression-induced oxidative stress in the body. In mice, C. nitidissima extract also effectively alleviated the depression symptoms. Compared with mice in the model group, the brain and serum serotonin, dopamine, and norepinephrine levels of mice administering C. nitidissima extract were increased. These results suggest that C. nitidissima extract displays its antidepressant activity via multiple targets and it has the promise to be applied in the treatment of depression.
C. nitidissima, though merely being taxonomically classified within a century, has a long history being used as an herb. Chemical analysis reveals that phenolic compounds, saponins, and polysaccharides are important components in C. nitidissima. Some of them are unique in C. nitidissima (e.g., nitidissimol A and some complex flavonol glucosides), some are featuring components in the Camellia genus (e.g., okicamelliaside), and some are commonly distributed in plants (e.g., kaempferol, quercetin, and epicatechin). Biological experiments prove that C. nitidissima exhibits multiple physiological functions, particularly in antioxidant, anti-cancer, anti-hyperglycemia, anti-hyperlipidemia, anti-allergy, and anti-depression. Scientific evidences of the pharmacological value of C. nitidissima and corresponding chemical basis are partially established.
It is noteworthy that most of the current biological studies of C. nitidissima are based on crude extract without a clear description of the chemical profile, which makes it difficult to figure out the predominant bioactive component. Some bioactivity of C. nitidissima is verified in vitro, whether it works in vivo or not still remains unknown. In addition, current understanding of the molecular mechanisms of C. nitidissima is relatively preliminary. In the future, more attentions should be drawn on the bioactivity of individual component in C. nitidissima. The assessments are recommended to be conducted both in vitro and in vivo. Detailed working mechanisms are encouraged to be explored. Researches of pharmacokinetics and pharmacodynamics are also necessary. By ascertaining these properties of individual component, investigations on interactions between bioactive components can be carried out more easily. The above information will help us better understand why C. nitidissima is capable of a specific physiological function and how it exhibits the activity.
It is also aware that some empirical therapeutic activity of C. nitidissima still lacks scientific proof. Little is known about the activity of some special compounds in C. nitidissima. Future researches on these aspects are needed. The results will certainly enhance the knowledges of C. nitidissima and benefit the applications of C. nitidissima in health industry.
Funding: This research was supported by the China Agriculture Research System of MOF and MARA (CARS-19) and the Innovation Project for the Chinese Academy of Agricultural Sciences.
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Cite this article as: Zheng H, Du Q, Yin J, Gao Y. A narrative review on the main chemical constituents and bioactivity of Camellia nitidissima Chi. Longhua Chin Med 2022;5:29.