|Year : 2021 | Volume
| Issue : 4 | Page : 235-242
Dendrobium nobile lindl: A review on its chemical constituents and pharmacological effects
Juan Zhang1, Hong- Xi Xu2, Zhi- Li Zhao3, Yan- Fang Xian1, Zhi- Xiu Lin4
1 School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
2 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China
3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
4 School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077; Hong Kong Institute of Integrative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
|Date of Submission||04-Oct-2021|
|Date of Acceptance||15-Nov-2021|
|Date of Web Publication||28-Dec-2021|
Prof. Yan- Fang Xian
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077
Prof. Zhi- Xiu Lin
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077; Hong Kong Institute of Integrative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077
Source of Support: None, Conflict of Interest: None
Dendrobium nobile Lindl (D. nobile), a well-known precious herb, has a long history of use as a medicine and health food in China. Phytochemically, D. nobile has been found to contain various bioactive compounds, such as alkaloids, bibenzyl, phenanthrene, phenylpropanoids, and polysaccharides. Its medicinal applications are closely correlated to its diverse pharmacological activities, including antitumor, anti-inflammatory, nervous system protective, antifatigue, hypoglycemic, and hypolipidemic actions. In this review, we provide a comprehensive summary of the main chemical constituents and pharmacological activities of D. nobile, as well as the underlying molecular mechanisms for its bioactivities. It is expected that this review will provide a helpful scientific reference for the development and use of D. nobile.
Keywords: Chemical constituents, Dendrobium nobile Lindl (D. nobile), pharmacological effect, Chinese medicine
|How to cite this article:|
Zhang J, Xu HX, Zhao ZL, Xian YF, Lin ZX. Dendrobium nobile lindl: A review on its chemical constituents and pharmacological effects. Chin Med Cult 2021;4:235-42
|How to cite this URL:|
Zhang J, Xu HX, Zhao ZL, Xian YF, Lin ZX. Dendrobium nobile lindl: A review on its chemical constituents and pharmacological effects. Chin Med Cult [serial online] 2021 [cited 2022 May 25];4:235-42. Available from: https://www.cmaconweb.org/text.asp?2021/4/4/235/334093
| Introduction|| |
Dendrobium nobile Lindl (D. nobile) is also known as Noble Dendrobium or Jin Chai Shi Hu (金钗石斛) in Chinese. It is a perennial epiphytic herb of the genus Dendrobium in the Orchidaceae family. D. nobile is one of the main Dendrobium species recorded in the Chinese Pharmacopoeia and it offers both ornamental and medicinal benefits. There are about 1,500 species of Dendrobium around the world, and 50 of them have been found to be medicinally valuable in China. The history of the utilization of medicinal Dendrobium is one of 1,500 years in China and the first record of its use was found in the Shen Nong Ben Cao Jing (《神农本草经》Shennong's Classic of Materia Medica). Dendrobium together with Dong Chong Xiao Cao (冬虫夏草 Cordyceps sinensis), Ren Shen (人参 Radix Ginseng) and Ling Zhi (灵芝 Ganoderma lucidum) have been regarded as precious and top-grade traditional Chinese medicines (TCM) in China for thousands of years. Dendrobium is widely used as a traditional medicine for nourishing Yin, clearing heat, relieving coughs, brightening eyes, strengthening body constitution, and promoting longevity.
In recent decades, phytochemical investigations have revealed that the active chemical components of D. nobile mainly include alkaloids, polysaccharides, and phenols. Pharmacological studies have shown that the active ingredients of D. nobile have multiple health-promoting effects, and many of the pharmacological effects have ethmomedicinal values, including anti-tumor, anti-inflammatory, immune enhancing, anti-fatigue, anti-aging, and blood sugar reducing properties have ethnomedicinal values. Furthermore, the application value of D. nobile is expanded from its medicinal property to ornamental plants in gardens. For instance, D. nobile is widely used for decoration purposes in houses or on the streets in Chinese cities because of its beautiful and elegant appearance. To date, to our knowledge, no authoritative systematic review has been published on D. nobile. Hence, the aim of this present summary is to provide an up-to-date and comprehensive literature review on D. nobile, with a particular focus on its botany, chemical constituents, and pharmacological effect, as well as on the potential molecular mechanisms underpinning the bioactivities of its components. It is expected that this review will provide new insights for further study and exploitation of D. nobile as medicinal agent or functional food in future.
| Botany and Ethnopharmacology|| |
D. nobile is known by other synonyms including “Callista nobilis (Lindl.) Kuntze; D. coerulescens Wall. ex Lindl., D. formosanum (H. G. Reichenbach) Masamune; D. lindleyanum Griff., D. nobile var. alboluteum Huyen and Aver., D. nobile var. formosanum H. G. Reichenbach and D. nobile var. nobilius (H. G. Reichenbach) M. Hiroe. D. nobile is known to be distributed in several Asian countries, including China, Bhutan, India, Laos, Myanmar, Nepal, Thailand, and Vietnam. D. nobile is native to several provinces of China including Anhui, Guizhou, Taiwan, Hainan, Hubei, and Guangxi provinces. It usually epiphytizes on tree trunks in mountain forests, lithophytes on rocks in mountain valleys at 500–1,700 m altitude, and grows mainly in warm and humid environments. Botanically, D. nobile is a small-sized plant with stems that are erect, fleshy and cylindric, reaching between 10 and 60 cm long and 1.3 cm in diameter with its upper part curving and dividing into sections,and turning to golden yellow when dry. The leaves are oblong, measuring (6-11) cm × (1-3) cm, leathery, apex obtuse and unequally bilobed, while its base is decorated with a cauline sheath. The pseudobulb of D. nobile is the main source of dendrobium recorded in the Chinese Pharmacopoeia. According to the Shennong's Classic of Materia Medica, it possesses the therapeutic effects of “nourishing Yin and benefiting essence, thickening intestines and stomach, supplementing deficiency of internal organs, and relieving the body to prolong life”.,
For thousands of years, D. nobile has been used as a traditional remedy for various diseases, such as diabetes, chronic atrophic gastritis, neurodegenerative conditions related to aging, and cardiovascular disease., The pseudobulb is used to alleviate thirst, calm restlessness, accelerate convalescence, and reduce dryness of the mouth. The leaf extract of D. nobile is effective on freshly cut wounds and is used agaianst dermatologic disorders. Overall, the fresh and dried pseudobulbs of this plant are well known as one of the most expensive tonics in TCM and may also be used as a dietary supplement. D nobile is worthy of been further studied and developed as a therapeutic agent or functional food in the management of human health. A photo of the entire D. nobile is shown in [Figure 1].
| Phytochemical Constituents|| |
To date, various phytochemical compounds have been isolated and identified from D. nobile and they are mainly alkaloids, bibenzyl, phenanthrene, phenylpropanoids, and polysaccharides, among other things. Some of them have been regarded as the biologically active components responsible for multiple bioactivities. Among these chemical compounds, alkaloids are high in content and widely used in research. The compounds isolated from D. nobile are listed in [Table 1].
Alkaloids are a huge group of naturally occurring organic compounds that contain at least one nitrogen atom or atoms (amino or amido in some cases) in their structures. These nitrogen atoms are responsible for the alkalinity of alkaloids compounds. Alkaloids play an essential role in both human medicine and in an organism's natural defenses. Alkaloids make up approximately 20% of the known secondary metabolites found in plants. Alkaloids are the earliest chemical compounds isolated and purified from Dendrobium genus, and they are also important active components in D. nobile. The alkaloids from D. nobile have been found to own the potential of exhibit anti-cancer and neuroprotective effects. Wang et al. isolated nine sesquiterpene alkaloids from the extracts of the stem of D. nobile, including N-methyldendrobinium (1), dendrobine (2), mubironine B (3), nobilonine (4), dendramine (5), 6-hydroxy-nobiline (6), N-isopentenyldendrobinium (7), N-isopentenyl-6-hydroxydendroxinium (8), and N-isopentenyldendroxinium (9). Dendroxine (10) and 6-hydroxy-dendroxine (11) have also been isolated as major alkaloids from D. nobile. Among them, dendrobine (2) is the first identified active alkaloid of D. nobile and is regarded as the standard agent for the qualitative and quantitative evaluation of D. nobile.
Bibenzyl is a type of organic compound that is a derivative of ethane in which one phenyl group is bonded to each carbon atom. It is chemically constructed by two lunularin moieties with two diaryl-ether bonds, or two biaryl bonds, or one diaryl-ether and one biaryl bond. Bibenzyls are found to be widespread in this plant. For instance, moscatilin (12), crepidatin (13), and chrysotobibenzyl (14) have been isolated from D. nobile by the screening of 31 extracts. Moreover, moscatilin (12) and gigantol (15) were isolated from nearly 20 species of Dendrobium. Zhang et al. also identified three new bibenzyl compounds from an ethanol-water extract of D. nobile, namely nobilin A (16), nobilin B (17), and nobilin C (18), all of which were found to possess antioxidant properties. In addition, seven bibenzyl compounds were isolated from the stem of D. nobile by using silica gel, MCI column chromatography, and preparative HPLC, among which 4,α-dihydroxy-3, 5, 3'-trimethoxybibenzyl was identified as a new compound and 4,5-dihydroxy-3,3'-dimethoxybibenzyl was isolated from the plant for the first time.
Phenanthrene is a polycyclic aromatic hydrocarbon consisting of three fused benzene rings. The phenanthrenes isolated from the stem of D. nobile include moscatin (19), nudol (20), bulbophyllanthrin (21), fimbriol B (22), plicatol A (23), lhridinusiant (24), coelonin (25), erianthridin (26), ephemeranthol A (EA) (27), ephemeranthol C (28), hircinol (29) and flavanthridin (30). Zhang et al. isolated 5 phenanthrene compounds including fimbriatone (31), flavanthrinin (32), 4, 9-dimethoxyphenanthrene (33), 2, 2, 6-diol (34), 2, 5-diol, 5, 7-dimethoxyphenanthrene (35) and confusarin (36) from stem extracts of D. nobile. Another three phenanthrene derivatives were isolated from D. nobile and were structurally characterized as 3,7-dihydroxy-2,4-dimethoxy-9,10-dihydrophenanthrene (37), 3,7-dihydroxy-2,4-dimethoxyphenanthrene (38), and 3,7-dihydroxy-2, 4, 8-trimethoxyphenanthrene (39). In addition, Kim et al. isolated three phenanthrenes, namely EA (27), 1, 5, 7-trimethoxyphenanthren-2-ol (40), and dehydroorchinol (DO) (41) from D. nobile. These phenanthrenes were found to possess anti-inflammatory activities.
Phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Five new phenylpropanoids were first isolated from D. nobile, namely decumbic acids A (42), decumbic acids B (43), (−)-decumbic acid (44), (−)-dendrolactone (45) and (+)-dendrolactone (46), which have been reported to possess antifungal and antitumor activities.
Polysaccharides are a type of biomacromolecule composed of ten or more monosaccharides for which the structure and sugar composition vary, and are one of the active and important ingredients of TCM. Several types of polysaccharides have been identified in Dendrobium plants. They are usually considered to be one of the main ingredients in D. nobile and have been shown to have obvious biological activity, such as immunomodulatory, anti-tumor, and antioxidant activities. Research findings have shown that five water-soluble polysaccharides, including Dendrobium Nobile polysaccharide (DNP)-W1 (47), DNP-W2 (48), DNP-W3 (49), DNP-W4 (50), and DNP-W5 (51) have been isolated from the stems of D. nobile and possess significant immune-modulatory activity., Among these, two water-soluble polysaccharides, namely, DNP-W1 (47) and DNP-W3 (49) exhibited significant antitumor activities. One study reported the isolation of four polysaccharides from the dry stem of D. nobile including L-arabinose (52), D-galactose (53), D-glucose (54), and D-mannose (55) through subcritical water extraction.
Fluorenone and phenolic acid
To date, apart from the above-mentioned chemical classes of components, other types of chemical constituents, such as phenolic acids and fluorenone, have also been purified from D. nobile. Briefly, compounds including syringic acid (56), 2-hydroxyphenylpropanol (57), vanillin (58), apocynin (59), coniferyl aldehyde (60), syringaldehyde (61), syringylethanone (62), p-hydroxybenzaldehyde (63), 3-hydroxy-4-methoxyphenylethanol (64), α-hydroxysyringylethanone (65), dihydroxyconiferyl alcohol (66), p-hydroxybenzoic acid (67), and p-hydroxyphenylpropionic acid (68) were identified as phenolic acids and were shown to exhibit antioxidant activity. Dendroflorin (A1) (69), denchrysan A (A1) (70), dengibsin (A1) (71), and nobilone (72) were identified as derivatives of fluorenone.
| Pharmacological Effects of D. nobile and the Associated Molecular Mechanisms|| |
D. nobile possesses multiple biological functions, including anti-tumor, anti-inflammatory, cardioprotective, neuroprotective, anti-aging, hypoglycemic, and hypolipidemic effects. The biological activities of D. nobile and the related molecular mechanisms are shown in [Table 2] and [Figure 2], respectively.
|Table 2: Chemical constituents of Dendrobium nobile and their pharmacological activities|
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|Figure 2: Schematic representation of the mechanisms underlying the bioactivities of the compounds isolated from D. nobile|
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Multiple in vitro and in vivo studies have demonstrated the significant inhibitory effect of D. nobile against a variety of tumor cells. The possible mechanisms responsible for the antitumor activity of the isolated compounds from D. nobile are shown in [Table 2]. Two water-soluble polysaccharides of D. nobile, namely DNP-W1 and DNP-W3 exhibited potent antitumor activities against Sarcoma 180 in vivo and human promyelocytic leukemia HL-60 cells in vitro. Similarly, another study demonstrated that Nudol (20), a phenanthrene compound from D. nobile, induced cell cycle arrest (G2/M phase) and apoptosis and inhibited migration in osteosarcoma U2OS cells. Dendrobine has been shown in an in vivo study to enhance the anticancer effect of cisplatin on non-small cell lung cancer cells via c-Jun N-terminal kinase (JNK)/p38 stress signaling, and could induce apoptosis via the pro-apoptotic proteins Bax and Bim. In addition, denbinobin, another phenanthrene from D. nobile, was reported to induce apoptosis and inhibit cancer cell invasion in human gastric SNU-484 cells. Moreover, two phenanthrenes compounds isolated from the aerial part of D. nobile viz, 4,7-dihydroxy-2-methoxy-9,10-dihydrophenanthrene and denbinobin, were found to be cytotoxic against A549 (human lung carcinoma), SK-OV-3 (human ovary adenocarcinoma), and HL-60 (human promyelocytic leukemia) cell lines. The compounds also showed antitumor activity and enhanced lifespan on sarcoma 180 ICR mice.
The anti-inflammatory effects of phenanthrenes EA (27), TP (40) and DO (41) were evaluated, and the results showed that EA, TP and DO at 50 μg/mL exhibited significant cytotoxic effects toward RAW 264.7 cells and attenuated inducible nitric oxide synthase protein level in the lipopolysaccharide (LPS)stimulated RAW 264.7 cells. EA significantly lowered the mRNA levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the LPS-activated cells. Notably, the mRNA levels of IL-6 and TNF-α decreased when compared with the level of the LPS-untreated control. DO also attenuated the mRNA levels of TNF-α, IL-6, and IL-1β in the LPS-activated cells, EA and DO downregulate the expression of LPS-stimulated COX-2 which is known as an inflammatory enzyme and a converting enzyme of prostaglandins. The inhibitory activities were associated with suppressing nuclear factor kappa-B (NF-κB) activation and phosphorylation of mitogen-activated protein kinases (MAP) kinases in macrophages.
Cardiovascular diseases are the major cause of mortality in many parts of the world. Cardiomyopathy and high blood pressure are the most significant risk factors for cardiovascular diseases. Studies have suggested that D. nobile exerts its cardioprotective activity by ameliorating myocardial ischemia/reperfusion (I/R) injury. It has been shown that Dendrobium nobile Lindl. alkaloids (DNLA) may alleviate myocardial injuries after I/R through inhibiting the abnormal expression of FAT/CD36, decreasing the uptake of free fatty acids and reducing the abnormal accumulation of long-chain acyl-coenzyme A in the myocardium. Studies have also laid bare that D. nobile-derived syringic acid attenuated renal I/R injury, and the related mechanisms were associated with downregulation of B-cell lymphoma 2 expression and suppression of the expression of Bcl-2-like protein 4 (Bax) and cleaved caspase-3 in H9c2 cardiomyocytes induced by hypoxia/reoxygenation. SA also alleviated H/R-induced phosphorylation of p38 MAP kinase and JNK in H9c2 cardiomyocytes. Moreover, D. nobile Lindl increased the potency of SA in protecting aged hearts against I/R injury, and the protective mechanism may be related to the reduction in the activity of the TLR4/MyD88/NF-κB signaling pathway and subsequent modulation of inflammatory cytokines and endogenous antioxidants.
Alzheimer, characterized by the progressive deterioration of learning, memory and cognition, is the most common form of neurodegenerative condition. D. nobile has been subjected to many studies for its neuroprotective activity. It was revealed that D. nobile-derived DNLA could reduce the cytotoxicity induced by Aβ25-35 in cultured rat primary neurons. The protective mechanism that DNLA confers on the synaptic integrity of cultured neurons might be mediated, at least in part, via the upregulation of neurogenesis related proteins synaptophysin and postsynaptic density-95. Another study showed that DNLA attenuated anxiety/depression-like behavior and neuronal damage in a chronic unpredictable stress rat model. The mechanisms may be related to the modulation of CUS-induced aberrant hippocampal gene expression, such as the decreasing of adrenocorticotropic hormones and expression of corticotropin-releasing hormone receptor-1, increasing expression of glucocorticoid receptor in the brain. Additionally, DNLA significantly improved learning and memory functions in APP/PS1 transgenic mice owing to its ability to promote intracellular Aβ degradation by increasing the protein level of v-ATPase A1 and improving autolysosomal acidification and proteolysis. Overall, DNLA displayed excellent neuroprotective properties and it could be a promising compound for development as a pharmaceutical drug for neurodegenerative diseases.
Aging is a natural phenomenon and is the primary risk factor for the functional decline observed in most human body organs. Aging is regulated by genes and the living environment. The human lifespan is partially determined by genetics (20%–30%) and partially by environmental factors such as lifestyle, diet, and intake of poisons and drugs. As alluded to the above aspects, DNLA is the active ingredient in D. nobile to improve learning and memory declines. Another study also reported the anti-aging effects out of long-term administration of DNLA during the aging process in the senescence-accelerated mouse-prone 8 (SAMP8) mice. The results showed that DNLA could protect against aging-related cognitive deficits, neuron aging, damage, and loss in SAMP8 mice and aging cells. The underlying mechanisms were associated with increased Aβ clearance, activation of autophagic activity, and upregulation of Klotho. Many lines of evidence suggest that oxidative stress is linked to human diseases and aging. The research results showed that pretreatment with D. nobile liquor extract (DNLE) could attenuate the oxidative damage to cells caused by H2O2 and suppress the aberrant protein expressions caused by oxidative stress. Moreover, DNLE was also capable of mitigating the unfolded protein response and cell cycle disorder caused by oxidative stress.
Metabolic syndrome is a common chronic disease characterized by obesity, dyslipidemia, raised blood pressure, and high glucose levels. MS significantly augments the risk of type 2 diabetes and adversely affects human health. Several studies have extensively explored the antidiabetic potential of D. nobile using various experimental models. The findings revealed that D. nobile exhibited an outstanding hypoglycemic effect. D. nobile has been proven for its hypoglycemic and lipid-lowering effects without obvious side effects. A number of experimental studies have shown that D. nobile plays an important role in glucose and lipid metabolism. D. nobile could reduce the serum levels of aspartate aminotransferase and alanine aminotransferase, attenuate the production of malondialdehyde (MDA), and improve ultrastructural morphology in hepatocytes to reduce the CCl4- induced liver damage. D. nobile is also beneficial to the expression of genes involved in glucose and lipid metabolism due to its ability to enhance the expression of genes related to the Nrf2-antioxidant pathway., Oral administration of polysaccharides from D. nobile (DNP) confers significant hypoglycemic activities evidenced by the decreased levels of fasting blood glucose and glycosylated serum protein, as well as by the increased level of serum insulin in alloxan-induced diabetic mice.
Other pharmacological effects
It was found that D. nobile also has hepatoprotective and hypolipidemic effects. One study showed that DNLA, a D. nobile-derived alkaloid, improved CCl4-induced liver injury, and the mechanism was related to the improvement of mitochondrial oxidative stress and mitochondrial dysfunction, evidenced by a decrease in mitochondrial H2O2 content and MDA production, as well as a marked increase in glutathione level and Mn-superoxide dismutase activity. The effect of DNLA-modulated hepatoprotection is dependent on the activation of the Nrf2 signaling pathway. Furthermore, DNLA has also been shown to have glucose-lowering and antihyperlipidemic effects. Repeated administration of DNLA for 8 days modulated liver metabolism genes for glucose (Glut2, Glut4, FoxO1, PGC1α) and lipid (Acox1, Cpt1a, Srebp1, PPARα and ATGL/Pnpla2). In addition, DNLA could also induce hepatic antioxidant components (MT-1 and Nqo1) and decrease mRNA transcription from the Srebp1 gene in the liver. DNLA treatment was able to 'program' the liver under normal physiological conditions and constitutes a pharmacological basis for DNLA use in hyperglycemia and hyperlipidemia treatment. In addition, DNP could not only extraordinarily modulate fat but also abate liver fatty degeneration in a hyperlipemia rat model. The mechanisms of the effects of DNP on hyperlipemia and liver fatty degeneration were possible through decreasing the levels of cholesterol, triglyceride, and low-density lipoprotein cholesterol, as well as increasing the level of high-density lipoprotein cholesterol.
| Conclusions and Future Perspectives|| |
D. nobile, is one of the most popular species of Dendrobium and it has long been considered as a precious herb and health food in TCM and folk medicine. This review has so far summarized the botany, phytochemical constituents, and pharmacological activities of D. nobile. The health and pharmaceutical industries have been increasingly interested in D. nobile due to its multiple biological properties, as well as its various health and nutritional benefits. Phytochemically, D. nobile mainly contains alkaloids, bibenzyl, phenanthrene, phenylpropanoids, polysaccharides, fluorenone, and phenolic acid [Table 1]. Some of these representative compounds are the biologically active constituents of D. nobile with extensive pharmacological properties which include anti-tumor, anti-inflammatory, cardioprotective, neuroprotective, anti-aging, hypoglycemic, hypolipidemic and hepatoprotective activities. The relevant research published so far indicates that D. nobile is a promising candidate to treat diabetes and cardiovascular diseases. Furthermore, D. nobile can be applied in the prevention and treatment of oxidative stress and aging-related diseases.
A number of problems exist in the research that aims to bridge the gap between biological activities and the bioactive constituents of D. nobile, and these need to be elucidated further. First, although many studies have so far concentrated on the crude extracts of D. nobile, the compounds from these crude extracts responsible for the observed bioactivities still remain largely elusive. Hence, in-depth investigations to clarify the biological actions and mechanisms of the active constituents found in D. nobile should be conducted further. Secondly, information related to the toxicity of D. nobile is still lacking. Further study on toxicity and safety studies of D. nobile should be carried out. Finally, efforts need making to clarify the pharmacokinetics of D. nobile involving absorption, distribution, metabolism, and excretion studies, and to identify the metabolites of the bioactive phytochemicals using in vivo experimental models.
In conclusion, D. nobile as one of the common medicinal herbs in TCM appears to have great potentials as a functional food and candidate for further development into pharmaceutical agents. Future investigations should focus on in-depth explorations of on the biological functions of this commonly prescribed Chinese herb to maximize its health-related benefits.
This study does not contain any studies with human or animal subjects performed by any of the authors.
Zhi-Xiu Lin, Hong-Xi Xu and Yan-Fang Xian conceived and designed the study. Juan Zhang drafted the manuscript. Zhi-Li Zhao provided the photo for the manuscript. Yan-Fang Xian, Hong-Xi Xu and Zhi-Xiu Lin revised the manuscript.
Conflict of interest
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[Figure 1], [Figure 2]
[Table 1], [Table 2]