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The American Journal of Chinese Medicine, Vol. 42, No. 3, 523–542 © 2014 World Scientific Publishing Company Institute for Advanced Research in Asian Science and Medicine DOI: 10.1142/S0192415X14500347
Platycladus orientalis Leaves: A Systemic Review on Botany, Phytochemistry and Pharmacology Ming-Qiu Shan, Jing Shang and An-Wei Ding Jiangsu Key Laboratory for Traditional Chinese Medicine Formulae Research Nanjing University of Chinese Medicine Nanjing 210046, China
Abstract: Platycladus orientalis leaves (Cebaiye) have been used for thousands of years as traditional Chinese medicine (TCM). According to the theory of TCM, they are categorized as a blood-cooling and hematostatic herb. In clinical practice, they were usually prescribed with heat-clearing herbs to reinforce the efficacy of hemostasis. The review provides the up-to-date information from 1980 to present that is available on the botany, processing research, phytochemistry, pharmacology and toxicology of the leaves. The information is collected from scientific journals, books, theses and reports via library and electronic search (Google Scholar, Pubmed and CNKI). Through literature reports, we can find that the leaves show a wide spectrum of pharmacological activities, such as anti-inflammatory, antioxidant, antimicrobial, disinsection, anticancer, diuretic, hair growth-promoting, neuroprotective and antifibrotic activities. Diterpene and flavonoids would be active constituents in P. orientalis leaves. Many studies have provided evidence for various traditional uses. However, there is a great need for additional studies to elucidate the mechanism of blood-cooling and hematostatic activity of the leaves. Therefore, the present review on the botany, traditional uses, phytochemistry and toxicity has provided preliminary information for further studies of this herb. Keywords: Platycladus orientalis Leaves; Cebaiye; Traditional Chinese Medicine; Botany; Phytochemistry; Pharmacology; Toxicology; Review.
Introduction Platycladus orientalis leaves (see Fig. 1B) are dry branchlet and leaves of P. orientalis (L.) Franco (syn. B. orientalis (L.) Endl and T. orientalis L.), which have been recorded in many ancient Chinese material medical works, including Shu Ben Cao, Rihuazi Ben Cao, Ben Cao Bei Yao, and De Pei Ben Cao (Chinese Pharmacopoeia Commission, 2010). Correspondence to: Dr. An-Wei Ding, Jiangsu Key Laboratory for Traditional Chinese Medicine Formulae Research, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210046, China. Tel: (þ86) 258581-1523, Fax: (þ86) 25-8581-1523, E-mail: [email protected]
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According to the theory of traditional Chinese medicine (TCM), it was classified as bloodcooling and hematostatic herb. Owing to centuries of clinical practice, it has been proved to be an effective herb with many indications, such as various hemorrhage in the interior or exterior of the body, cough due to lung heat, chronic bronchitis and chincough, tuberculosis, seborrheic alopecia and empyrosis (Liu, 2000). In recent years, new methods and technologies have been used in herbal medicine research (Ushiroyama et al., 2012; Wang et al., 2012b; Shergis et al., 2013). In this paper, we aimed to compile an up-to-date, comprehensive and evidence-based review of the leaves that covered its traditional uses, botany, phytochemistry, pharmacology, processing research, and toxicity. We hope that the review would highlight the importance of this herbal medicine and provide a new direction for researchers in the area of TCM (Tong et al., 2012; Wang et al., 2012a; Xutian et al., 2012). Specifically, we aim to answer the following questions. What information is available on botany, process, phytochemistry, pharmacology and toxicity of the leaves? Are there any present studies that validate its traditional uses? What are the different therapeutic potentials and future research opportunities for leaves? Botany and Distribution P. orientalis (see Fig. 1C) is a ever-green and monoecious shrub, with the height of 15 to 20 feet and spread of 10 to 15 feet. Its bark is thin, little brown and diastema into strips. Branchlet is flat, erect or spreading. Leaves are scale-like and in opposite-decussate pairs with height of less than 2 inches. The tip of leaves is blunt. Exposed part in the upper and lower sides of branchlet is rhombic. There is gland groove in the back of leaves (Orwa et al., 2009; Srivastava et al., 2012). Pollen cone grows at the top of little branchlet. Male cone is yellow and ovalis, with height of 2 mm. Seed cones is glaucous green at first, with height of 20 to 25 mm, and turns reddish brown after mature. Seed is ovate, dark brown and wingless, with height of 4 to 6 mm. P. orientalis prefers sandy or loam soil, but it can also tolerate a wide range of soil types and climatic conditions. Therefore, it is widely distributed around the world in places such as China, Japan, Korea and so on. Its leaves can be collected throughout the year, but the best is in the summer and fall (State Administration of Traditional Chinese Medicine, 1998). P. orientalis is known by various vernacular names in different geographical regions, such as in Chinese (baishu, xiangbai, cebai, bianbai); English (biota, tree of life, book leaf pine, oriental arborvitae, Chinese arborvitae, Chinese thuja); French (thuya oriental, thuya d’orient, thuya de chine); German (Morgenlaendischer Lebensbaum, Chinesiche Thuja, Lebensbaum, Orientalischer Lebensbaum); Italian (tuia orientale); Japanese (konotegashiwa); Spanish (uya de la China) and Trade name (Chinese arborvitae) (Orwa et al., 2009). Processing Research In clinical practice, P. orientalis leaves were used in three forms, including fresh, raw, and charred leaves (see Figs. 1A and 1B) (Pharmaceutical Affairs Bureau of the Ministry of
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Figure 1. Charred herb (A), raw herb (B) and P. orientalis (C).
Health of the People’s Republicof China, 1988). According to the theory of TCM, charring can weaken the cold property of the raw leaves, and additionally, charring can reinforce the efficacy of hemostasis (Shan et al., 2008). Zhao et al. (1997) showed that charred leaves had more potent hemostasis than raw leaves, which may be attributed to stronger absorbability of charred leaves (Chen et al., 2009). In addition, a rat model with blood-heat and hemorrhage syndrome has been established. Based on this model, Liu et al. (2012; 2013) has studied the effect and mechanism of charred herbs. The result showed that the charred product can ameliorate blood heat symptoms and pathologic hemorrhage of the model by inhibiting thyroid functions and correcting hemorheological and coagulation disorders. Ideally, the processing-induced transforming components would be potential chemical markers for the quality control of processed herbs. Studies have proven that the quantity of essential oils, tannins and total flavonoids decreased after charring (Yu et al., 2010; Zhang, 2008; Sun et al., 2006). In addition, Wu et al. (2009) found that charring can transform quercitrin into quercetin. Based on our researches, two peaks, tR 4.30 min and 5.65 min in charred herb, can be considered as differentiating markers, which were identified as quercetin and kaempferol (Fig. 2). Whether or not these two compounds can explain the hemostasis of charred herb needs further investigation. As to quality control, Shan et al. (2009, 2011) have built an HPLC fingerprint of charred leaves and established a UHPLC method for simultaneous determination of five flavonoids.
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Figure 2. BPI chromatograms of raw and processed herbs.
Traditional Uses P. orientalis leaves have been used for thousands of years as Chinese medicine, which is firstly recorded in Ming Yi Bie Lu. The records about the leaves in different dynasties showed little difference. For example, the property of the leaves in Han dynasty was slightly warm, but the property changed into slightly cold after the Song dynasty. However, owing to thousands of years of clinical practice, people have a better understanding of the leaves. The properties and tastes of the leaves are bitter, astringent, and slightly cold. Its meridian tropism is lung, liver, and large intestine (Liu, 2000). Table 1 listed the ethnomedicinal uses of the leaves for 36 ailments in China, India, Egypt, and Iran. The ailments ranged from simple ailments (e.g., cough/cold) to very complicated ailments (e.g., hypertension and rheumatoid arthritis). From the table, we can conclude that the fresh leaves were often prescribed singly to treat various diseases, and raw and charred herbs were often prescribed with other herbal medicines (e.g., Sophora flavescens Ait and Isatis Root). As to preparation, the leaves were often used in traditional ways (e.g., decoction and paste), and scarcely in modern ways (e.g., tablet and injection).
Unspecified 20 g Fresh leaves is soaked with 70% alcohol, and the extract is applied on the bald skin 3–4 times daily
The leaves is soaked in 18% alcohol for 4 days, and 50 ml filtrate each time, 3 times daily The decoction of 3.7 kg leaves is concentrated into 1:2 extract. The extract and 300 g leave powder are mixed, dried and made into tablet, 0.5 g each tablet and 3 times daily Decoction of the leaves is drunk as tea Unspecified Unspecified Decoction of 100 g leaves is used to wash affected part, 2 times daily Unspecified Decoction of the leaves is drunk as tea Fresh pounded leaves is made into paste with albumen Combined with other herb through enema Consumed with other herb Decoction of 25 g fresh leaves is drunk as tea
The leaves are put into pillow The pounded leaves are applied to affected part Unspecified Ethyl acetate extract of the leaves is added into toilet cream
Arthralgia Baldness
Bacillary dysentery
Gonorrhoea Hematohidrosis Herpes zoster Hemorrhoid bleeding Hematemesis Hypertension
Insomnia Incision infection after fracture Impetigo Skin lightening
Diarrhoea Excessive phlegm Flu Flat wart
Chronic tracheitis
Consumed with other herb 300–400 g Fresh pounded leaves is made into paste with 75% alcohol, 3 times daily
Mode of Use
Acute vaginal bleeding Ambustion/burn
Ailment/Use
China China Egypt China
China China China China China China
China Korea Guatemala China
China
China
Japanese China
China China
Place/Country
Table 1. Traditional Uses of P. orientalis Leaves References
(Continued )
Amit et al. (2011) He (2009) An (2004); Chen (1998); Huang (2002) Web 1 (2007); Wang et al. (1997) China Pharmaceutical University (1996) Chung and Shin (1990); Panthong et al. (1986) Duan (2006) Ye and Zhang (2003) Ibrahim et al. (2004) Zhao et al. (2010)
Nanjing University of Chinese Medicine (2005); Jiangsu College of New Medicine (1977) China Pharmaceutical University (1996) Chung and Shin (1990) Comerford (1996) Dai and Tang (2000)
Zhang (2008) State Administration of Traditional Chinese Medicine (1998); Li (2001); Rong and Xu (1989) Mikage et al. (1984) Ran (1993); Li (2001); Chen (2004); Pan (2003); Zhou and Chen (2005); Wang (1999) China Pharmaceutical University (1996)
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Whooping cough
Suppurative mastitis Scabies Seborrheic dermatitis Tinea mannum
Rheumatoid arthritis Subcutaneous hemorrhage
Purpura Recurrent oral ulcer Rhagas
Pompholyx
Decoction of fresh leaves is given orally, 20 g for 0–1 year old, 30–50 g for 1–5 year old and 60–100 g for 6–10 year old daily
Decoction of 400 g leaves is used to wash affected part, 2 times daily Consumed with other herb The leave paste is applied to affected part The leave powder is mixed with tung oil, which is applied on affected part Juice of the leaves is used to make wine 100 g fresh pounded leaves and 2 g borneol are made into paste with albumen Fresh pounded leaves is made into paste with sugar Unspecified Consumed with other herb Decoction of 250 g leaves is applied externally
Fresh pounded leaves is made into paste with albumen, 2 times daily Unspecified Decoction of 120 g leaves, 3 times daily The leaves is made into injection for intravenous administration
Mumps
Malnutrition Metrorrhagia Pulmonary tuberculosis
The pounded leaves are applied to affected part
Mode of Use
Lymphoid tuberculosis
Ailment/Use
Table 1. (Continued)
China
China Egypt China China
China China
China China China
China
Iran China China
China
China
Place/Country
References
Li (2001) Ibrahim et al. (2004) Zhang et al. (1997); Wei (2002) State Administration of Traditional Chinese Medicine (1998) Fang (1988); Li (2000)
Jiangsu College of New Medicine (1977) Yuan and Bing (2002)
Yan et al. (2003) Wang et al. (2002) Li (2001)
Emami et al. (2011a) Wang and Wang (1990); Zhang (2008) Nanjing University of Chinese Medicine (2005) Xie (2011)
State Administration of Traditional Chinese Medicine (1998) Li (1998, 2001); Zang (1985)
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Phytochemistry P. orientalis leaves contained different secondary metabolites, including monoterpenes (Fig. 3), deterpenes (Fig. 4), flavonoids (Fig. 5), lignans and glycosides (Fig. 3) (Inoue et al., 1985; Ohmoto et al., 1988; Kawai et al., 1994; Sung et al., 1998; Kuo et al., 1999; Chang et al., 2000; Kuo et al., 2000; Ren and Ye, 2006; Wang et al., 2008; Lee et al., 2009; Xu et al., 2009). The frequently occurring active constituents of the leaves were labdane-type and pimarane-type deterpenes, such as isopimaric acid, sandaracopimaric acid, pinusolide and 15-methoxypinusolidic acid (15-MPA), and flavonoids, such as quercetin, quercitrin and amentoflavone (Koo et al., 2006; Choi et al., 2008; Lee et al., 2009; Jin et al., 2012). Several glycosides have also been isolated from the leaves, for example, 4-E-propenyl-phenol-1-O-β-D-rutinoside and degalloylmacarangioside B (Fig. 2) (Fan et al., 2011a). As to essential oil, four kinds of extraction methods, including steam distillation, pyrolysis, headspace sampling and enzyme extract have been applied (Liu et al., 2000; Hui et al., 2006; Gao et al., 2009; Gong et al., 2011). The result showed that constituents and their content of essential oil of the leaves were different, due to different habit, but -pinene was still the major constituent (Sun and Xie, 2001; Ibrahim et al., 2004; Guleria et al., 2008; Emami et al., 2011a; 2011b; Afsharypuo et al., 2012). In addition, -cedrol can be converted into -cedrene in an enzyme extract method (Hui et al., 2006).
Figure 3. Structures of two monoterpenes and two glycosides isolated from P. orientalis leaves.
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O
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O
OCH3
H HO
H
HO CH2OH 8(9), 15-isopimaradien-3β-ol
8(14), 15-pimaradien-3β, 18-diol
H COOH
COOCH3
Pinusolide
O
15-Methoxypinusolidic acid
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CHO
HO
Hinokiol
H
HOOC
HO H Abietatriene-3β-ol
HOOC
Lambertianic acid
15-nor-14-oxolabda-8(17),13(16)-dien-19-oic acid
H
H
COOH
COOH
H HO
HO
COOH
H Isopimara-8(9), 15-dien-3β-ol
3β-hydroxysandaraopimaric acid
Sandaracopimaric acid
Isopimaric acid
Figure 4. Structures of some diterpenes isolated from P. orientalis leaves.
There were several reports for determination of flavonoids quantification in P. orientalis leaves (Ding et al., 2010; Lu et al., 2006; Luo et al., 2010; Zhong and Sun, 1999). Quantification of isopimaric acid in P. orientalis leaves has also been researched (Cui et al., 2004; Chen et al., 2004, 2007). Flavonoids and diterpenes are important in the context of the medicinal properties of P. orientalis leaves, but there has been no OH HO OCH3
O
HO
O
OH
OH
OH O
HO OH
OH
O Acacetin
HO
HO OH
O HO
OH
OH
OH OH
CH2OH
Quercitrin
Isoquercitrin
CH2OH O
OH HO
O OH OH OH
HO OH
O OH
O
Amentoflavone
O
OH
O
O
OH
O OH H3C
O
HO
O
O
OH
O
OH
O OH
OH
O Quercetin
OH
O
HO O
Rutin
OH O
OH
OH
HO OH
H3 C O
CH2 O
OH O
OH
OH
O
Hypoletin-7-O-β-D- xylopyranoside
Figure 5. Structures of some flavonoids isolated from P. orientalis leaves.
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simultaneous quantification for these two types of compounds. The simultaneous determination of diterpenes and flavonoids in P. orientalis leaves may have a significant impact on its quality. An effective quantification method for these two types of compounds in P. orientalis leaves needs to be developed. Pharmacological Reports
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Anti-Inflammatory Effect Digest of P. orientalis leaves can reduce the mPGE2 concentration in IL-1-stimulated cartilage explants (Pearson et al., 2008). Methylene chloride fraction of the leaves can significantly inhibit IL-6 in a time-dependent manner (12–48 h) and dose-dependent manner (10–50 g/mL) in the LPS-stimulated RAW 264.7 cell, it also can inhibit LTB4 and 5-HETE formation in a concentration-dependent manner (12.5–100 g/mL) (Kim et al., 2011; Fan et al., 2011b). Liang et al. (2001) found ethanol extract can inhibit biosynthesis of 12-HHT, 5-HETE and LTB4 in an in vitro experiment. Pinusolide at 1–10 M can inhibit LTC4 generation in a concentration-dependent manner, and it also showed potent PAF receptor binding antagonistic activity, with IC50 of 2:5 10 7 M, which was comparable of ginkgolide B (Yang et al., 1995). Lambertianic acid at 0–60 M can inhibit the production of IL-6, PGD2 and LTC4 in bone marrow-derived mast cells (BMMC) (Jin et al., 2012; Chae and Chin, 2012). Additionally, hinokiol and acacein can inhibit LTB4 and 5-HETE formations between 12.5 and 100 M. Furthermore, many studies showed that extracts and compounds of the leaves can inhibit NO production (Koo et al., 2006; Choi et al., 2008; Ju et al., 2010; Fan et al., 2011a; 2011b; Kim et al., 2011; 2013; Jung et al., 2013). Above all, the leaves have a potent anti-inflammatory effect, which may be related to blood-cooling and haemostasis activity. Unfortunately, most of the data of anti-inflammatory study are acquired through in vitro experiments. Therefore, an in vivo investigation is required to validate its anti-inflammatory activity. Antioxidant Effect A lot of studies showed that the essential oil of P. orientalis leaves can be considered as a natural antioxidant (Ibrahim et al., 2004; Emami et al., 2011a; 2011b). In addition, both lipophilic and hydrophilic fractions can inhibit ROS production (Koo et al., 2006, 2007; Sang et al., 2010; Ju et al., 2010; Lee et al., 2010). Piunsolide and 15-MPA would be responsible for ROS inhibition of the lipophilic fraction, while flavonoid glycoside would be responsible for ROS inhibition of the hydrophilic fraction (Xu et al., 2009). Further investigation has indicated that the antioxidant effect of piunsolide and 15-MPA would be associated with improving the cellular antioxidative defense system, inhibiting GSH and MDA production, preserving SOD activity and inhibiting Ca 2þ influx (Koo et al., 2006, 2007). Ibrahim et al. (2004) found that essential oils of the leaves can restore decreased levels of glutathione in alloxan-diabetic rats, which was comparable with that of vitamin E.
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The potent antioxidant activity demonstrates that the leaves have the potential to be health maintaining agents.
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Antimicrobial Effect P. orientalis leaves extract has broad antimicrobial activities against bacteria and fungi. Methanol extract, ethanol extract, and essential oils showed antiviral activity toward SARS-CoV, patato leaf roll virus and egg plant blister mottled virus (Loizzo et al., 2008; Al-Ani et al., 2010, 2011). Dichloromethane extract showed fungistatic activities toward Alternaria alternate and Curvularia lunata (Guleria and Kumar, 2006). As to the antimicrobial activity of compounds in the leaves, Guleria et al. (2008) found -cedrol showed fungistatic activities on Alternaria alternate. In addition, 8(9),15-isopimaradien-3β-ol showed potent antiplasmodial activity, with an IC50 value of 25 M. The compound also induced echinocytic or stomatocytic changes of the erythrocyte membrane curvature. Therefore, the antiplasmodial activity may be indirect effect on the erythrocyte host cell, which needs further investigation to validate (Asili et al., 2004). In addition, the influenza A/PR/8/34 virus infected MDCK cells were used to test anti virus activity of P. orientalis leaves. 100 g/mL MeOH extract showed percentages of viable cells at 89.5%, while the oseltamivir showed 95% viability. 100 g/mL MeOH extract can also prevent the virusinduced cytopathic effect. The infection prevention mechanism of the plant extract might involve the inhibition of viral mRNA synthesis (Ji-Na et al., 2013). However, ethyl acetate extract cannot inhibit Aspergillus parasiticus growth, and essential oils also had no antimicrobial activity against Bacillus subtilis, Candida albicans, E. coli, Staphylococcus aureus and HSV-1, respectively (Hassanzadeh et al., 2001; Loizzo et al., 2008; Alinezhad et al., 2011). In summary, further studies are necessary to validate the antimicrobial effect. Insecticidal Activity Ethanol extract and thujone have shown molluscicidal activity on Lymnaea acuminate, with an IC50 value of 22.86 mg/L and 2.75 mg/L after 96 h (Singh and Singh, 2009; Singh et al., 2010). Hashemi and Safavi (2012a; 2012b) found that essential oils had fumigant toxicity against adults of cowpea weevil (Callosobruchus maculatus Fab.), rice weevil (Sitophilus oryzae L.), red flour beetle (Tribolium castaneum Herbst) and adults of cigarette beetle (Lasioderma serricorne). The essential oils also showed larvicidal activities on Aedes aegypti and Culex pipiens pallens (Jeon et al., 2005). In addition, ethanol extract showed stronger larvicidal activities toward Anopheles stephensi and Culex quinquefasciatus, with an IC50 value of 9.02 ppm and 16.72 ppm after 48 h (Sharma et al., 2005). The essential oils may be responsible for the insecticidal activity of P. orientalis leaves, and thujone may be the active constituent. More constituents, contributing to insecticidal activity, should be isolated. Anticancer Effect Cytotoxic evaluations of ethanol extract of P. orientalis leaves on cancer cells were studied by MTT. Percent cell survival was 80.3 6.9 on Hela cell, 93.2 2.1 on KB cell,
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62.5 1.6 on an MDA-MB-468 cell at 20 mg/mL of ethanol extract (Emami et al., 2005). A549 (nonsmall cell lung adenocarcinoma), SK-OV-3 (ovarian cancer cells), SK-MEL-2 (skin melanoma), and HCT-15 (colon cancer cells) were used to evaluate anticancer effect of compounds in P. orientalis leaves, through using in vitro SRB assays. Isopimara-8(9), 15-dien-3β-ol, abietatriene-3β-ol and pinusolide showed moderate cytotoxicity, with IC50 values ranging from 5.72 to 34.84 M (Kim et al., 2012). In addition, pinusolide can decrease the proliferation activity of Burkitt lymphoma cell line (BJAB) at 5–50 M, and can induce apoptosis in up to 70% at 100 M, which was mediated by loss of mitochondrial membrane potential (Shults et al., 2006). Diterpenes in the leaves may contribute the anticancer effect in vitro, and in vivo studies are required to evaluate the anticancer effect. Diuretic Activity Ibrahim et al. (2004) found that the essential oils can induce a remarkable increase in urinary excretion as well as a significant rise in sodium excretion without inducing hypokalemia at dose level of 500 mg/kg.b.wt. Hair Growth-Promoting Activity P. orientalis leaves are traditionally used to promote hair growth. Studies proved that the leaves contained strong 5-reductase inhibitors, which may be associated with hair growthpromoting activity (Takahashi et al., 1998). Another study showed the decoction of the leaves can promote hair growth by inducing anagen in telogenic C57BL/6 N mice. In decoction-treated mice, an increase in the number and size of hair follicles can be observed, which served as a piece of evidence for the induction of anagen phases. Using the immunohistochemical analysis, an earlier induction of β-catenin and Sonic hedgehog (Shh) proteins in the decoction-treated group also can be seen, compared to the control or 1% minoxidil-treated group (Zhang et al., 2013). Therefore, the hair growth-promoting activity can be explained by the inhibition of 5-reductase and induction of β-catenin and Shh proteins. Effect on Nervous System A study has found that isopimaric acid and sandaracopimaric acid possessed GABAA receptor modulatory activity, and sandaracopimaric acid showed higher potencies (EC50 Þ than isopimaric acid on six GABAA receptor subtypes. In vivo test, i.p. administration of sandaracopimaric acid induced a dose-dependent decrease of locomotor activity in a range of 3 to 30 mg/kg body weight in mice, and no significant anxiolytic-like activity was observed in doses between 1 and 30 mg/kg body weight in mice (Zaugg et al., 2011). Sandaracopimaric acid is a molecule with suitable physicochemical properties for oral bioavailability (Lipinski, 2004). However, further study is required to validate whether this compound can penetrate through the blood–brain barrier. In addition, whether this
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compound is transformed into inactive metabolites also needs more investigation. In addition, 15-MPA within 12.5–50 M/L can induce apoptosis in murine microglial cells, presumably via the inhibition of the cell cycle progression. As microglial activation is detrimental in CNS injuries, these data suggested a strong therapeutic potential of 15-MPA for CNS injuries (Choi et al., 2009).
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Antifibrotic Activity HSC-T6 cells were used to assess the antifibrotic activity of 12 compounds, isolated from P. orientalis leaves. Totarol and isopimara-8(14),15-dien-19-oic acid dramatically reduced cell proliferation in dose- and time-dependent manner at the concentration of 0–100 M within 0–40 h. The pathway study showed that totarol-reduced cell proliferation in part by necrosis as demonstrated by cell morphology as well as an increase of LDH release, and isopimara-8(14),15-dien-19-oic acid may involve different pathways, which needs further research (Lee et al., 2008). Anti-Hyperuricemic Action The anti-hyperuricemic action of P. orientalis leaves was examined with oxonate-induced hyperuricemic mice. The result showed that ethanol extract of the leaves and its flavonoid constituents, quercetin and rutin, can reduce the serum urate levels. In addition, orally treating hyperuricemic mice with quercetin and rutin at a daily dose of 25–150 mg/kg for three times, produced dose-dependent decreases in the urate level. They also showed the anti-hyperuricemic action would be related to inhibitory actions on the xanthine dehydrogenase/xanthine oxidase (XDH/XO) activities in the mouse liver. However, its antihyperuricemic activity is partly different from that of allopurinol. Therefore, the other active principles of the leaves, responsible for the hyperuricemic effects, and the detailed mechanism should be warranted with further investigation (Zhu et al., 2004). Toxicity P. orientalis leaves are usually considered as not very toxic. At oral dose of 60 g/kg in mice, there was no death during 72 h. As to decoction, the LD50 of intraperitoneal injection was 15.20 g/Kg. After alcohol precipitation, the LD50 of intraperitoneal injection was 30.50 g/kg. At an oral dose of 24 g/kg in rats for 6 weeks, animal activity decreased and food intake reduced slightly, compared to the control group. In addition, the growth, liver function and blood indices were significantly affected. As to the petroleum ether extract, the LD50 of the oral dose in mice was 2964 mg/kg (Yin, 1995; Xiao, 2001). However, the essential oil of the leaves can cause severe adverse effects. The clinical toxicity pictures of essential oils included a period of latency, after ingestion, lasting a few minutes to 2 h. During this period, the patient sometimes described a state of undefined indisposition, and then vomiting, hypersialorrhea, and tonic or/and clonic convulsions, looking like epileptic fits, sometimes with cyanosis, biting of the tongue, but never with urinary emission would appear (Hazeman et al., 1975; Millet et al., 1981). In severe cases,
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foaming, breathing difficulties, hematuria, proteinuria, pulmonary edema, coma, circulatory failure and miscarriage can be observed (Ran, 1993; Nanjing University of Chinese Medicine, 2005). In addition, Ibrahim et al. found that the LD50 of the leaf oil in oral administration was 4.5 g/kg.b.wt. for rats using the Karber method (Ibrahim et al., 2004). The toxicity of essential oils can be attributed to the high contents of thujone (Nash et al., 2005). Thujone was reported to be the toxic agent in absinthe, a liqueur popular in the 19th and early 20th centuries (Höld et al., 2000). The acute toxicity information available for thujone was reported as follows (LD50 in mg/kg): rat oral, 500; rabbit i.v., 0.031; rabbit dermal, 5000. The lethal dose appeared at 0.2 ml/kg body weight (BW) (Millet et al., 1981). The Committee on Veterinary Medicinal Products noted that the LD50 values stated for thujone were 87.5 mg/kg of BW after subcutaneous administration in mice and 240 mg/kg BW after intraperitoneal administration to rats (EMEA, 1999). Summary and Conclusion The available scientific research on P. orientalis leaves has shown the leaves are a very important medicinal herb with a wide range of ethnomedical treatments, especially for baldness, chronic tracheitis, excessive phlegm, flu, malnutrition, cough and rheumatoid arthritis. The pharmacological study of the leaves validated its anti-inflammatory, antioxidant, antimicrobial and hair growth-promoting activities. However, to-date one of the most important TCM claims for the leaves, treating blood heat and hemorrhage syndrome, has not been sufficiently researched. According to the theory of TCM, the possible clinical manifestations of this syndrome include hemoptysis, haematemesis, hemorrhinia, hematuria, hematochezia, hypermenorrhea, metrorrhagia and metrostaxis. Studies have found that the syndrome may be mainly associated with glycerophospholipid and arachidonic acid metabolisms (Shang et al., 2014). Therefore, further studies are required to elucidate the effect of the leaves on these two metabolisms. As to processed herb, there is no research about the chemical constituents of charred leaves. In addition, only quercetin is now determined as the differentiating marker between the raw and processed herb. More potential markers should be searched, which would be useful to elucidate the mechanism of charring. Furthermore, essential oils of the leaves can cause a toxic effect. Quality control of the essential oils can guarantee clinical safety. Diterpenes in P. orientalis leaves, especially isopimaric acid, sandaracopimaric acid, pinusolide and 15-MPA have potent pharmacological activities. Such active compounds can be considered new drug candidates for further research. In conclusion, the present review on the botany, traditional uses, phytochemistry, pharmacology and toxicity has provided preliminary information for further investigations and commercial exploitations of the herb. Acknowledgments The work was co-financed by grants from National Natural Science Foundation of China (Nos. 81173547 and 81001599), Doctoral Foundation of Youth Scholars of Ministry of
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Education of China (No. 20103237120010) and Graduate research and innovation projects in Jiangsu Province (No. 12-0621).
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The American Journal of Chinese Medicine, Vol. 42, No. 3, 523–542 © 2014 World Scientific Publishing Company Institute for Advanced Research in Asian Science and Medicine DOI: 10.1142/S0192415X14500347
Platycladus orientalis Leaves: A Systemic Review on Botany, Phytochemistry and Pharmacology Ming-Qiu Shan, Jing Shang and An-Wei Ding Jiangsu Key Laboratory for Traditional Chinese Medicine Formulae Research Nanjing University of Chinese Medicine Nanjing 210046, China
Abstract: Platycladus orientalis leaves (Cebaiye) have been used for thousands of years as traditional Chinese medicine (TCM). According to the theory of TCM, they are categorized as a blood-cooling and hematostatic herb. In clinical practice, they were usually prescribed with heat-clearing herbs to reinforce the efficacy of hemostasis. The review provides the up-to-date information from 1980 to present that is available on the botany, processing research, phytochemistry, pharmacology and toxicology of the leaves. The information is collected from scientific journals, books, theses and reports via library and electronic search (Google Scholar, Pubmed and CNKI). Through literature reports, we can find that the leaves show a wide spectrum of pharmacological activities, such as anti-inflammatory, antioxidant, antimicrobial, disinsection, anticancer, diuretic, hair growth-promoting, neuroprotective and antifibrotic activities. Diterpene and flavonoids would be active constituents in P. orientalis leaves. Many studies have provided evidence for various traditional uses. However, there is a great need for additional studies to elucidate the mechanism of blood-cooling and hematostatic activity of the leaves. Therefore, the present review on the botany, traditional uses, phytochemistry and toxicity has provided preliminary information for further studies of this herb. Keywords: Platycladus orientalis Leaves; Cebaiye; Traditional Chinese Medicine; Botany; Phytochemistry; Pharmacology; Toxicology; Review.
Introduction Platycladus orientalis leaves (see Fig. 1B) are dry branchlet and leaves of P. orientalis (L.) Franco (syn. B. orientalis (L.) Endl and T. orientalis L.), which have been recorded in many ancient Chinese material medical works, including Shu Ben Cao, Rihuazi Ben Cao, Ben Cao Bei Yao, and De Pei Ben Cao (Chinese Pharmacopoeia Commission, 2010). Correspondence to: Dr. An-Wei Ding, Jiangsu Key Laboratory for Traditional Chinese Medicine Formulae Research, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210046, China. Tel: (þ86) 258581-1523, Fax: (þ86) 25-8581-1523, E-mail: [email protected]
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According to the theory of traditional Chinese medicine (TCM), it was classified as bloodcooling and hematostatic herb. Owing to centuries of clinical practice, it has been proved to be an effective herb with many indications, such as various hemorrhage in the interior or exterior of the body, cough due to lung heat, chronic bronchitis and chincough, tuberculosis, seborrheic alopecia and empyrosis (Liu, 2000). In recent years, new methods and technologies have been used in herbal medicine research (Ushiroyama et al., 2012; Wang et al., 2012b; Shergis et al., 2013). In this paper, we aimed to compile an up-to-date, comprehensive and evidence-based review of the leaves that covered its traditional uses, botany, phytochemistry, pharmacology, processing research, and toxicity. We hope that the review would highlight the importance of this herbal medicine and provide a new direction for researchers in the area of TCM (Tong et al., 2012; Wang et al., 2012a; Xutian et al., 2012). Specifically, we aim to answer the following questions. What information is available on botany, process, phytochemistry, pharmacology and toxicity of the leaves? Are there any present studies that validate its traditional uses? What are the different therapeutic potentials and future research opportunities for leaves? Botany and Distribution P. orientalis (see Fig. 1C) is a ever-green and monoecious shrub, with the height of 15 to 20 feet and spread of 10 to 15 feet. Its bark is thin, little brown and diastema into strips. Branchlet is flat, erect or spreading. Leaves are scale-like and in opposite-decussate pairs with height of less than 2 inches. The tip of leaves is blunt. Exposed part in the upper and lower sides of branchlet is rhombic. There is gland groove in the back of leaves (Orwa et al., 2009; Srivastava et al., 2012). Pollen cone grows at the top of little branchlet. Male cone is yellow and ovalis, with height of 2 mm. Seed cones is glaucous green at first, with height of 20 to 25 mm, and turns reddish brown after mature. Seed is ovate, dark brown and wingless, with height of 4 to 6 mm. P. orientalis prefers sandy or loam soil, but it can also tolerate a wide range of soil types and climatic conditions. Therefore, it is widely distributed around the world in places such as China, Japan, Korea and so on. Its leaves can be collected throughout the year, but the best is in the summer and fall (State Administration of Traditional Chinese Medicine, 1998). P. orientalis is known by various vernacular names in different geographical regions, such as in Chinese (baishu, xiangbai, cebai, bianbai); English (biota, tree of life, book leaf pine, oriental arborvitae, Chinese arborvitae, Chinese thuja); French (thuya oriental, thuya d’orient, thuya de chine); German (Morgenlaendischer Lebensbaum, Chinesiche Thuja, Lebensbaum, Orientalischer Lebensbaum); Italian (tuia orientale); Japanese (konotegashiwa); Spanish (uya de la China) and Trade name (Chinese arborvitae) (Orwa et al., 2009). Processing Research In clinical practice, P. orientalis leaves were used in three forms, including fresh, raw, and charred leaves (see Figs. 1A and 1B) (Pharmaceutical Affairs Bureau of the Ministry of
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Figure 1. Charred herb (A), raw herb (B) and P. orientalis (C).
Health of the People’s Republicof China, 1988). According to the theory of TCM, charring can weaken the cold property of the raw leaves, and additionally, charring can reinforce the efficacy of hemostasis (Shan et al., 2008). Zhao et al. (1997) showed that charred leaves had more potent hemostasis than raw leaves, which may be attributed to stronger absorbability of charred leaves (Chen et al., 2009). In addition, a rat model with blood-heat and hemorrhage syndrome has been established. Based on this model, Liu et al. (2012; 2013) has studied the effect and mechanism of charred herbs. The result showed that the charred product can ameliorate blood heat symptoms and pathologic hemorrhage of the model by inhibiting thyroid functions and correcting hemorheological and coagulation disorders. Ideally, the processing-induced transforming components would be potential chemical markers for the quality control of processed herbs. Studies have proven that the quantity of essential oils, tannins and total flavonoids decreased after charring (Yu et al., 2010; Zhang, 2008; Sun et al., 2006). In addition, Wu et al. (2009) found that charring can transform quercitrin into quercetin. Based on our researches, two peaks, tR 4.30 min and 5.65 min in charred herb, can be considered as differentiating markers, which were identified as quercetin and kaempferol (Fig. 2). Whether or not these two compounds can explain the hemostasis of charred herb needs further investigation. As to quality control, Shan et al. (2009, 2011) have built an HPLC fingerprint of charred leaves and established a UHPLC method for simultaneous determination of five flavonoids.
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Figure 2. BPI chromatograms of raw and processed herbs.
Traditional Uses P. orientalis leaves have been used for thousands of years as Chinese medicine, which is firstly recorded in Ming Yi Bie Lu. The records about the leaves in different dynasties showed little difference. For example, the property of the leaves in Han dynasty was slightly warm, but the property changed into slightly cold after the Song dynasty. However, owing to thousands of years of clinical practice, people have a better understanding of the leaves. The properties and tastes of the leaves are bitter, astringent, and slightly cold. Its meridian tropism is lung, liver, and large intestine (Liu, 2000). Table 1 listed the ethnomedicinal uses of the leaves for 36 ailments in China, India, Egypt, and Iran. The ailments ranged from simple ailments (e.g., cough/cold) to very complicated ailments (e.g., hypertension and rheumatoid arthritis). From the table, we can conclude that the fresh leaves were often prescribed singly to treat various diseases, and raw and charred herbs were often prescribed with other herbal medicines (e.g., Sophora flavescens Ait and Isatis Root). As to preparation, the leaves were often used in traditional ways (e.g., decoction and paste), and scarcely in modern ways (e.g., tablet and injection).
Unspecified 20 g Fresh leaves is soaked with 70% alcohol, and the extract is applied on the bald skin 3–4 times daily
The leaves is soaked in 18% alcohol for 4 days, and 50 ml filtrate each time, 3 times daily The decoction of 3.7 kg leaves is concentrated into 1:2 extract. The extract and 300 g leave powder are mixed, dried and made into tablet, 0.5 g each tablet and 3 times daily Decoction of the leaves is drunk as tea Unspecified Unspecified Decoction of 100 g leaves is used to wash affected part, 2 times daily Unspecified Decoction of the leaves is drunk as tea Fresh pounded leaves is made into paste with albumen Combined with other herb through enema Consumed with other herb Decoction of 25 g fresh leaves is drunk as tea
The leaves are put into pillow The pounded leaves are applied to affected part Unspecified Ethyl acetate extract of the leaves is added into toilet cream
Arthralgia Baldness
Bacillary dysentery
Gonorrhoea Hematohidrosis Herpes zoster Hemorrhoid bleeding Hematemesis Hypertension
Insomnia Incision infection after fracture Impetigo Skin lightening
Diarrhoea Excessive phlegm Flu Flat wart
Chronic tracheitis
Consumed with other herb 300–400 g Fresh pounded leaves is made into paste with 75% alcohol, 3 times daily
Mode of Use
Acute vaginal bleeding Ambustion/burn
Ailment/Use
China China Egypt China
China China China China China China
China Korea Guatemala China
China
China
Japanese China
China China
Place/Country
Table 1. Traditional Uses of P. orientalis Leaves References
(Continued )
Amit et al. (2011) He (2009) An (2004); Chen (1998); Huang (2002) Web 1 (2007); Wang et al. (1997) China Pharmaceutical University (1996) Chung and Shin (1990); Panthong et al. (1986) Duan (2006) Ye and Zhang (2003) Ibrahim et al. (2004) Zhao et al. (2010)
Nanjing University of Chinese Medicine (2005); Jiangsu College of New Medicine (1977) China Pharmaceutical University (1996) Chung and Shin (1990) Comerford (1996) Dai and Tang (2000)
Zhang (2008) State Administration of Traditional Chinese Medicine (1998); Li (2001); Rong and Xu (1989) Mikage et al. (1984) Ran (1993); Li (2001); Chen (2004); Pan (2003); Zhou and Chen (2005); Wang (1999) China Pharmaceutical University (1996)
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Whooping cough
Suppurative mastitis Scabies Seborrheic dermatitis Tinea mannum
Rheumatoid arthritis Subcutaneous hemorrhage
Purpura Recurrent oral ulcer Rhagas
Pompholyx
Decoction of fresh leaves is given orally, 20 g for 0–1 year old, 30–50 g for 1–5 year old and 60–100 g for 6–10 year old daily
Decoction of 400 g leaves is used to wash affected part, 2 times daily Consumed with other herb The leave paste is applied to affected part The leave powder is mixed with tung oil, which is applied on affected part Juice of the leaves is used to make wine 100 g fresh pounded leaves and 2 g borneol are made into paste with albumen Fresh pounded leaves is made into paste with sugar Unspecified Consumed with other herb Decoction of 250 g leaves is applied externally
Fresh pounded leaves is made into paste with albumen, 2 times daily Unspecified Decoction of 120 g leaves, 3 times daily The leaves is made into injection for intravenous administration
Mumps
Malnutrition Metrorrhagia Pulmonary tuberculosis
The pounded leaves are applied to affected part
Mode of Use
Lymphoid tuberculosis
Ailment/Use
Table 1. (Continued)
China
China Egypt China China
China China
China China China
China
Iran China China
China
China
Place/Country
References
Li (2001) Ibrahim et al. (2004) Zhang et al. (1997); Wei (2002) State Administration of Traditional Chinese Medicine (1998) Fang (1988); Li (2000)
Jiangsu College of New Medicine (1977) Yuan and Bing (2002)
Yan et al. (2003) Wang et al. (2002) Li (2001)
Emami et al. (2011a) Wang and Wang (1990); Zhang (2008) Nanjing University of Chinese Medicine (2005) Xie (2011)
State Administration of Traditional Chinese Medicine (1998) Li (1998, 2001); Zang (1985)
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Phytochemistry P. orientalis leaves contained different secondary metabolites, including monoterpenes (Fig. 3), deterpenes (Fig. 4), flavonoids (Fig. 5), lignans and glycosides (Fig. 3) (Inoue et al., 1985; Ohmoto et al., 1988; Kawai et al., 1994; Sung et al., 1998; Kuo et al., 1999; Chang et al., 2000; Kuo et al., 2000; Ren and Ye, 2006; Wang et al., 2008; Lee et al., 2009; Xu et al., 2009). The frequently occurring active constituents of the leaves were labdane-type and pimarane-type deterpenes, such as isopimaric acid, sandaracopimaric acid, pinusolide and 15-methoxypinusolidic acid (15-MPA), and flavonoids, such as quercetin, quercitrin and amentoflavone (Koo et al., 2006; Choi et al., 2008; Lee et al., 2009; Jin et al., 2012). Several glycosides have also been isolated from the leaves, for example, 4-E-propenyl-phenol-1-O-β-D-rutinoside and degalloylmacarangioside B (Fig. 2) (Fan et al., 2011a). As to essential oil, four kinds of extraction methods, including steam distillation, pyrolysis, headspace sampling and enzyme extract have been applied (Liu et al., 2000; Hui et al., 2006; Gao et al., 2009; Gong et al., 2011). The result showed that constituents and their content of essential oil of the leaves were different, due to different habit, but -pinene was still the major constituent (Sun and Xie, 2001; Ibrahim et al., 2004; Guleria et al., 2008; Emami et al., 2011a; 2011b; Afsharypuo et al., 2012). In addition, -cedrol can be converted into -cedrene in an enzyme extract method (Hui et al., 2006).
Figure 3. Structures of two monoterpenes and two glycosides isolated from P. orientalis leaves.
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H HO
HO
COOH
H Isopimara-8(9), 15-dien-3β-ol
3β-hydroxysandaraopimaric acid
Sandaracopimaric acid
Isopimaric acid
Figure 4. Structures of some diterpenes isolated from P. orientalis leaves.
There were several reports for determination of flavonoids quantification in P. orientalis leaves (Ding et al., 2010; Lu et al., 2006; Luo et al., 2010; Zhong and Sun, 1999). Quantification of isopimaric acid in P. orientalis leaves has also been researched (Cui et al., 2004; Chen et al., 2004, 2007). Flavonoids and diterpenes are important in the context of the medicinal properties of P. orientalis leaves, but there has been no OH HO OCH3
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O
O
OH
O OH H3C
O
HO
O
O
OH
O
OH
O OH
OH
O Quercetin
OH
O
HO O
Rutin
OH O
OH
OH
HO OH
H3 C O
CH2 O
OH O
OH
OH
O
Hypoletin-7-O-β-D- xylopyranoside
Figure 5. Structures of some flavonoids isolated from P. orientalis leaves.
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simultaneous quantification for these two types of compounds. The simultaneous determination of diterpenes and flavonoids in P. orientalis leaves may have a significant impact on its quality. An effective quantification method for these two types of compounds in P. orientalis leaves needs to be developed. Pharmacological Reports
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Anti-Inflammatory Effect Digest of P. orientalis leaves can reduce the mPGE2 concentration in IL-1-stimulated cartilage explants (Pearson et al., 2008). Methylene chloride fraction of the leaves can significantly inhibit IL-6 in a time-dependent manner (12–48 h) and dose-dependent manner (10–50 g/mL) in the LPS-stimulated RAW 264.7 cell, it also can inhibit LTB4 and 5-HETE formation in a concentration-dependent manner (12.5–100 g/mL) (Kim et al., 2011; Fan et al., 2011b). Liang et al. (2001) found ethanol extract can inhibit biosynthesis of 12-HHT, 5-HETE and LTB4 in an in vitro experiment. Pinusolide at 1–10 M can inhibit LTC4 generation in a concentration-dependent manner, and it also showed potent PAF receptor binding antagonistic activity, with IC50 of 2:5 10 7 M, which was comparable of ginkgolide B (Yang et al., 1995). Lambertianic acid at 0–60 M can inhibit the production of IL-6, PGD2 and LTC4 in bone marrow-derived mast cells (BMMC) (Jin et al., 2012; Chae and Chin, 2012). Additionally, hinokiol and acacein can inhibit LTB4 and 5-HETE formations between 12.5 and 100 M. Furthermore, many studies showed that extracts and compounds of the leaves can inhibit NO production (Koo et al., 2006; Choi et al., 2008; Ju et al., 2010; Fan et al., 2011a; 2011b; Kim et al., 2011; 2013; Jung et al., 2013). Above all, the leaves have a potent anti-inflammatory effect, which may be related to blood-cooling and haemostasis activity. Unfortunately, most of the data of anti-inflammatory study are acquired through in vitro experiments. Therefore, an in vivo investigation is required to validate its anti-inflammatory activity. Antioxidant Effect A lot of studies showed that the essential oil of P. orientalis leaves can be considered as a natural antioxidant (Ibrahim et al., 2004; Emami et al., 2011a; 2011b). In addition, both lipophilic and hydrophilic fractions can inhibit ROS production (Koo et al., 2006, 2007; Sang et al., 2010; Ju et al., 2010; Lee et al., 2010). Piunsolide and 15-MPA would be responsible for ROS inhibition of the lipophilic fraction, while flavonoid glycoside would be responsible for ROS inhibition of the hydrophilic fraction (Xu et al., 2009). Further investigation has indicated that the antioxidant effect of piunsolide and 15-MPA would be associated with improving the cellular antioxidative defense system, inhibiting GSH and MDA production, preserving SOD activity and inhibiting Ca 2þ influx (Koo et al., 2006, 2007). Ibrahim et al. (2004) found that essential oils of the leaves can restore decreased levels of glutathione in alloxan-diabetic rats, which was comparable with that of vitamin E.
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The potent antioxidant activity demonstrates that the leaves have the potential to be health maintaining agents.
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Antimicrobial Effect P. orientalis leaves extract has broad antimicrobial activities against bacteria and fungi. Methanol extract, ethanol extract, and essential oils showed antiviral activity toward SARS-CoV, patato leaf roll virus and egg plant blister mottled virus (Loizzo et al., 2008; Al-Ani et al., 2010, 2011). Dichloromethane extract showed fungistatic activities toward Alternaria alternate and Curvularia lunata (Guleria and Kumar, 2006). As to the antimicrobial activity of compounds in the leaves, Guleria et al. (2008) found -cedrol showed fungistatic activities on Alternaria alternate. In addition, 8(9),15-isopimaradien-3β-ol showed potent antiplasmodial activity, with an IC50 value of 25 M. The compound also induced echinocytic or stomatocytic changes of the erythrocyte membrane curvature. Therefore, the antiplasmodial activity may be indirect effect on the erythrocyte host cell, which needs further investigation to validate (Asili et al., 2004). In addition, the influenza A/PR/8/34 virus infected MDCK cells were used to test anti virus activity of P. orientalis leaves. 100 g/mL MeOH extract showed percentages of viable cells at 89.5%, while the oseltamivir showed 95% viability. 100 g/mL MeOH extract can also prevent the virusinduced cytopathic effect. The infection prevention mechanism of the plant extract might involve the inhibition of viral mRNA synthesis (Ji-Na et al., 2013). However, ethyl acetate extract cannot inhibit Aspergillus parasiticus growth, and essential oils also had no antimicrobial activity against Bacillus subtilis, Candida albicans, E. coli, Staphylococcus aureus and HSV-1, respectively (Hassanzadeh et al., 2001; Loizzo et al., 2008; Alinezhad et al., 2011). In summary, further studies are necessary to validate the antimicrobial effect. Insecticidal Activity Ethanol extract and thujone have shown molluscicidal activity on Lymnaea acuminate, with an IC50 value of 22.86 mg/L and 2.75 mg/L after 96 h (Singh and Singh, 2009; Singh et al., 2010). Hashemi and Safavi (2012a; 2012b) found that essential oils had fumigant toxicity against adults of cowpea weevil (Callosobruchus maculatus Fab.), rice weevil (Sitophilus oryzae L.), red flour beetle (Tribolium castaneum Herbst) and adults of cigarette beetle (Lasioderma serricorne). The essential oils also showed larvicidal activities on Aedes aegypti and Culex pipiens pallens (Jeon et al., 2005). In addition, ethanol extract showed stronger larvicidal activities toward Anopheles stephensi and Culex quinquefasciatus, with an IC50 value of 9.02 ppm and 16.72 ppm after 48 h (Sharma et al., 2005). The essential oils may be responsible for the insecticidal activity of P. orientalis leaves, and thujone may be the active constituent. More constituents, contributing to insecticidal activity, should be isolated. Anticancer Effect Cytotoxic evaluations of ethanol extract of P. orientalis leaves on cancer cells were studied by MTT. Percent cell survival was 80.3 6.9 on Hela cell, 93.2 2.1 on KB cell,
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62.5 1.6 on an MDA-MB-468 cell at 20 mg/mL of ethanol extract (Emami et al., 2005). A549 (nonsmall cell lung adenocarcinoma), SK-OV-3 (ovarian cancer cells), SK-MEL-2 (skin melanoma), and HCT-15 (colon cancer cells) were used to evaluate anticancer effect of compounds in P. orientalis leaves, through using in vitro SRB assays. Isopimara-8(9), 15-dien-3β-ol, abietatriene-3β-ol and pinusolide showed moderate cytotoxicity, with IC50 values ranging from 5.72 to 34.84 M (Kim et al., 2012). In addition, pinusolide can decrease the proliferation activity of Burkitt lymphoma cell line (BJAB) at 5–50 M, and can induce apoptosis in up to 70% at 100 M, which was mediated by loss of mitochondrial membrane potential (Shults et al., 2006). Diterpenes in the leaves may contribute the anticancer effect in vitro, and in vivo studies are required to evaluate the anticancer effect. Diuretic Activity Ibrahim et al. (2004) found that the essential oils can induce a remarkable increase in urinary excretion as well as a significant rise in sodium excretion without inducing hypokalemia at dose level of 500 mg/kg.b.wt. Hair Growth-Promoting Activity P. orientalis leaves are traditionally used to promote hair growth. Studies proved that the leaves contained strong 5-reductase inhibitors, which may be associated with hair growthpromoting activity (Takahashi et al., 1998). Another study showed the decoction of the leaves can promote hair growth by inducing anagen in telogenic C57BL/6 N mice. In decoction-treated mice, an increase in the number and size of hair follicles can be observed, which served as a piece of evidence for the induction of anagen phases. Using the immunohistochemical analysis, an earlier induction of β-catenin and Sonic hedgehog (Shh) proteins in the decoction-treated group also can be seen, compared to the control or 1% minoxidil-treated group (Zhang et al., 2013). Therefore, the hair growth-promoting activity can be explained by the inhibition of 5-reductase and induction of β-catenin and Shh proteins. Effect on Nervous System A study has found that isopimaric acid and sandaracopimaric acid possessed GABAA receptor modulatory activity, and sandaracopimaric acid showed higher potencies (EC50 Þ than isopimaric acid on six GABAA receptor subtypes. In vivo test, i.p. administration of sandaracopimaric acid induced a dose-dependent decrease of locomotor activity in a range of 3 to 30 mg/kg body weight in mice, and no significant anxiolytic-like activity was observed in doses between 1 and 30 mg/kg body weight in mice (Zaugg et al., 2011). Sandaracopimaric acid is a molecule with suitable physicochemical properties for oral bioavailability (Lipinski, 2004). However, further study is required to validate whether this compound can penetrate through the blood–brain barrier. In addition, whether this
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compound is transformed into inactive metabolites also needs more investigation. In addition, 15-MPA within 12.5–50 M/L can induce apoptosis in murine microglial cells, presumably via the inhibition of the cell cycle progression. As microglial activation is detrimental in CNS injuries, these data suggested a strong therapeutic potential of 15-MPA for CNS injuries (Choi et al., 2009).
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Antifibrotic Activity HSC-T6 cells were used to assess the antifibrotic activity of 12 compounds, isolated from P. orientalis leaves. Totarol and isopimara-8(14),15-dien-19-oic acid dramatically reduced cell proliferation in dose- and time-dependent manner at the concentration of 0–100 M within 0–40 h. The pathway study showed that totarol-reduced cell proliferation in part by necrosis as demonstrated by cell morphology as well as an increase of LDH release, and isopimara-8(14),15-dien-19-oic acid may involve different pathways, which needs further research (Lee et al., 2008). Anti-Hyperuricemic Action The anti-hyperuricemic action of P. orientalis leaves was examined with oxonate-induced hyperuricemic mice. The result showed that ethanol extract of the leaves and its flavonoid constituents, quercetin and rutin, can reduce the serum urate levels. In addition, orally treating hyperuricemic mice with quercetin and rutin at a daily dose of 25–150 mg/kg for three times, produced dose-dependent decreases in the urate level. They also showed the anti-hyperuricemic action would be related to inhibitory actions on the xanthine dehydrogenase/xanthine oxidase (XDH/XO) activities in the mouse liver. However, its antihyperuricemic activity is partly different from that of allopurinol. Therefore, the other active principles of the leaves, responsible for the hyperuricemic effects, and the detailed mechanism should be warranted with further investigation (Zhu et al., 2004). Toxicity P. orientalis leaves are usually considered as not very toxic. At oral dose of 60 g/kg in mice, there was no death during 72 h. As to decoction, the LD50 of intraperitoneal injection was 15.20 g/Kg. After alcohol precipitation, the LD50 of intraperitoneal injection was 30.50 g/kg. At an oral dose of 24 g/kg in rats for 6 weeks, animal activity decreased and food intake reduced slightly, compared to the control group. In addition, the growth, liver function and blood indices were significantly affected. As to the petroleum ether extract, the LD50 of the oral dose in mice was 2964 mg/kg (Yin, 1995; Xiao, 2001). However, the essential oil of the leaves can cause severe adverse effects. The clinical toxicity pictures of essential oils included a period of latency, after ingestion, lasting a few minutes to 2 h. During this period, the patient sometimes described a state of undefined indisposition, and then vomiting, hypersialorrhea, and tonic or/and clonic convulsions, looking like epileptic fits, sometimes with cyanosis, biting of the tongue, but never with urinary emission would appear (Hazeman et al., 1975; Millet et al., 1981). In severe cases,
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foaming, breathing difficulties, hematuria, proteinuria, pulmonary edema, coma, circulatory failure and miscarriage can be observed (Ran, 1993; Nanjing University of Chinese Medicine, 2005). In addition, Ibrahim et al. found that the LD50 of the leaf oil in oral administration was 4.5 g/kg.b.wt. for rats using the Karber method (Ibrahim et al., 2004). The toxicity of essential oils can be attributed to the high contents of thujone (Nash et al., 2005). Thujone was reported to be the toxic agent in absinthe, a liqueur popular in the 19th and early 20th centuries (Höld et al., 2000). The acute toxicity information available for thujone was reported as follows (LD50 in mg/kg): rat oral, 500; rabbit i.v., 0.031; rabbit dermal, 5000. The lethal dose appeared at 0.2 ml/kg body weight (BW) (Millet et al., 1981). The Committee on Veterinary Medicinal Products noted that the LD50 values stated for thujone were 87.5 mg/kg of BW after subcutaneous administration in mice and 240 mg/kg BW after intraperitoneal administration to rats (EMEA, 1999). Summary and Conclusion The available scientific research on P. orientalis leaves has shown the leaves are a very important medicinal herb with a wide range of ethnomedical treatments, especially for baldness, chronic tracheitis, excessive phlegm, flu, malnutrition, cough and rheumatoid arthritis. The pharmacological study of the leaves validated its anti-inflammatory, antioxidant, antimicrobial and hair growth-promoting activities. However, to-date one of the most important TCM claims for the leaves, treating blood heat and hemorrhage syndrome, has not been sufficiently researched. According to the theory of TCM, the possible clinical manifestations of this syndrome include hemoptysis, haematemesis, hemorrhinia, hematuria, hematochezia, hypermenorrhea, metrorrhagia and metrostaxis. Studies have found that the syndrome may be mainly associated with glycerophospholipid and arachidonic acid metabolisms (Shang et al., 2014). Therefore, further studies are required to elucidate the effect of the leaves on these two metabolisms. As to processed herb, there is no research about the chemical constituents of charred leaves. In addition, only quercetin is now determined as the differentiating marker between the raw and processed herb. More potential markers should be searched, which would be useful to elucidate the mechanism of charring. Furthermore, essential oils of the leaves can cause a toxic effect. Quality control of the essential oils can guarantee clinical safety. Diterpenes in P. orientalis leaves, especially isopimaric acid, sandaracopimaric acid, pinusolide and 15-MPA have potent pharmacological activities. Such active compounds can be considered new drug candidates for further research. In conclusion, the present review on the botany, traditional uses, phytochemistry, pharmacology and toxicity has provided preliminary information for further investigations and commercial exploitations of the herb. Acknowledgments The work was co-financed by grants from National Natural Science Foundation of China (Nos. 81173547 and 81001599), Doctoral Foundation of Youth Scholars of Ministry of
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Education of China (No. 20103237120010) and Graduate research and innovation projects in Jiangsu Province (No. 12-0621).
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