The ethnobotanical, phytochemical and pharmacological profile of the genus Pinellia

Fitoterapia 93 (2014) 1–17

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Fitoterapia journal homepage: www.elsevier.com/locate/fitote

Review

The ethnobotanical, phytochemical and pharmacological profile of the genus Pinellia Xiao Ji, Baokang Huang ⁎, Guowei Wang, Chunyan Zhang School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

a r t i c l e

i n f o

Article history: Received 31 July 2013 Accepted in revised form 9 December 2013 Available online 25 December 2013 Keywords: Pinellia species Pinellia ternata Traditional uses Chemical constituents Pharmacological activities Toxicology

a b s t r a c t The genus Pinellia (Araceae), consisting of nine species, is mainly distributed in Eastern Asia. In traditional medicine, some Pinellia species have long been used for the treatment of various ailments, such as cough, vomiting, inflammation, epilepsy, cervical cancer and traumatic injury. Pharmacological studies revealed that Pinellia species possess a wide range of biological activities including cytotoxic, anti-tumor, antiemetic, insecticidal, antitussive, antimicrobial and anticonvulsant activities. However, some species also showed significant toxicity such as reproductive toxicity, mucosal irritation and hepatotoxicity. Most of these bioactivities and toxicity can be explained by the presence of various alkaloids and lectins. This review summarizes the ethnopharmacological uses, phytochemical constituents, pharmacological activities and toxicity of Pinellia species. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . Ethnopharmacological uses . . . . . . . . . . . . . 2.1. Traditional uses . . . . . . . . . . . . . . . 2.2. Adulterants and their identification . . . . . . Chemical constituents . . . . . . . . . . . . . . . . 3.1. Alkaloids . . . . . . . . . . . . . . . . . . . 3.2. Lectins . . . . . . . . . . . . . . . . . . . . 3.3. Fatty acids . . . . . . . . . . . . . . . . . . 3.4. Cerebrosides . . . . . . . . . . . . . . . . . 3.5. Volatile oils . . . . . . . . . . . . . . . . . 3.6. Others . . . . . . . . . . . . . . . . . . . . Pharmacological activities . . . . . . . . . . . . . . 4.1. Cytotoxicity and anti-tumor activity . . . . . . 4.2. Antiemetic activity . . . . . . . . . . . . . . 4.3. Insecticidal activity . . . . . . . . . . . . . . 4.4. Antitussive activity . . . . . . . . . . . . . . 4.5. Antimicrobial, antifungal and antiviral activities 4.6. Sedative, hypnotic and anticonvulsive activities 4.7. Other biological activity . . . . . . . . . . . .

⁎ Corresponding author. Tel./fax: +86 21 81871301. E-mail address: [email protected] (B. Huang). 0367-326X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.fitote.2013.12.010

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5.

Toxicology . . . . . . . . . . . 5.1. Acute and long-term toxicity 5.2. Reproductive toxicity . . . 5.3. Irritation . . . . . . . . . 5.4. Hepatotoxicity . . . . . . 6. Concluding remarks . . . . . . . Conflict of interest . . . . . . . . . . References . . . . . . . . . . . . . .

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1. Introduction The genus Pinellia (Araceae) is mainly distributed in Eastern Asia (China, Japan and Korea), and comprises the following nine species: Pinellia tripartita (Blume) Schott, Pinellia pedatisecta Schott, Pinellia integrifolia N. E. Brown, Pinellia ternata (Thunb.) Breit., Pinellia cordata N. E. Brown, Pinellia peltata C. Pei, Pinellia polyphylla S. L. Hu, Pinellia yaoluopingensis X. H. Guo & X. L. Liu and Pinellia fujianensis H. Li & G. H. Zhu [1–3]. In traditional Chinese medicine (TCM), Pinellia species have been used throughout history, and P. ternata (Chinese name “Banxia”) has been recorded in Chinese Pharmacopoeia (2010 Edition) as a common TCM for the treatment of cough, vomiting, infection and inflammation [4,5]. Also, P. ternata is widely used in many traditional medicine preparations, such as Banxia Houpu Decoction and Xiaoqinglong Decoction [6,7]. However, due to its toxicity, processed products, especially Rhizoma Pinelliae Praeparatum (Chinese name “fabanxia”) and Rhizoma Pinelliae Praeparatum Cum Alumine (Chinese name “qingbanxia”), are a better choice in clinical use. In addition, P. pedatisecta has also been in folk medicine to cure thanatophidia bite, nameless swelling and toxicum, and cancer [8]. Over the past decades, the chemical constituents and pharmacological activities of different Pinellia species have been extensively studied. A lot of compounds including alkaloids, lectins, fatty acids, cerebrosides, volatile oils and phenylpropanoids have been isolated from Pinellia species. Pharmacological investigations revealed that the chemical constituents and extract of Pinellia species possess diverse bioactivities, such as cytotoxic, anti-tumor, antiemetic, insecticidal, antitussive, antimicrobial, antifungal, antiviral, sedative, hypnotic and anticonvulsant activities. Toxicological studies have been reported about the reproductive toxicity, mucosal irritation and hepatotoxicity. Recently, Pinellia species have been the focus of many scientific researches investigating their alkaloids and lectins for different bioactivities, especially cytotoxicity against various human cancer cell lines and antitumor activity in preclinical animal models as well as the toxicity. The present review is an up-to-date and comprehensive analysis of the ethnopharmacological uses, chemical constituents, pharmacological activities and toxicology of Pinellia species.

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13 13 13 14 14 14 15 15

eliminate phlegm, inhibit vomiting, dispel wind and relieve convulsion, and eliminate stagnation [1,9,10]. P. ternata was first record in the ancient Chinese medical book “Shen Nong Ben Cao Jing” and has been traditionally used to treat cough, vomiting, infection and inflammation [4,5,11]. Its rhizome is also used in many empirical formulas (Table 1) which are used clinically for the therapy of exogenous diseases, miscellaneous disease and gynecological disease [27]. A traditional Chinese medicine preparation “Banxia Houpu Decoction” has recently received much interest because of its good therapeutic effect on depression-related diseases and vomiting caused by cancer chemotherapy [6,28]. P. pedatisecta tuber was recorded to possess efficacy in dispelling wind and relieving convulsion, drying dampness to eliminate phlegm, and eliminating stagnation, and has been used as an anticancer agent for hundreds of years [1,8,9]. The tubers of P. cordata are traditionally used for all kinds of pain, envenomization, stomachache, traumatic injuries, arthritis, rheumatism, cancerous tumors and skin diseases. Its powders encased in No. 0 capsules (0.5 g each tablet) are clinically used as analgesic and anti-inflammatory agents in Zhejiang province [1,9,10]. P. peltata tubers are used to treat viper bites, traumatic injuries, mammary abscess and pyogenic infections [29]. P. integrifolia herbs have been used for the treatment of traumatic injuries and gonorrhea [30]. In Japanese Kampo medicine, P. ternata is used as an active herbal component. Sho-seiryu-to (Chinese name: Xiao-QingLong-Tang) has been used clinically for the treatment of allergic rhinitis, bronchitis, bronchial asthma and cold symptoms [7,31]. Kakkon-to (Chinese name: Ge-Gen-Tang), are also used for the treatment of cold syndromes [32,33]. Choto-san (Chinese name: Gou-Teng-San) has been used for a long time to treat chronic headache, vertigo, tinnitus, painful tension of the shoulders and cervical muscle, hypertension, vascular dementia and insomnia, particularly in middle-aged or older patients with weak physical constitutions. Moreover, the clinical efficacy in patients with vascular dementia has been demonstrated by a double blind and placebo controlled study [34–36]. Saiboku-To showed good therapeutic effect for bronchial asthma, chronic bronchitis and bronchiectasis which has been established by multicenter trials [37,38]. To guide clinical applications and offer a reference for quality control of these decoctions, further studies should focus on their active constituents and systemic quality control methods.

2. Ethnopharmacological uses 2.2. Adulterants and their identification 2.1. Traditional uses The uses of Pinellia species for ethnomedicinal purpose in China can be dated back to 2000 years ago. According to the TCM theory, Pinellia species have been mainly used to

Typhonium flagelliforme (Lodd) Blume (Araceae family) is a counterfeit drug. Its antitussive and antiemetic effect is slightly weaker than P. ternata, while its toxicity is three times higher than that of P. ternata [39,40]. Therefore, it is essential

X. Ji et al. / Fitoterapia 93 (2014) 1–17

3

Table 1 Formulas applications of P. ternata in TCM. Prescriptions

Source and status

Traditional therapeutic functions

Clinical applications

Reference

Banxia Houpu Decoction

Synopsis of Prescriptions of the Golden Chamber. A classic prescription for the treatment of emotional illness Treatise on Febrile Disease. The representative prescription for reconciling stomach in reconciliation agent and the preferred prescription for the treatment of epigastric fullness Medicine Comprehended. A common prescription for the treatment of wind phlegm syndrome

Regulate the flow of Qi, resolve masses and dissipate phlegm

Depression, chronic pharyngitis, epigastralgia, vomit, cough, headache vertigo, intractable rhinitis, simple goiter Digestive system disease such as intractable hiccups, chronic atrophic gastritis, enteritis, peptic ulcer, functional dyspepsia

[6,12–15]

Huangdi Neijing·Lingshu. The first prescription for the treatment of insomnia. Prescriptions of the Bureau of Taiping People's Welfare Pharmacy. The representative prescription of expectorant in TCM.

Eliminate phlegm and harmonize stomach, calm the nerves

Banxia Xiexin Decoction

Banxia Baizhu Tianma Decoction

Banxia Shumi Decoction

Erchen Decoction

Calm the adverse-rising energy to control vomit, disintegrate abdominal lumps and resolve masses, reconcile yin and yang of stomach

Eliminate dampness and phlegm, calm the liver to dispel wind

Remove dampness to reduce phlegm, regulate the flow of Qi and harmonize stomach

that P. ternata should be distinguished from T. flagelliforme, especially in powdered samples. From its morphological characteristics, the tuber of P. ternata is spherical, round and flat top with a depressed stem scar in the center, while the T. flagelliforme rhizome is oval, conical or semicircular with a prominent stem scar on the top. Anatomic characters under light microscopy such as cork layer cells, starch grains, calcium oxalate crystals and spiral vessels, are valuable evidences for differentiation [40–42]. Chromatography is a common method to assess the quality and authenticity of P. ternata. The High Performace Liquid Chromatography (HPLC) fingerprints of Shandong trueborn P. ternata and six local varieties have been established [43,44]. P. ternata and T. flagelliforme could be rapidly distinguished by Fourier Transform Infrared Spectroscopy (FTIR) combined with two-dimensional correlation spectroscopy technology [45]. The identification of characteristic chemical constituents is also another useful method to distinguish P. ternata from adulterants. For example, inosine is not detected in any adulterants and can be used as a characteristic compound [46]. The content of amino acids in P. ternata especially arginine is higher than that of other adulterants. Therefore, under specific Thin Layer Chromatography (TLC) conditions, arginine is also used as a characteristic compound to identify P. ternata [47,48]. Some molecular biology methods, including conventional polyacrylamide gel electrophoresis technology, the concentration gradient of SDS polyacrylamide gel slab electrophoresis, and isoelectric focusing electrophoresis, etc. were developed to identify the counterfeit [49,50]. High-performance Capillary Electrophoresis (HPCE) analysis showed that the absorption peaks of the proteins from P. ternata and P. pedatisecta had clear difference and good reproducibility [51]. Random Amplified Polymorphic DNA (RAPD) could used to distinguish P. ternata from P. pedatisecta due to their distinct S10 and S17 as shown in DNA fingerprints [52]. Besides, Polymerase Chain Reaction (PCR) direct sequencing technology and the gene chips based

Dampness type hypertension, Meniere's syndrome, epilepsy, stroke caused by wind phlegm blocking meridians and its sequelae Dizziness, intractable insomnia due to disharmonizing between spleen and stomach Epigastralgia, acute gastroenteritis, vertigo, hyperemesis gravidarum, cough, coronary heart disease, diabetes mellitus caused by damp phlegm

[16–20]

[21,22]

[23,24]

[25,26]

on the result could also distinguish the true from the false [53,54]. 3. Chemical constituents Phytochemical study of the genus Pinellia has been mainly focused on P. ternata and P. pedatisecta. So far, a lot of chemical constituents including alkaloids, lectins, fatty acids, cerebrosides, volatile oils and phenylpropanoids have been isolated and identified from Pinellia species. Among them, alkaloids and lectins are considered as principal active constituents. Herein, the isolated compounds from different Pinellia species are documented and listed in Table 2 and the structures of the main active constituents, including alkaloids and other active constituents, are shown in Figs. 1–2. 3.1. Alkaloids Alkaloids have been considered as the main active components of Pinellia species. So far, a total of 40 alkaloids (compounds 1–40) were isolated from Pinellia species. Their structures include nucleoside alkaloids, cyclic dipeptide alkaloids and indole alkaloids [55–66]. Inosine (5) is a distinctive characteristic compound of P. ternata which has potential chemotaxonomic significance [46]. Pedatisectines D–G (12– 15) are four pyrazines isolated from the tubers of P. pedatisecta [60,61]. Guanosine (3), adenosine (7) and uridine (8) are often used as quality control markers for Pinellia species to study the difference between the processed and wild medicinal materials [58,59,67]. 3.2. Lectins Lectins are carbohydrate-binding proteins possessing at least one non-catalytic domain that can reversibly bind to specific mono- or oligosaccharides with high specificity and affinity. Mannose-binding lectins in Pinellia are a group of

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Table 2 Chemical constituents of the genus Pinellia. No. Alkaloids 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Fatty acids 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Cerebrosides 61 62 63 64 65 66 67

Chemical constituents

Species

Ref.

L-Ephedrine

Choline Guanosine Thymidine Inosine Cytidine Adenosine Uridine Pedatisectine A Pedatisectine B Pedatisectine C Pedatisectine D Pedatisectine E Pedatisectine F Pedatisectine G 3-Acetamino-2-piperidone Hypoxanthine Trigonelline Uracil 5-Methyl uracil Nicotinamide 2-Methyl-3-hydroxy pyridine β-Carboline 1-Acetyl-β-carboline L-Prolyl-L-alanine anhydride L-Phenylalany-L-seryl anhydride L-Tyrosyl-L-alanine anhydride L-Prolyl-L-valine anhydride L-Valyl-L-valine anhydride 3-Isopropyl-6-tert-butyl-2,5- diketopiperazine L-Valyl-L-alanine anhydride L-Prolyl-L-proline anhydride L-Valyl-L-leucine anhydride L-Phenylalanyl-L-alanine anhydride L-Glycyl-L-proline anhydride L-Tyrosyl-L-leucine anhydride L-Tyrosyl-L-valine anhydride L-Alanyl-L-leucine anhydride L-Alanyl-L-isoleucine anhydride Neoechinulin A

P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P.

ternata ternata ternata ternata ternata ternata ternata, P. pedatisecta ternata P. pedatisecta pedatisecta ternata, P. pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta pedatisecta cordata

[55] [55] [55] [56] [46] [57] [57,60] [57,61] [64] [57,63] [65] [60] [60] [61] [61] [60] [61] [62] [63] [63] [63] [63] [63] [63] [60] [60] [60] [64] [64] [64] [64] [65] [65] [65] [65] [65] [65] [65] [65] [66]

Linoleic acid Palmitic acid 8-Octadecenoic acid Pentadecanoic acid 9-Hexadecenoic acid Hexadecanoic acid Hexadecanoic acid Heptadecanoic acid 7-Hexadecenoic acid Oleic acid Octadecanoic acid 9-Oxo-nonanoic acid 11-Eicosenoic acid Eicosanoic acid 10,13-Eicosadienoic acid Docosanoic acid α-Linolenic acid β-Linolenic acid Pinellic acid Succinic acid

P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P.

ternata, P. cordata ternata ternata ternata ternata cordata ternata ternata ternata ternata ternata ternata ternata ternata ternata ternata pedatisecta pedatisecta ternata ternata

[76,77] [76] [76] [76] [76] [77] [76] [76] [76] [76] [76] [76] [76] [76] [76] [76] [63] [63] [78] [79]

1-O-glucosyl-N-2′-acetoxypalmitoyl-4,8-sphingodienine 1-O-glucosyl-N-2′-hydroxypalmitoyl-4,8-sphingodienine 1-O-glucosyl-N-2′-acetoxystearoyl-4,8-sphingodienine 1-O-glucosyl-N-2′-hydroxystearoyl-4,8-sphingodienine 1-O-glucosyl-N-2′-palmitoyl-4,8-sphingodienine 1-O-glucosyl-N-2′-hydroxyeicosanoyl-4,8-sphingodienine Pinelloside

P. P. P. P. P. P. P.

ternata ternata ternata ternata ternata ternata ternata

[80] [80] [80] [80] [80] [80] [81]

X. Ji et al. / Fitoterapia 93 (2014) 1–17

5

Table 2 (continued) No. Volatile oils 68 69 70 71 72 73 74 75 76 77 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 Phenylpropanoids 119 120 121 122 Sterols 123 124 125 126 127 128 Flavonoids 129 130 131 132 133 134

Chemical constituents

Species

Ref.

Butyl-ethylene ether 3-Methyleicosane 1,5-Pentadiol 3-Decyne 2-Methyldecane Octadecane 2,6,10-Trimethyltetradecane 2,5-Dimethyltetradecane Dodecane Vinylcyclohexane 1-Octene Hexadecylendioic acid 2-Ethenyl butenal 6-Methyl-2-heptanone 3-Nonanone Cis-4-decenal 2-Undecanone 9-Heptadecanol 2-Ethyl propyl crotonate 1-Dodecyl enol acetates Ethylpalmitate Anethole Citronellal Citral Aromandendrene Farnesane β-Patchoulene Bisabolene α-Elemol β-Eudesmol β-Elemene 4-Hydroxy terpinene Octahydro-4α-5-dimethyl-3-isopropyl-naphthalene 1-Methyl-4-(1-methylethenyl)-cyclohexene Benzaldehyde Methyl phenanthrene Dibutyl phthalate 2,6-Di-tert-butyl-4-methylphenol 5-Amyl-2-pyrone 2-Pentylfuran 2-Methoxy-dihydropyran Furfural 2,4-Dimethyl furan 5-Methyl-2-oxo-2,3-dihydrofuran Anisic acid Pulegone Isopulegol 2,5-Dimethyl-n-tetradecane 3-Nonyne 2-Methylnonane

P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata

[24,82] [24,82] [24,82] [24] [24] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [24,82] [82] [82] [82] [82] [82] [82]

E-p-coumaryl alcohol 3,4-Dihydroxycinnamyl alcohol Sachaliside 1 Coniferin

P. P. P. P.

ternata ternata ternata ternata

[83] [83] [83] [83]

β-Sitosterol Stigmast-4-en-3-one Cycloartenol 5α,8α-Epidioxyergosta-6,22-dien-3β-ol Daucosterol T-Sitosterol

P. P. P. P. P. P.

ternata, P. pedatisecta, P. cordata ternata ternata ternata ternata cordata

[77,85,86] [84] [84] [84] [85] [86]

Baicalin Baicalein 6C-β-D-Xylopyraose-8C-β-D-galactopyranosyl-5,7,4′-three hydroxyl flavone 6C-β-D-Galactopyranosyl-8C-β-D-xylopyraose-5,7,4′-three hydroxyl flavone 6C-β-Galactose-8C-β-arabinose-5,7,4′-three hydroxyl flavone 6C-β-Arabinose-8C-β-galactose-5,7,4′-three hydroxyl flavone

P. P. P. P. P. P.

ternata ternata ternata ternata ternata ternata

[56] [56] [89] [89] [89] [80] (continued on next page)

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X. Ji et al. / Fitoterapia 93 (2014) 1–17

Table 2 (continued) No. Furans 135 136 137 138 139 Others 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164

Chemical constituents

Species

Ref.

5-Hydroxymethyl-2-furancarboxaldehyde 5-(2,3-Dihydroxypropoxy) methyl-2-furancarboxaldehyde 5-(1,3-Dihydroxypropan-2-yloxy) methyl-2-furancarboxaldehyde 5-O-β-D-glucoside-methyl-2-furan carboxaldehyde 5-Hydroxymethyl -2-furancarbaldehyde

P. P. P. P. P.

ternata ternata ternata ternata ternata

[80] [80] [80] [80] [85]

Protocatechuic aldehyde Shogaol Gingerol Erythritol Melissane Nonacosane Hydroxycinnamic acid Ferulic acid Caffeic acid Vanillic acid Homogentisic acid β-Sitosterol-3-O-β-D-glucoside-6′-O-eicosanate α-Monpalmitin 8-Dihydroxy-3-methyl-anthraquinone Benzene-1,4-diol Benzene-1,2-diol Heptadecanoic acid-2,3-dihydroxy-propyl ester Octadeca-9,12-dienoic acid ethylester Monogalactosyldiacy glycerol 3-O-(6′-O-hexadecanoyl-β-D-glucopyranoside) stigmast-5-en 1,6:3,4-Dianhydro-β-D-allosep 1,6;2,3-Dianhydro-β-D-allosep Soyacerebroside I Soyacerebroside II N-acetylglutamate

P. ternata P. ternata P. ternata P. ternata P. cordata P. cordata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata P. ternata

[56] [56] [56] [61] [77] [77] [80] [80] [80] [80] [82] [84] [84] [85] [85] [85] [85] [85] [85] [85] [85] [85] [85] [85] [88]

newly discovered plant lectins with unique carbohydratebinding properties and various biological activities, and have received much interest over the past decades [68]. The predominant P. ternata lectin (PTL) was a heterotetrameric protein with three mannose-binding sites, and composed of four non-covalently linked polypeptide chains, each with similar size (11–14 kDa) but with different isoelectric points (pI). Analysis of the secondary and three-dimensional structures showed that it consisted of twenty-one β-sheets connected with turns and coils, and the signal peptide and the C-terminal formed α-helix, of which β-sheets occurred predominantly [69]. However, proteome analysis on subunit composition of PTL showed that it consisted of two subunits (11 kDa and 25 kDa) which were linked by hydrogen bonds and these subunits could form many lectin aggregates of different sizes. So far, nine isomers of lectins from P. ternata tubers were successfully identified by MS/MS analysis [70]. 6KDP, another characterized lectin with a 6 kDa molecular mass (M.W.), was separated from the crude globulin fraction of P. ternata, and its contents varied from 5.75 to 8.30% [71]. A novel Araceae lectin with remarkable antitumor activity was purified from the bulbs of P. ternata. The lectin is a homodimer consisting of two identical subunits of 12.09 kDa and was found to contain 3.22% of neutral sugars. It is the first lectin with a unique N-terminal 10-amino acid sequence (QGVNISGQVK) [72]. The subunit of PTL with the M.W. of 12.165 kDa was isolated by mannose–Sepharose 4B affinity chromatography. It was a single strand protein possessing strong agglutination activity on mouse red blood cells and anti-tumor activity, and mainly contained 15 varieties of amino acids [73].

P. pedatisecta lectin (PPL) was a homogenous tetrameric protein of 40 kDa isolated from P. pedatisecta, which was composed of two polypeptide chains that are slightly different in size (about 12 kDa) and pI (5.8) [74]. The difference between PTL and PPL probably leads to distinct pharmacologic variability of P. ternata and P. pedatisecta [75]. Therefore, it is worthy of further investigation on the structural or conformational features and structure–activity relationship of PTL and PPL. 3.3. Fatty acids P. ternata is rich in fatty acids (41–60), including a relatively high content of linoleic acid (41, 37.096%), palmitic acid (42, 15.157%) and 8-octadecenoic acid (43, 6.503%) [76–79]. Pinellic acid (59) is a novel compound isolated from the tuber of P. ternata with oral adjuvant activity for nasally administered influenza HA vaccine. The structure of pinellic acid was identified as 9S,12S,13S-trihydroxy-10E-octadecenoic acid, and all its stereoisomers (9S,12S,13S, 9S,12S,13R, 9S,12R,13S, 9S,12R,13R, 9R,12S,13S, 9R,12S,13R, 9R,12R,13S and 9R,12R, 13R-trihydroxy-10E-octadecenoic acid) have been synthesized [78,79]. The total synthesis pathway for all stereoisomers is proposed in Scheme 1 and Scheme 2 (Fig. 3). 3.4. Cerebrosides Seven cerebrosides, 61–67, were isolated from P. ternata [57]. Pinelloside (67) is a new antimicrobial cerebroside isolated from the air-dried tubers of P. ternata, and its chemical structure was illustrated as 1-O-β-D-glucopyranosyl-(2S,3R,4E,11E)-2-

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7

Fig. 1. Chemical structures of alkaloids obtained from P. ternata, P. pedatisecta and P. cordata.

(2′R-hydroxyhexadecenoylamino)-4,11-octadecadiene-1,3-diol by chemical transformation, extensive spectroscopic analysis and methanolysis [80].

11.88%), 3-methyleicosane (69, 9.78%) and 1,5-pentadiol (70, 4.76%) [82]. 3.6. Others

3.5. Volatile oils Fifty-two chemical constituents (68–118), were identified from the volatile oils of P. ternata by GC/MS [24,82]. The predominant components were butyl-ethylene ether (68,

Four phenylpropanoids, 119–122, was isolated from the rhizome of P. ternata as minor constituents. The four compounds have been used as markers to evaluate the unprocessed and processed rhizomes of P. ternata as well as large quantities

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of raw materials obtained commercially by detecting the content of the phenylpropanoids based on a rapid, accurate and reliable HPLC method using a 250 × 4.6 mm C18 column with methanol–acetonitrile–water–phosphoric acid (20:5:75: 0.3) as mobile phase and 260 nm as the detection wavelength [83]. Six Sterols, 123–128, were isolated from the genus Pinellia [77,84–86]. β-Sitosterol (123) were isolated from P. ternata, P. pedatisecta and P. cordata possessing significant inhibition on the viability of SiHa cells with low toxicity [77,85,86]. Cycloartenol (125) was the first reported triterpenoid from this genus. 5α,8α-Epidioxyergosta-6,22-dien-3β-ol (126) was isolated from petroleum ether extraction of P. ternata ethanol extract with in vitro antitumor activity [85]. In addition, six flavonoids (129–134), five furans (135– 139) and other constituents (140–164) were isolated from P. ternata [56,80,87].

4. Pharmacological activities 4.1. Cytotoxicity and anti-tumor activity The anti-tumor activity of Pinellia species was examined with the use of in vitro as well as in vivo models. Alkaloids and lectins may be responsible for the anti-tumor activity. In vitro, P. ternata ethanol extract at doses of 15 μg/mL displayed strong cytotoxicity against HepG2 with kill rates of 85%, and exerted moderate cytotoxicity against HRT-18 with kill rates of 43%. In vivo, intragastric administration of the ethanol extract at a dose of 30 mg/mL for 15 d significantly prolonged the survival time (67% prolongation) of ascitic mice, and also inhibited the growth of tumors (34% inhibition) in tumor-bearing mice [89]. The viability of human cervical cancer cells (SNU 17) treated with Pinelliae rhizoma herbalacupuncture solution (PRHS) at concentrations of 10, 50, 100

Fig. 2. Chemical structures of some active or characteristic constituents from the genus Pinellia.

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9

Fig. 2 (continued).

and 500 μg/mL for 24 h was 105.7 ± 14.4%, 88.0 ± 9.2%, 80.0 ± 6.2% and 57.8 ± 7.3% of a control group value, respectively. The cytotoxicity of PRHS may be related with cell apoptosis induced via Bax-related caspase-3 activation [90]. Both alkaloids of five processed products of P. ternata were significantly cytotoxic to chronic myeloid leukemia cells (K562) with IC50 values less than 100 μg/mL, especially alkaloids of Pinellia Rhizoma Praeparatum Cum Alumine (IC50 of 30.04 μg/mL) and Ginger dip P. ternata (IC50 of 37.20 μg/mL). However, alkaloids of raw P. ternata exhibited no cytotoxic activity against K562 (IC50 of 122.43 μg/mL). It was concluded that processing enhanced the biological effects and declined the toxicity [91]. P. ternata alkaloids at doses of 400, 200 and 100 μg/mL could reduce the cell proliferation of human hepatocarcinoma cell strain Bel-740 (36.98%, 15.20% and 12.97% inhibition, respectively) compared with a negative control group (P b 0.05). The inhibitory effect was enhanced in a dose- and time-dependent manner, but the definite mechanism was unclear [92]. The 30% (NH4)2SO4 deposition part of proteins from P. ternata rhizome and its eluting peak 0.05 mol/L and 0.1 mol/L of NaCl at 0.1, 0.05 and 0.025 mg/mL inhibited the growth of Bel-7402 (20.95–33.12%, 27.79–47.88% and 30.02–34.85% inhibition, respectively) compared with PBS positive control (P b 0.05). Their inhibition may be related to

the induction of apoptosis [93]. PTL of high concentrations (0.5 and 1 mg/ml) significantly inhibited the proliferation of HeLa cells in a time– and dose-dependent manner. The maximum inhibition ratios of them were 62.3% and 71.89% at 72 h, respectively [73]. The subunits of PTL (40 μg/mL for 48 h) of 12.1 kDa displayed significant anti-proliferation property against Sarcoma 180 (S180), HeLa and K562 cell lines and the maximum inhibition ratios were 85.2%, 74.6% and 59.4%, respectively. Moreover, the inhibition ratio showed a concentration- and time-dependent manner. Intraperitoneal injection of the lectin to mice bearing S180 at the concentration of 0.85, 2.30 and 3.25 mg/kg significantly lighter tumor weight compared with a control group (P b 0.005) and the inhibition rates were 15.6%, 32.1% and 36.2%, respectively. The significant inhibition of the lectins was accomplished through inhibiting the transition of G1/S and subsequently inducing G0/G1 cell cycle arrest [72]. Organic acids isolated from P. ternata exhibited a significant cytotoxic effect against the gastric cancer cells (IC50 of 17.96 μg/mL) with a dose–effect relationship. [94]. The inhibition of P. ternata polysaccharides (60, 300 and 600 mg/kg) occurred at 26.0–50.7% in S180 cells, 31.5–36.3% in hepatoma H22 cells and 20.5–33.0% in Ehrlich ascites tumor (EAC) cells. The polysaccharides also inhibited the proliferation of mice adrenal pheochromocyte (PC12) in a dose-dependent manner and induced the apoptosis of PC12 and karyomorphism of human

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neuroblastoma (SH-SY5Y) [95]. 5α,8α-Epidioxyergosta-6,22dien-3-ol (126) isolated from P. ternata was found to be cytotoxic against the human tumor cell lines HCT-8, Bel-7402, BGC-823, A 549 and A 2780 with IC50 values of 2.12, 3.44, 4.88, 2.43 and 3.05 μg/mL, respectively [84]. Since the 1970s, P. pedatisecta has been mainly used for treatment of cervical cancer in clinical applications. Intraperitoneal injection of P. pedatisecta proteins to mice showed significant inhibition on the growth of S180 with inhibition ratio of 58.3% [96]. The proteins also exhibited significant cytotoxicity against AO cell lines with IC50 values of 1.26 ± 0.263 μg/mL, possessed weak cytotoxicity against 3AO cell lines with IC50 values of 40 ± 0.543 μg/mL, and exerted moderate cytotoxicity against SKOV3 (IC50 of 24 ± 0.52 μg/mL) and OVCAR (IC50 of 25 ± 0.57 μg/mL). However, it showed no cytotoxic activity against human umbilical cord blood hematopoietic cells. The selective cytotoxicity on ovarian cancer cell lines differed from the general cytotoxicity. The mechanism may be achieved by affecting apoptosis-related gene, and protein expression or interfering with cell signal transduction pathways [97,98]. β-Sitosterol (123) significantly inhibited the viability of SiHa cells in a time- and dose-dependent manner. It could induce the accumulation of SiHa cells in S phase in the cell cycle, increase the percents of apoptosis and necrosis, and significantly change the morphology and microstructure of SiHa cells. These effects may be achieved by interfering with cell signal transduction pathways or affecting tumor cell metabolism. Therefore, it is a prospect safe and low toxicity anti-cervical

cancer agent [99]. The anti-tumor activity of PPL was investigated through exogenous expression. Results revealed that PPL translocated into the nucleus, colocalized with DNA, and induced cell death through targeting the MEP50/PRMT5 methylosome. Moreover, Ad.surp-PPL, a replication-defective adenovirus carrying a survivin promoter controlled PPL gene elicited a selective cytotoxicity to H1299, Huh7 and PLC cells. The PPL gene might be developed into a novel agent in cancer gene therapy [100]. A novel lipid-soluble extract from P. pedatisecta (PE) markedly decreased the viability of CaSki and HeLa cells in a time- and dose-dependent manner. The proliferation of CaSki and HeLa cells was reduced by about 50% after 48 h of exposure to 150 μg/mL PE. After treatment with 150 μg/mL PE for 24 h, these two cell lines undergo typical apoptosis. The apoptotic-inducing activities were achieved via mitochondria-dependent and death receptor-dependent apoptotic pathways, and HPV E6 may be the key target of its action [101]. 4.2. Antiemetic activity The processed product of P. ternata has antiemetic activity that may be related to the alkaloids and proteins. Intragastric administration of alkaloids of P. ternata to minks at a dose of 30 mg/kg showed significant inhibition on the emesis model induced by cisplatin (7.5 mg/kg, intraperitoneal injection) and apomorphine (1.6 mg/kg, subcutaneous injection) compared with a control group (P b 0.05), while it showed an

Fig. 3. The total synthesis pathway for pinellic acid and all stereoisomers. Scheme 1. Synthesis of 9S, 12S, 13S and 9S, 12R, 13R-trihydroxy-10E-octadecenoic acid. Scheme 2. Synthesis of 9S, 12S, 13R, 9S, 12R, 13S, 9R, 12R, 13S, 9R, 12S, 13R, 9R, 12S, 13S, and 9R, 12R, 13R-trihydroxy-10E-octadecenoic acid.

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Fig. 3 (continued).

indistinctive inhibition on the emesis model induced by copper sulfate and rotation. The mechanism may be related to its inhibiting property on the central nervous system [102]. 6KDP is one of the major proteins in the tubers of P. ternata. Oral administration of 6KDP at a dose of 50 mg/kg to male young chickens with vomiting induced by copper sulfate showed moderately anti-emetic activity, and the inhibition rate was 49.8% [71]. 4.3. Insecticidal activity Pinellia lectins are effective and safe insecticides compared to using pesticides. PPL displayed high insecticidal activities towards cotton aphids (Aphis gossypii Glover, 1.2 g/L) and peach potato aphids (Myzus persicae Sulzer, 1.5 g/L) when incorporated into artificial diets, and the corrected mortalities up to 90% (4 d) and 50% (2 d), respectively [103]. Transgenic

tobacco with strong expression PTL gene significantly inhibited the growth of M. persicae. Over a 14-day assay period, the aphid number declined from 10 insects per plant (initial inoculum) to an average of 1.7 (less than 1% of the controls) [104]. The insecticidal activities against white backed planthopper (WBPH) of PTL expressed using SJ-10 (an endophytic bacterium of rice) were measured after colonizing rice. After 19 d, the fecundity of WBPH inoculated with rSJ-10 (including the PTL gene) or with wild-type SJ-10 was decreased by 86.1% and 25.6%, respectively. After 26 d, numbers of WBPH in the control were 19.4 times greater than a treatment group. PTL obtained by recombinant gene exhibited notable insecticidal activities but whether the rice plants expressing PTL are toxic to mammals needs to be further studied [105]. PTL also showed significant anti-nematode activity in concentration- and time-dependent relationships. The nematode number treated with PTL (500 μg/mL, 96 h) significantly declined to an average

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of 32.2 (approximately 53.3% of the PBS buffer control group without PTL) nematodes. However, the mechanism is not clear and more detailed research is needed [106]. 4.4. Antitussive activity Experiments revealed that P. ternata had obvious antitussive activity and the maintenance time (the antitussive inhibition rate below 30%) was 120 min generally in vivo. The antitussive experiment in mice with cough induced by aqua ammonia showed that the water or the ethanol extract of P. ternata notably prolonged the incubation period and reduced the times of coughing compared with a control group (P b 0.05). Organic acid was regarded as one of the active ingredients, since the antitussive effect of free organic acids at 12 mg/kg was similar to ethanol extract (360 mg/kg) and the yield of free organic acids in ethanol extract approximately was 3.51% [94,107]. Tubers of P. ternata growing in different environments exhibited an obvious antitussive effect on cough induced by aqua ammonia with ED50 values of 0.47–14.34 g/kg (crude drug) [108]. Intragastric administration of compound P. ternata water extract to mice with cough induced by inhalation of alkaline air at doses of 0.15, 0.3, and 0.6 g/kg significantly prolongs the latency of cough (from 17 to 38 s, 43 and 46 s) and reduced the frequency of cough (from 48 to 36, 35 and 33 in 3 min) compared with a control group (P b 0.05) [109].

with influenza HA vaccine (1 μg) to BALBC mice showed that the former enhanced antiviral IgA antibody (Ab) titers 5.2and 2.5-fold in nasal and bronchoalveolar washes, respectively, and antiviral IgG Ab titers 3-fold in bronchoalveolar wash and serum, while the latter slightly enhanced antiviral IgG Ab titers in bronchoalveolar wash and serum but not antiviral IgA Ab titers in nasal and bronchoalveolar washes. Moreover, pinellic acid (59) had more potent adjuvant activity against nasal influenza vaccine than the known mucosal adjuvant, the B subunit of cholera toxin containing a trace amount of holotoxin (CTB). The adjuvant activity may be related to the mononuclear phagocyte system [45,79]. A subsequent study showed that pinellic acid in combination with 9S,12R,13R isomer (defined as PAM) in a weight ratio of 90.4:9.6 was regarded as a potent oral adjuvant. Oral administration of the PAM at a dose of 1 μg/mouse followed by nasal influenza vaccination (1 μg/mouse) and infection with A/PR8 (1 μg/mouse) significantly increased the survival rates (78%) compared with the mice not administered the PAM (22%). The potent adjuvant activity of PAM was suggested to be associated with the activation of T-cell in Peyer's patch lymphocyte and stimulation of production of anti-influenza virus IgA antibody in nasal lymphocyte, but the definite structure–activity relationship in molecular level needs to be further studied [111]. 4.6. Sedative, hypnotic and anticonvulsive activities

4.5. Antimicrobial, antifungal and antiviral activities The ethanol extract of P. ternata tubers exhibited pronounced antimicrobial activity and pinelloside (67) was the antimicrobial component. P. ternata extract effectively inhibited the growth of Gram-positive and -negative bacteria in a concentration-dependent manner. The MICs (minimum inhibitory concentrations) on Escherichia coli, Pseudomonas putida, Staphylococcus aureus, Micrococcus luteus, Bacillus subtilis, Saccharomyces pombe, Saccharomyces cerevisiae, Aspergillus niger and Melon fusarium were 25, 12.5, 12.5, 12.5, 10, 20, 10, 12.5 and 25 mg/mL, respectively. However, the bacteriostatic action against fungi was not clear [110]. The test of antimicrobial activity against Gram-positive and -negative bacteria as well as fungi using the agar dilution method indicated that pinelloside (67) inhibited the growth of bacteria B. subtilis and S. aureus, and fungi A. niger and Candida albicans, with MICs of 20, 50, 30 and 10 μg/mL, respectively. However, it showed no inhibition to other test bacteria such as E. coli, Pseudomonas fluorescens and Helicobacter pylori and the fungus Trichophyton rubrum. The MICs of the positive control penicillin G against bacteria B. subtilis, S. aureus, E. coli, P. fluorescens and H. pylori were 0.80, 0.34, 0.56, 1.34 and 0.92 μg/mL, respectively, and those of ketoconazole against fungi A. niger, C. albicans and T. rubrum were 0.90, 0.65 and 1.0 μg/mL, respectively [81]. The nasal cavity is the primary site of influenza virus infection and nasal administrations of vaccines by themselves provide insufficient immunostimulation, so the use of safe and effective adjuvants is a nice choice. Pinellic acid (59) with an effective oral adjuvant activity for nasal influenza HA vaccine may be a useful and safe oral adjuvant. Oral administration of pinellic acid (1 μg) with primary and secondary intranasal inoculations of influenza HA vaccine (1 μg) and intranasal administration of pinellic acid (1 μg)

The seizure latency of penicillin (PNC) chronically kindled rats treated with Pinellia alkaloids at doses of 0.5 and 1 g/kg were 21.8 ± 2.76 and 28.4 ± 3.05 min significantly differed from the model group without alkaloids (15.7 ± 2.39 min). Gly and γ-aminobutyric acid (GABA) and Glu receptors are crucial to the genesis of epilepsy. Pinellia alkaloids (0.5 and 1 g/kg) significantly increased the level of GABA (4.78 ± 0.59 and 5.21 ± 0.66 μmol/g, respectively) and decreased the level of Glu in the hippocampus (11.04 ± 3.09 and 10.87 ± 1.47 μmol/g, respectively) compared with a model group (P b 0.05). Moreover, it promoted the expression of GABAA receptor and up-regulated its concentration. The antiepileptic effect may be related to the above factors [112]. Rhizoma Pinelliae Praeparatum (EFRP), the product of raw P. ternata processed with alkaline solution and Licorice, possesses sedative and hypnotic activities. Oral administration of 60% ethanol fraction of EFRP at doses of 8 and 12 g/kg reduced the locomotion activity of mice dose dependently from 184.0 ± 14.2 (control) to 149.0 ± 32.8 (P N 0.05) and 103.6 ± 22.5 min (P b 0.05), respectively. Intragastric administration of 60% ethanol fraction of EFRP with identical doses not only prolonged the sleeping time induced by pentobarbital (45 mg/kg) in mice (P b 0.01), but also increased the number of mice falling asleep and shortened the sleeping latency (P b 0.05). However, L-malic acid (blocker of synthetic enzyme for GABA) and flumazenil (an antagonist of GABAA-benzodiazepine receptor) significantly antagonized the synergistic effects of EFRP on pentobarbital-induced sleeping. EFRP also promote a significant protection to nikethamideinduced convulsion. EFRP at doses of 24 and 48 mg/kg remarkably increased the death latency (P b 0.05) and the highest dosage reduced the mortality to 80%. Moreover, the anti-convulsant activities of P. ternata and P. pedatisecta

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(12 g/kg) were equivalent to the intensity of diazepam (0.5 mg/kg). The above-mentioned activities may be related to the GABAergic system [113,114]. Supercritical CO2 ethanol extract from P. pedatisecta (SEE-CO2PP) at doses of 15 and 30 g/kg prolonged the seizure latency in PNCinduced rat dose dependently from 64 ± 11 (control) to 145 ± 24 and 162 ± 42 min respectively, and reduced stage V seizure to mild seizure by 30% and 60%. It also prolonged the latent period of epileptiform discharge, reduced the frequency and decreased amplitude of the highest wave in both cortex and hippocampus. Meanwhile, the level of GABA in hippocampus was significantly increased by SEE-CO2PP, which suggests that the anticonvulsive mechanism maybe related with the increase of GABA content [115]. 4.7. Other biological activity Proteins of P. ternata (30 mg/kg) showed significant antiearly pregnancy effect on mice and the anti-early pregnancy rate was 100%. The inhibitory effect on the secretion of ovarian flavonoids and decreased levels of plasma progesterone may be responsible for miscarriage [116]. Uterus injection of P. ternata proteins at a dose of 500 μg had strong anti-blastocyst implantation effect in rabbits and mice, and the antiimplantation rate was 100%. However, oral administration of P. ternata proteins showed no described activity. The mechanism might be that P. ternata proteins induced the biological behavior of cell membrane to bind some structures of sugar on the parent or subsidiary body [117]. P. ternata shows a bright future in the therapy of diabetes mellitus induced by dampness–phlegm and its complications. The water extract of P. ternata (PE) mixing with diet to Zucker rats once a day (400 mg/kg) for 6 weeks lowered the levels of triglyceride and free fatty acids (P b 0.05) in blood of the obese rats and the body weight was also reduced slightly [118]. The so-called flavone C-glycoside (100 μmol/L) isolated from the rhizomes of P. ternata could inhibit 64.7% of aldose reductase [87,119]. In addition, Pinellia species possess anti-inflammatory, analgesic, anti-arrhythmic, anti-hyperlipidemia activities, and could promote blood circulation, reduce intraocular pressure and prevent the side effects of contrast agent [77, 107,120,121]. 5. Toxicology Pinellia species are regarded as poisonous plants due to the content of alkaloids and toxic raphides composed of calcium oxalate, proteins and microamount of polysaccharides. Among them, the lectins are the major toxic proteins. These constituents may cause tongue numbing and swelling, salivation, slurred speech, hoarseness, vomit, fetal abnormalities or death, inflammatory reaction and liver injury [122–126]. 5.1. Acute and long-term toxicity The acute toxicity of P. ternata was evaluated by LD50. The LD50 of P. ternata extractum given by intraperitoneal administration to mice was 325 mg/kg (crude drug), while the LD50 of suspension of raw P. ternata given by intragastric

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administration was 42.7 ± 1.27 g/kg [127]. The acute toxicity of different components of P. ternata showed that the maximum dosage (MLD) values of all-components and water extract were 34.8 and 300.0 g/kg, and the maximum tolerated dose (MTD) of alcohol extract was 99.2 g/kg. These doses were equal to 270.7, 2333.3 and 771.6 times of 70 kg people's daily dried medicinal herb expenses, respectively. The study demonstrated that toxic components were mostly in the alcohol soluble part [128]. 75% alcohol-filtered extract and 75% alcohol-extracted extract of P. ternata were given to mice by intragastric administration at a dosage of 40 mL/kg for 14 days, and the MTD values were 94.4 and 99.2 g/kg/d respectively, which are equal to 734.2 and 771.6 times of daily dosage in clinic. Acute toxic tests of P. ternata extract showed that the MTD values of the acid–water extracted group and acid–alcohol extracted group were 29.6 and 27.2 g/kg/d respectively, which are equal to 230.2 and 211.6 times of dosage in clinic, while the LD50 value of the acid–water filter group and acid–alcohol filtered group is 14.15 and 14.27 g/kg/d respectively, which are equal to 110.0 and 111.0 times of daily dosage in clinic. The high-concentration alcohol extract of P. ternata was rich in total alkaloids and the content of total alkaloids in different extracts was: acid–alcohol filtered group N acid–alcohol extracted group N acid–water filtered group N acid–water extracted group. Therefore, it can be concluded that total alkaloids are one of the toxic substances with an obvious toxicity [129,130]. A previous animal study indicated that excessive or long-term use of crude P. ternata would cause renal and liver damage. Intragastric administration of raw P. ternata at a dosage of 0.5 g/kg/day for 40 days to rabbits showed no signs of toxicity. However, the majority of rabbits had diarrhea and half of them died within 20 days when the dose was doubled [127]. 5.2. Reproductive toxicity P. ternata has a significant toxicity on pregnancy maternal mice and embryo. Intragastric administration of raw P. ternata powder (9 g/kg) and P. ternata decoction (30 g/kg, equivalent to approximately 150 times of clinical dose) to pregnant rats significantly increased the mortality of early embryo compared with control, and the stillborn percentages were 85.7% and 50.0%, respectively. Those two dosages also decreased the fetal weight (P b 0.05) and caused colporrhagia of pregnant rats by 62.5% and 50%, respectively [131]. Oral administration of P. ternata extract to pregnant rats at a high dose (2000 mg/kg) remarkably increased the rates of ureteric dilatation, renal malposition, skeletal malformation and variations of fetuses, resulting in visceral malformations (33.3%, 15.7% in a control group), fetus-position variations (15.8%, 4.3% in a control group), asymmetric alignment of ribs (11.1%), dumbbell ossification of thoracic centrum (5.0%) and 14th supernumerary ribs (12.1%). The study showed that maternal exposure to high doses of P. ternata extract might cause fetal abnormalities by influencing the expression of antioxidant, growth factor, apoptosis and tumor-related genes [132]. Micronuclei experiments showed that P. ternata processed with Ginger (PG) at high doses (20 and 30 g/kg) significantly increased the micronucleus rates of maternal sternal bone marrow (3.40 ± 0.83‰ and 5.60 ± 1.09‰, respectively) and fetal rat liver blood (8.00 ± 1.51‰ and 13.00 ± 1.78‰, respectively) compared

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with a control group (P b 0.01). Single cell gel electrophoresis (SCGE) confirmed that PG at high doses (20 and 30 g/kg) remarkably enhanced the percentage of mouse tail blood cells (61.33% and 80.00%, respectively). These two tests suggested that PG has mutagenic effects to a certain extent [133]. Taken together, it should be with caution when P. ternata is used for the treatment of vomiting during pregnancy in clinical use. 5.3. Irritation P. ternata has a noteworthy irritant effect on mucosa. Experiments confirmed that P. ternata stimulated the vocal mucosa and caused inflammation, edema or even aphonia in rabbit, pigeons, guinea pigs, mice, etc. [134]. P. ternata can affect eye conjunctiva leading to edema, blisters and eyelid mild ectropion [72]. P. ternata was emetogenic and could induce diarrhea as well as stomach pain. Intragastric administration of tubers of P. ternata at a dose of 0.5 g/kg for 3 days to rats significantly inhibited the activity of pepsin (219.12 ± 29.78 U/mol), and decreased the acidity of gastric juice (pH = 1.44 ± 0.10) as well as the content of prostaglandin E2 (PGE2, 167.82 ± 22.26 μg/mL) compared with a control group (P b 0.01). Moreover, it also induced serious damage of gastric mucosa (damage rate: 75%). The reduction of PGE2 may be the main reason of the gastrointestinal mucosa irritation [135]. The effect of taste stimulation of P. ternata, Zingiberis rhizoma and their mixture was investigated in the anesthetized rats. The result showed that P. ternata (50 mg/mL, 10 min) exhibited an inhibitory effect on vagal gastric nerve activity, while Z. rhizoma (50 mg/mL, 10 min) caused facilitation in efferent activity and the mixture (5:1, 50 mg/mL, 10 min) showed no suppressive effect on gastric nerve activity. Therefore, it is reasonable to prescribe P. ternata with Z. rhizoma to prevent its suppressive effect on gastric function [136]. The irritant toxicity of raphides from P. ternata shows severe inflammation in vivo. The toxic raphides at doses of 5, 10 and 15 mg/kg significantly enhanced capillary permeability compared with a control group (P b 0.01). The content of PGE2, nitric oxide (NO) and malondialdehyde (MDA) in peritoneal exudate of mice treated with the toxic raphides increased in a dose-dependent manner. Moreover, it also could cause toe swelling in rats and significantly increase the content of PGE2 and cyclooxygenase (COX-2) in toes of rats, which showed a typical dose–response relationship in a certain dose range [137]. The irritant toxicity of PTL and PPL purified from toxic raphides was measured by the model of rats' peritoneal inflammation. Intraperitoneal administration of PTL and PPL could promote neutrophil migration leading to inflammation, and the content of proteins, PGE2 and NO significantly increased in peritoneal exudate compared with a control group (P b 0.01) [124]. The irritant toxicity may be related to the production of inflammatory mediators induced by the toxic raphides or lectins, but the specific mechanisms still need further study. 5.4. Hepatotoxicity The hepatotoxicity of mice induced by a single intragastric administration of water extraction and percolation liquid of acid from Rhizoma Pinelliae was detected with alanine aminotransferase (ALT) and aspartate aminotransferase

(AST) as evaluation index. The activities of serum ALT and AST are changing with the time, and its toxic peak appears at the 4th hour after administration (at a dose of 62.5 g/kg) and last for about 48 h. The activities of serum ALT and AST of high dosage groups (82.5, 70.1 and 59.6 g/kg) were significantly increased in comparison with the normal group, and hydroncus, fatty degeneration and necrosis in hepatocyte also appeared. The results indicated that a single intragastric administration of water extraction might induce acute hepatotoxic injury in mice with an obvious “dosage–time– toxicity” relationship. The study on time–toxicity relationship caused by single dosage percolation liquid of acid from Rhizoma Pinelliae to mice showed that the ALT and AST levels in serum were peaked after 2 hours' administration and last for about 48 h. Compared with the normal group, ALT and AST levels increased significantly with the increased dosage. Groups at high dosage (2.68, 2.14 and 1.72 g/kg) have different levels of edema and fatty degeneration in liver cells, and appear to be necrosis, lobular structure unclear. It can be concluded that percolation liquid of acid extract in a single dose gavage caused acute liver injury or even death, and suggested certain time–dosage–toxicity relationships [138,139]. In short, toxicity is a non-negligible problem of the genus, and the systemic toxicity and safety evaluations of Pinellia remain inadequate, so further studies are needed to confirm the reasonable and safe use of Pinellia. 6. Concluding remarks The review paper mainly discussed the phytochemistry, pharmacological activities and toxicity of Pinellia species. Notably, the majority of research focused on two species: P. ternata and P. pedatisecta. Phytochemical investigations on the two species have led to the isolation of alkaloids, lectins, fatty acids, cerebrosides, volatile oils and other constituents. However, the relationships of these biologically produced chemicals to other Pinellia species have not been investigated. Therefore, a comprehensive investigation on phytochemistry is necessary to provide information on taxonomic relationships within Pinellia. Pinellia species have long been used in traditional medicine for the treatment of cough, vomiting, inflammation, epilepsy, cervical cancer and traumatic injury. Modern in vitro and in vivo pharmacological studies have increasingly confirmed the traditional use of Pinellia species. These species possess many kinds of pharmacological properties, of which the cytotoxic and anti-tumor activities of alkaloids and lectins are the most potential bioactivities, while the antimicrobial, antifungal, insecticidal activities and the adjuvant activity are worthy of being exploited. Moreover, the reproductive toxicity, mucosal irritation and hepatotoxicity of the genus have received more attention in recent years. According to the literature, the most recent pharmacological studies were carried out on an uncharacterized crude extract of Pinellia, thus the isolation of a single compound is necessary for the desired pharmacological activities without side effects, and more precise studies to elucidate the bioactivities' mechanisms of action are needed. Furthermore, due to the toxicity, the dosage–effect and –toxicity should be further investigated to determine the maximum tolerated

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dose and the proper pharmaceutical formulation. Finally, systemic methods to control the quality of medical materials and preparations on the basis of the active and toxic components are also needed. Based on the review of this article, it is anticipated that the genus Pinellia is of great importance in medicinal applications and its phytochemical, pharmacological and toxicological studies will reach a new stage in future. Conflict of interest

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We declare that there is no conflict of interests. References

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