Article history:Received 31 July 2013Accepted in revised form 9 December 2013Available online 25 December 2013
The genus Pinellia (Araceae), consisting of nine species, is mainly distributed in Eastern Asia. Intraditional medicine, some Pinellia species have long been used for the treatment of variousailments, such as cough, vomiting, inflammation, epilepsy, cervical cancer and traumaticinjury. Pharmacological studies revealed that Pinellia species possess a wide range of biologicalactivities including cytotoxic, anti-tumor, antiemetic, insecticidal, antitussive, antimicrobialand anticonvulsant activities. However, some species also showed significant toxicity such asreproductive toxicity, mucosal irritation and hepatotoxicity. Most of these bioactivities andtoxicity can be explained by the presence of various alkaloids and lectins. This reviewsummarizes the ethnopharmacological uses, phytochemical constituents, pharmacologicalactivities and toxicity of Pinellia species.
The genus Pinellia (Araceae) is mainly distributed in EasternAsia (China, Japan and Korea), and comprises the following ninespecies: Pinellia tripartita (Blume) Schott, Pinellia pedatisectaSchott, Pinellia integrifolia N. E. Brown, Pinellia ternata (Thunb.)Breit., Pinellia cordata N. E. Brown, Pinellia peltata C. Pei, Pinelliapolyphylla S. L. Hu, Pinellia yaoluopingensis X. H. Guo & X. L. Liuand Pinellia fujianensis H. Li & G. H. Zhu [1–3]. In traditionalChinese medicine (TCM), Pinellia species have been usedthroughout history, and P. ternata (Chinese name “Banxia”)has been recorded in Chinese Pharmacopoeia (2010 Edition) as acommon TCM for the treatment of cough, vomiting, infectionand inflammation [4,5]. Also, P. ternata is widely used in manytraditional medicine preparations, such as Banxia HoupuDecoction and Xiaoqinglong Decoction [6,7]. However, due toits toxicity, processed products, especially Rhizoma PinelliaePraeparatum (Chinese name “fabanxia”) and Rhizoma PinelliaePraeparatum Cum Alumine (Chinese name “qingbanxia”), are abetter choice in clinical use. In addition, P. pedatisecta has alsobeen in folk medicine to cure thanatophidia bite, namelessswelling and toxicum, and cancer [8].
Over the past decades, the chemical constituents andpharmacological activities of different Pinellia species havebeen extensively studied. A lot of compounds includingalkaloids, lectins, fatty acids, cerebrosides, volatile oils andphenylpropanoids have been isolated from Pinellia species.Pharmacological investigations revealed that the chemicalconstituents and extract of Pinellia species possess diversebioactivities, such as cytotoxic, anti-tumor, antiemetic, insec-ticidal, antitussive, antimicrobial, antifungal, antiviral, sedative,hypnotic and anticonvulsant activities. Toxicological studieshave been reported about the reproductive toxicity, mucosalirritation and hepatotoxicity. Recently, Pinellia species havebeen the focus of many scientific researches investigating theiralkaloids and lectins for different bioactivities, especiallycytotoxicity against various human cancer cell lines and anti-tumor activity in preclinical animal models as well as thetoxicity. The present review is an up-to-date and comprehen-sive analysis of the ethnopharmacological uses, chemicalconstituents, pharmacological activities and toxicology ofPinellia species.
2. Ethnopharmacological uses
2.1. Traditional uses
The uses of Pinellia species for ethnomedicinal purpose inChina can be dated back to 2000 years ago. According to theTCM theory, Pinellia species have been mainly used to
eliminate phlegm, inhibit vomiting, dispel wind and relieveconvulsion, and eliminate stagnation [1,9,10]. P. ternata wasfirst record in the ancient Chinese medical book “Shen NongBen Cao Jing” and has been traditionally used to treat cough,vomiting, infection and inflammation [4,5,11]. Its rhizome isalso used in many empirical formulas (Table 1) which areused clinically for the therapy of exogenous diseases, miscella-neous disease and gynecological disease [27]. A traditionalChinese medicine preparation “Banxia Houpu Decoction” hasrecently receivedmuch interest because of its good therapeuticeffect on depression-related diseases and vomiting caused bycancer chemotherapy [6,28]. P. pedatisecta tuber was recordedto possess efficacy in dispelling wind and relieving convulsion,drying dampness to eliminate phlegm, and eliminating stagna-tion, and has been used as an anticancer agent for hundreds ofyears [1,8,9]. The tubers of P. cordata are traditionally usedfor all kinds of pain, envenomization, stomachache, traumaticinjuries, arthritis, rheumatism, cancerous tumors and skindiseases. Its powders encased in No. 0 capsules (0.5 g eachtablet) are clinically used as analgesic and anti-inflammatoryagents in Zhejiang province [1,9,10]. P. peltata tubers are used totreat viper bites, traumatic injuries, mammary abscess andpyogenic infections [29]. P. integrifolia herbs have been used forthe treatment of traumatic injuries and gonorrhea [30].
In Japanese Kampo medicine, P. ternata is used as an activeherbal component. Sho-seiryu-to (Chinese name: Xiao-Qing-Long-Tang) has been used clinically for the treatment ofallergic rhinitis, bronchitis, bronchial asthma and cold symp-toms [7,31]. Kakkon-to (Chinese name: Ge-Gen-Tang), are alsoused for the treatment of cold syndromes [32,33]. Choto-san(Chinese name: Gou-Teng-San) has been used for a long timeto treat chronic headache, vertigo, tinnitus, painful tension ofthe shoulders and cervical muscle, hypertension, vasculardementia and insomnia, particularly in middle-aged or olderpatients with weak physical constitutions. Moreover, theclinical efficacy in patients with vascular dementia has beendemonstrated by a double blind and placebo controlled study[34–36]. Saiboku-To showed good therapeutic effect forbronchial asthma, chronic bronchitis and bronchiectasiswhich has been established by multicenter trials [37,38]. Toguide clinical applications and offer a reference for qualitycontrol of these decoctions, further studies should focus ontheir active constituents and systemic quality control methods.
2.2. Adulterants and their identification
Typhonium flagelliforme (Lodd) Blume (Araceae family) isa counterfeit drug. Its antitussive and antiemetic effect isslightly weaker than P. ternata, while its toxicity is three timeshigher than that of P. ternata [39,40]. Therefore, it is essential
Table 1Formulas applications of P. ternata in TCM.
Prescriptions Source and status Traditional therapeutic functions Clinical applications Reference
Banxia Houpu Decoction Synopsis of Prescriptions ofthe Golden Chamber. A classicprescription for the treatmentof emotional illness
Regulate the flow of Qi, resolvemasses and dissipate phlegm
Banxia Xiexin Decoction Treatise on Febrile Disease. Therepresentative prescription forreconciling stomach in reconciliationagent and the preferred prescriptionfor the treatment of epigastricfullness
Calm the adverse-rising energy tocontrol vomit, disintegrate abdominallumps and resolve masses, reconcileyin and yang of stomach
Digestive system disease such asintractable hiccups, chronicatrophic gastritis, enteritis, pepticulcer, functional dyspepsia
[16–20]
Banxia Baizhu TianmaDecoction
Medicine Comprehended. A commonprescription for the treatment ofwind phlegm syndrome
Eliminate dampness and phlegm,calm the liver to dispel wind
Dampness type hypertension,Meniere's syndrome, epilepsy,stroke caused by wind phlegmblocking meridians and its sequelae
[21,22]
Banxia Shumi Decoction Huangdi Neijing·Lingshu. The firstprescription for the treatment ofinsomnia.
Eliminate phlegm and harmonizestomach, calm the nerves
Dizziness, intractable insomnia dueto disharmonizing between spleenand stomach
[23,24]
Erchen Decoction Prescriptions of the Bureau ofTaiping People's Welfare Pharmacy.The representative prescription ofexpectorant in TCM.
Remove dampness to reduce phlegm,regulate the flow of Qi and harmonizestomach
that P. ternata should be distinguished from T. flagelliforme,especially in powdered samples. From its morphologicalcharacteristics, the tuber of P. ternata is spherical, round andflat top with a depressed stem scar in the center, while the T.flagelliforme rhizome is oval, conical or semicircular with aprominent stem scar on the top. Anatomic characters underlight microscopy such as cork layer cells, starch grains, calciumoxalate crystals and spiral vessels, are valuable evidences fordifferentiation [40–42].
Chromatography is a common method to assess thequality and authenticity of P. ternata. The High PerformaceLiquid Chromatography (HPLC) fingerprints of Shandongtrueborn P. ternata and six local varieties have beenestablished [43,44]. P. ternata and T. flagelliforme could berapidly distinguished by Fourier Transform Infrared Spec-troscopy (FTIR) combined with two-dimensional correlationspectroscopy technology [45]. The identification of charac-teristic chemical constituents is also another useful methodto distinguish P. ternata from adulterants. For example, inosineis not detected in any adulterants and can be used as acharacteristic compound [46]. The content of amino acids inP. ternata especially arginine is higher than that of otheradulterants. Therefore, under specific Thin Layer Chromatog-raphy (TLC) conditions, arginine is also used as a characteristiccompound to identify P. ternata [47,48].
Some molecular biology methods, including conventionalpolyacrylamide gel electrophoresis technology, the concentra-tion gradient of SDS polyacrylamide gel slab electrophoresis,and isoelectric focusing electrophoresis, etc.were developed toidentify the counterfeit [49,50]. High-performance CapillaryElectrophoresis (HPCE) analysis showed that the absorptionpeaks of the proteins from P. ternata and P. pedatisectahad cleardifference and good reproducibility [51]. Random AmplifiedPolymorphic DNA (RAPD) could used to distinguish P. ternatafrom P. pedatisecta due to their distinct S10 and S17 as shownin DNA fingerprints [52]. Besides, Polymerase Chain Reaction(PCR) direct sequencing technology and the gene chips based
on the result could also distinguish the true from the false[53,54].
3. Chemical constituents
Phytochemical study of the genus Pinellia has been mainlyfocused on P. ternata and P. pedatisecta. So far, a lot of chemicalconstituents including alkaloids, lectins, fatty acids, cerebro-sides, volatile oils and phenylpropanoids have been isolatedand identified from Pinellia species. Among them, alkaloids andlectins are considered as principal active constituents. Herein,the isolated compounds from different Pinellia species aredocumented and listed in Table 2 and the structures of themain active constituents, including alkaloids and other activeconstituents, are shown in Figs. 1–2.
3.1. Alkaloids
Alkaloids have been considered as the main activecomponents of Pinellia species. So far, a total of 40 alkaloids(compounds 1–40) were isolated from Pinellia species. Theirstructures include nucleoside alkaloids, cyclic dipeptide alka-loids and indole alkaloids [55–66]. Inosine (5) is a distinctivecharacteristic compound of P. ternata which has potentialchemotaxonomic 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 oftenused as quality control markers for Pinellia species to study thedifference between the processed andwildmedicinalmaterials[58,59,67].
3.2. Lectins
Lectins are carbohydrate-binding proteins possessing atleast one non-catalytic domain that can reversibly bind tospecific mono- or oligosaccharides with high specificity andaffinity. Mannose-binding lectins in Pinellia are a group of
Table 2Chemical constituents of the genus Pinellia.
No. Chemical constituents Species Ref.
Alkaloids1 L-Ephedrine P. ternata [55]2 Choline P. ternata [55]3 Guanosine P. ternata [55]4 Thymidine P. ternata [56]5 Inosine P. ternata [46]6 Cytidine P. ternata [57]7 Adenosine P. ternata, P. pedatisecta [57,60]8 Uridine P. ternata P. pedatisecta [57,61]9 Pedatisectine A P. pedatisecta [64]10 Pedatisectine B P. ternata, P. pedatisecta [57,63]11 Pedatisectine C P. pedatisecta [65]12 Pedatisectine D P. pedatisecta [60]13 Pedatisectine E P. pedatisecta [60]14 Pedatisectine F P. pedatisecta [61]15 Pedatisectine G P. pedatisecta [61]16 3-Acetamino-2-piperidone P. pedatisecta [60]17 Hypoxanthine P. pedatisecta [61]18 Trigonelline P. pedatisecta [62]19 Uracil P. pedatisecta [63]20 5-Methyl uracil P. pedatisecta [63]21 Nicotinamide P. pedatisecta [63]22 2-Methyl-3-hydroxy pyridine P. pedatisecta [63]23 β-Carboline P. pedatisecta [63]24 1-Acetyl-β-carboline P. pedatisecta [63]25 L-Prolyl-L-alanine anhydride P. pedatisecta [60]26 L-Phenylalany-L-seryl anhydride P. pedatisecta [60]27 L-Tyrosyl-L-alanine anhydride P. pedatisecta [60]28 L-Prolyl-L-valine anhydride P. pedatisecta [64]29 L-Valyl-L-valine anhydride P. pedatisecta [64]30 3-Isopropyl-6-tert-butyl-2,5- diketopiperazine P. pedatisecta [64]31 L-Valyl-L-alanine anhydride P. pedatisecta [64]32 L-Prolyl-L-proline anhydride P. pedatisecta [65]33 L-Valyl-L-leucine anhydride P. pedatisecta [65]34 L-Phenylalanyl-L-alanine anhydride P. pedatisecta [65]35 L-Glycyl-L-proline anhydride P. pedatisecta [65]36 L-Tyrosyl-L-leucine anhydride P. pedatisecta [65]37 L-Tyrosyl-L-valine anhydride P. pedatisecta [65]38 L-Alanyl-L-leucine anhydride P. pedatisecta [65]39 L-Alanyl-L-isoleucine anhydride P. pedatisecta [65]40 Neoechinulin A P. cordata [66]
Fatty acids41 Linoleic acid P. ternata, P. cordata [76,77]42 Palmitic acid P. ternata [76]43 8-Octadecenoic acid P. ternata [76]44 Pentadecanoic acid P. ternata [76]45 9-Hexadecenoic acid P. ternata [76]46 Hexadecanoic acid P. cordata [77]47 Hexadecanoic acid P. ternata [76]48 Heptadecanoic acid P. ternata [76]49 7-Hexadecenoic acid P. ternata [76]50 Oleic acid P. ternata [76]51 Octadecanoic acid P. ternata [76]52 9-Oxo-nonanoic acid P. ternata [76]53 11-Eicosenoic acid P. ternata [76]54 Eicosanoic acid P. ternata [76]55 10,13-Eicosadienoic acid P. ternata [76]56 Docosanoic acid P. ternata [76]57 α-Linolenic acid P. pedatisecta [63]58 β-Linolenic acid P. pedatisecta [63]59 Pinellic acid P. ternata [78]60 Succinic acid P. ternata [79]
Cerebrosides61 1-O-glucosyl-N-2′-acetoxypalmitoyl-4,8-sphingodienine P. ternata [80]62 1-O-glucosyl-N-2′-hydroxypalmitoyl-4,8-sphingodienine P. ternata [80]63 1-O-glucosyl-N-2′-acetoxystearoyl-4,8-sphingodienine P. ternata [80]64 1-O-glucosyl-N-2′-hydroxystearoyl-4,8-sphingodienine P. ternata [80]65 1-O-glucosyl-N-2′-palmitoyl-4,8-sphingodienine P. ternata [80]66 1-O-glucosyl-N-2′-hydroxyeicosanoyl-4,8-sphingodienine P. ternata [80]67 Pinelloside P. ternata [81]
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Table 2 (continued)
No. Chemical constituents Species Ref.
Volatile oils68 Butyl-ethylene ether P. ternata [24,82]69 3-Methyleicosane P. ternata [24,82]70 1,5-Pentadiol P. ternata [24,82]71 3-Decyne P. ternata [24]72 2-Methyldecane P. ternata [24]73 Octadecane P. ternata [24,82]74 2,6,10-Trimethyltetradecane P. ternata [24,82]75 2,5-Dimethyltetradecane P. ternata [24,82]76 Dodecane P. ternata [24,82]77 Vinylcyclohexane P. ternata [24,82]79 1-Octene P. ternata [24,82]80 Hexadecylendioic acid P. ternata [24,82]81 2-Ethenyl butenal P. ternata [24,82]82 6-Methyl-2-heptanone P. ternata [24,82]83 3-Nonanone P. ternata [24,82]84 Cis-4-decenal P. ternata [24,82]85 2-Undecanone P. ternata [24,82]86 9-Heptadecanol P. ternata [24,82]87 2-Ethyl propyl crotonate P. ternata [24,82]88 1-Dodecyl enol acetates P. ternata [24,82]89 Ethylpalmitate P. ternata [24,82]90 Anethole P. ternata [24,82]91 Citronellal P. ternata [24,82]92 Citral P. ternata [24,82]93 Aromandendrene P. ternata [24,82]94 Farnesane P. ternata [24,82]95 β-Patchoulene P. ternata [24,82]96 Bisabolene P. ternata [24,82]97 α-Elemol P. ternata [24,82]98 β-Eudesmol P. ternata [24,82]99 β-Elemene P. ternata [24,82]100 4-Hydroxy terpinene P. ternata [24,82]101 Octahydro-4α-5-dimethyl-3-isopropyl-naphthalene P. ternata [24,82]102 1-Methyl-4-(1-methylethenyl)-cyclohexene P. ternata [24,82]103 Benzaldehyde P. ternata [24,82]104 Methyl phenanthrene P. ternata [24,82]105 Dibutyl phthalate P. ternata [24,82]106 2,6-Di-tert-butyl-4-methylphenol P. ternata [24,82]107 5-Amyl-2-pyrone P. ternata [24,82]108 2-Pentylfuran P. ternata [24,82]109 2-Methoxy-dihydropyran P. ternata [24,82]110 Furfural P. ternata [24,82]111 2,4-Dimethyl furan P. ternata [24,82]112 5-Methyl-2-oxo-2,3-dihydrofuran P. ternata [24,82]113 Anisic acid P. ternata [82]114 Pulegone P. ternata [82]115 Isopulegol P. ternata [82]116 2,5-Dimethyl-n-tetradecane P. ternata [82]117 3-Nonyne P. ternata [82]118 2-Methylnonane P. ternata [82]
Phenylpropanoids119 E-p-coumaryl alcohol P. ternata [83]120 3,4-Dihydroxycinnamyl alcohol P. ternata [83]121 Sachaliside 1 P. ternata [83]122 Coniferin P. ternata [83]
Sterols123 β-Sitosterol P. ternata, P. pedatisecta, P. cordata [77,85,86]124 Stigmast-4-en-3-one P. ternata [84]125 Cycloartenol P. ternata [84]126 5α,8α-Epidioxyergosta-6,22-dien-3β-ol P. ternata [84]127 Daucosterol P. ternata [85]128 T-Sitosterol P. cordata [86]
Flavonoids129 Baicalin P. ternata [56]130 Baicalein P. ternata [56]131 6C-β-D-Xylopyraose-8C-β-D-galactopyranosyl-5,7,4′-three hydroxyl flavone P. ternata [89]132 6C-β-D-Galactopyranosyl-8C-β-D-xylopyraose-5,7,4′-three hydroxyl flavone P. ternata [89]133 6C-β-Galactose-8C-β-arabinose-5,7,4′-three hydroxyl flavone P. ternata [89]134 6C-β-Arabinose-8C-β-galactose-5,7,4′-three hydroxyl flavone P. ternata [80]
(continued on next page)
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Table 2 (continued)
No. Chemical constituents Species Ref.
Furans135 5-Hydroxymethyl-2-furancarboxaldehyde P. ternata [80]136 5-(2,3-Dihydroxypropoxy) methyl-2-furancarboxaldehyde P. ternata [80]137 5-(1,3-Dihydroxypropan-2-yloxy) methyl-2-furancarboxaldehyde P. ternata [80]138 5-O-β-D-glucoside-methyl-2-furan carboxaldehyde P. ternata [80]139 5-Hydroxymethyl -2-furancarbaldehyde P. ternata [85]
Others140 Protocatechuic aldehyde P. ternata [56]141 Shogaol P. ternata [56]142 Gingerol P. ternata [56]143 Erythritol P. ternata [61]144 Melissane P. cordata [77]145 Nonacosane P. cordata [77]146 Hydroxycinnamic acid P. ternata [80]147 Ferulic acid P. ternata [80]148 Caffeic acid P. ternata [80]149 Vanillic acid P. ternata [80]150 Homogentisic acid P. ternata [82]151 β-Sitosterol-3-O-β-D-glucoside-6′-O-eicosanate P. ternata [84]152 α-Monpalmitin P. ternata [84]153 8-Dihydroxy-3-methyl-anthraquinone P. ternata [85]154 Benzene-1,4-diol P. ternata [85]155 Benzene-1,2-diol P. ternata [85]156 Heptadecanoic acid-2,3-dihydroxy-propyl ester P. ternata [85]157 Octadeca-9,12-dienoic acid ethylester P. ternata [85]158 Monogalactosyldiacy glycerol P. ternata [85]159 3-O-(6′-O-hexadecanoyl-β-D-glucopyranoside) stigmast-5-en P. ternata [85]160 1,6:3,4-Dianhydro-β-D-allosep P. ternata [85]161 1,6;2,3-Dianhydro-β-D-allosep P. ternata [85]162 Soyacerebroside I P. ternata [85]163 Soyacerebroside II P. ternata [85]164 N-acetylglutamate P. ternata [88]
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newly discovered plant lectins with unique carbohydrate-binding properties and various biological activities, and havereceived much interest over the past decades [68]. Thepredominant P. ternata lectin (PTL) was a heterotetramericprotein with three mannose-binding sites, and composed offour non-covalently linked polypeptide chains, each withsimilar size (11–14 kDa) but with different isoelectric points(pI). Analysis of the secondary and three-dimensionalstructures showed that it consisted of twenty-one β-sheetsconnected with turns and coils, and the signal peptide andthe C-terminal formed α-helix, of which β-sheets occurredpredominantly [69]. However, proteome analysis on subunitcomposition of PTL showed that it consisted of two subunits(11 kDa and 25 kDa) which were linked by hydrogen bondsand these subunits could form many lectin aggregates ofdifferent sizes. So far, nine isomers of lectins from P. ternatatubers were successfully identified by MS/MS analysis [70].6KDP, another characterized lectin with a 6 kDa molecularmass (M.W.), was separated from the crude globulin fractionof P. ternata, and its contents varied from 5.75 to 8.30% [71].A novel Araceae lectin with remarkable antitumor activitywas purified from the bulbs of P. ternata. The lectin is ahomodimer consisting of two identical subunits of 12.09 kDaand was found to contain 3.22% of neutral sugars. It is thefirst lectin with a unique N-terminal 10-amino acid sequence(QGVNISGQVK) [72]. The subunit of PTL with the M.W. of12.165 kDa was isolated by mannose–Sepharose 4B affinitychromatography. It was a single strand protein possessing strongagglutination activity on mouse red blood cells and anti-tumoractivity, and mainly contained 15 varieties of amino acids [73].
P. pedatisecta lectin (PPL) was a homogenous tetrameric proteinof 40 kDa isolated from P. pedatisecta, which was composed oftwo polypeptide chains that are slightly different in size(about 12 kDa) and pI (5.8) [74]. The difference between PTLand PPL probably leads to distinct pharmacologic variabilityof P. ternata and P. pedatisecta [75]. Therefore, it is worthy offurther investigation on the structural or conformationalfeatures and structure–activity relationship of PTL and PPL.
3.3. Fatty acids
P. ternata is rich in fatty acids (41–60), including a relativelyhigh 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 tuberof P. ternatawith oral adjuvant activity for nasally administeredinfluenza HA vaccine. The structure of pinellic acid wasidentified 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 synthe-sized [78,79]. The total synthesis pathway for all stereoiso-mers 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 fromthe air-dried tubers of P. ternata, and its chemical structurewas illustrated as 1-O-β-D-glucopyranosyl-(2S,3R,4E,11E)-2-
Fig. 1. Chemical structures of alkaloids obtained from P. ternata, P. pedatisecta and P. cordata.
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(2′R-hydroxyhexadecenoylamino)-4,11-octadecadiene-1,3-diolby chemical transformation, extensive spectroscopic analysisand methanolysis [80].
3.5. Volatile oils
Fifty-two chemical constituents (68–118), were identifiedfrom the volatile oils of P. ternata by GC/MS [24,82]. Thepredominant components were butyl-ethylene ether (68,
11.88%), 3-methyleicosane (69, 9.78%) and 1,5-pentadiol (70,4.76%) [82].
3.6. Others
Four phenylpropanoids, 119–122, was isolated from therhizome of P. ternata as minor constituents. The four com-pounds have been used asmarkers to evaluate the unprocessedand processed rhizomes of P. ternata as well as large quantities
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of raw materials obtained commercially by detecting thecontent of the phenylpropanoids based on a rapid, accurateand reliable HPLC method using a 250 × 4.6 mm C18 columnwith 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 inhibitionon the viability of SiHa cells with low toxicity [77,85,86].Cycloartenol (125) was the first reported triterpenoid fromthis genus. 5α,8α-Epidioxyergosta-6,22-dien-3β-ol (126)was isolated from petroleum ether extraction of P. ternataethanol extract with in vitro antitumor activity [85].
In addition, six flavonoids (129–134), five furans (135–139) and other constituents (140–164) were isolated fromP. ternata [56,80,87].
Fig. 2. Chemical structures of some active or charac
4. Pharmacological activities
4.1. Cytotoxicity and anti-tumor activity
The anti-tumor activity of Pinellia species was examinedwith the use of in vitro as well as in vivomodels. Alkaloids andlectins may be responsible for the anti-tumor activity.
In vitro, P. ternata ethanol extract at doses of 15 μg/mLdisplayed strong cytotoxicity against HepG2 with kill rates of85%, and exerted moderate cytotoxicity against HRT-18 withkill rates of 43%. In vivo, intragastric administration of theethanol extract at a dose of 30 mg/mL for 15 d significantlyprolonged the survival time (67% prolongation) of ascitic mice,and also inhibited the growth of tumors (34% inhibition) intumor-bearing mice [89]. The viability of human cervicalcancer cells (SNU 17) treated with Pinelliae rhizoma herbal-acupuncture solution (PRHS) at concentrations of 10, 50, 100
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 withcell apoptosis induced via Bax-related caspase-3 activation[90].
Both alkaloids of five processed products of P. ternatawere significantly cytotoxic to chronic myeloid leukemiacells (K562) with IC50 values less than 100 μg/mL, especiallyalkaloids of Pinellia Rhizoma Praeparatum Cum Alumine(IC50 of 30.04 μg/mL) and Ginger dip P. ternata (IC50 of37.20 μg/mL). However, alkaloids of raw P. ternata exhibitedno cytotoxic activity against K562 (IC50 of 122.43 μg/mL). Itwas concluded that processing enhanced the biologicaleffects and declined the toxicity [91]. P. ternata alkaloids atdoses of 400, 200 and 100 μg/mL could reduce the cellproliferation of human hepatocarcinoma cell strain Bel-740(36.98%, 15.20% and 12.97% inhibition, respectively) com-pared with a negative control group (P b 0.05). The inhibi-tory effect was enhanced in a dose- and time-dependentmanner, but the definite mechanism was unclear [92].
The 30% (NH4)2SO4 deposition part of proteins fromP. ternata rhizome and its eluting peak 0.05 mol/L and0.1 mol/L of NaCl at 0.1, 0.05 and 0.025 mg/mL inhibitedthe growth of Bel-7402 (20.95–33.12%, 27.79–47.88% and30.02–34.85% inhibition, respectively) compared with PBSpositive 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 ofHeLa cells in a time– and dose-dependent manner. Themaximum inhibition ratios of themwere 62.3% and 71.89% at72 h, respectively [73]. The subunits of PTL (40 μg/mL for48 h) of 12.1 kDa displayed significant anti-proliferationproperty against Sarcoma 180 (S180), HeLa and K562 celllines and the maximum inhibition ratios were 85.2%, 74.6%and 59.4%, respectively. Moreover, the inhibition ratioshowed a concentration- and time-dependent manner.Intraperitoneal injection of the lectin to mice bearing S180 atthe concentration of 0.85, 2.30 and 3.25 mg/kg significantlylighter tumor weight compared with a control group(P b 0.005) and the inhibition rates were 15.6%, 32.1% and36.2%, respectively. The significant inhibition of the lectins wasaccomplished through inhibiting the transition of G1/S andsubsequently inducing G0/G1 cell cycle arrest [72].
Organic acids isolated from P. ternata exhibited a signif-icant cytotoxic effect against the gastric cancer cells (IC50 of17.96 μg/mL) with a dose–effect relationship. [94]. The inhibi-tion of P. ternata polysaccharides (60, 300 and 600 mg/kg)occurred at 26.0–50.7% in S180 cells, 31.5–36.3% in hepatomaH22 cells and20.5–33.0% in Ehrlich ascites tumor (EAC) cells. Thepolysaccharides also inhibited the proliferation of mice adrenalpheochromocyte (PC12) in a dose-dependent manner andinduced the apoptosis of PC12 and karyomorphism of human
neuroblastoma (SH-SY5Y) [95]. 5α,8α-Epidioxyergosta-6,22-dien-3-ol (126) isolated from P. ternata was found to becytotoxic 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 fortreatment of cervical cancer in clinical applications. Intraperi-toneal injection of P. pedatisecta proteins to mice showedsignificant inhibition on the growth of S180 with inhibitionratio of 58.3% [96]. The proteins also exhibited significantcytotoxicity against AO cell lines with IC50 values of 1.26 ±0.263 μg/mL, possessedweak cytotoxicity against 3AO cell lineswith IC50 values of 40 ± 0.543 μg/mL, and exerted moderatecytotoxicity against SKOV3 (IC50 of 24 ± 0.52 μg/mL) andOVCAR (IC50 of 25 ± 0.57 μg/mL). However, it showed nocytotoxic activity against human umbilical cord blood hemato-poietic cells. The selective cytotoxicity on ovarian cancer celllines differed from the general cytotoxicity. The mechanismmay be achieved by affecting apoptosis-related gene, andprotein expression or interfering with cell signal transductionpathways [97,98]. β-Sitosterol (123) significantly inhibited theviability of SiHa cells in a time- and dose-dependent manner. Itcould induce the accumulation of SiHa cells in S phase in the cellcycle, increase the percents of apoptosis and necrosis, andsignificantly change the morphology and microstructure ofSiHa cells. These effectsmay be achieved by interferingwith cellsignal transductionpathways or affecting tumor cellmetabolism.Therefore, it is a prospect safe and low toxicity anti-cervical
Fig. 3. The total synthesis pathway for pinellic acid and all stereoisomers. Scheme 1.Scheme 2. Synthesis of 9S, 12S, 13R, 9S, 12R, 13S, 9R, 12R, 13S, 9R, 12S, 13R, 9R, 12S
cancer agent [99]. The anti-tumor activity of PPL was investigat-ed through exogenous expression. Results revealed that PPLtranslocated into the nucleus, colocalizedwithDNA, and inducedcell death through targeting the MEP50/PRMT5 methylosome.Moreover, Ad.surp-PPL, a replication-defective adenovirus car-rying a survivin promoter controlled PPL gene elicited a selectivecytotoxicity to H1299, Huh7 and PLC cells. The PPL gene mightbe 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 atime- and dose-dependent manner. The proliferation ofCaSki and HeLa cells was reduced by about 50% after 48 h ofexposure to 150 μg/mL PE. After treatment with 150 μg/mLPE for 24 h, these two cell lines undergo typical apo-ptosis. The apoptotic-inducing activities were achieved viamitochondria-dependent and death receptor-dependentapoptotic pathways, and HPV E6 may be the key target ofits action [101].
4.2. Antiemetic activity
The processed product of P. ternata has antiemetic activitythat may be related to the alkaloids and proteins. Intragastricadministration of alkaloids of P. ternata to minks at a dose of30 mg/kg showed significant inhibition on the emesis modelinduced by cisplatin (7.5 mg/kg, intraperitoneal injection)and apomorphine (1.6 mg/kg, subcutaneous injection) com-pared with a control group (P b 0.05), while it showed an
Synthesis of 9S, 12S, 13S and 9S, 12R, 13R-trihydroxy-10E-octadecenoic acid., 13S, and 9R, 12R, 13R-trihydroxy-10E-octadecenoic acid.
indistinctive inhibition on the emesis model induced bycopper sulfate and rotation. The mechanism may be relatedto 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 maleyoung chickens with vomiting induced by copper sulfateshowed moderately anti-emetic activity, and the inhibitionrate was 49.8% [71].
4.3. Insecticidal activity
Pinellia lectins are effective and safe insecticides comparedto using pesticides. PPL displayed high insecticidal activitiestowards cotton aphids (Aphis gossypii Glover, 1.2 g/L) andpeach potato aphids (Myzus persicae Sulzer, 1.5 g/L) whenincorporated into artificial diets, and the corrected mortalitiesup to 90% (4 d) and 50% (2 d), respectively [103]. Transgenic
tobaccowith strong expression PTL gene significantly inhibitedthe growth ofM. persicae. Over a 14-day assay period, the aphidnumber 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 bacteri-um of rice) were measured after colonizing rice. After 19 d, thefecundity of WBPH inoculated with rSJ-10 (including the PTLgene) or with wild-type SJ-10 was decreased by 86.1% and25.6%, respectively. After 26 d, numbers ofWBPH in the controlwere 19.4 times greater than a treatment group. PTL obtainedby recombinant gene exhibited notable insecticidal activitiesbut whether the rice plants expressing PTL are toxic tomammals needs to be further studied [105]. PTL also showedsignificant anti-nematode activity in concentration- andtime-dependent relationships. The nematode number treatedwith PTL (500 μg/mL, 96 h) significantly declined to an average
of 32.2 (approximately 53.3% of the PBS buffer control groupwithout PTL) nematodes. However, the mechanism is not clearand more detailed research is needed [106].
4.4. Antitussive activity
Experiments revealed that P. ternata had obvious antitus-sive activity and the maintenance time (the antitussiveinhibition rate below 30%) was 120 min generally in vivo. Theantitussive experiment in mice with cough induced by aquaammonia showed that the water or the ethanol extract ofP. ternata notably prolonged the incubation period and reducedthe times of coughing compared with a control group(P b 0.05). Organic acid was regarded as one of the activeingredients, since the antitussive effect of free organic acids at12 mg/kg was similar to ethanol extract (360 mg/kg) and theyield of free organic acids in ethanol extract approximatelywas3.51% [94,107]. Tubers of P. ternata growing in differentenvironments exhibited an obvious antitussive effect on coughinduced by aqua ammonia with ED50 values of 0.47–14.34 g/kg(crude drug) [108]. Intragastric administration of compoundP. ternatawater extract tomicewith cough inducedby inhalationof alkaline air at doses of 0.15, 0.3, and 0.6 g/kg significantlyprolongs the latency of cough (from 17 to 38 s, 43 and 46 s) andreduced the frequency of cough (from 48 to 36, 35 and 33 in3 min) compared with a control group (P b 0.05) [109].
4.5. Antimicrobial, antifungal and antiviral activities
The ethanol extract of P. ternata tubers exhibited pro-nounced antimicrobial activity and pinelloside (67) was theantimicrobial component. P. ternata extract effectively inhibitedthe growth of Gram-positive and -negative bacteria in aconcentration-dependent manner. The MICs (minimum inhib-itory concentrations) on Escherichia coli, Pseudomonas putida,Staphylococcus aureus, Micrococcus luteus, Bacillus subtilis,Saccharomyces pombe, Saccharomyces cerevisiae, Aspergillusniger andMelon fusariumwere 25, 12.5, 12.5, 12.5, 10, 20, 10,12.5 and 25 mg/mL, respectively. However, the bacteriostaticaction against fungi was not clear [110]. The test of antimicro-bial activity against Gram-positive and -negative bacteria aswell as fungi using the agar dilution method indicated thatpinelloside (67) inhibited the growth of bacteria B. subtilis andS. aureus, and fungi A. niger and Candida albicans, with MICs of20, 50, 30 and 10 μg/mL, respectively. However, it showed noinhibition to other test bacteria such as E. coli, Pseudomonasfluorescens and Helicobacter pylori and the fungus Trichophytonrubrum. The MICs of the positive control penicillin G againstbacteria B. subtilis, S. aureus, E. coli, P. fluorescens and H. pyloriwere 0.80, 0.34, 0.56, 1.34 and 0.92 μg/mL, respectively, andthose 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 virusinfection and nasal administrations of vaccines by themselvesprovide insufficient immunostimulation, so the use of safeand effective adjuvants is a nice choice. Pinellic acid (59)with an effective oral adjuvant activity for nasal influenza HAvaccine may be a useful and safe oral adjuvant. Oraladministration of pinellic acid (1 μg) with primary andsecondary intranasal inoculations of influenza HA vaccine(1 μg) and intranasal administration of pinellic acid (1 μg)
with influenza HA vaccine (1 μg) to BALBC mice showed thatthe former enhanced antiviral IgA antibody (Ab) titers 5.2-and 2.5-fold in nasal and bronchoalveolar washes, respec-tively, and antiviral IgG Ab titers 3-fold in bronchoalveolarwash and serum, while the latter slightly enhanced antiviralIgG Ab titers in bronchoalveolar wash and serum but notantiviral IgA Ab titers in nasal and bronchoalveolar washes.Moreover, pinellic acid (59) had more potent adjuvantactivity against nasal influenza vaccine than the knownmucosal adjuvant, the B subunit of cholera toxin containinga trace amount of holotoxin (CTB). The adjuvant activity maybe related to the mononuclear phagocyte system [45,79]. Asubsequent study showed that pinellic acid in combinationwith 9S,12R,13R isomer (defined as PAM) in a weight ratio of90.4:9.6 was regarded as a potent oral adjuvant. Oraladministration of the PAM at a dose of 1 μg/mouse followedby nasal influenza vaccination (1 μg/mouse) and infectionwith A/PR8 (1 μg/mouse) significantly increased the survivalrates (78%) compared with the mice not administered thePAM (22%). The potent adjuvant activity of PAM wassuggested to be associated with the activation of T-cell inPeyer's patch lymphocyte and stimulation of production ofanti-influenza virus IgA antibody in nasal lymphocyte, butthe definite structure–activity relationship in molecular levelneeds to be further studied [111].
4.6. Sedative, hypnotic and anticonvulsive activities
The seizure latency of penicillin (PNC) chronically kindledrats treated with Pinellia alkaloids at doses of 0.5 and 1 g/kgwere 21.8 ± 2.76 and 28.4 ± 3.05 min significantly differedfrom the model group without alkaloids (15.7 ± 2.39 min).Gly and γ-aminobutyric acid (GABA) and Glu receptors arecrucial to the genesis of epilepsy. Pinellia alkaloids (0.5 and1 g/kg) significantly increased the level of GABA (4.78 ± 0.59and 5.21 ± 0.66 μmol/g, respectively) and decreased thelevel 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 antiepilep-tic effect may be related to the above factors [112]. RhizomaPinelliae Praeparatum (EFRP), the product of raw P. ternataprocessed with alkaline solution and Licorice, possessessedative and hypnotic activities. Oral administration of 60%ethanol fraction of EFRP at doses of 8 and 12 g/kg reduced thelocomotion activity ofmicedose dependently from184.0 ± 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 onlyprolonged the sleeping time induced by pentobarbital(45 mg/kg) in mice (P b 0.01), but also increased the numberof mice falling asleep and shortened the sleeping latency(P b 0.05). However, L-malic acid (blocker of syntheticenzyme for GABA) and flumazenil (an antagonist of GABA-A-benzodiazepine receptor) significantly antagonized thesynergistic effects of EFRP on pentobarbital-induced sleeping.EFRP also promote a significant protection to nikethamide-induced convulsion. EFRP at doses of 24 and 48 mg/kgremarkably increased the death latency (P b 0.05) and thehighest dosage reduced the mortality to 80%. Moreover, theanti-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 relatedto the GABAergic system [113,114]. Supercritical CO2
ethanol extract from P. pedatisecta (SEE-CO2PP) at doses of15 and 30 g/kg prolonged the seizure latency in PNC-induced rat dose dependently from 64 ± 11 (control) to145 ± 24 and 162 ± 42 min respectively, and reducedstage V seizure to mild seizure by 30% and 60%. It alsoprolonged the latent period of epileptiform discharge,reduced the frequency and decreased amplitude of thehighest wave in both cortex and hippocampus. Meanwhile,the level of GABA in hippocampus was significantlyincreased by SEE-CO2PP, which suggests that the anticon-vulsive mechanismmaybe related with the increase of GABAcontent [115].
4.7. Other biological activity
Proteins of P. ternata (30 mg/kg) showed significant anti-early pregnancy effect on mice and the anti-early pregnancyrate was 100%. The inhibitory effect on the secretion of ovarianflavonoids and decreased levels of plasmaprogesteronemay beresponsible for miscarriage [116]. Uterus injection of P. ternataproteins at a dose of 500 μg had strong anti-blastocystimplantation effect in rabbits and mice, and the anti-implantation rate was 100%. However, oral administration ofP. ternata proteins showed no described activity. The mecha-nism might be that P. ternata proteins induced the biologicalbehavior of cell membrane to bind some structures of sugar onthe parent or subsidiary body [117].
P. ternata shows a bright future in the therapy of diabetesmellitus induced by dampness–phlegm and its complica-tions. The water extract of P. ternata (PE) mixing with diet toZucker rats once a day (400 mg/kg) for 6 weeks lowered thelevels of triglyceride and free fatty acids (P b 0.05) in blood ofthe obese rats and the body weight was also reduced slightly[118]. The so-called flavone C-glycoside (100 μmol/L) isolatedfrom the rhizomes of P. ternata could inhibit 64.7% of aldosereductase [87,119].
In addition, Pinellia species possess anti-inflammatory,analgesic, anti-arrhythmic, anti-hyperlipidemia activities,and could promote blood circulation, reduce intraocularpressure and prevent the side effects of contrast agent [77,107,120,121].
5. Toxicology
Pinellia species are regarded as poisonous plants due to thecontent of alkaloids and toxic raphides composed of calciumoxalate, proteins and microamount of polysaccharides. Amongthem, the lectins are the major toxic proteins. These constit-uents 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 intraperitonealadministration to mice was 325 mg/kg (crude drug), while theLD50 of suspension of raw P. ternata given by intragastric
administration was 42.7 ± 1.27 g/kg [127]. The acute toxicityof different components of P. ternata showed that themaximum dosage (MLD) values of all-components and waterextract were 34.8 and 300.0 g/kg, and the maximum tolerateddose (MTD) of alcohol extract was 99.2 g/kg. These doseswere equal to 270.7, 2333.3 and 771.6 times of 70 kg people'sdaily dried medicinal herb expenses, respectively. The studydemonstrated that toxic components were mostly in thealcohol soluble part [128]. 75% alcohol-filtered extract and75% alcohol-extracted extract of P. ternata were given to miceby intragastric administration at a dosage of 40 mL/kg for14 days, and the MTD values were 94.4 and 99.2 g/kg/drespectively, which are equal to 734.2 and 771.6 times ofdaily dosage in clinic. Acute toxic tests of P. ternata extractshowed that theMTD values of the acid–water extracted groupand acid–alcohol extracted group were 29.6 and 27.2 g/kg/drespectively, which are equal to 230.2 and 211.6 times ofdosage in clinic, while the LD50 value of the acid–water filtergroup and acid–alcohol filtered group is 14.15 and 14.27 g/kg/drespectively, which are equal to 110.0 and 111.0 times ofdaily dosage in clinic. The high-concentration alcohol extractof P. ternata was rich in total alkaloids and the content oftotal alkaloids in different extracts was: acid–alcohol filteredgroup N acid–alcohol extracted group N acid–water filteredgroup N acid–water extracted group. Therefore, it can beconcluded that total alkaloids are one of the toxic substanceswith an obvious toxicity [129,130]. A previous animal studyindicated that excessive or long-term use of crude P. ternatawould cause renal and liver damage. Intragastric administra-tion of raw P. ternata at a dosage of 0.5 g/kg/day for 40 days torabbits showed no signs of toxicity. However, the majority ofrabbits had diarrhea and half of them died within 20 dayswhen the dose was doubled [127].
5.2. Reproductive toxicity
P. ternata has a significant toxicity on pregnancy maternalmice and embryo. Intragastric administration of raw P. ternatapowder (9 g/kg) and P. ternata decoction (30 g/kg, equivalentto approximately 150 times of clinical dose) to pregnant ratssignificantly increased themortality of early embryo comparedwith control, and the stillborn percentages were 85.7% and50.0%, respectively. Those two dosages also decreased the fetalweight (P b 0.05) and caused colporrhagia of pregnant rats by62.5% 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, renalmalposition, skeletal malformation and variations of fetuses,resulting in visceral malformations (33.3%, 15.7% in a controlgroup), fetus-position variations (15.8%, 4.3% in a controlgroup), asymmetric alignment of ribs (11.1%), dumbbellossification of thoracic centrum (5.0%) and 14th supernumer-ary ribs (12.1%). The study showed that maternal exposure tohigh doses of P. ternata extract might cause fetal abnormalitiesby influencing the expression of antioxidant, growth factor,apoptosis and tumor-related genes [132]. Micronuclei exper-iments showed that P. ternata processed with Ginger (PG) athigh doses (20 and 30 g/kg) significantly increased themicronucleus 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
14 X. Ji et al. / Fitoterapia 93 (2014) 1–17
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 suggestedthat PG has mutagenic effects to a certain extent [133]. Takentogether, it should be with caution when P. ternata is used forthe 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 vocalmucosa and caused inflammation, edema or even aphonia inrabbit, pigeons, guinea pigs, mice, etc. [134]. P. ternata canaffect eye conjunctiva leading to edema, blisters and eyelidmild ectropion [72]. P. ternata was emetogenic and couldinduce diarrhea as well as stomach pain. Intragastricadministration of tubers of P. ternata at a dose of 0.5 g/kgfor 3 days to rats significantly inhibited the activity of pepsin(219.12 ± 29.78 U/mol), and decreased the acidity of gastricjuice (pH = 1.44 ± 0.10) as well as the content of prosta-glandin E2 (PGE2, 167.82 ± 22.26 μg/mL) compared with acontrol group (P b 0.01). Moreover, it also induced seriousdamage of gastric mucosa (damage rate: 75%). The reductionof PGE2 may be the main reason of the gastrointestinalmucosa irritation [135]. The effect of taste stimulation ofP. ternata, Zingiberis rhizoma and their mixture was investi-gated in the anesthetized rats. The result showed that P. ternata(50 mg/mL, 10 min) exhibited an inhibitory effect on vagalgastric 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 gastricnerve activity. Therefore, it is reasonable to prescribe P. ternatawith Z. rhizoma to prevent its suppressive effect on gastricfunction [136]. The irritant toxicity of raphides from P. ternatashows severe inflammation in vivo. The toxic raphides atdoses of 5, 10 and 15 mg/kg significantly enhanced capillarypermeability compared with a control group (P b 0.01). Thecontent of PGE2, nitric oxide (NO) andmalondialdehyde (MDA)in peritoneal exudate of mice treated with the toxic raphidesincreased in a dose-dependent manner. Moreover, it also couldcause toe swelling in rats and significantly increase the contentof PGE2 and cyclooxygenase (COX-2) in toes of rats, whichshowed a typical dose–response relationship in a certain doserange [137]. The irritant toxicity of PTL and PPL purified fromtoxic raphides was measured by the model of rats' peritonealinflammation. Intraperitoneal administration of PTL and PPLcould promote neutrophil migration leading to inflammation,and the content of proteins, PGE2 and NO significantlyincreased in peritoneal exudate compared with a controlgroup (P b 0.01) [124]. The irritant toxicity may be related tothe production of inflammatorymediators induced by the toxicraphides or lectins, but the specific mechanisms still needfurther study.
5.4. Hepatotoxicity
The hepatotoxicity of mice induced by a single intragastricadministration of water extraction and percolation liquidof acid from Rhizoma Pinelliae was detected with alanineaminotransferase (ALT) and aspartate aminotransferase
(AST) as evaluation index. The activities of serum ALT andAST are changing with the time, and its toxic peak appears atthe 4th hour after administration (at a dose of 62.5 g/kg) andlast for about 48 h. The activities of serum ALT and AST ofhigh dosage groups (82.5, 70.1 and 59.6 g/kg) were signifi-cantly increased in comparison with the normal group, andhydroncus, fatty degeneration and necrosis in hepatocytealso appeared. The results indicated that a single intragastricadministration of water extraction might induce acutehepatotoxic injury in mice with an obvious “dosage–time–toxicity” relationship. The study on time–toxicity relation-ship caused by single dosage percolation liquid of acid fromRhizoma Pinelliae to mice showed that the ALT and AST levelsin serum were peaked after 2 hours' administration and lastfor about 48 h. Compared with the normal group, ALT andAST levels increased significantly with the increased dosage.Groups at high dosage (2.68, 2.14 and 1.72 g/kg) havedifferent levels of edema and fatty degeneration in livercells, and appear to be necrosis, lobular structure unclear. Itcan be concluded that percolation liquid of acid extract in asingle 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 Pinelliaremain inadequate, so further studies are needed to confirmthe 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 onthe two species have led to the isolation of alkaloids, lectins,fatty acids, cerebrosides, volatile oils and other constituents.However, the relationships of these biologically producedchemicals to other Pinellia species have not been investigat-ed. Therefore, a comprehensive investigation on phytochem-istry is necessary to provide information on taxonomicrelationships within Pinellia.
Pinellia species have long been used in traditional medicinefor the treatment of cough, vomiting, inflammation, epilepsy,cervical cancer and traumatic injury.Modern in vitro and in vivopharmacological studies have increasingly confirmed thetraditional use of Pinellia species. These species possess manykinds of pharmacological properties, ofwhich the cytotoxic andanti-tumor activities of alkaloids and lectins are the mostpotential bioactivities, while the antimicrobial, antifungal,insecticidal activities and the adjuvant activity are worthy ofbeing exploited. Moreover, the reproductive toxicity, mucosalirritation and hepatotoxicity of the genus have received moreattention in recent years.
According to the literature, the most recent pharmaco-logical studies were carried out on an uncharacterized crudeextract of Pinellia, thus the isolation of a single compound isnecessary for the desired pharmacological activities withoutside effects, and more precise studies to elucidate thebioactivities' mechanisms of action are needed. Furthermore,due to the toxicity, the dosage–effect and –toxicity should befurther investigated to determine the maximum tolerated
15X. Ji et al. / Fitoterapia 93 (2014) 1–17
dose and the proper pharmaceutical formulation. Finally,systemic methods to control the quality of medical materialsand preparations on the basis of the active and toxiccomponents are also needed. Based on the review of thisarticle, it is anticipated that the genus Pinellia is of greatimportance in medicinal applications and its phytochemical,pharmacological and toxicological studies will reach a newstage in future.
Conflict of interest
We declare that there is no conflict of interests.
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