Traditional Chinese Herbal Medicine Penthorum chinense Pursh: A Phytochemical and Pharmacological Review.

The American Journal of Chinese Medicine, Vol. 43, No. 4, 601–620 © 2015 World Scientific Publishing Company Institute for Advanced Research in Asian Science and Medicine DOI: 10.1142/S0192415X15500378

Am. J. Chin. Med. 2015.43:601-620. Downloaded from www.worldscientific.com by UNIVERSITY OF IOWA on 08/09/15. For personal use only.

Traditional Chinese Herbal Medicine Penthorum chinense Pursh: A Phytochemical and Pharmacological Review Anqi Wang, Ligen Lin and Yitao Wang State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau, China Published 29 June 2015

Abstract: Penthorum chinense Pursh (Ganhuangcao), a traditional Chinese medicine, is used for the prevention and treatment of liver diseases, including hepatitis B, hepatitis C, and alcoholic liver damage. A wide range of investigations have been carried out on this herbal medicine from pharmacognosy to pharmaceuticals, as well as pharmacology. The extract of P. chinense was reported to have significant liver protective effects through anti-oxidation, reduction of key enzyme levels, inhibition of hepatitis B virus DNA replication, and promotion of bile secretion. Based on the current knowledge, flavonoids and phenols are considered to be responsible for P. chinense’s bioactivities. The main purpose of this review is to provide comprehensive and up-to-date knowledge of the phytochemical and pharmacological studies performed on P. chinense during the past few decades. Moreover, it intends to provide new insights into the research and development of this herbal medicine. Keywords: Penthorum chinense Pursh; Phytochemistry; Pharmacology; Liver Protection; Anti-Hepatitis Virus; Alcoholic Liver Damage; Anti-Oxidation; Review.

Introduction Penthorum chinense Pursh (PCP), Ganhuangcao in Chinese, is a plant from the family of Penthoraceae (Flora of China Editorial Committee, 2001), which is widely distributed in China (Feng et al., 2003; Chi et al., 2009; Hu et al., 2009). The whole grass of PCP has been used in the region of the Miao nationality for thousands of years. According to the narration of local people, the alcoholic people who sometimes drank the water decoction of this plant were protected from liver injury resulting from the intake of excessive alcohol. Correspondence to: Dr. Ligen Lin and Prof. Yitao Wang, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China. Tel: (þ853) 8822-8041, E-mail: [email protected] (L. Lin), [email protected] (Y. Wang)

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A. WANG, L. LIN & Y. WANG

Currently, PCP extract is involved in about 80 Chinese patents of food or health products used for liver protection and treatment of liver diseases. Due to its wide clinical use, more and more investigations have been carried out on this plant in recent years, from pharmacognosy (Flora of China Editorial Committee, 2001; Wei et al., 2012) to pharmaceuticals (Yu et al., 2011; Xiang et al., 2013) as well as pharmacology (Lu et al., 2012; Yu et al., 2012). Both clinical and basic studies have observed that the water extract of PCP is responsible for treatment of hepatitis B (Zhao et al., 2002; Zhu et al., 2009; Yu et al., 2012), hepatitis C (Xiao et al., 1999), hepatocarcinoma (Lu et al., 2012; Kapoor, 2013), and other related liver injuries (Yuan et al., 2011; Lu et al., 2012). Phytochemical studies identified dozens of bioactive constituents from PCP, including flavonoids, polyphenols and steroids (Feng et al., 2001; Deng and Yang, 2007; Huang et al., 2014; Wang et al., 2014). However, research progress of PCP has rarely been summarized. The current review seeks to lead readers to better understanding of this herbal medicine and provide comprehensive information for better research and development of PCP. Medicinal Resources PCP is distributed in most of China, including Sichuan, Shanxi, and Guizhou Provinces (Feng et al., 2003). Gulin county (Sichuan Province) is considered to be the geo-authentic habitat of PCP (Chi et al., 2009). The best harvest time of PCP is the flowering or fruiting phase in summer or autumn since the contents of total flavonoids or quercetin reach to the maximum amount (Yu et al., 2010; Sun et al., 2013). The whole grass of PCP could be used for medical purposes, and the stems of PCP are commonly used for preparations (Fig. 1). The leaves are especially made into tea or drinks. Morphological characteristics of PCP are described as follows: (1) perennial herbs grow in forests, scrub meadows, wet places along rivers in lowlands, by water; large, 40–65(90) cm tall; rhizome branched; stems usually simple, rarely branched at base, proximally glabrous, distally sparsely brown glandular hairy; (2) leaves sessile or subsessile; leaf blade lanceolate to narrowly so, 4–10 cm 4–12 mm, glabrous, margin serrulate, apex acuminate; (3) cyme 1.5–4 cm;

(A)

(B)

Figure 1. The morphological character of original material of PCP (A, stems of P. chinense; B, inflorescences and leaves of P. chinense).

PENTHORUM CHINENSE AS A LIVER PROTECTIVE MEDICINE

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branches brown glandular hairy; bracts ovate to narrowly so, small; pedicels 1–2.2 mm, brown glandular hairy; (4) Flowers yellowish, small; (5) Sepals 5, triangular, ca. 1:5 1:1 mm, leathery, glabrous, 1-veined; (6) Petals 5 or absent; (7) Stamens 10, ca. 2.5 mm. Pistil ca. 3.1 mm; carpels 5 (or 6), connate near base; ovary 5/6-loculed; styles 5 (or 6); (8) Capsule red-purple, 4–5 mm in diameter; (9) Seeds ovoid-oblong, tuberculate (Flora of China Editorial Committee, 2001). Microscopic identification of PCP powder: (1) stems, developed aerenchyma, broad hip account for about 1/3 of the transverse section; (2) radially arranged vascular bundle. Powder characteristics are consistent with organizational characteristics (Ou et al., 2010; Zhu et al., 2010). Chemical Constituents Phytochemical investigation is extremely important in exploring bioactive principles of herbal medicine. According to the preparation process of Gan-Su granules, consisting of PCP extract and other excipients, the water soluble constituents were the main focus of most studies. Until now, many studies have been conducted to identify about 30 compounds from PCP, including flavonoids, flavonoid glycosides, phenylpropanoids, organic acids, phenols and steroids (Table 1). Among them, flavonoids and flavonoid glycosides account for the major constituents (Chen et al., 1998; Zhang et al., 2007; Lu et al., 2012; Fu et al., 2013; Wang et al., 2014; Huang et al., 2014). Besides, several bioactive phenols were isolated and identified (Lu et al., 2012; Fu et al., 2013; Huang et al., 2014). In addition, some phenylpropanoids, organic acids, and steroids were also reported (Zhang et al., 2007; Fu et al., 2013). Terpenoids, volatile oil, and polysaccharide were reported in this plant, which were not summarized in this review due to the lack of a corresponding pharmacological effect (Feng et al., 2003; Deng et al., 2009). Pharmacological Activities Anti-Oxidation It is increasingly recognized that reactive oxygen species (ROS) play a key role in pathogenesis of liver diseases (Nishida and Kudo, 2013; Wang et al., 2014). Excessive ROS results in significant damage to biological structures required for cellular integrity and survival. It has long been recognized that some naturally occurring substances in plants possess anti-oxidative activity, which could be beneficial for scavenging ROS in vitro or in vivo. Many chemical based methods have been developed to determine antioxidative capacity of compounds or extracts from traditional Chinese medicines, such as hydroxyl radical averting capacity (HORAC) (Antolovich et al., 2002), trolox equivalent anti-oxidant capacity (TEAC), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging assay (ABTS), Folin–Ciocalteu method, oxygen radical absorbance capacity (ORAC) (Prior et al., 2005) and diphenylpicrylhydrazyl (DPPH) radical scavenging ability assay (Jara et al., 2008; Milan et al., 2010). He et al. tested the radical scavenging ability of PCP extracts prepared by different methods using a DPPH assay, and found that the ethyl

1

Flavonoids/ glycosides

4

3

2

No.

Categories

HO

R1

OH

R2

O

O

O

O

R1

R2

OH

R1¼OH R2¼H

R1¼O–Glc R2¼O-Me

R1¼O–Glc R2¼OH R1¼OH R2¼OH

Substituent

Pharmacological/ Clinical Effects

Molecular Mechanism(s)

References

(Wang et al., 2014) 5-methoxy-pinocembrin-7-O-β-D-glucoside kaempferol Anti-inflammation; Inhibition of STAT-1 and NF-κB acti- (Sloley et al., 2000; Antidiabetes; Anvations, iNOS expression and NO Kowalski et al., ticancer production; Modulate COX-2 and 2004; GarcíaCRP expression, NF-κB; Modulate Mediavilla et al., IL-1β; Partial agonists of prolifera2007; Hämäläition-activated receptor gamma nen et al., 2007; (PPAR); ROS-Bcl-2-caspase-3/ Fang et al., 2008; cleaved PARP; Inhibition of PFu et al., 2013; Glycoprotein function and expresLimtrakul et al., sion 2013)

(Fu et al., 2013) pinocembrin-7-O-β-Dglucopyranoside pinocembrin Vasorelaxant; Neuro- Endothelium-dependent (NO-cGMP) (Guang and Du, 2006; protection; Cogand endothelium-independent pathZhu et al., 2007; nitive improveGao et al., 2008; way (K þ /Ca 2þ channels); Reduce ment Liu et al., 2008; ROS, iNOS, increase glutathione, Fu et al., 2013) down-regulation of Caspase-3, decrease poly-ADP-ribose polymerase (PARP) degradation; p53-Bax–Bcl2cytochrome c; Decrase brain mitochondria ROS

Name

Table 1. Summary of Compounds Isolated from PCP


604 A. WANG, L. LIN & Y. WANG

Categories

HO

OH

O

R1 OH

10

9

O

R1¼O-Rha R2¼OH R1¼O-Xyl R2¼OH

7

R1¼H

R1¼OXyl! Gal R2¼OH

2

R1¼O–Rha R2¼H

6

8

R1¼OH R2¼OH

Substituent

5

No.



References

Anti-inflammation; Inhibition of STAT-1 and NF-κB acti- (García-Mediavilla Antidiabetes; Anvations, iNOS expression and NO et al., 2007; ticancer production; Modulate COX-2 and Hämäläinen CRP expression, NF-κB; Partial et al., 2007; Fang agonists of PPAR; Inhibition of Pet al., 2008; Fu Glycoprotein function and expreset al., 2013; sion Limtrakul et al., 2013) kaempferol-3-O-α-L- Antileishmanial; (Matsuda et al., 2002; Inhibition of TNF-α production, derhamnopyranoMuzitano et al., Hepatoprotection crease sensitivity of hepatocytes to side 2006; Fu et al., TNF-α, and protection of hepato2013) cytes against D-galactosamine (dGalN) quercetin-3-α-L(Chen et al., 1998) rhamnoside quercetin-3-O(Wang et al., 2014) β-D-xyloside Antidiabetes; Inhibi- Inhibition of α-Glucosidase; Down-reg- (Jong-Anurakkun quercetin-3-O-β-Dxylopyranosyltion of TG accuulation of PPAR, CCAAT/enet al., 2007; An (1!2)-β-D-galacmulation hancer-binding protein α (CEBP/α) et al., 2011; topyranoside and aP2 Kumar et al., 2011; Fu et al., 2013) apigenin Anticancer; AntiInhibition of extracellular signal-regu- (Liang et al., 1999; inflammation lated kinase (ERK) mitogen-actiWang et al., vated protein (MAP) kinase 1999; Yin et al., phosphorylation; Suppression of 2000; Zhang inducible cyclooxygenase and et al., 2007) iNOS; ROS-cytochrome c-caspase3-cleaved PARP pathway

quercetin

Name

Table 1. (Continued)


PENTHORUM CHINENSE AS A LIVER PROTECTIVE MEDICINE 605

Organic acid

Categories

O

R1¼H R2¼OH

OH

R1¼OMe R2¼H

15

O

OH

OH

R1¼OH R2¼OH

R2

OH

HO

R1

HO

OH

R1¼OH

Substituent

14

13

12

11

No.

protocatechuic acid

gallic acid

vanillic acid

catechin

luteolin

Name

Table 1. (Continued) Molecular Mechanism(s)

References

Anticancer; Hepatoprotection; antioxidation; antiinflammation

Anti-oxidation; anti-inflamation; anticancer

(Aruoma et al., 1993; Scavenging of superoxide anions, Kroes et al., inhibition of myeloperoxidase 1993; Inoue release and interference with et al., 2000; Fu NADPH-oxidase; Enhancement of et al., 2013) intracellular ROS and increase intracellular Ca 2þ levels Decrease of hypophosphorylated reti- (Cuvelier et al., 1992; noblastoma and down-regulation of Tseng et al., Bcl-2 2000; Liu et al., 2002; Guan et al., 2006; Fu et al., 2013)

Anti-oxidation anti- Suppression of the NF-κB pathway and (Kim et al., 2000; inflammation; inhibition of pro-inflammatory subHorinaka et al., anti-allergy; stances; inhibition of alpha-glucosi2005; Zhang Antidiabetes; Andase and amylase; up-regulation of et al., 2007; Seeticancer death receptor 5 (DR5) linger et al., 2008) Anti-oxidation; (Mangiapane et al., reduction of plas1992; Matsumoto ma glucose et al., 1993; Yillevels; inhibit oxmaz and Toledo, idation of LDL 2004; Fu et al., 2013) Hepatoprotectiion Suppression of inflammatory cytokines (Itoh et al., 2009; TNF-α, interferon-gamma and IL-6 Fu et al., 2013)




Phenols

20

19

HO

HO HO

HO

HO

HO

HO

O

O

O

OH

O

O

O

OH

O

OH

O

R2

OH

OH

OH O

Glc-O

O

OH

O

OH

R1¼OH R2¼O-Gall

O

OH O

R1¼OH R2¼OH

18

HO

MeO

R1

R1¼O-Gall R2¼OH

16

Phenylpropanoids

Substituent

17

No.

Categories

Hepatoprotection; antifungi; Antidiabetes; antihypolipidemic and anti-oxidation


Thonningianins A

Anti-oxidation; anticancer

26-dihydroxAnti-oxidation; DNA yacetophenon-4damage protecO-β-D-glucoside tion

11-O-galloylbergenin Analgesic and anti-inflammatory activities; antioxidation; anti-plasmodial activities 4-O-galloylbergenin antibacteria

bergenin

Name


Inhibtion of glutathione S-transferases



(Gyamfi and Aniya, 2002; Gyamfi et al., 2004; Lu et al., 2012)

(Bajracharya et al., 2012; Fu et al., 2013) (Chen et al., 1998; Gao et al., 2012)

(Arfan et al., 2010; Fu et al., 2013; Uddin et al., 2014)

(Prithiviraj et al., 1997; Lim et al., 2000; Kumar et al., 2012; Fu et al., 2013)

References


Categories

23

22

21

No.

HO

HO

HO

HO

HO

O

O

O

O

O

O

O

O

OH

HO

O

O

O

OH

O

OH

O

OH

O O

OH

OH

O

O

O

HO HO

O

HO

HO

HO

O

OH

HO OH

O

HO

HO

HO

HO

HO HO

O

O

OH

OH

OH O

O

OH O

O

OH

OH

Substituent


2,6-dihydroxyacetophenone4-O-[4 0 ,6 0 -(S)hexahydroxydiphenoyl]β-D-glucose

penthorumin C

Pinocembrin-7-O-[3- Antiproliferation O-galloyl-4 00 ,6 00 hexahydroxydiphenoyl]β-glucose

Name

Table 1. (Continued) Molecular Mechanism(s)


(Huang et al., 2014)


(Lu et al., 2012)

References


26

25

24

No.

HO

HO

HO

HO

O

O

O

O

O O

O

H H

O

OH

OH

H

OH

HO

O

OH

O

OH

OH

O

HO

O

HO HO

HO

HO HO

OH O

OH

OH O

O

Substituent

β-sitosterol

thonningianin B

pinocembrin-7-O[4 00 ,6 00 -hexahydroxydiphenoyl]β-D-glucose

Name

Anticancer

Anti-oxidation; Antiproliferation


(Ohtani et al., 2000; Huang et al., 2014)


References

Activation of the sphingomyelin cycle; (von Holtz et al., induction of Bax and activition of 1998; Choi et al., caspases 2003; Zhang et al., 2007)


Notes: Me — CH3; Glc — β-D-glucopyranosyl; Gal — β-D-galactopyranosyl; Rha — α-L-rhamnopyranosyl; Xyl — β-D-xylopyranosyl; Gall — galloyl.

Sterol

Categories





610


acetate fraction of 95% ethanol PCP extract showed the strongest radical scavenging ability (He et al., 2009c). In 2012, Gao et al. determined the anti-oxidative activity of 75% ethanol PCP extract using DPPH, ABTS, and hydroxyl radical scavenging assay, as well as a lipid peroxidation inhibitory assay. The results showed that the PCP extract had strong capabilities in radical scavenging and lipid peroxidation inhibition, which might be linked to its DNA damage protective activity (Gao et al., 2012). In addition, Zeng et al. found 60.89% ethanol enriched flavonoids contents at 7.19% in PCP extract, which showed significant radical scavenging effects compared with vitamin C (Zeng et al., 2013). Further investigations demonstrated that compounds 21 and 22 (Table 1), isolated from the ethyl acetate fraction of 70% ethanol extract of PCP, exhibited more potent anti-oxidative ability than other compounds using DPPH assay and ferric reducing/anti-oxidant power (FRAP) assay (Lu et al., 2012). Combined together, PCP possesses significant anti-oxidative activity, which might be due to flavonoid and polyphenol constituents. Anti-Hepatitis Virus China is the highest carrier prevalence of hepatitis B virus (HBV) in the world: nearly 10% of the general population, and the rate of hepatitis C virus (HCV) infections is also increasing in an alarming speed. The disease burden of HBV and HCV infections is likely to be substantial (Tanaka et al., 2011). The ultimate goal in treatment of hepatitis is to eradicate the virus before irreversible liver damage occurs. Unfortunately, few agents are available that are efficacious, economic and safe enough to fully eradicate HBV or HCV. In China, different medicinal preparations with PCP have been clinically used for the treatment of chronic active hepatitis, hepatitis B, as well as acute viral hepatitis for a long time. Many researches have been conducted on the effects of PCP extract or combination of PCP with other drugs for treatment of hepatitis virus. In 1999, Xiao and his colleagues reported the anti-HCV effect of Gan-Su capsules (Xiao et al., 1999). Zhao et al. tested the anti-HBV effect of PCP extract on HepG2.2.15 cells, which demonstrated that the inhibition rate of hepatitis Be antigen (HBeAg) was 54.09% and therapeutic index (TI) was > 2 at concentration of 57 g/ml (Zhao et al., 2002). According to the clinical report by Chen et al., the concentration of alanine aminotransferase (ALT), asparate aminotransferase (AST), hepatitis Bs antigen (HBsAg) and HBeAg as well as the amount of HBV DNA in 90 HBV patients’ plasma were significantly reduced when administration of Gan-Su granules for three months (Chen et al., 2004). In clinical practice, the PCP products also combined with other western medicines for better potency, such as pegasys and adefovir dipivoxil (Zhu et al., 2009; Mo and Wang, 2013). The studies showed that Gan-Su granules had beneficial effects on improvement of liver function, inhibition of HBV DNA replication as well as reduction of the side effects when combined with other medicines. Until now, many evidences, both basic and clinical studies, have demonstrated PCP extracts and its related preparations could be well developed for treatment of viral hepatitis (Yu et al., 2012). However, the chemical principles and underlying mechanisms of PCP for the treatment of viral hepatitis remain unknown.


611


Alcoholic/Non-Alcoholic Liver Protection and Choleretic Effects Many factors, including excessive alcohol intake (Bellentani et al., 1997), drugs, hepatitis virus infection, high fat diet and autoimmune disorders, can cause liver inflammation and damage (Friedman, 1997; Albanis and Friedman, 2001). In cells, both internal and external factors can induce the release of some cytokines and chemokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-12, inducible nitric oxide synthase (iNOS), transforming growth factor-β (TGF-β) and ROS, which could activate hepatic stellate cells (HSC), induce kupffer cells infiltration, and further lead to liver fibrosis, cirrhosis and carcinoma (Dixon et al., 2013; Friedman, 1997; Li and Friedman, 1999; Bataller and Brenner, 2005). Previous studies demonstrated that iNOS, cyclooxygenase-2 (COX-2) and reactive C-protein (CRP) protein levels in Chang liver cells could be significantly decreased by quercetin and kaempferol, respectively (García-Mediavilla et al., 2007). In the Sprague-Dawley rats bile duct ligation model, it was also reported that quercetin had hepatoprotective, anti-inflammatory and antifibrotic effects on cholestatic liver injury, in which the expressions of TGF-β1, nuclear factor kappa B (NF-κB), IL-1β and collagen were attenuated by daily consumptions of quercetin for 4 weeks (Lin et al., 2014). These results suggested that flavonoids in PCP might play a key role in liver protection. According to related reports, excessive and long term consumption of alcohol account for about 40% of liver damage patients (Bellentani et al., 1997). Hence, the liver protective effect of PCP from alcoholic damage is attracting more and more investigations. Yin’s study found that the duration of drunkenness and the concentration of alcohol in the blood were significantly decreased by the administration of PCP water extract, which suggested PCP might alleviate alcohol intoxication (Yin et al., 2000). Yuan’s studies showed that the serum concentrations of ALT, AST, total cholesterol (TC), and triacylglycerol (TG) in alcoholic fatty liver rats were significantly reduced by the administration of PCP extract for 6 weeks, which demonstrated that it has preventive effect on alcoholic fatty liver (Yuan et al., 2011, 2012). In addition, it was reported that the concentrations of ALT, total bilirubin (TBIL), TC, and TG in serum, as well as TG and non-esterified fatty acid (NEAF) in liver tissue were significantly decreased after the administration of PCP extract in nonalcoholic fatty liver mice model. Moreover, the concentration of high density lipoproteincholesterol (HDL-C) in serum and the activity of glutathione peroxidase (GSH-Px) in the liver were significantly increased by the administration of PCP extract for 9 weeks. These results indicated that PCP extract might be beneficial for the treatment of non-alcoholic fatty liver in the regulation of lipid metabolism and protection from oxidant damage (Xiao et al., 2014). Another study showed PCP extract negatively regulated the level of TBIL and the activities of alkaline phosphatase (ALP), glutamyl transpeptidase (GGT), AST, and ALT in serum in alpha-naphthyl-isothiocyanate-induced cholestasis and the ligating common bile duct induced obstructive jaundice mouse model, which indicated that PCP had potent effect on choleretic and jaundice relief (Zhang and Huang, 2008). The underlying molecular mechanisms for the liver protective effects of PCP extract were also clarified. In He’s study, the authors showed that PCP extract down-regulated the expression of collagen I, α-smooth muscle actin (α-SMA) and extracellular regulated protein kinases

612


(ERK) phosphorylation through the inhibition of the ERK signal transduction of TGF-β1 in HSC (He et al., 2009a). Huang et al. isolated polyphenols from PCP and found compounds 21 and 24 showed significant anti-proliferative activity on platelet derived growth factor (PDGF) induced HSC-T6 cells with IC50 values of 19.2 and 12.7 M, respectively, which might have beneficial effects for the treatment of liver fibrosis (Huang et al., 2014). Based on the above studies, the liver protective effects of PCP are well documented. Further researches might be performed to better understand the chemical principles and other possible mechanisms of liver protection in different models.


Other Effects Besides the above reports, Gao et al. reported that PCP extract inhibited DNA damage in vitro and showed an antimutation effect (Gao et al., 2012). Lu et al. reported compounds 21 and 22 from PCP possessed anti-proliferative activity on hepatoma cell SMMC-7721 (Lu et al., 2012). However, the underlying molecular mechanisms for the anti-hepatocarcinoma activity of these components need to be further investigated. Separation and Analysis Technologies Separation Technologies To ensure the pharmacological effects and quality control of PCP, many efforts have been made to determine potential bioactive components and optimize the extraction process. Different extraction and analysis technologies were developed for different objectives. According to the preparation process of Gan-Su granules recorded in Drug standard of Ministry of Public Health (Chinese Medicine 13th Volume, WS3-B-2526-97), the decoction and 60% alcohol precipitation method were used for the extraction and preparation of the raw material. Due to the content of quercetin ruled both in raw materials and preparations, the recovery rate of quercetin in PCP was mainly selected as an index in the process of extraction and optimization (Yu et al., 2011; Tian et al., 2006; Xin et al., 2009). Besides, the recovery rates of gallic acid, quercetin as well as total flavonoids were also considered as indexes for extraction process optimization (Yuan et al., 2011; Xu et al., 2012; Xiang et al., 2013). Some traditional methods, such as heating reflux, sonic and percolation, were also used for the extraction of flavonoids in PCP. About 50–80% ethanol was usually used for extraction of flavonoids in PCP. Recently, a new separation technology, CO2 supercritical fluid extraction, was developed for the extraction of flavonoids in PCP, which possessed the inherent merit of high purity, stability for products and with no heavy metal (Zhang et al., 2013). The advantages and disadvantages of different separation technologies for the extraction of PCP are listed in Table 2. Analysis Technologies The content of flavonoids is usually selected as an object for quality control and evaluation of PCP extract and preparations since they are considered the main bioactive constituents.

CE

HPLC/UV

HPLC/ELSD

Method

High recovery rate of total flavone and quercetin; high purity, stability for products and with no heavy metal

CO2 supercritical fluid extraction

(Chen et al., 2009)

Advantage

Low sensitivity for determination of trace compounds Constituents with no or poor UV absorption cannot be determined Constituents with no or poor UV absorption cannot be determined

Disadvantage

(Ganzera and Stuppner, 2005; Liu, 2006) (Shang et al., 2005; Xu et al., 2007; Limtrakul et al., 2013) (Bellentani et al., 1997; Liu et al., 2010)

References

(Zhang et al., 2013)

Time consuming Big proportion of ethanol (70%); high pressure; costly equipment

(Xin et al., 2009) (Xu et al., 2012)

References

Big proportion of ethanol (82%) Big volume (26 times, w/v) of ethanol

Disadvantage

Table 3. Advantages and Disadvantages of Analysis Technologies for Compounds in PCP

Percolation extract

High recovery rate of quercetin Fractions account for the strongest anti-oxidant capacity were extracted High recovery rate of gallic acid

Heating reflux extract Sonic extract

Advantage

Constituents with no or poor UV absorption can be determined High performance and sensitivity for determination of flavonoids and phenols Combined with the characteristic of speed, quantitation, and reproducibility; High performance and sensitivity for determination of flavonoids and phenols

Non-solvent extract

Solvent extract

Method

Table 2. Advantages and Disadvantages of Separation Technologies for Extraction of PCP




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HPLC-UV method was usually used to determine the content of flavonoids (Shang et al., 2005; Xu et al., 2007; He et al., 2009b), which have specific and strong UV absorption at 270 and 365 nm (Marston and Hostettmann, 2006; Du et al., 2011). However, some constituents in PCP could not be detected by UV due to their poor absorption or relatively low content. Liu developed a HPLC-ELSD method for the detection of quercetin in GanSu granules (Liu, 2006). Due to the disadvantage of low sensitivity of ELSD, this analysis technology might be not suitable for determination of flavonoids in PCP (Ganzera and Stuppner, 2005). Capillary electrophoresis (CE) was another powerful analytical technology used for the determination of rutin and quercetin in PCP preparations, which brings speed, quantitation, and reproducibility together (Grossman and Colburn, 1993; Liu et al., 2010). Fingerprint technology, possessing the character of integrality and vagueness, is very popularly used in quality control of herbal medicines. To better quality control and scientifically validate the selected medicinal parts of PCP, a HPLC based fingerprint method was applied, and results demonstrated that there was significant difference between stems and leaves in the chemical profile (Han et al., 2013). The advantages and disadvantages of analysis technologies used for determination of compounds in PCP are briefly summarized in Table 3. Conclusion PCP and its preparations (Gan-Su) are widely used for the treatment of liver damage induced by oxidant, hepatitis virus and alcohol, etc. Though there are increasing reports about the chemical components of PCP, the underlying mechanisms and potential biological targets remain unknown. The water soluble components in PCP are considered to be responsible for protecting liver from injury. According to some pharmacological studies, the bioactive components of PCP were inferred to be flavonoids. Some other studies identified several polyphenols from PCP, which also contributed to the pharmacological effects. To better understand the chemical principles of this herbal medicine, it is advised to identify bioactive components of PCP using bioassay guided isolation strategy, which organically combines pharmacological assay and phytochemical study together. Additionally, more efforts should be made to elucidate underlying mechanisms of PCP for treatment of hepatic virus, liver protection as well as anti-hepatocarcinoma. Both well-conducted chemical and pharmacological studies on PCP will bring great benefit to better quality control of this herbal medicine on the basis of bioactive compounds. Although we’re facing huge difficulties and challenges in studies of PCP nowadays, this review might be helpful to point out the direction of further investigation, enlighten practical use of PCP and eliminate the gap for modernization of PCP, which is an urgent priority in today’s TCM development. Acknowledgments Financial support by the Macau Science and Technology Development Fund (074/2012/ A3) and the Research Fund of University of Macau (MRG013/WYT/2013/ICMS and MYRG2014-00020-ICMS-QRCM) are gratefully acknowledged.


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