Cistanches Herba:Chemical Constituents And Pharmacological Effects

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Lin–lin Wang et al

ABSTRACT

Cistanches Herba, known as 'Ginseng of the desert', is authenticated from the dried succulent stems of Cistanche deserticola and Cistanche tubulosa. As a famous remedy in China for tonic the kidney, it is used to treat 'kidney-deficiency syndrome' -induced diseases such as infertility, forgetfulness, hearing loss, chronic constipation, etc. As various biological activities, including anti-aging, antioxidant, estrogenic, anti-osteoporotic, and anti-inflammation effects, have been discovered, here we reviewed Cistanches Herba in biological characteristics, chemical constituents, and pharmacological activities.

Keywords
bioactive constituents; Cistanches Herba; pharmacological effects

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1 Introduction

Cistanches Herba is dried succulent stems of Cistanche deserticola Y. C. Ma and C. tubulosa (Schrenk) Weight, belonging to Cistanche Hoffman. et Link in the Orobanchaceae family. It is a well known Chinese materia medica (CMM) for the treatment of kidney deficiency, infertility, and chronic constipation (Pharmacopoeia Committee of P. R. China, 2010) that was first described in Shen Nong’s Herbal Classic as a top-grade medicine followed by several classical works, such as Bencao Jingshu, Bencao Huiyan, and Yue Hua Zi Bencao. Cistanches Herba is a remedy of over 2000 years old in China which is for tonifying the kidney (Zhang et al, 1994) and invigorating the Yang (Leong et al, 2015; Jiang et al, 2005), next to ginseng in rank. Also, it can enrich and nourish essence and blood, moisten dryness, and so on. It was used to treat impotence, infertility, waist and knee crymodynia, and constipation induced by blood exhaustion.

The original plants of Cistanches Herba are parasitic to the plants in the genus Cistanche Hoffman. et Link including around 20 species widely spread in warm drily regions of Europe and Asia, from the Iberian Peninsula to northern Africa, Arabia, Iran, Afghanistan, Pakistan, northern India, ex-Soviet Central Asian state, Mongolia, and northwest of China. In China, there are four main species such as C. deserticola in Inner Mongolia, Gansu province, and northern Xinjiang Uygur Autonomous Region, C. salsa (C. A. Mey.) G. Beck in Inner Mongolia, Gansu and Qinghai provinces, Ningxia Hui Autonomous Region, and Xinjiang Uygur Autonomous Region, C. tubulosa in southern Xingjiang Uygur Autonomous Region, and C. Sinensis G. Beck in Inner Mongolia, Gansu, Qinghai, and Ningxia Hui Autonomous Region, and a variant species C. salsa var. albiflor P. F. Tu et Z. C. Lou in Ningxia Hui Autonomous Region and Xinjiang Uygur Autonomous Region. In addition, due to a special ability of hardiness and drought resistance, it is mainly distributed in the north latitude of 36°í37° and dotted in the region from east to west across Inner Mongolia, Shaanxi, Gansu, Qinghai provinces, Ningxia Hui, and Xinjiang Uygur Autonomous Regions (Chen et al, 2005; Shi et al, 2009).

Here we reviewed Cistanches Herba in bioactive compounds, pharmacological effects, and other aspects, which may be a reference to further study and use of this drug.

2 Chemical constituents

There are various bioactive constituents in the stems of the plants in the genus Cistanche Hoffman. et Link including phenylethanoid glycosides (PhGs), polysaccharides, oligosaccharides, galactitol, volatile components, iridoids, lignin, and its glycosides, flavonoids, alkaloids, etc (Table 1).

2.1 Phenylethanoid glycosides

Phenylethanoid glycosides (PhGs) are the major bioactive components in Cistanche species including cinnamic acid, ȕ-glucopyranose, and hydroxyphenylethyl moieties, connected by ester and glycosidic linkages.

Saccharides of PhGs are only composed of glucose (Glc) and rhamnose (Rha), and the center glucose is connected with aglycone directly. In addition, the structures of PhGs are classified as follows: Glc commonly links directly with the aglycone with a (3 ĺ 1) Rha linkage, and a

coumaroyl or caffeoyl is usually located at C-4 or C-6 of Glc. Furthermore, an additional Glc or Rha usually are attached at C-6 of the inside Glc when PhG is a trisaccharide glycoside, such as ferulic acid or coumaroyl benzene acryloyl group (Tu et al, 1997; Liu et al 2011; Morikawa et al 2010; Liu et al 2013; Nan et al 2013). PhGs mainly consist of echinacoside (ECH), acteoside, isoacteoside, 2'-acetylacteoside, decaffeoy- lacteoside, cistanosides A-E, G, and H, 2ƍ-acetylcistanoside C, isocistanoside C, tubulosides A-E, isotubuloside E, cistantubuloside A, cistantubuloside B1, B2, cistantubuloside C1, and C2, salsasides D-F, kankanosides F-G, osmanthuside B, 2'-acetyl-osmanthuside, cistansinenside A, syringalide A, 3'-α-L-rhamnopyranoside, isosyringalide A 3'-α-L-rhamnopyranoside, salidroside, crenatoside I, jionoside D, poliumoside, eutigoside, pheliposide, and campneosides I and II (Figure 1).

2.2 Saccharides

Saccharides occupy a high proportion of Cistanche species, among which polysaccharides, oligosaccharides, and galactitol are the main bioactive compounds and are intensively studied. They will be investigated particularly in pharmacological activities.

2.2.1 Polysaccharides

Polysaccharides (Poly), the carbohydrate component of Cistanches Herba, consist of more than ten simple sugars which are connected by glycosidic linkages. The composition of monosaccharides, is mainly as follows: glucose, galactose, rhamnose, arabinose, and fructose. To elucidate the structural characteristic of Poly including its molecular weight, molecular weight distribution, monosaccharide compositions, glycosidic linkages, and monosaccharides- glycosidic bond types, as well as the repeat units of Poly are all the current and future research focused with priority (Lei et al, 2008). Polysaccharides mainly include cistan A, CDA-1A, CDA-3B, CDP-4, ACDP-2 (Figure 2), and SPA (Figure 3).

2.2.2 Oligosaccharides
Oligosaccharides are a straight-chain or branched-chain polymer that is connected with two to ten monosaccharides by a glycosidic bond. Oligosaccharides, as well as the corresponding derivatives, are actually a product of PhGs after losing phenethylol aglycones, including
cistantubuloses A1, A2, cistanoside I, and cistanoside F.
2.2.3 Galactitol
Galactitol, one of the monosaccharides that can be absorbed in the intestine fastest, is also one determining quota of quality standards of Cistanches Herba in Hong Kong, China. Galactitol is the reduction product of galactose, responsible for laxative bioactivity.

2.3 Volatile components

Volatile components of Cistanches Herba mainly consist of alcohols, alkanes, aldehydes, and heterocyclic, of which eugenol is the main component of C. deserticola and palmitic acid, and linoleic acid are the major compounds of C. tubulosa (Jiang et al, 2009).

2.4 Iridoids

The iridoid glycosides from Cistanches Herba have the following characteristics: C-1 even with glucose, C-5 and C-9 for the ȕ-H, C-4 sometimes exist carboxyl, a hydroxyl often exists at C-6, C-7, C-8, or C-10, or hydroxy is lost to form a double bond or an epoxy ether bond. Iridoids include cistachlorin, cistanin, kankanol, and argyol. Iridoid glycosides include adoxosidic acid, antirrhide, bartsioside, catalpol, 6-deoxycatalpol, 8-epideoxyloganic acid, 8-epiloganic acid, 8-epiloganin, geniposidic acid, gluroside, geniposide, kankanosides A — D, leonuride (ajugol), mussaenosidic acid, and phelypaeside II.

2.5 Lignin and its glycosides

Researchers have isolated one lignan and several lignan glycosides. The lignan is (+)-pinoresinol, and the lignan glycosides were, dehydrodiconiferyl alcohol-4- O-β-D-glucoside, dehydrodiconiferyl alcohol-4-O-γ'-D- glucoside, (+)-pinoresinol monomethyl ether-β-D-glucopyranoside, (+)-syringaresinol-4’-O-β-D-glucopyranoside, (+) -isoeucommin A, eucommin A, lariciresinol, 4'-O-β-D-glucopyranoside, lariciresinol 4-O-β-D-glucopyranoside, conical side, dehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside, dehydrodiconiferyl alcohol γ'-O-β-D-glucoside, citrus A, and alaschanioside A (Nan et al, 2015).

2.6 Other components

There are other components including flavonoids (Song, 2013), alkaloids such as betaine and N, N-dimethyl glycine methyl ester (Gong et al, 2007), fatty acids, sterols, or their glycosides, etc.

3. Pharmacological activities

3.1 PhGs

Comprehensive literature has reported that more than 20 PhGs with a type of polyphenolic compounds, in which echinacoside (Each) and acteoside (Act) are the representatives and major active ingredients with various bioactivities such as anti-oxidation, neuroprotection, anti-apoptotic, etc. Among them, neuroprotection, anti-apoptotic, phytoestrogen, and treatment of osteoporosis are becoming hot topics. The pharmacological effects of PhGs are related to the following.

3.1.1 AntiͲoxidation

Xiong et al (1996) indicated that Each, polyphenolic compound, contained many phenolic hydroxyls which could bind with free radicals. Therefore the body could be protected from oxidative damage due to free radicals failure in largely accumulating in the body.

Several studies (Lei et al, 2004; Tu et al, 2004; Liu et al, 2005) showed that Each could better inhibit the ·OH and O2· radicals in vitro. It also could increase the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), decrease the malondialdehyde (MDA) content, and inhibit aging induced by D-galactose.
Other studies (Li et al, 2009; Yang et al, 2009) showed that Each, Act, and isoacteoside had activities of eliminating (DPPH·) and antioxidant.

3.1.2 Improvement of memory and neuroprotection
The researchers found that PhGs could significantly improve the sexual function of mice, and they could be used to treat low sexual function and enhance memory.

Gao et al (2005) and Li et al (2011) indicated that PhGs (with 44.3% Each) could improve the learning and memory in a focal cerebral ischemia-reperfusion model of vascular dementia mice, and also could improve intelligence.
Chen et al (2007a) and other researchers also indicated that Each could prevent acute injury caused by 6-OHDA rat striatal extracellular DA and its metabolite content decreased. Ech also could protect and treat Parkinson’s disease (An et al, 2011).
Liu et al (2011) studied the effect of PhGs in Cistanches Herba on learning and memory impairment induced by scopolamine in mice and found that PhGs could increase the content of choline acetylase (ChAT) and SOD while decreasing the level of cholinesterase (AChE) and malondialdehyde (MDA) in brain tissues significantly and improve the learning and memory ability.
Min et al (2013) revealed that Each could cross the blood-brain barrier freely and activate Trk receptors which were critical to the survival of neurons, and their downstream signal pathways, to elicit a neuroprotection effect. However, another study indicated that Ech protected neuronal cells through free radical scavenging (Kuang et al, 2009).

3.1.3 Protection on brain cells and antiͲapoptotic effect
Apoptosis is a variety of pathogenic factors leading to programmed cell death in the developing nervous system. Neurodegenerative disease and injury in both excitatory neurons promote cell apoptosis and oxidative damage. Deng et al (2005) exposed that Ech could inhibit cells or animal brain particles apoptosis and decrease apoptosis rate. And Xu et al (2011) indicated that PhGs could delay aging by their antioxidant activity.

3.1.4 Antitumor activity
Several studies (Li et al, 1995; Liu et al, 2008) showed that ECH isolated from the plants of Pedicularis Linn. had the antitumor activity.
3.1.5 Hepatoprotective effect
Wu et al (2007) showed that IP injection of Each (50 mg/kg) could significantly weaken the hepatotoxicity induced by CCl4 in rats. Xiong et al (1996) reported that four phenethyl alcohol glycosides (including Ech) were obtained from the plants of Cistanche Hoffmg. et Link had hepatoprotective activity.
3.1.6 Phytoestrogen effect
Wang et al (2015) and Zhao et al (2007) found that Ech and Act isolated from Cistanches Herba with a phytoestrogens activity through stimulating ERE-increase reporter gene activity.
3.1.7 Treatment of osteoporosis and fracture healing
In traditional Chinese medicine (TCM) theory, the kidney generates marrow and dominates bone. Modern pharmacological studies have shown that the kidney-reinforcing drugshave varying degrees of exciting the function of the pituitary-adrenal-gonadal system, and bone metabolism is closely related. Estrogen could enhance osteogenesis-related androgens and promote protein synthesis and bone matrix to increase the role of calcium and phosphate deposition. PhGs, isoacteoside, and betaine in Cistanches Herba all have androgen-like effects and can promote bone marrow mesenchymal stem cells (BMSCs) directed differentiation into osteoblasts. For the treatment of osteoporosis, fracture healing will have good prospects (Zeng and Liu, 2010).
Hai et al (2013), Liang et al (2013), Gao et al (2013), and Liu et al (2013) discovered that the Cistanches Herba aqueous extract through affecting the level of serum BGP, TRAP, E2, FSH, and LH, the level of E2, Smad1, Smad5, TGF-γ'1, and TIEG1 mRNA, and the protein expression in a model of postmenopausal osteoporosis, molding by ovariectomized (OVX) rats, to prevent bone loss or treat osteoporosis disease.

3.1.8 Immunomodulatory effect
Li et al (1997) observed that PhGs could enhance SOD activity in erythrocytes, decrease MDA content in mice serum, increase DNA and RNA contents in the liver and kidney, enhance immunity and anti-aging and also have some other effects.
3.1.9 Protective effect on healing and antiradiation
Speroni et al (2002) exposed that ECH had a protective effect on the skin and connective tissues, and promoted wound healing.
Li et al (1992) indicated that ECH had protective and therapeutic effects on UVA/UVB radiation-induced skin damage. PhGs had a strong protective effect on irradiated mice.

3.1.10 AntiͲinflammatory
Xiong et al (1999; 2000) found that PhGs especially Act showed a strong anti-inflammatory effect by eliminating NO radical based on its antioxidant activity.
Jia et al (2014) indicated that PhGs could treat colitis in mice induced by dextran sulfate sodium (DSS), and protect intestinal epithelium cells from inflammatory injury by upregulating the transforming growth factor (TGF)-ȕ1.
3.1.11 Treatment of high altitude diseases
Several researchers (Jin et al, 2014; Tao et al, 2014; Luo et al, 2014) discovered that PhGs could prevent high altitude pulmonary edema and high-altitude cerebral edema by increasing the enzymatic activity of GSH-Px, SOD and decreasing the IL-6, TNF-Į, MDA in lung homogenate. This effect may be related to its anti-oxidative and anti-inflammation activities.
3.1.12 Hypoglycemic effect
Morikawa et al (2014) indicated that Each and Act of C. tubulosa could not only inhibit the increase in postprandial blood glucose levels but also significantly improve the glucose tolerance in starch-loaded mice. These effects might be related to the inhibitory activities of PhGs against human intestinal maltase and lens aldose reductase. And the detailed mode of action should be studied further. Thus, PhGs were a kind of potential antihyperglycemic component.
3.1.13 Other effects
Pan et al (2004) and Min et al (2004) showed that PhGs could enhance the hypothalamic-pituitary-adrenal function, promote in vivo release of related neurotransmitters and hormones, increase libido, and improve physical skills for antifatigue.
Wu et al (2003) exposed that some Cistanches Herba glycosides had structural similarities with vitamin E, which had a phenolic hydroxyl group and a hydroxyl functional group.

3.2 Polysaccharides

3.2.1 Immunomodulatory effect
Zeng et al (1998; 2002) showed that Cistanche polysaccharides (CPS) could increase the proliferative response of spleen and thymus lymphocytes and have a synergistic effect with concanavalin (ConA) and phytohemagglutinin. CPS can stimulate the proliferation of murine
thymocytes and significantly improve murine splenic T lymphocytes to secrete interleukin-2 (IL-2).
Several studies (Wang et al, 2009; Qi et al, 2009) showed that CPS could significantly promote the normal cell proliferation on mitogen (ConA and lipopolysaccharide) activated and non-activated lymphocytes and the secretion of IL-2. The IP administration with CPS could significantly improve the spleen indexes of both normal and immunocompromised mice.

Xu et al (1997) reported that CPS had a recovery effect on spleen weight loss in mice with the stagnation of liver Qi induced by carbon tetrachloride (CCl4), and also could improve the immune cells and humoral immune function and enhance the ability of its occurrence allergy.

3.2.2 AntiͲoxidative and antiͲaging effects
Xue et al (1995) indicated that CPS could significantly delay animal skin aging, enhance skin elasticity, increase hydroxyproline content in animal skin, increase the collagen fiber content and SOD activation, and reduce body ester lipofuscin accumulation.
Wu et al (2004) and Fu et al (2004) reported that CPS showed significant anti-lipid peroxidation functions on subacute aging mice caused by D-galactose.
Xu et al (2008) reported that CPS could significantly improve the activity of Ca2+-ATP enzyme in the liver of aging model rat, the membrane fluidity of liver mitochondrial, the activities of respiratory chain complexes I + III and II + III.
Researchers (Sun et al, 2001; Xu et al, 2011; Wang et al, 2011) have reported that CPS could enhance the lung, erythrocyte SOD, and GSH-Px vitality of aging mice, and be resistant to oxidative damage and senescence.
3.2.3 AntiͲhepatitis
Zhang et al (1996) reported that CPS significantly inhibited the hepatic damage while reducing the increase of serum alanine aminotransferase and aspartate aminotransferase due to the liver and spleen functional impairment.
3.2.4 Effect on the proliferation of fibroblasts
Gao et al (1998) observed the effect of CPS with different concentrations on cultured human fibroblast cells and proved that the drug could significantly promote the in vitro growth of human fibroblasts.
3.2.5 Hematopoietic function
Chen et al (2007b) have reported that CPS could significantly promote bone marrow cells in G0/G1 phase to S phase as well as cells in the S phase to G2/M phase transformation. So cells in the G2/M phase were significantly increased in number, and proliferation index (PI) was also
significantly increased. CPS could promote the recovery of bone marrow function and growth of blood erythroid megakaryocytes by inducing the transformation of the cell cycle in the bone marrow of anemia mice.
3.2.6 Inhibitory effect
CPS solution had a different degree of inhibiting the growth of Colon Bacillus, Bacillus subtilis, Saccharomyces cerevisiae, and Penicillium citrinum, which laid the foundation for the reasonable development and utilization of the plants in Cistanche Hoffmg. et Link (Wang and Zhu, 2009).

3.3 Oligosaccharides

Functional oligosaccharide is difficult to be or not digested when absorbed by the body. So it is provided as a low or no energy value, and used as low energy food for people with diabetes, obesity, or low blood sugar. At the same time, it can activate the intestinal bifidobacteria and promote their growth and reproduction. Since the functional oligosaccharides, as water-soluble dietary fiber, are not digested and absorbed by the body, they have some physiological functions of dietary fiber, such as lowering serum cholesterol and preventing colon cancer. Although they belong to small molecules, they do not change the original organization of food texture and physical properties when added to food basically (Bai, 2006).

3.4 Galactitol

Tu et al (1997b) reported that the laxative active ingredients were galactitols in the plants of Cistanche Hoffmg. et Link. The dose-effect relationship study showed that 1.1% galactitols had a laxative effect, as the dose increased gradually the laxative effect increased. However, the dose-response curve for the 10% galactitol went to flat. The laxative effect was not stronger with the dose increase. (Zhang and Zhao, 2003a; 2003b; Tu and He, 1997; Pharmacopoeia Committee of P. R. China, 2010).

Ren et al (1987) proposed that drugs for the treatment of constipation were numerous but many had varying degrees of side effects or had the disadvantages of being hurt. Cistanches Herba was sweet, sour, salty, warm, and non-toxic, and nourished the essence and blood of the liver and kidney. After taking the herb, the liver and kidney functions of the patients were not aware of any injuries.

3.5 Volatile components

Currently, few reports are available upon bioactive effects of volatile components, in which ȕ-sitosterol is the major active component.

3.5.1 Hepatoprotective effect

β-sitosterol has been demonstrated as one of the biological activity continents of Cistanches Herba. β-sitosterol, having the hepatoprotection effect, could protect the liver against CCl4-induced hepatotoxicity through enhancing mitochondrial glutathione redox cycling to improve the mitochondrial glutathione redox status (Wong et al, 2014). And β-sitosterol is a potential bioactive compound to prevent oxidative stress-induced injury in the liver.

3.5.2 Weight reduction effect
Wong et al (2015; 2014) found that β-sitosterol could induce the mitochondrial uncoupling and the activation of the AMPK/PGC-1 pathway in C2C12 myotubes to increase energy consumption. β-sitosterol can prevent diet-induced obesity and be related to metabolic abnormalities.

3.5.3 Cardioprotective effect
Wong et al (2013) and Siu et al (2010) reported that ȕ-sitosterol had the myocardial protection effect. The mechanism could be that β-sitosterol was able to increase the production of mitochondrial reactive oxygen species by up-regulating mitochondrial glutathione redox cycling.

3.6 Other pharmacological effects

In addition, Cistanches Herba could reverse or alleviate the reproductive toxicity induced by glycoside of Tripterygii Radix et Rhizoma through regulating the generation of normal sperm which is helpful for reproductive health (Li et al, 2014).

Cistanches Herba also could alleviate the testicular toxicity induced by hydroxyurea and alleviate the degeneration of spermatogenetic cells. And this effect may be related to its ectogenous androgen-like effect (Li et al, 2013). However, Cistanches Herba could dose-dependently induce testis cytotoxicity through eliminating hormonal function, inhibiting spermatogenesis, and damaging testicles (San et al, 2012).

3.7 Pharmacological effects of other ingredients

Flavonoids and alkaloids in addition to their traditional pharmacological effects have not been reported. In addition, Cistanches Herba flooding fluid, ethanol-water extract, and ethanol leaching solution could be used to anesthetize dogs, cats, and rabbits, and also have the antihypertensive effect.

Cistanches Herba can stimulate saliva and palsy respiratory. Some organic acid-like substances could stimulate saliva, and glycosides could make respiratory paralysis.

4. Conclusion and perspective

Since reports have indicated that PhGs of Cistanches Herba with the improvement of memory and neuroprotection effect and the cognitive behavior related to memory ability, Cistanches Herba will be a potential candidate for Parkinson’s disease and cognitive enhancement.

As we know, Cistanches Herba has estrogenic activity. and estrogen could regulate bone metabolism and has played an important role in maintaining the balance of bone resorption and bone formation. We speculated that Cistanches Herba has the effect of anti-osteoporosis as a result of phytoestrogen action. Therefore, combined with the effect of estrogenic, anti-osteoporosis, and gentle laxative activity, Cistanches Herba may have certain prevention and cure functions to osteoporosis of patients with senile hypofunction. Furthermore, PhGs, especially Each, maybe the potential for clinically treating inflammatory bowel disease and being an alternative to antibiotics due to being responsible for the anti-inflammatory effect.
Saccharides, especially oligosaccharides and galactitol, could activate the intestinal bifidobacteria, promote their growth and reproduction, and have a purgative function. This effect will be a breakthrough in the treatment of constipation induced by intestinal flora imbalance or elderly functional constipation.
Otherwise, obesity, defined as an immoderate accumulation of body fat, has become a public health threat. And obesity has been proved to contribute to some comorbidities, such as cardiovascular diseases, type 2 diabetes, and obesity-related cancers. Since ȕ-sitosterol of Cistanches Herba, has the weight reduction effect, cardioprotective effect and PhGs has the hypoglycemic effect, Cistanches Herba might be the pharmacological agent to treat obesity in the future. Cistanches Herba, a traditional valuable Chinese herbal medicine, has a laudatory title of 'Ginseng of the Desert'. As intensive studies are been paid attention to biological, chemical, and pharmacological activities, there is significant interest in Cistanches Herba as an invigoration, tonic kidney, and anti-aging mainstream medicine. So far, studies have shown that some chemical constituents have the same similarities or cross synergies reflecting pharmacological activities, consisting of the overall concept of the TCM principles. In addition, the active ingredients and their unknown pharmacological effects are being further studied.

Cistanche products

From: 'Cistanches Herba: Chemical Constituents and Pharmacological Effects' by Lin–lin Wang et al

---Wang LL et al. Chinese Herbal Medicines, 2015, 7(2): 135-142