Part Ⅰ：Herba Cistanche (Rou Cong Rong): A Review Of Its Phytochemistry And Pharmacology

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Huibo Lei, Xinyu Wang, Yuhao Zhang, Taofang Cheng, Rui Mi, Xike Xu, Xianpeng Zu, and Weidong Zhan

Abstract:

Herba Cistanche, known as Rou Cong Rong in Chinese, is a very valuable Chinese herbal medicine that has been recorded in the Chinese Pharmacopoeia. Rou Cong Rong has been extensively used in clinical practice in traditional herbal formulations and has also been widely used as a health food supplement for a long time in Asian countries such as China and Japan. There are many bioactive compounds in Rou Cong Rong, the most important of which are phenylethanoid glycosides. This article summarizes the up-to-date information regarding the phytochemistry, pharmacology, processing, toxicity, and safety of Rou Cong Rong to reveal its pharmacodynamic basis and potential therapeutic effects, which could be of great value for its use in the future research.

Herba Cistanche

Introduction

Herba Cistanche comprises 22 species all over the world and is distributed mainly in arid lands and even deserts across Eurasia and North Africa, such as in China, Japan, Iran, India, and Mongolia.1) Among all these plants, four main species and a variant species are found in China according to the Taxonomical Index of Chinese Higher Plants; all of these species are called Rou Cong Rong in Chinese.2) These species include Cistanche deserticola Y.Cistanche Ma, Cistanche tubulosa (Schenk)R. Wight, Cistanche Sinensis G. Beck, Cistanche salsa (CistancheA. Mey.) G. Beck, and Cistanche salsa var. albiflora P.F. Tu et Z.Cistanche Lou.3) The dried succulent stems of the genus Cistanche Hoffmg. Et Link belongs to the Orobanchaceae family.4) Among these four Cistanche plants, only Cistanche deserticola and Cistanche tubulosa have been authenticated as officinal plants in the Chinese Pharmacopoeia (2015 edition), though Cistanche salsa and Cistanche Sinensis are commonly used in the regions of Ningxia and Xinjiang due to their remarkable medicinal effects and the source shortage of Cistanche deserticola and Cistanche tubulosa. As for the Japanese Pharmacopoeia, the dried stems of Cistanche salsa, Cistanche deserticola, and Cistanche tubulosa are authorized as a crude drug “Nikujuyou.”5) Besides, three species including Cistanche tubulosa, which mainly distributed in the Central Sahara (Tassili N’Ajjer); Cistanche tincture, which is locally known as denouncing to treat diabetes, diarrhea, and abdominal pains in the Saharo-Mediterranean region, Cistanche violence, which is a holoparasitic plant on Chenopodiaceae and Limoniastrum in Northern Africa are the represented Cistanche in the Algerian Sahara.6) Cistanche was first recorded in Shen Nong’s Herbal Classic and has had a very long medical history in China.7) Cistanche tubulosa (Kanka-nikujuyou in Japanese) has traditionally been used to promote blood circulation.8) In Korea, Cistanche also has a long medicinal history and Cistanche salsa has been reported to be efficacious in the treatment of sexual dysfunction diseases in a Korean medicine book called the DonguiBogam.9) Currently, it is generally used to treat chronic renal disease, female infertility, morbid leucorrhea, profuse metrorrhagia, and constipation in the elderly.10) It has also been used since ancient times as an herbal drug to treat kidney deficiency.11) Among the tonics in traditional Chinese medicine (TCM), this medicine is widely accepted as superior and has been honored as the “Ginseng of the desert.” Besides the remarkable uses in China, Herba Cistanche is also used as a healthy food supplement in Japan and Southeast Asia, and scholars in many countries like Japan, Korea, Germany, Russian, Australia, Greece, Algérie, and Italy have made a lot of modern scientific researches on this plant since the 1980s.12) Chemical research has indicated that phenylethanoid glycosides (PhGs), iridoids, lignans, and polysaccharides are the major constituents of these species,13,14) and Herba Cistanche extracts have been proved to have a range of pharmacologically active functions that include improving chronic renal disease and constipation in the elderly, increasing learning or memorization abilities, treating Alzheimer’s disease (AD), and improving immunity by researchers all over the world. This paper mainly updates the available information about the phytochemical constituents, pharmacological activities, and safety of Cistanches Herba to provide useful information for the development of plant-derived drugs and Chinese medicine preparations from this medicinal plant.

Herba Cistanche

Phytochemistry

As the oriental medicinal tonic in Japan, C. salsa has been reported to have the constituents, such as monoterpene glucoside, iridoid glucoside, phenylpropanoid glycoside, and lignan glycoside early in 1983–1986 by Kobayashi, which may be the earliest modern research report on the chemical constituents of Cistanche. Until now, 213 compounds, including PhGs, benzyl glycosides, phenylacetate oligosugars, iridoids, monoterpenoids, lignans, sterols, alkaloids, polysaccharides, and other compounds, have been obtained from Cistanche plants. Among them, PhGs account for the largest proportion relative to the other types of compounds. Chemical structures that have previously been reported from Cistanche plants are shown in Figs. 1–9.

PhGs

PhGs have been thought to be the primary active components in the Cistanche species. They are a type of phenolic compound characterized by a β-glucopyranoside structure bearing a hydroxy phenylethyl moiety as the aglycone. This kind of compound commonly includes a number of acyl groups, such as cinnamic acid, p-coumaric acid, caffeic acid, ferulic acid, and is ferulic acid, and various sugars, such as rhamnose and xylose, that are attached to the glucose residue through ester or glycosidic linkages, respectively. In the past few decades, 85 PhGs including 6 monosaccharide glycosides, 52 disaccharide glycosides, and 27 trisaccharide glycosides (Table 1) have been reported in Cistanche plants. The structures of PhG compounds are presented in Fig. 1. Generally, monosaccharide glycosides only contain a glucosyl linked at the C-8 position of the phenylethanoid. The disaccharide glycosides generally contain a Rha (1→3) Glc linkage. In the trisaccharide glycosides, there is another glucose or rhamnose at the C-6 position of the inside glucose.

cistanche extract

Benzyl Glycosides

Lei et al. obtained four benzyl glycosides from C. salsa for the first time in 2007.⁴⁷⁾ Then, in 2013, another three benzyl glycosides were isolated and identified from C. deserticola.⁴⁴⁾ The structures of the benzyl glycosides are similar to those of the PhGs. The glucosyl often links directly to the benzyl alcohol aglycone, and a coumaroyl or caffeoyl group is usually located at the glucosyl C-4 or C-6 position (Fig. 2; Table 2).

Phenylacylated Oligosugars

To date, nine phenyl-acylated oligosugars have been obtained from the genus Cistanche (Fig. 3; Table 3). In these phenylacetate oligosugars, the sugar moiety consists of glucose and rhamnose connected by a Rha (1→3) Glc linkage, and there is generally a coumaroyl or caffeoyl group linked at the glucosyl C-4 position. Occasionally, an additional glucosyl moiety is linked at the glucosyl C-6 position.

Iridoids

Iridoids are a type of monoterpenoid constructed from a 10-carbon skeleton of isoprene building units with a cyclopentanopyran ring system. During structure identification and elucidation studies of iridoid constituents from the Cistanche species, 4 iridoid aglycones and 23 iridoid glycosides were isolated (Table 4; Fig. 4). Their structural features can be summarized as follows. A glucosyl is generally linked at the aglycone C-1 position, a carboxyl is usually linked at the aglycone C-4 position and H-5 and H-9 are β-oriented. Hydrogenation accidentally appears at C-3 and C-4 whereas hydroxylation often occurs at C-6, C-7, C-8, and C-10.

Sometimes, dehydration may occur between the C-10 hydroxyl and that at C-1 or C-3 to form an epoxy substructure.

Monoterpenoids

To date, 14 monoterpenoids have been isolated from Cistanche plants, among which 4 are monoterpenes and 10 belong to monoterpene glycosides (Table 5; Fig. 5). Their structural characteristics can be summarized as follows: a methyl is generally linked at the aglycone C-2 or C-6 position and a double bond occur between C-2 and C-3. The positions between C-6 and C-7 or between C-7 and C-8 also often have a double bond. Hydroxyl or carboxyl groups are often linked at the C-1 position and a hydroxyl is usually linked at C-8 in monoterpenes. Monoterpene glycosides are all monoglycosides that only contain a glucosyl linked at the aglycone C-1 or C-8 position.

Lignans

Until now, there have been 2 lignans agly- cones and 15 lignan glycosides purified from Cistanche plants (Table 6; Fig. 6).

Sterols

Sterols are relatively rare in Cistanche plants, and only five such compounds have been reported in this genus (Table 7). The structures of the sterol compounds are presented in Fig. 7.

Alkaloids

Cistanche plants also contain alkaloids, and approximately 19 compounds have been found and elucidated (Fig. 8; Table 8）.

Other Types of Compounds

Some other compounds, such as phenolic glycosides, flavonoids, and long-chain fatty acid derivatives, have been isolated from Cistanche plants (Table 9; Fig. 9). A considerable proportion of polysaccharides have also been reported in Cistanche species.⁷⁵⁾ A large number of studies have shown that the polysaccharides are regarded as active constituents to advance body immunity and show antiaging and anticancer activities in Herba Cistanche.^76–78)

Pharmacology

Cistanches Herba has wide medicinal uses as a kind of TCM. Many researchers have investigated its pharmacological actions in traditional records and have validated its therapeutic potential in modern methods. Biological activity studies have shown that Cistanches Herba exhibits a wide spectrum of pharmacological activities such as antioxidation, antisenile dementia, anti-Parkinson’s disease, immunoregulation, antiaging, hepatoprotection, and anti myocardial ischemia effects, which may mainly be attributed to its bioactive components, including PhGs, polysaccharides and so on. As the major active components in Cistanche plants, components 2 and 11 were selected as reference substances for quality control in Chinese Pharmacopoeia. And it is stipulated that the total content of these two compounds should not be less than 0.30 and 1.5% in C. deserticola, C. tubulosa, respectively, which may indicate the varying pharmacological reactions based on PhGs.⁸⁶⁾ Nevertheless, it is insufficient to evaluate the quality of Cistanche herbs only based on these two PhGs compounds due to they could not represent the other effective PhGs ingredients. Until now, dozens of bioactive PhGs have been used as reference substances for quality evaluation of Cistanche herbs even their corresponding formulations.⁸⁷⁾ A method of RPLC- hydrophilic interaction chromatography (HILIC)-MS/MS for the 23 analytes, including three organic acids, four nucleo- sides, two sugars, one amino acids, one benzylglucoside, two lignans, seven PhGs, and three iridoids, was conducted in C. tubulosa by Yan et al. in 2017, and the results showed that those 23 components exhibited wide content ranges and sig- nificant variations among 20 batches of C. tubulosa, of which compounds 2, 11, and 202 were abundant in content, whereas ferulic acid showed trace distributions in these 20 batches.⁸⁸⁾ In 2018, Dong et al. conducted a comparison of the seven PhGs including compounds 1, 2, 3, 5, 11, 12, and 67 between C. deserticola and C. tubulosa by only one marker using a new calculate method of the relative correction factor. The analysis results showed that the chemical compositions and content of these 7 PhGs were quite different.⁸⁹⁾ In 2019, Zhang et al.⁹⁰⁾ analyzed the changes of the total PhGs, total polysaccharides, and four PhGs content in the raw product of C. deserticola and its processed product by using UV spectrophotometry method, the phenol-sulfuric acid method, and HPLC method, respectively. The results exhibited that the processed C. deserticola has higher amounts of total polysaccharides, total PhGs, compounds 12 and 14 than raw C. deserticola, while the content of compounds 1 and 2 decreased after processing. Moreover, there are also many other research on the quantitative analysis of Cistanche Herba due to their obvious and remarkable pharmacological activity.^91–97) It should be affirmed that the related quantitative research on the active ingredients of Cistanche has laid a solid foundation for its related research on pharma- cological activities.

Cistanch supplements

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