Herba Cistanche (Rou Cong Rong): A Review of Its Phytochemistry and Pharmacology

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 future research.

1. 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.C. Ma, C. tubulosa (Schenk) R. Wight, C. sinensis G. Beck, C. salsa (C.A. Mey.) G. Beck, and C. salsa var. albiflora P.F. Tu et Z.C. Lou.³⁾ The dried succulent stems of the genus Cistanche Hoffmg. Et Link belong to the Orobanchaceae family.⁴⁾ Among these four Cistanche plants, only C. deserticola and C. tubulosa have been authenticated as officinal plants in the Chinese Pharmacopoeia (2015 edition), though C. salsa and C. sinensis are commonly used in the regions of Ningxia and Xinjiang due to their remarkable medicinal effects and the source shortage of C. deserticola and C. tubulosa. As for the Japanese Pharmacopoeia, the dried stems of C. salsa, C. deserticola, and C. tubulosa are authorized as a crude drug “Nikujuyou.”⁵⁾ Besides, three species including C. tubulosa, which mainly distributed in the Central Sahara (Tassili N’Ajjer); C. tinctoria, which is locally known as danoun to treat diabetes, diarrhea and abdominal pains in Saharo-Mediterranean region, C. violacea, which is a holoparasitic plant on Chenopodiaceae and Limoniastrum in the Northern Africa are the reperesented 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⁾ C. tubulosa (Kanka-nikujuyou in Japanese) has traditionally been used to promote blood circulation.⁸⁾ In Korea, Cistanche also has a long medicinal history and C. salsa has been reported to be efficacious in the treatment of sexual dysfunction diseases in 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 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.^1,15–18) 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.

2. Phytochemistry

As the oriental medicinal tonic in Japan, C. salsa have 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, phenylacylated 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.

2.1. 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 isoferulic 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 phenylethanol. 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.

Table 1. PhGs from Cistanche Species

No.	Compound	Source	References
1	2′-Acetylacteoside	Cd, Ct, Cp, Csi, Csa	19–24)
2	Acteoside	Cd, Ct. Cp Csa, Csi	19–22, 24–26)
3	Cistanoside A	Cd, Ct, Csa	21, 26–28)
4	Cistanoside B	Cd	28, 29)
5	Cistanoside C	Cd, Csa	19, 29)
6	Cistanoside D	Cd, Csa	19)
7	Cistanoside E	Cd	19)
8	Cistanoside G	Cd, Ct	30, 31)
9	Cistanoside H	Cd	29, 32)
10	Decaffeoylacteoside	Cd, Ct	25, 32)
11	Echinacoside	Cd, Ct, Cp, Csa, Csi	20–25, 33)
12	Isoacteoside	Cd, Ct, Csa, Csi	20, 24, 25, 33, 34)
13	Isosyringalide 3′-α-L-rhamnopyranoside	Cd, Ct	35, 36)
14	Osmanthuside B	Cd, Ct, Csa	19, 36)
15	Salidroside	Cd, Ct	25, 30, 37, 38)
16	Syringalide A 3′-α-L-rhamnopyranoside	Cd, Ct, Cp	25, 34, 35, 37)
17	Tubuloside A	Cd, Ct, Cp	20, 25, 34, 39)
18	Tubuloside B	Cd, Ct, Cp, Csi, Csa	20, 21, 33, 37)
19	Tubuloside C	Ct	20)
20	E-Tubuloside D	Ct	20)
21	Z-Tubuloside D	Ct	20)
22	E-Tubuloside E	Cd, Ct, Cp	35, 39, 40)
23	Z-Tubuloside E	Cd, Ct, Cp	35, 39, 40)
24	Cistantubuloside A	Ct	41)
25	Cistantubuloside B1	Ct	41)
26	Cistantubuloside B2	Ct	41)
27	Cistansinenside A	Csi	42)
28	Jionoside D	Csi	42)
29	Poliumoside	Csi	42)
30	Kankanoside F	Ct	31)
31	Kankanoside G	Ct	31)
32	Eutigoside A	Csa	33)
33	Cistantubuloside C1	Ct	41)
34	Cistantubuloside C2	Ct	41)
35	2′-Acetylcistanoside C	Csa	43)
36	Cistansinenside B	Csi	24)
37	Campneoside II	Ct, Csi	24, 37)
38	Brandioside	Csi	24)
39	Cistanoside K	Cd	44)
40	Isocistanoside C	Cd	44)
41	2′-Acetyl osmanthuside	Csa	43)
42	Kankanoside H1	Ct	37)
43	Kankanoside H2	Ct	37)
44	Kankanoside I	Ct	37)
45	Kankanosides J1	Ct	45)
46	Kankanosides J2	Ct	45)
47	Kankanosides K1	Ct	45)
48	Kankanosides K2	Ct	45)
49	Isocampneoside I	Ct	45)
50	Campneoside I	Ct	37, 41)
51	cis-Acteoside	Ct	37)
52	Arenarioside	Ct	37)
53	Wiedemannioside C	Ct	37)
54	E-Osmanthuside B6	Cd	40)
55	Z-Osmanthuside B6	Cd	40)
56	Cistanoside M	Cd	44)
57	Pheliposide	Cp	46)
58	Salsaside D	Cd, Csa	40, 47)
59	Salsaside E	Cd, Csa	40, 47)
60	Salsaside F	Csa	47)
61	Cistanoside J	Cd	44)
62	Cistanoside L	Cd	44)
63	Cistanoside N	Cd	44)
64	Epimeridinoside A	Cd	44)
65	Plantainoside C	Cd	40)
66	6'-Acetylsalidroside	Cd	44)
67	Acetylacteoside	Cd, Ct	48)
68	Calceolarioside A	Cd, Ct	49)
69	cis-Cistanoside J	Cd	50)
70	cis-Cistanoside K	Cd	50)
71	cis-Isocistanoside C	Cd	50)
72	Cistansalside A	Csa	51)
73	Cistansalside D	Csa	51)
74	Cistansalside E	Csa	51)
75	Cistubuloside B	Cd	50)
76	Cistubuloside D	Cd, Ct	52)
77	cis-Verbascoside	Cd, Ct	52)
78	Isocistanoside J	Cd, Ct	52)
79	Isocistanoside K	Cd, Ct	52)
80	Isomartynoside	Cd, Ct	50)
81	Isopoliumoside	Cd, Ct	53)
82	Jionoside C	Csa	51)
83	Phenylethyl-glucopyranoside	Cd	50)
84	β-D-Glucopyranoside,2-(4-hydroxyphenyl)ethyl,6-acetate	Cd	44, 54)
85	Crenatoside	Cd, Ct	25)

Cd, C. deserticola; Ct, C. tubulosa; Cp, C. phelypaea; Csa, C. salsa; Csi, C. sinensis.

Fig. 1. Structures of PhGs from Cistanche Species

Ac, acetyl; OMe, methoxyl; Cm, trans-coumaroyl; c-Cm, cis-coumaroyl; Cf, trans-caffeoyl; c-Cf, cis-caffeoyl; Fr, trans-feruloyl; c-Fr, cis-feruloyl; Glc, β-D-glucopyranosyl; Rha, α-L-rhamnopyranosyl; Xyl, β-D-xylopyranosyl; TA-Rha, 2‴,3‴,4‴-triacetyl-α-L-rhamnopyranosyl.

2.2. 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).

Fig. 2. Benzyl Glycosides from Cistanche Species

Table 2. Benzyl Glycosides from Cistanche Species

No.	Compound	Source	References
86	Salsaside A	Csa	47)
87	Salsaside B	Cd, Csa	44, 47)
88	Salsaside C1	Csa	47)
89	Salsaside C2	Csa	47)
90	3,4-Dimethoxybenzyl-β-D-glucoside	Cd	44)
91	4-Hydroxybenzyl-β-D-glucoside	Cd	44)
92	Benzyl-glucopyranoside	Cd	44)

2.3. Phenylacylated Oligosugars

To date, nine phenylacylated oligosugars have been obtained from the genus Cistanche (Fig. 3; Table 3). In these phenylacylated 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.

Fig. 3. Phenylacylated Oligosugars from Cistanche Species

Table 3. Phenylacylated Oligosugars from Cistanche Species

No.	Compound	Source	References
93	Cistanoside F	Cd, Ct	31, 34, 36, 37, 41, 55, 56)
94	Cistanoside I	Cd	32)
95	Cistansinensose A1/A2	Csi	42)
96	Kankanose (Cistantubulose A1/A2)	Ct	31, 37, 41)
97	Cistansalside B	Csa	51)
98	Cistansalside C	Csa	51)
99	α-L-Rhamnopyranosyl-(1→3)-2-O-acetyl-(4-O-caffeoyl)-O-β-glucopyranoside	Cd	57)

2.4. 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.

Table 4. Iridoids from Cistanche Species

No.	Compound	Source	References
100	Bartsioside	Cd, Ct	58, 59)
101	6-Incatalpol	Cd, Ct, Cp	11, 35, 39, 59, 60)
102	Catalpol	Cd, Ct	38)
103	8-Epideoxyloganic acid	Cd, Ct, Csi	24, 59, 61)
104	8-Epiloganic acid	Cd, Ct, Csa, Csi	11, 24, 27, 35, 60, 62–65)
105	8-Epiloganin	Ct	24, 42)
106	Geniposide	Cd, Csi	24, 42, 66)
107	Geniposidic acid	Cd, Ct, Csi, Csa	58, 59, 61, 64)
108	Gluroside	Cd, Ct, Cp	39, 58, 59, 61)
109	Leonuride	Cd, Ct, Cp, Csi, Csa	24, 39, 58, 59, 65)
110	Mussaenosidic acid	Cd, Ct	58, 59, 61, 64)
111	Adoxosidic acid	Ct	64)
112	Kankanoside A	Cd, Ct	50, 58, 61)
113	Kankanoside B	Ct	58)
114	Phelypaeside	Cp	39)
115	Kankanoside C	Ct	58)
116	Kankanoside D	Ct	58)
117	Antirrhide	Ct	58)
118	Kankanoside L	Ct	61)
119	Kankanoside M	Ct	61)
120	Kankanoside N	Ct	61)
121	Mussaenoside	Csi	24)
122	Cistadesertoside A	Cd	67)
123	Cistachlorin	Cd, Ct	58, 66)
124	Cistanin	Cd, Ct	38, 58, 66)
125	Kankanol	Ct	58)
126	Argyol	Ct	58)

Fig. 4. Iridoids from Cistanche Species

2.5. 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 occurs 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.

Table 5. Monoterpenoids from Cistanche Species

No.	Compound	Source	References
127	(2E)-2,6-Dimethyl-2,7-octadiene-1,6-diol	Cd	62)
128	(2E,6R)-8-Hydroxy-2,6-dimethyl-2-octenoic acid	Ct, Csa	68)
129	(2Z)-2,6-Dimethyl-2,7-octadiene-1,6-diol	Cd	62)
130	8-Hydroxygeraniol	Ct	64)
131	(2E,6E)-8-Hydroxy-2,6-dimethyl-2,6-octadien-1-yl-O-β-D-glucopyranoside	Ct	61)
132	(2E,6Z)-8-O-β-D-Glucopyranosyloxy-2,6-dimethyl-2,6-octadienoic acid	Ct	58, 61)
133	8-Hydroxygeraniol-8-O-β-D-glucopyranoside	Ct, Csa	61, 69)
134	8-Hydroxygeraniol 1-β-D-glucopyranoside	Cd, Ct, Csa	35, 62, 69)
135	Betulalbuside A	Ct	61)
136	Kankanoside E	Ct	58, 61)
137	Kankanosides O	Ct	61)
138	Kankanosides P	Ct	61)
139	2,6-Dimethyloctan-1,8-diol diglucoside	Cd	57)
140	(2E,6E)-3,7-Dimethyl-8-hydroxyoctadien-1-yl-O-β-D-glucopyranoside	Ct	61)

Fig. 5. Monoterpenoids from Cistanche Species

2.6. Lignans

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

Fig. 6. Lignans from Cistanche Species

Table 6. Lignans from Cistanche Species

No.	Compound	Source	References
141	(+)-Pinoresinol	Cd, Ct	30)
142	(+)-Syringaresinol	Cd	50)
143	Liriodendrin	Cd, Ct	11, 29, 35, 55, 60)
144	(+)-Pinoresinol-O-β-D-glucopyranoside	Ct	35)
145	(+)-Syringaresinol-O-β-D-glucopyranoside	Cd, Ct	35, 50, 55, 64)
146	Eucommin A	Cd, Ct	50, 61)
147	(+)-Pinoresinol-monomethylether-β-D-glucoside	Cd	50)
148	(+)-Syringaresinol-4′-O-β-D-glucoside	Cd	70)
149	Isoeucommin A	Cd, Ct	50, 61)
150	Citrusin A	Cd	50)
151	Dehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside	Cd, Ct	35, 50)
152	Dehydrodiconiferyl alcohol γ′-O-β-D-glucopyranoside	Cd, Ct	35, 50)
153	Lariciresinol-4′-O-β-D-glucopyranoside	Cd	50)
154	Conicaoside	Cd	50)
155	Isolariciresinol-9′-O-β-D-glucopyranoside	Csi	24)
156	Lariciresinol-4-O-β-D-glucopyranoside	Cd	50)
157	Alaschanioside A	Cd	50)

2.7. 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.

Table 7. Sterols from Cistanche Species

No.	Compound	Source	References
158	β-Daucosterol	Cd, Csa, Ct	27, 38, 60, 63, 66, 69)
159	β-Sitosterol 3-O-β-D-xylopyranoside	Cd	50)
160	β-Sitosterol	Cd, Cp, Csa, Ct	27, 38, 39, 66)
161	β-Sitosteryl glucoside 3′-O-heptadecoicate	Cd, Csa	60, 69)
162	20-Hydroxyecdysone	Ct	35)

Fig. 7. Sterols from Cistanche Species

2.8. Alkaloids

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

Table 8. Alkaloids from Cistanche Species

No.	Compound	Source	References
163	(3R)-3-Hydroxy-1-methyl-2-pyrrolidinone	Ct	58)
164	(3R)-3-Hydroxy-2-pyrrolidinone	Ct	58)
165	2,5-Dioxo-4-imidazolidinyl-carbamic acid	Cd, Csa	13, 38)
166	DL-Proline	Cd	71)
167	Succinimide	Csa	13)
168	Allantoin	Cd	40, 72)
169	Nicotinamide	Cd	50)
170	2-Methanol-5-hydroxy-pyridine	Csa	69)
171	Adenosine	Cd	50, 72)
172	2'-Deoxyadenosine	Cd	55)
173	2′-O-Methyladenosine	Cd	55)
174	Inosine	Cd	55)
175	Uridine	Ct	58)
176	Betaine	Cd, Csa	38, 69, 73, 74)
177	D-Alanine	Cd, Ct	72)
178	L-Methioinicnine	Cd, Ct	72)
179	N,N-Dimethylglycine methyl ester	Ct	56)
180	Valine	Cd, Ct	72)
181	L(+)-Arginine	Cd, Ct	72)

Fig. 8. Alkaloids from Cistanche Species

2.9. 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)

Fig. 9. Other Types of Compounds from Cistanche Species

Table 9. Other Types of Compounds from Cistanche Species

No.	Compound	Source	References
182	E-Coniferin	Cd, Ct	50, 61)
183	Syringin	Cd, Ct, Cp	30, 35, 38, 39, 61)
184	Demethyl syringing	Cd	50)
185	Sinapic aldehyde 4-O-β-D-glucopyranoside	Ct	61)
186	Sinapaldehyde glucoside	Ct	46)
187	Vanillic acid	Csa	43)
188	P-Hydroxybenzoic acid	Cd	50)
189	P-Coummaric acid	Cd	57)
190	3-(2′-β-O-Pyranoglaucoside)-phenyl-2-transpropenoic acid	Csa	79)
191	Androsin	Cd	50, 72)
192	4-Hydroxy-benzeneethanol	Cd	50)
193	4-Hydroxybenzyl-β-D-glucoside	Cd	80)
194	Ononin	Cd	40)
195	1-O-Hexadecanoyl-3-O-β-D-galactopyranosyl glycerol	Cd	50)
196	Triacontanoic acid	Cd	72, 81)
197	Stearic acid	Cd	38)
198	1-Triacontanol	Cd	73, 81, 82)
199	Panaxytriol	Cd	50)
200	2-Nonacosanone	Cd	81)
201	2S,3S,4S-Trihydroxypentanoic acid	Cd	80)
202	D-Mannitol	Cd, Ct, Csa	27, 38, 63, 66, 83)
203	Galactitol	Cd, Ct, Csi, Csa	11, 40, 42, 60)
204	3-Methyl-but-2-en-1-yl-β-D-giucopyranoside	Cd	50)
205	3-Methylbutanol β-D-glucopyranoside	Ct	31)
206	Ethyl β-D-glucopyranoside	Ct	31)
207	D(−)-Fructose	Ct	84)
208	D(+)-Glucose	Cd, Ct, Csa	29, 60, 84, 85)
209	Succinic acid	Cd, Ct, Csa	66, 73, 82, 84, 85)
210	D(+)-Sucrose	Cd	29, 60)
211	n-Butyl-α-D-fructofuranoside	Cd	50)
212	(±)-γ-Valerolactone	Cd	60)
213	Phelypaeside	Cp	39)

3. 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 antimyocardial 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 less than 0.30 and 1.5% in C. deserticola, C. tubulosa, respectively, which may indicate the varying pharmacological reactions that 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 nucleosides, 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 significant 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 relative correction factor. The analysis results showed that 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 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 pharmacological activities.

3.1. Antioxidation

Antioxidation activity is against free radicals. Antioxidant drugs can reduce the damage of oxygen free radicals to the blood vessel wall, thus playing an antiarterial sclerosis role. Shi et al.⁹⁸⁾ first found that extracts from Cistanche species had a lipid peroxidation suppression-effect and an immunological enhancement effect. The PhGs from Cistanches Herba could obviously lower the levels of lipid hydroperoxide in humans, which was regarded as effective for antioxidative activity.^99,100) The phenolic hydroxyl group in PhGs is necessary for the antioxidant activity. A study found that because of the phenolic hydroxy structure, PhGs can combine with free radicals and activate antioxidant defense systems, and by increasing the number of phenolic hydroxyl groups, the antioxidant activity is increased.³⁴⁾ In another study, Cistanche glycosides showed inhibitory effects on lipid hydroperoxide and thromboxane production in rabbit blood, revealing that these glycosides had protective effects against hemorrhagic shock and reperfusion injury.¹⁰¹⁾ Wu et al.¹⁰²⁾ found that PhGs from C. salsa possessed very high antioxidant activities. Other studies found that PhGs from C. deserticola dramatically increased super oxide dismutase activities, which decreased malondialdehyde levels in mouse hearts, livers, and brains; thus, the authors believed that PhGs could protect skeletal muscles from oxidative injury by eliminating the over-accumulation of free radicals.¹⁰³⁾ Researchers focused attention on natural antioxidants to combat diabetic-nephropathy disease, and study results have indicated that PhGs from C. deserticola could inhibit reactive oxygen free radicals in vitro and repair free radical damage related to diabetic nephropathy.¹⁰⁴⁾ Liang et al.¹⁰⁵⁾ pointed out that PhGs extracted from Herba Cistanche had protective effects on human sperm DNA with oxidative damage in 2015. Compound 18 obtained from Cistanche plants could increase pheochromocytoma cell (PC12 cell) viability against H₂O₂-induced cytotoxicity and decrease the apoptotic rate at the same time.¹⁰⁶⁾ Wang and Zhao¹⁰⁷⁾ established the antioxidant activity of C. deserticola polysaccharides in vitro and found that polysaccharides could obviously scavenge free radicals including the hydroxyl radical, superoxide anion radical, singlet oxygen and diphenyl acyl. In 2016, an efficient ultrasonic-cellulase-assisted extraction of C. tubulosa polysaccharides was established, and its polysaccharides showed appreciable antioxidant activity.¹⁰⁸⁾ Another study pointed out that polysaccharides from C. tubulosa also had great antioxidant activities when evaluated for diphenyl acyl and hydroxyl radicals as well as the scavenging ability of copper ions in vitro.¹⁰⁹⁾ In summary, PhGs and polysaccharides in Cistanche plants are the main antioxidants.

3.2. Anti-Alzheimer’s Disease

AD is one of the most harmful neurological diseases facing elderly individuals and is the focus of much research. As a TCM, studies have proven that water and alcohol extracts of Cistanches Herba have good anti-Alzheimer’s effects. The Consumer Price Index database of China announced that glycosides in Cistanche and Cistanche Yizhi capsules are authorized for the treatment of AD.¹¹⁰⁾ Nerve growth factor (NGF) can enhance memory function, and Korea scholars¹¹¹⁾ found that Cistanches Herba could stimulate NGF secretion, improving cognitive behaviors related to memory abilities. An intracisternal infusion of amyloid β peptide 1–42 (Aβ_1–42) into rats was primarily deposited in the frontal cortex and hippocampus, causing memory deficits in behavioral tasks and inducing an AD-like pathology. The extracts from C. tubulosa have been proven to reduce cognitive impairment caused by Aβ_1–42 by reversing cholinergic neuronal function and blocking amyloid deposition.¹¹²⁾ Amyloid β peptide 25–35 (Aβ_25–35) neurotoxicity can lead to cholinergic system damage, which is an important determinant of cognitive dysfunction. AD. Luo¹¹³⁾ explained the effects and mechanism of Cistanche glycosides in a rat model of AD induced by Aβ_25–35, proposing that PhGs could decrease acetylcholinesterase activities and Ca²⁺ contents in the hippocampus in AD model rats, which would promote normal acetylcholine levels and improve the learning and memory capabilities of AD rats.¹¹⁴⁾ Additionally, C. tubulosa extract, which contains PhGs, similar to compounds 2 and 11, could ameliorate the cognitive dysfunction caused by Aβ_1–42 via blocking amyloid deposition and reversing cholinergic and hippocampal dopaminergic neuronal function.¹¹⁵⁾ Li et al.¹¹⁶⁾ evaluated the neuroprotective effects of Cistanches Herba on AD patients and found that the levels of total tau protein, tumor necrosis factor-α, and interleukin-1β were decreased in the Cistanches Herba capsule group, which proved that this plant has potential neuroprotective effects for AD. PhGs have protective effects on cognitive dysfunction by improving synaptic plasticity in an AD rat model. Jia et al.¹¹⁷⁾ revealed that this AD protective mechanism may inhibit cytotoxicity mediated by Aβ_1–42 administration and reduce oxidant stress. Another experiment also found that PhGs protect neurons by lowering the expression of Aβ_1–42 and Aβ_1–40 protein in the mouse hippocampus. All of these results provide theoretical support for the further development of new drugs against AD.¹¹⁸⁾

3.3. Anti-Parkinson’s Disease

PD is a chronic neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, and its main clinical manifestations include dyskinesia, muscle stiffness, postural instability and resting tremors.¹¹⁹⁾ To date, the etiology of PD has not been fully revealed. However, previous studies consider oxidative stress due to the cellular dysfunction between the production and scavenging of free radicals as the primary mechanism associated with neuronal death.¹¹⁰⁾ Echinacoside (11), a PhG compound, has been proven by many studies to have anti-PD effects. This compound showed neuroprotection in PD mice induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).¹²⁰⁾ Geng et al.¹²¹⁾ found that compound 11 could improve the behavioral and neurochemical outcomes in a MPTP mouse model of PD, which suggested that it can be used as a therapeutic compound for PD. Moreover, Chen et al.¹²²⁾ also concluded that compound 11 could protect striatal dopaminergic neurons by increasing the levels of monoamine neurotransmitters including dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in 6-hydroxydopamine (6-OHDA) lesion rats and may be useful in the prevention and treatment of PD. Compound 11 also protected PC12 cells against 6-OHDA by increasing the mitochondrial membrane potential while decreasing the mitochondria-mediated apoptosis rate, which reduced cytotoxicity and produced a significant neuroprotective effect.¹²³⁾ Furthermore, acteoside (2), an isomer of compound 11, is another important active PhG compound from Cistanche species that showed anti-PD potential by inhibiting 1-methyl-4-phenylpyridinium ion (MPP⁺)-induced SH-SY5Y cell apoptosis; the mechanism of action was also elucidated.¹²⁴⁾ Additionally, compound 2 also had a significant protective effect on MPP⁺-induced cerebellar granule neurons, which may be due to the inhibition of active caspase-3 and proteolytic poly polymerase fragment expression.¹²⁵⁾ Compounds 18 and 37, which are bioactive compounds from Cistanche plants, have also been indicated to possess effective neuroprotective effects against PD.^126,127)

3.4. Endocrine Regulation Activities

Androgen play a key role in the development of male reproductive tissues, and its imbalance can cause kinds of symptoms, including kidney-yang deficiency. As we all know, Cistanches Herba is one of the most frequently used tonic drugs in the prescription for invigorating the kidney-yang. Research has confirmed that there are two main ways to replenish the kidney-yang. One is by enhancing the function of the hypothalamus–pituitary–adrenal axis and promoting the release of related neurotransmitters and hormones in body, the other is by fighting fatigue and improving physical function.¹²⁸⁾ Cistanche can increase the number of pituitary cells, promote the secretion of ovarian progesterone, enhance the expression of estrogen receptor and progesterone receptor of gonadal axis, and inhibit the expression of interleukin-2 receptor in ovaries and interstitial. At the same time, it also can stimulate the production of androgen due to the result of one test that the index of prostate and testis increased significantly in the castrated mice group compared with healthy group.^129–132) PhGs in Cistanche have some intervention on lipid peroxidation damage of sperm membrane in test rats, and they also play a protective role in the structure and function of sperm membrane.¹³³⁾ Studies have shown that PhGs has obvious therapeutic effect on spermatogenic disorders induced by cyclophosphamide in mice, and its mechanism may be related to the improvement of testosterone level in testis.¹³⁴⁾ PhGs have the function of inhibiting the disorder of sexual hormones in perimenopausal model rats and mice, adjusting the imbalance of androgen receptor and estrogen receptor and improving the pathological changes of uterus, thymus, spleen and pituitary.¹³⁵⁾ In addition, decoction of Cistanche can improve the anti-fatigue effect of yang deficiency mice.¹³⁶⁾ In 2004, Pan and Min¹³⁷⁾ found that the alcohol extracts from Cistanche could prevent atrophy of the adrenal cortex in mice with kidney-yang deficiency, and also had a certain protective effects on renal function. Wu et al.¹³⁸⁾ thought that C. deserticola and C. tubulosa both had certain tonic effect on kidney-yang, and their decoction could significantly increase the weight and obviously prolong the cold tolerance time of kidney yang deficiency model mice. C. deserticola decoction was reported to be able to increase the content of serum testosterone and the weight of seminal vesicles and the prostate gland in male rats.¹³⁹⁾ In another research, C. deserticola decoction eased the reproductive toxicity in male rats caused by Leigongteng glycoside.¹⁴⁰⁾ Jiang et al.¹⁴¹⁾ pointed out that a 70% ethanol extract of C. tubulosa could reverse testicular and sperm damage in Sprague-Dawley (SD) rats by upregulating steroidogenesis enzymes in the gonad axis, and compound 11 was one of the active constituents. Moreover, Wang et al.¹⁴²⁾ found that C. tubulosa extracts could improve SD rat progesterone and testosterone levels. In 1996, Zong et al.¹⁴³⁾ researched the androgen-like action on male rats and the effect on phagocytosis of peritoneal macrophages in female mice using C. deserticola, C. tubulosa and C. deserticola that soaked in water for 2 d in order to compare their pharmacological effects. The results showed that C. tubulosa could significantly increase the weight of the anterior space of spermatic sac in castrated rats compared with the other two plants. As for the function on phagocytosis of peritoneal macrophages, C. deserticola and C. tubulosa were similar which both could obviously increase the phagocytic activity. The results of this study may highly be related to the water-soluble compounds with androgen-like effects in these plants. In the same year, a comparison of pharmacological effects of tonifying kidney yang on mice model of yang deficiency caused by hydrocortisone was conducted. The results showed that C. salsa decoction had the best effect, C. deserticola decoction took the second place, and C. tubulosa decoction had the worst effect, which was related to the difference in the content of the three plant medicinal ingredients.¹⁴⁴⁾ Wu et al.¹⁴⁵⁾ studied the pharmacological effects of C. deserticola and C. tubulosa on defecation and invigorating yang, and found that the water extracts of them both had certain laxative effects, and could significantly shorten the defecation time of animals. For the kidney-yang deficiency mice, the cold tolerance time of the mice were both prolonged. So they drew a conclusion that C. tubulosa can be used instead of C. deserticola when the current resources of C. deserticola are rapidly reduced. Studies have shown that the ethanol extracts of Cistanche can significantly increase the weight of testis and seminal vesicle prostate of castrated young mice and rats, the water decoction can improve the phagocytic function of peritoneal macrophages of mice. So the hormonal-like effect, androgen-like effects and non-specific immune function of C. deserticola were confirmed.¹⁴⁶⁾

3.5. Antidepressant

A large amount of evidence suggests that depression, a neuropsychiatric disorder, is linked with the gut microbiome through the gut-brain axis. Iridoids from Herba Cistanche, such as Catalpol (102) and Geniposide (106), have been found to ameliorate chronic unpredictable stress-induced depression-like behaviors, while compound 102 can also upregulate brain-derived neurotrophic factor expression.^147,148) Through experiments, Wang et al.¹⁴⁹⁾ found that decoctions of C. deserticola and C. tubulosa exhibited antidepressant effects and improved spatial learning and memory abilities in a mouse model, which strongly suggests that Cistanche species possess potential antidepressant-like qualities. Moreover, extracts from C. tubulosa can restore brain levels of 5-hydroxytryptamine and brain-derived neurotrophic factor expression in a rat depression model induced by chronic unpredictable stress, and significantly improved depression-like behaviors.⁵³⁾ Li et al.¹⁵⁰⁾ investigated the metabolism of a C. tubulosa extract in normal and chronic unpredictable stress-induced depressive rats, and the results contributed to understanding the therapeutic mechanism of antidepressant properties.

3.6. Anti-osteoporosis Activities

Osteoporosis is a very common chronic disease. This disease is often characterized by low bone mass, which is most commonly seen in middle aged and elderly people, especially women; for example, the loss of estrogen is thought to be the major reason for bone loss in postmenopausal woman. A previous research indicated that Cistanches Herba can guide bone mesenchymal stem cells to differentiate into osteoblasts, which leads to good prospects for the treatment of osteoporosis and bone fracture disunion.¹⁵¹⁾ Liang et al.¹⁵²⁾ reported that a water extract of Cistanches Herba could reverse bone loss and prevent the occurrence of osteoporosis in female rats. Chen et al.¹⁵³⁾ pointed out that Cistanches Herba polysaccharides may accelerate the bone marrow cell cycle transition, promote the recovery of hematopoietic function in bone marrow-depressed anemic mice, and expedite hematogenesis in rubrum and macronucleus strains. By combining the in vivo and in vitro experimental data, compound 11 isolated from C. tubulosa has remarkable activity against osteoporosis.^154,155) Li et al.¹⁵⁶⁾ used Western blotting to investigate the mechanism of action of C. deserticola extract and concluded that C. deserticola may be a novel bone formation agent for the treatment of osteoporosis. In 2013, another researcher aimed to elucidate the molecular mechanism of Cistanches Herba aqueous extracts on postmenopausal osteoporosis in an ovariectomized rat model and concluded that Cistanches Herba has a protective effect against bone degeneration by partially regulating some bone metabolism-related genes.¹⁵⁷⁾ Xu et al.¹⁵⁸⁾ focused their attention on Cistanoside A (3), a compound from C. deserticola, for osteoporosis treatment. Their study revealed that compound 3 could promote bone formation by downregulating TNF-receptor-associated factor 6 and coordinating the inhibition of nuclear factor kappa-light chain enhancer in activated B cells and stimulation of the phosphatidylinositol 3-kinase/Akt pathway.

3.7. Hepatoprotective Activities

The liver plays a key role in detoxifying the body and synthesizing useful substances. Hepatic fibrosis is a pathophysiological process considered as the wound-healing response of the liver to various toxic stimuli, such as hepatitis, alcohol and immunostimulant compounds, and the long-term development of fibrosis may lead to serious disease consequences. However, despite the high incidence of liver fibrosis worldwide, there is no generally accepted anti-fibrosis therapy to date. Previous studies focused on the preventive and therapeutic effects of PhGs on bovine serum albumin-induced hepatic fibrosis in rats have provided a direction for the treatment of this disease. An experiment on the hepatoprotective effects of four PhGs, namely, compounds 1, 2, 12, and 18, on both carbon tetrachloride- and D-galactosamine-induced hepatotoxicity in vitro, as well as the effects of compound 2 against carbon tetrachloride-intoxication in vivo, showed that these four PhGs all possessed hepatoprotective activities.¹⁵⁹⁾ Morikawa et al. from Japan found that acylated phenylethanoid oligoglycosides from fresh stems of C. tubulosa showed hepatoprotective effects in 2010.³⁷⁾ The ability to block carbon tetrachloride bioactivation and free radical scavenging effects may be the mechanisms of compound 2 against carbon tetrachloride-induced hepatotoxicity, which was confirmed by the scholars of South Korea.¹⁶⁰⁾ In another study, free radical damage of the liver caused by carbon tetrachloride in rats was tested with compound 11, and the results showed that serum alanine aminotransferase and aspartate aminotransferase levels, hepatic malondialdehyde contents, and reactive oxygen species production were reduced dramatically. Additionally, histopathological damage to the liver and the number of apoptotic hepatocytes were all distinctly ameliorated.¹⁶¹⁾ By increasing free radical-clearing activities, alleviating lipid-overoxidation damage, and improving respiratory chain function in the mitochondria, compound 3 could protect the liver from carbon tetrachloride-induced hepatotoxicity in mice.¹⁶²⁾ Moreover, Luo et al.¹⁶³⁾ also demonstrated that compound 3 could enhance the survival rate of primary cultured hepatocytes and alleviate apoptosis and necrosis. By inhibiting apoptosis and inflammation, compound 11 could provide a pronounced protection against D-galactosamine-induced acute liver injury in mice.¹⁶⁴⁾ You et al.¹⁶⁵⁾ demonstrated that compounds 2 and 11 can block transforming growth factor-β1 signaling pathways and inactivate hepatic stellate cells, indicating that C. tubulosa may be a potential herbal medicine for the treatment of liver fibrosis. Guo et al.¹⁶⁶⁾ discovered that polysaccharides from C. deserticola possessed hepatoprotective activities against chronic hepatic injury induced by alcohol, and the underlying mechanism was also proposed. Recent studies have proven that PhGs possess hepatoprotective properties against alcohol-induced chronic hepatic disease¹⁶⁷⁾ and induced apoptosis in hepatocellular carcinoma cells through both the intrinsic and extrinsic signaling pathways.¹⁶⁸⁾

3.8. Antidiabetic Activities

Diabetes can cause a variety of complications such as coronary heart disease, myocardial infarction, and cerebral infarction. In recent years, numerous investigations have demonstrated that PhGs, polysaccharides and polyphenols exert anti-hyperglycemic effects or have beneficial influences in type 2 diabetes mellitus through their cholesterol-lowering and free radical-scavenging effects and their modulation of glucose-induced oxidative stress by researchers from Japan, the United States and Australia.^169–172) These findings suggested that PhGs and polysaccharides are both main active ingredients in Herba Cistanche. For the first time, Xiong et al.¹⁷³⁾ demonstrated that C. tubulosa could be used to fight diabetes by lowering blood sugar and lipid levels in type 2 diabetic male mice. The injection of compounds 2 and 11 lowered postprandial blood glucose levels, elevated glucose tolerance in starch-loaded mice and inhibited rat intestinal α-glucosidases, lens aldose reductase and human intestinal maltas activity in vitro.¹⁷⁴⁾ Wong et al.¹⁷⁵⁾ reported that a Cistanches Herba ethanol extract markedly reduced weight gain and improved the insulin sensitivity of diabetic mice, probably due to mitochondrial uncoupling and increased energy consumption.

3.9. Cardiovascular Protection

Once cardiovascular disease appears, it does great harm to the human body and can even cause sudden death. Phenylethanoid oligoglycoside and acylated oligosugar compounds from the methanol extraction of C. tubulosa displayed vasorelaxant activities in isolated rat aortic strips.³¹⁾ Extracts from C. deserticola could stimulate ATP generation via enhancing oxidative phosphorylation in H9c2 cells; thus, rat hearts were protected against myocardial ischemia/reperfusion (I/R) injury.¹⁷⁶⁾ To explain the role of the mitochondria in the cardioprotective actions of Herba Cistanche, Siu and Ko from Hong Kong, China¹⁷⁷⁾ investigated the treatment of Herba Cistanche on mitochondrial glutathione status in rat hearts and observed enhanced mitochondrial glutathione status and functional ability as well as the putative induction of uncoupling proteins, which may be related to the cardioprotection by Herba Cistanche. Wong and Ko¹⁷⁸⁾ revealed the mechanism underlying the cardioprotective actions of Herba Cistanche via mitochondrial respiration and glutathione antioxidant status in H9c2 cardiomyocytes. Combining in vivo and in vitro approaches, Yu and Cao ¹⁷⁹⁾ discussed the cardioprotective effects and mechanism of PhGs from C. deserticola against I/R injury. The in vitro and in vivo effects of compound 2 on human platelet aggregation were examined by scholars from Italy, and it was found that long-term administration of compound 2 at a dose of 100 mg/kg significantly reduced platelet aggregation in subjects with cardiovascular risk factors.^180,181) The vasorelaxant activity of compound 11 was proven by its ability to improve endothelium-dependent relaxation through the NO-cGMP signal pathway in rat aortic rings.¹⁸²⁾ Cai et al.¹⁸³⁾ demonstrated that compound 11 suppressed noradrenaline-induced contraction of the rat pulmonary artery by reducing intracellular Ca²⁺ levels; compound 11 induced its relaxation and achieved its vasorelaxant effects through the NO-cGMP pathway and by opening K⁺ channels.

3.10. Anti-inflammation Activities

Inflammation is a common defensive response of the body to external stimuli that is characterized by redness, swelling, fever, pain, and dysfunction. As we all know, nitric oxide (NO) is a pro-inflammatory molecule that plays an important role in the lipopolysaccharide (LPS)-mediated inflammatory process. In 1997, Shimamura et al. in Japan found that the free fatty acids especially the cis-isomers from C. Salsa were the main components had the suppressive effect of the SOS-inducing activity of Trp-P-1(3-amino-l,4-dimethyl-5H-pyrido[4,3-b]indol) by GC and GC-MS method, which suggested they can be used as an anti-inflammatory substances.¹⁸⁴⁾ Seven PhGs compounds, namely, compounds 1, 2, 3, 11, 12, 17 and 18 from the stems of C. deserticola, were investigated and proven to possess NO radical-scavenging activities by Japanese researchers, which may contribute to their anti-inflammatory effects.¹⁸⁵⁾ Lin et al.¹⁸⁶⁾ from China Taiwan found that the butanoic and aqueous layers from C. deserticola are the main active constituents with analgesic and anti-inflammatory effects. Nan et al.⁴⁴⁾ found compounds 18 and 39 can potently inhibit NO production induced by LPS in mouse microglial cells (BV-2 cells). Acteoside (2) is a well-known PhG with antioxidant and anti-inflammatory activities, and many studies focused on its anti-inflammatory activities have been conducted. Systematic studies on the anti-inflammatories activity of compound 2 were carried out in vitro and in vivo by Hayashi and his co-workers from Japan.^187,188) Lee et al.¹⁸⁹⁾ from South Korea discovered that compound 2 could inhibit NO synthase expression induced by LPS in the RAW264.7 macrophage cell line. In 2010, Japanese researchers Yamada¹⁹⁰⁾ and his team investigated the effects of compound 2 extracted from C. tubulosa on the basophilic cell-mediated allergic reaction, and the results suggested that it could be a good candidate for the therapeutic treatment of various allergic diseases. Combination of the C. tubulosa extract with fucoidan inhibited NO and prostaglandin E₂ production in an air pouch inflammation mouse model caused by carrageenan.¹⁹¹⁾ Additionally, compound 2 also decreased lung inflammatory responses in an LPS-induced acute lung injury mouse model, the mechanism of which might be partially attributed to the inhibition of pro-inflammatory cytokine production and nuclear factor-kappaB (NF-κB) activation.¹⁹²⁾ Moreover, a study on anti-inflammation found that compound 2 not only exhibits antinociceptive effects but also has antioxidant properties.¹⁹³⁾ In 2015, Shin et al.¹⁹⁴⁾ from Korea demonstrated that combination oral treatment of Laminaria japonica extract and C. tubulosa extract at appropriate doses and ratios can prevent hair loss and improve alopecia. Their conclusion is consistent with the results obtained by Seok from their own country in the same year.¹⁹⁵⁾ C. salsa extracts also showed antiproliferative effects on benign prostatic hyperplasia rats by regulating inflammatory cytokines or depressing apoptosis-associated proteins, which was proven by Korean researchers.¹⁹⁶⁾ In 2007, Hausmann et al. from Germany proved that PhGs could alleviate intestinal inflammation in dextran sulphate sodium-induced colitis.¹⁹⁷⁾ Researchers from Australia and Greece found compound 2 could alleviate intestinal mucositis in mice by preventing inflammation in 2015.¹⁹⁸⁾ In 2016, the chemical compounds in C. violacea and their anti-inflammatory activities were studied by scholars from Algérie and Italy.⁶⁾

3.11. Gastrointestinal Tract Protection Activities

Cistanches Herba has always been a good medicine for gastrointestinal diseases and constipation. Compound 2 not only ameliorated mucosal tissue damage in acute and chronic colitis mouse models and could be a therapeutic alternative for inflammatory bowel disease treatment but also alleviated mucosal layer damage in mice by potentially preventing inflammation.^197,198) A C. deserticola water extraction could increase gastrointestinal tract peristalsis and shorten the defecation time in a mouse model.¹⁹⁹⁾ The water extract from C. deserticola reduced the number of mucosal hyperplasias and intestinal helicobacter infection in mice, indicating that this plant may prevent intestinal inflammation disorders including colorectal cancer.²⁰⁰⁾ Gao et al.²⁰¹⁾ proved that the total oligosaccharides and galactitol were the main active laxative components in a mouse model. Compound 11 improved mucosal tissue repair and prevented dextran sulfate sodium-induced colitis in mice via cell and rat experiments, implying the potential of this compound to clinically treat inflammatory bowel disease.^202,203) Japanese scholars found that the medicinal extract from C. tubulosa could alter the route of intestinal absorption, which may lead to better management of human health.²⁰⁴⁾ A study of the chemical constituents and pharmacological effects of C. salsa and C. deserticola was conducted by Xu et al. early in 1995. Compared with C. deserticola, C. salsa not only contained similar chemical components, but also had the same functions of moistening intestines and defecating, nourishing yang, but the pharmacological effect of C. salsa was better than C. deserticola to a certain extent.²⁰⁵⁾ Also the cathartic action of C. deserticola, C. salsa and C. tubulosa was compared in another research and their effects were basically the same.²⁰⁶⁾

3.12. Immunoregulatory Activities

Many different types of polysaccharides with various immunomodulatory activities have been reported. Ebringerova et al.²⁰⁷⁾ from Slovakia reported that the isolated polysaccharide cistan A exhibited remarkable immunomodulatory activities that exceeded those of the commercial immunomodulator Zymosan. In an in vitro immune test on mitogen-induced lymphocyte proliferation, one crude polysaccharide fraction from Cistanches Herba showed significant stimulating activities towards both T- and B-cell proliferation, while another polysaccharide showed stimulating activities towards LPS-induced B-cell proliferation. These findings demonstrated that these two polysaccharides probably play an important role in the expression of immunological activity.²⁰⁸⁾ Japanese scholars Maruyama et al.²⁰⁹⁾ reported that a C. salsa extract could stimulate the production of immunoglobulin M (IgM) and immunoglobulin G (IgG) in human lymph node lymphocytes and speculated that the increase in antibody production may be related to interleukin-6 receptor expression in B-cell activation. Both naive T and natural killer cells in blood and spleen cell populations in tested animals were significantly increased after the mice were orally administered a C. deserticola extract for 4 weeks. The results showed that C. deserticola possessed significant effects to extend life span, and this was probably achieved by antagonizing immunosenescence.²¹⁰⁾ Li et al.²¹¹⁾ remarked that PhGs from C. tubulosa inhibited the growth of melanoma B16-F10 cells in vitro and in vivo probably through immunoregulatory functions. Polysaccharides from C. deserticola are a safe and effective vaccine adjuvant for eliciting both humoral and cellular immunity.²¹²⁾ This has also been proven in seasonal influenza vaccines in young adult mice, in which polysaccharides enhanced the immunogenicity of the seasonal influenza vaccine by inducing hemagglutinin inhibition antibody generation. This study provided evidence for the induction of humoral and cellular responses, which were rapid immune responses in mice after intramuscular injection with aqueous extracts of a C. deserticola-adjuvanted vaccine.²¹³⁾ Shi et al.⁹⁸⁾ carried out immunopharmacological tests with ethyl acetate extracts in different species of Herba Cistanche, and the results showed that they all could activate lymphocytes to kill K562 cells at a certain concentration and C. tubulosa had the strongest medicinal effect to enhance the immunity among them. Taken together, we can conclude that polysaccharides are closely linked with immunoregulatory activities.

3.13. Other Biological Activities

Many other biological activities have been discovered during studies. A fatty acid from C. sala showed a suppressing effect on SOS-induced mutagenesis activity.¹⁸⁴⁾ Lu²¹⁴⁾ reported that C. deserticola extracts had sedative effects. Huang et al.²¹⁵⁾ found that compound 2 could alleviate hyperuricemia in a potassium oxonate-induced hyperuricemic mouse model, and Cai et al.²¹⁶⁾ found that a C. deserticola extract showed antifatigue effects. Compound 11 isolated from C. salsa had antisenescence activities by decreasing p53 expression and could improve the recovery of hematopoietic functions in a bone marrow depression mouse model by activating the granulocyte macrophage colony-stimulating factor (GM-CSF)/phosphatidylinositol 3-kinase (PI3K) pathway.^217,218) Wong et al.¹⁷⁵⁾ conducted a study demonstrate that Cistanches Herba had obesity-suppressing activities through mitochondrial uncoupling. Wu et al.²¹⁹⁾ found a new protective effect of C. tubulosa extract, whereby it can resist low-luminance blue light-induced degenerative retinopathy. Furthermore, water-soluble PhGs from C. tubulosa displayed effective anti-tumor effects in esophageal cancer by inducing apoptosis in Eca-109 cells through a mitochondrial-dependent pathway.²²⁰⁾

4. Processing

As a tonic, Herba Cistanche has been used as medicine after multiple processing for a long time. “steaming or stewing with wine” is the processing methods of Cistanche in the 2015 Pharmacopoeia. Raw product of Cistanche can nourish the kidney, stop turbidity, and has a strong laxative effect. After processing according to method of Pharmacopoeia, it can strengthen the power of tonifying the kidney, and is mostly used for impotence, infertility. On the basis of the main chemical composition and pharmacological action of Cistanche, it is necessary to explain the processing principle of increasing efficiency about this plant, so as to provide necessary scientific basis for processing technology of Herba Cistanche. Cai et al. studied the processing technology of fresh C. tubulosa that was cut into 4 mm thick slices and killed enzyme at 70°C for 6 min. Compared with direct drying in traditional method, the compound content of 2 and 11 were greatly increased.²²¹⁾ Wang et al.²²²⁾ researched the effect of different processing temperature on the chemical composition of C. deserticola. The content of PhGs was similar in natural temperature and drying at 40°C, but there was a downward trend when the processing temperatures exceed 40°C. The total amount of 2 and 11 was the highest in natural air-drying, while polysaccharide was the highest at 60°C. It is showed that the thickness, drying method, drying time and different enzyme inhibition methods of the decoction pieces could greatly affect the content changes of PhGs in C. deserticola.²²³⁾ Liu²²⁴⁾ optimized the three cutting processing technologies including moistening, softening, and steaming of C. tubulosa, the result showed that the steaming method had the highest recovery rate, and the content of ethanol extracts meets the requirements of the Pharmacopoeia, which can be used as the optimal cutting technology. Jiang et al.²²⁵⁾ examined the factors of the processing method of C. deserticola and considered that the slices were steamed for 2 h, softened, cut into 6 mm thick slices and dried at 70°C was the best processing technology. Based on the ancient and modern literature, according to the Pharmacopoeia and the national processing standards, through the experimental screening, combined with the appearance, color, odor, content of 176 and PhGs, Chen et al. determined that the best processing method of C. deserticola was adding 30% yellow wine and 25% water, steaming and stewing for 12 h.²²⁶⁾ Using high-pressure sterilization cabinet to steam C. deserticola could avoid the decrease in the content of active ingredients due to the loss of medicinal juice in traditional steaming method. Qian and He found that under the condition of 686 kpa and 120°C, steaming for 2 h is the best processing method of C. deserticola.²²⁷⁾ Yu et al.²²⁸⁾ found that the Cistanche processed by steam could increase the DNA synthesis rate and metal trace elements in yang deficiency animals, which indicated that the traditional processing method of Cistanche was significant. Duan et al.²²⁹⁾ studied the effects of processing of different concentrations of yellow wine on the laxative effect of Cistanche deserticolata and showed that within a certain range, the increase of the concentration of yellow wine would promote the laxative effect. In the study of modern processing of Cistanche, besides the processing method in the trueborn areas, more other studies are on the different technologies using yellow wine and its influence on the chemical compositions and pharmacological activities of Cistanche. It has been shown that the PhGs in Herba Cistanche, which have the function of tonifying kidney yang, will undergo hydrolysis reaction and isomerization reaction in the process of wine processing, but whether there will be further hydrolysis reaction and decaffeoyl reaction, and whether these components produced in the process of wine processing are the medicinal substance basis for the efficacy of Cistanche remains to be further studied. According to historical records, C. deserticola processed by wine can weaken its purgative effect, and modern research has also proved that the effect of raw products on defecation is better than that of wine products. Although wine products can also increase the intestinal propulsion of mice, the laxative time is not significantly shortened. Duan et al.²³⁰⁾ also confirmed that when the concentration of rice wine was below 9.5%, the effect of Cistanche deserticola on the progress of intestinal push in mice increased with the increase of alcohol concentration. Further studies have shown that galactitol is one of the effective components of Cistanche deserticola for moistening intestines and defecating.^231,232) One study showed that there were no significant differences between the water decoction (for phagocytosis experiment) and the alcohol-soluble part (for aphrodisiac experiment) of C. deserticae and its processed product which was stewed with rice wine for 24 h, indicating that there was no significant difference between the two in kidney tonic and Yang tonic effects.²³³⁾ The appearance characters were softer, the powder color was brighter in steaming group than those of sun drying group. Except for cistanoside A (compound 3), the contents of PhGs (compounds 1, 2, 11 and 12), polysaccharides, soluble saccharides and ethanol-soluble extract in the steaming group were all higher than those in the sun drying group, and the antioxidant activity was significantly stronger, which indicated that steaming can be adopted in the large-scale post-harvest processing of C. deserticola.²³⁴⁾

5. Toxicity and Safety Evaluation

Cistanches Herba has been regarded as an important tonic in traditional eastern medicine for centuries. Owing to its excellent nourishing functions, the stem of this herb has also been developed as a nourishing supplement and is popular in the health food market. Research data on the toxicity and safety evaluation of Cistanches Herba revealed that this medicine is truly safe. The acute, 90-d feeding test has been performed in rats, and genetic toxicities of Rou Cong Rong tea have been evaluated. The LD₅₀ values of acute oral toxicity of Rou Cong Rong tea were greater than 60 g/kg. No severe genetic toxicity was observed in the experiments.²³⁵⁾ Studies focused on the acute toxicity, genetic toxicity and subchronic toxicity of C. tubulosa extract on Kunming mice and Wistar rats²³⁶⁾ as well as the subchronic toxicity of C. tubulosa extract on SD rats²³⁷⁾ have been conducted, and both experiments showed no apparent toxicity. In 2014, acute toxicity tests, including the bone marrow cell micronucleus test, mice sperm abnormality test, and Ames test, and a 90-d feeding study were conducted to toxicologically evaluate C. deserticola. The results showed that the acute oral maximum tolerated dose of C. deserticola to mice was greater than 20 g/kg body weight, which was over 600 times higher than the recommended human dose, indicating that C. deserticola was nontoxic.²³⁸⁾ The acute toxicity reaction of mice was observed after treatment with an ethanol extract from artificially planted C. deserticola for 14 successive days, and no acute toxicity was found.²³⁹⁾ In 2015, an acute oral toxicity test; mouse genetic toxicity tests, including the Ames test, mouse sperm abnormality test, and bone marrow cell micronucleus test; and a rat 30-d feeding test were conducted to evaluate the toxicological safety of Herba Cistanche granules. The results indicated that Herba Cistanche granules had no acute toxicity, genetic toxicity or subacute toxicity.²⁴⁰⁾ In 2016, a study of the acute toxicity and long-term feeding subchronic toxicity of C. deserticola was performed, and after 90 d of mixed feeding, animal indexes for food consumption, food utilization rate, blood, biochemistry, organ coefficients and tissue pathology were explored by using the maximum-tolerated dose (MTD) method, with no obvious toxicity observed.²⁴¹⁾ The same year, Qiao²⁴²⁾ examined the acute toxicity of allantoin extract from Rou Cong Rong in mice fed the maximum concentration of 6.5 g crude drug/mL and the largest volume of 20 mL/kg twice a day for 14 d. The test results showed that allantoin extract from Herba Cistanche is safe. Herba Cistanche is also safe to maternal and fetal rats according to the results of a study testing the effect of C. deserticola on reproductive toxicity and teratogenicity in rats.²⁴³⁾ Acute toxicity test on rats and a 30-d feeding test were conducted to study the safety of C. tubulosa compound tablets. It showed that C. tubulosa compound tablets were safe to rats given a dose of 26.4 g/kg, and no poisoning symptoms were observed.²⁴⁴⁾ The potential toxicity of powdered C. deserticola as a novel food ingredient was examined in a subchronic toxicity study (90 d) in SD rats; this toxicological assessment included mortality, body and organ weight, food consumption, blood biochemistry, hematology, gross necropsy and histopathological examinations. The results showed no signs of toxicity or treatment-related changes in the rats treated with powdered C. deserticola.²⁴⁵⁾ C. tubulosa extract product Memoregain^® was proved no genotoxicity based on the Ames test, chromosomal aberrations assay, and mammalian micronucleus test, and no observed adverse effect which was determined by both male and female rats.²⁴⁶⁾ Presently, no severe adverse drug events have been reported with Herba Cistanche, and Rou Cong Rong products are widely used in both the clinic and health food markets. More toxicity and safety data focused on Herba Cistanche and its products should be collected to ensure the safety and effectiveness of this medicine.

6. Discussion and Future Perspectives

Herba Cistanche, a folk herbal medicine, has been commonly used as a tonic herb in China for a thousand years and traditionally for tonifying kidneys and invigorating yang. PhGs are the most important active ingredients that have been proven to possess multiple medical functions, including those for the male reproductive system, bone metabolism, immune system, and neural system, through in vivo and in vitro studies and deserve to be studied more in the future. To date, most studies have mainly focused on compounds 2 and 11; thus, other PhG compounds should be deeply investigated to better understand their pharmacological mechanisms.

In view of evident therapeutic efficiency, Cistanches Herba needs to be further developed into new pharmaceutical agents for the treatment of various diseases such as kidney yang deficiency and neurological and intestinal disorders. However, the difficulties associated with the development these agents are obvious, as most studies have only focused on phenotype analysis, such as morphocytology detection, immunohistochemistry and biochemical indicator analysis. Therefore, more bioactivity studies that investigate molecular biology, bioinformatics and chemical biology technologies should be carried out, as they may provide useful information and solid evidence for clinical applications. These may be important future challenges and opportunities for Cistanches Herba.

In this article, we reviewed the information available on Cistanches Herba, including its phytochemistry, pharmacology, toxicity and safety, to provide useful knowledge for future studies and for the commercial exploitation of Cistanches Herba.

Acknowledgments

The work was supported by Professor of Chang Jiang Scholars Program, the National Natural Science Foundation of China (81520108030, 21472238), Shanghai Engineering Research Center for the Preparation of Bioactive Natural Products (16DZ2280200), the Scientific Foundation of Shanghai China (13401900103, 13401900101), the National Key Research and Development Program of China (2017YFC1700200).

Conflict of Interest

The authors declare no conflict of interest.

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