Chinese Journal of Natural Medicines  2018, Vol. 16Issue (11): 811-828  DOI: 10.3724/SP.J.1009.2018.00811
0

Cite this article as: 

ZHANG Ben-Mei, WANG Zhi-Bin, XIN Ping, WANG Qiu-Hong, BU He, KUANG Hai-Xue. Phytochemistry and pharmacology of genus Ephedra[J]. Chinese Journal of Natural Medicines, 2018, 16(11): 811-828.
[Copy]

Research funding

The study was supported by the Major State Basic Research Development Program (973 Program) of China (No. 2013CB531800)

Corresponding author

KUANG Hai-Xue, Tel:86-451-87267188, Fax:86-451-8726-7188, E-mail:hxkuang@yahoo.com

Article history

Received on: 28-Dec-2017
Available online: 20 November, 2018
Phytochemistry and pharmacology of genus Ephedra
ZHANG Ben-Mei1 , WANG Zhi-Bin1 , XIN Ping1 , WANG Qiu-Hong2 , BU He1 , KUANG Hai-Xue1     
1 Key Laboratory of Chinese Materia Medica(Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin 150040, China;
2 Department of Natural Medicinal Chemistry, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510000, China
[Abstract]: The genus Ephedra of the Ephedraceae family contains more than 60 species of nonflowering seed plants distributed throughout Asia, America, Europe, and North Africa. These Ephedra species have medicinal, ecological, and economic value. This review aims to summarize the chemical constituents and pharmacological activities of the Ephedra species to unveil opportunities for future research. Comprehensive information on the Ephedra species was collected by electronic search (e.g., GoogleScholar, Pubmed, SciFinder, and Web of Science) and phytochemical books. The chemical compounds isolated from the Ephedra species include alkaloids, flavonoids, tannins, polysaccharides, and others. The in vitro and in vivo pharmacological studies on the crude extracts, fractions and few isolated compounds of Ephedra species showed anti-inflammatory, anticancer, antibacterial, antioxidant, hepatoprotective, anti-obesity, antiviral, and diuretic activities. After chemical and pharmacological profiling, current research is focused on the antibacterial and antifungal effects of the phenolic acid compounds, the immunosuppressive activity of the polysaccharides, and the antitumor activity of flavonoids.
[Key words]: Ephedra     Phytochemistry     Pharmacology    
Introduction

Ephedra is a genus of non-flowering seed plants belonging to the Ephedraceae family [1], which includes approximately 67 species, mainly in the desert areas of Asia, America, Europe and North Africa. Among these species, 15 ones and four varieties can be found in China. Ephedra sinica is a member of genus Ephedra and is the primary species that has been used in China for more than 5000 years [2].

Ephedrae Herba is defined as the stem of Ephedra sinica Stapf, Ephedra intermedia Schrenket C. A. Meyer, or Ephedra equisetina Bunge (Ephedraceae) in the Chinese Pharmacopoeia 15th edition. Dried E. sinica stems are traditionally used to treat cold, bronchial asthma, cough, fever, flu, headache, edema and allergies. E. sinica has become a natural product source of ephedrine, pseudoephedrine, and other compounds [3]. In addition, in some western countries, Ephedra sinica has been used as a dietary supplement [4]. It can also be used to lose weight by increasing sweating and basal metabolism and by stimulating the central nervous system [5]. Moreover, it has also been combined with cardiovascular drugs to treat cardiovascular diseases [6]. Many reports about the side effects of E. sinica have emerged, especially in western countries. A number of side effects of over-the-counter drugs containing ephedrine have been reported, such as myocardial infarction, arrhythmia, epilepsy, loss of consciousness, and death [7]. In 2004, the FDA announced the prohibition of dietary supplements containing E. sinica [8]. With the restriction on the use of E. sinica and its related preparations in the US, other countries have also joined the ban, which has led to difficulties in the use and development of ephedra drugs. To resolve this problem, novel pharmacological effects of ephedra should be investigated. In addition to ephedrine alkaloids, there are other substances in ephedra, such as polysaccharides, flavonoids (30-71), tannins (72-118), and miscellaneous compounds (119-145). These substances have anti-inflammatory, anticancer, antibacterial, antioxidant, and hepatoprotective activities. We conducted a systematic review of the literature to summarize the currently reported chemical constituents and pharmacological activities of Ephedra.

Historical and Botanical Characterization of Ephedra

E. sinica is one of the original species of the Ephedraceae family that was recorded in the Chinese Pharmacopoeia as "Ma Huang". As a stimulant and an anti-asthmatic, E. sinica has a long medicinal history for the treatment of cold, fever, headache, rhinobyon and other symptoms [9]. In the ancient Han Dynasty, E. sinica was recorded as a stimulant and antitussive agent. During the time of the Roman Empire, E. sinica was well known until it was eventually dropped from medieval European literature [10]. However, in the beginning of the 20th century, Ephedra sinica emerged as a weight loss and performance enhancement drug and gradually attracted interest. However, products containing Ephedra were banned in the US in 2004 after several years of high-profile reports of adverse events [11].

E. sinica plants are perennial herbs standing, more than one meter tall, with thin stems, no leaves, and a strong smell of pine and astringency [12]. Furthermore, E. sinica is a drought-tolerant shrub distributed in both temperate and subtropical arid environments in the northern hemisphere and South America [13].

Progress in Phytochemical Studies on the Genus Ephedra

Until now, phytochemical studies have revealed that more than 145 compounds have been isolated and identified from the genus Ephedra, including alkaloids, flavonoids, tannins, and polysaccharides. The compounds isolated from each species are documented in Tables 1-6. Their chemical structures are shown in Figs. 1-5.

Table 1 Alkaloids different species of the genus Ephedra (the structures of main compounds are illustrated in Fig. 1)
Figure 1 Alkaloids isolated from the genus Ephedra
Table 2 Flavonoids of different species of the genus Ephedra (the structures of main compounds are illustrated in Fig. 2)
Figure 2 Flavonoids isolated from the genus Ephedra
Table 3 Tannins compounds of different species of the genus Ephedra
Table 4 Monosaccharide composition and proportion of polysaccharides from Ephedra sinica
Table 5 Monosaccharide composition and proportion of polysaccharides from Ephdra distachya
Table 6 Miscellaneous compounds of different species of the genus Ephedra
Figure 3 Tannins isolated from the genus Ephedra
Figure 4 The tentative structures of the arabinan (ESP-B1H)
Figure 5 Structures of miscellaneous compounds from different species of the genus Ephedra
Alkaloids

Alkaloids are the main components of this genus. Twenty-nine alkaloids, 1-29, were isolated from this genus. Structural characteristics of these compounds are listed as follows: (1) the amphetamine-type alkaloids (6-18) are the main active ingredients of E. sinica, including amphetamine alkaloids of three stereoisomers (6-11). In addition, compound 12, structurally similar to ephedrine, is an anti-inflammatory compound isolated from Ephedra sinica and belongs to the oxazolone derivatives. Compounds 13 and 14 may also belong to the oxazolidine alkaloid of the structure. Compounds 15 and 16, structurally similar to pseudoephedrine and ephedrine, are trace alkaloids in E. sinica. Compound 18 is a new amphetamine-type alkaloid, which is isolated from the ethanol extract from the E. sinica stem. (2) Ephedrines isolated from the E. sinica root are mainly macrocyclic spermine alkaloids (1-4) and an imidazole alkaloid (5). (3) In recent years, five new quinoline alkaloids have been isolated from other species of Ephedra (19-23). These quinoline alkaloids have a carboxyl group on the C-2 position and have oxygen-containing substitutions on the benzene ring (20, 22-23). Generally, these substitutions are methoxyl and hydroxyl groups. (4) A pyrrolidine alkaloid (24) is isolated from the seeds of E. foeminea and E. foliata. (5) Other alkaloids (25-29) have been isolated from other species of Ephedra. The plant sources, names and structures of these alkaloid compounds are shown in Table 1 and Fig. 1.

Flavonoids

Flavonoids are the most common class of secondary metabolites within this genus. More than forty flavonoids (30-71) have been identified from the genus Ephedra, which are classified as flavonols (30-46), dihydroflavonols (47-48), flavonones (49-51), flavanols (52-57), flavones (58-69), and anthocyans (70-71). Flavones and their glycosides, as well as flavonols and their 3-O-glycosides constituents, are the most common flavonoids in Ephedra. The sugar moieties of these flavonoid glycosides are commonly made up of glucose and rhamnose. Formerly, it was believed that most flavonoids in the genus were derivatives of the flavonol aglycones kaempferol, herbacetin or quercetin. Recently, some other aglycones such as apigenin, catechin, luteolin, and hesperetin have been characterized. Most flavonoid glycosides are mono-glycosides or di-glycosides. In addition, three glycosides (35) and four glycosides (69) are also present. Information about flavonoids is shown in Table 2 and Fig. 2.

Tannins

Tannins are also important compounds in Ephedra, which mainly exist in the form of condensation. Tannins, mainly proanthocyanidins, have been proven to be present in many Ephedra plants (e.g., Eurasian Ephedra: E. przewalskii, E. alata, E. distachya, E. fragilis and E. intermedia; North American Ephedra: E. californica, E. nevadensis, E. fasciculata, E. trifurca, E. torreyana, and E. viridis) [14]. At present, the condensed tannins of procyanidin A-type (Fig. 4) are the most common in Ephedra [15], containing dimers (72-98), trimers (99-110, 112, 113), and tetramers (114-118). These compounds are made of flavan-3-ol monomer units, which are linked together through C4-C6 (107, 108), C4-C8, or C2-O-C7 bonds. Compound 111 belongs to the B-type proanthocyanidins, which do not contain C-O-C bonds. In addition, all the flavan-3-ol monomer units are afzelechin/epiafzelechin, catechin/epicatechin, and gallocatechin/ epigallocatechin. The plant species, chemical names, and structures of tannins are shown in Table 3 and Fig. 3.

Polysaccharides

Large-molecule components in Ephedra species have also been studied. Ephedra sinica contains a high amount of polysaccharides, which range from 3% to 5% of the total dry weight [16]. Additionally, it has been reported that the concentration of uronic acid measured by the phenol sulfuric acid method is 45.9% [17]. A water-soluble arabinan (Mw 6.15 kDa) has been isolated from the E. sinica stems and investigation of its structure has indicated that the polysaccharide consists of (1→5)-Araf, (1→3, 5)-Araf, T-Araf, (1→3)-Araf, and (1→2, 5)-Araf residues at proportions of 10 : 2 : 3 : 2 : 1. The structure includes a branched (1→5)-α-Araf backbone where branching exists at the O-2 and O-3 positions of the residues with 7.7% and 15.4% of the 1, 5-linked α-Araf substituted at the O-2 and O-3 positions. The presence of a branched structure contains a much longer linear (1→5)-α-Araf backbone as a repeating unit. Generally, the tentative structure of the arabinan (ESP-B1H) is shown in Fig. 4 [18]. Another acidic hetero-polysaccharide (ESP-B4) has been isolated from E. sinica and shows an immunosuppressive effect [19]. It contains a repeating unit of [→4]-GalpA-(1→2)-Rhap-(1→) as a hairy region, substituted by arabinose, xylose, galactose, glucose, mannose, and glucuronic acid [20]. Three acidic hetero- polysaccharides (ESP-A3, ESP-A4, and ESP-B4) have also been isolated and purified from the stem of E. sinica. Their monosaccharide compositions and corresponding molar ratios are shown in Table 4 [21]. Furthermore, a pure polysaccharide (ESP-B1) was isolated from E. sinica. It consisted of mannose, glucose, galactose, and arabinose. The ratios of the substances are shown in Table 4 [22]. Additionally, two polysaccharides (ESP-A1 and ESP-A2) have been isolated from the cold water extract of E. sinica [23]. Their monosaccharide compositions and ratios are also shown in Table 4. Moreover, monosaccharide composition and proportion of polysaccharides from Ephedra root have been analyzed. The results are shown in Table 4 [24]. In addition, five hypoglycemic glycans (ephedrans A, B, C, D, and E) are isolated from Ephedra distachya [25]. Their monosaccharide compositions and proportions have been determined. The results are shown in Table 5.

Miscellaneous compounds

Three phenolic glycoside compounds (129-131) are isolated from E. nebrodensis and four phenolic acids (134-136, 140) are isolated from E. equisetina. Some other phenolic compounds which have been isolated from the stems of E. sinica are trans-cinnamic acid (132), syringing (133), quinaldic acid (137), caffeic acid (141), chlorogenic acid (142), and a new glycoside of phenylpropionic acid (143), while 2-hydroxyl- 5-methoxybenzoic acid (138) and iso-ferulic acid (139) are also isolated from the E. sinica roots. Additionally, six terpenoid compounds (123-128), a lignin compound (120), and an ester compound (122) are isolated from the E. sinica roots. Furthermore, a new naphthalene derivative, 1-methyl-2, 3-methylenedioxy-6-naphthalenecarboxylic acid methyl ester (121), and two quinones (144-145) are isolated from the E. sinica stems. In addition, a lignin compound (119) is isolated from E. alata. These compounds are shown in Table 6, and their structures are presented in Fig. 5.

Pharmacological Properties of Ephedra

Ephedra sinicahas been used for thousands of years in the treatment of allergies, bronchial asthma, cold, fever, etc. Since Professor Nagayoshi Nagai reported ephedrine analogs as the active constituents in E. sinica, most of the pharmacological effects of E. sinica have been attributed to ephedrine analogs, although E. sinica also contains other chemical components, such as flavonoids, tannins, and other compounds. However, these ephedrine analogs have some side effects, including insomnia, palpitations, arrhythmia, and hypertension, because these compounds can stimulate the sympathetic and parasympathetic nerves. Additionally, the synthetic form of ephedrine, amphetamine, is more addictive and toxic. The US Food and Drug Administration banned the use of dietary supplements containing ephedrine analogs in 2004. To solve this problem, the pharmacological effects of other components of E. sinica need to be further studied, such as flavonoids, polysaccharides, tannins, organic acids and others. The following sections mainly describe the pharmacological effects of crude extracts and isolated compounds from the genus Ephedra.

Anti-inflammatory activity

As early as 1985, it was reported that ephedrine analogs, mainly including ephedrine (6), pseudoephedrine (7), and ephedroxane (12), had potent anti-inflammatory activity in vivo. This anti-inflammatory effect was likely due to the inhibition of prostaglandin E2 biosynthesis [70].

Another study on the possible effects of ephedra- monkshood-asarum-soup ("Mahuang-Fuzi-Xixin-Tang" in Chinese) on the IgE-mediated anaphylaxic response was measured in 2004. Interestingly, only E. sinica and ephedra-monkshood- asarum-soup inhibit IgE-mediated histamine release and increase cAMP levels from rat basophilic leukemia (RBL-2H3) cells. However, the components responsible for the inhibitory effect of E. sinica are not ephedrines [71]. It may be another component distinct from the ephedrine derivatives, which should be studied further. Another study showed that E. sinica could suppress the expression of cyclooxygenase (COX-2) in C6 rat glioma cells [72]. Prostaglandins (PGs) are major mediators in the regulation of inflammation and immune function. COX is the rate-limiting enzyme in PG production. Activation of nuclear factor-κB (NF-κB) participates in the transcriptional activation of the COX-2 gene. The E. sinica plays an anti-inflammatory role by inhibiting the expression of COX-2 protein and NF-κB-dependent transcription.

In 2005, the water distillates of E. sinica were injected into the ST36 acupoint on each knee joint in adjuvant-induced arthritic rats. The E. sinica herb-acupuncture showed an anti- arthritic effect [73]. The experiment was performed using an in vitro phorbol 12-myristate 13-acetate (PMA)/lipopolysaccharide (LPS)-induced human macrophage model and an in vivo adjuvant-induced arthritic (AIA) rat model. After treatment with E. sinica, the mRNA expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 genes were down- regulated. Interestingly, Ephedra did not work in the non-acupoint. It exerted a medicinal effect when injected only into the appropriate acu-point. The E. sinica herb-acupuncture therapy could reduce adverse effects associated with the disease. It could be an alternative to traditional therapy.

Wang et al. found that the acidic polysaccharides from E. sinica had immunosuppressive activity and confirmed that the main acidic polysaccharide ESP-B4 had potential therapeutic effects on rheumatoid arthritis. ESP-B4 reduces the release of inflammatory factors and cytokines by inhibiting the TLR4 signaling pathway [19].

Iksoo et al found that in the Ephedra root extracts, ephedrannin A (72) and ephedrannin B (73) had anti-inflammatory effects. They could suppress the transcription of TNF-α and IL-1β and inhibit LPS-induced inflammation. They suppressed the translocation of NF-κB and the phosphorylation of p38 mitogen-activated protein (MAP) kinase [61].

The complement-inhibiting components of E. sinica could treat the second injury after spinal cord injury (SCI). E. sinica reduced inflammation and improved motor function after SCI by inhibiting the activity of complement. These results showed that E. sinica could inhibit the activity of complement hemolysis and myeloperoxidase, decrease the complement deposition and improve motor function [74]. Furthermore, Ling et al. extracted and purified the complement-inhibiting component of E. sinica. C3 complement is harmful to the neurological function of patients with subarachnoid hemorrhage (SAH), which can cause brain damage, including brain cell death, blood-brain barrier damage, and brain edema. The extracts of E. sinica could not only improve the neurological function of rats after brain injury, but could also improve the early blood-brain barrier and brain edema after SAH [75].

Antibacterial and antifungal activities

The phenolic compounds isolated from the Ephedra herbs exhibit substantial antimicrobial activity against Gram- positive bacteria and Gram-negative bacteria [76]. Among E. strobilacea, E. pachyclada and E. Procera, the E. strobilacea showed the highest antimicrobial activity against three microorganisms, including Pseudomonas aeruginosa, a Gram negative bacterium, Staphylococcus aureus, a Gram positive bacterium, and Aspergillus nigra a fungus. The plant methanolic extracts of E. pachyclada show significant antimicrobial activity against Klebsiella pnemoniae, a Gram negative bacterium, Bacillus subtilis, a Gram positive bacterium and highest antifungal activity against the Candida albicans microorganism. There is a strong relationship among total phenol content and antioxidant, antimicrobial activity, as phenols are very important plant constituents because their hydroxyl groups can scavenge free radicals [77].

From the n-BuOH-soluble fraction of the EtOH extracts from E. sinica, 12 A-type proanthocyanidins are isolated and identified. These compounds are tested by measuring the minimum inhibitory concentrations (MIC) against bacteria (both Gram-positive and Gram-negative) and fungi, with a concentration range of 0.00 515-1.38 mmol·L-1[65].

Additionally, other secondary metabolites from E. transitoria have been assessed for their antibacterial activity. One of the isolated quinolone alkaloid (4-quinolone-2-carboxylic acid) (19) exhibits significant inhibitory activity against common bacteria, including Enterobacter cloacae, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa [39].

Another study evaluated the effects of E. major on fungal growth and aflatoxin (AF) production by Aspergillus parasiticus NRRL 2999. It was found that the methanolic extracts of plant aerial parts and roots inhibited fungal growth and aflatoxin B1 (AFB1) production dose-dependently with IC50 values of 559.74 and 3.98 μg·mL-1 for AFB1, respectively. Meanwhile, essential oil extracts of plant aerial parts significantly inhibited fungal growth at the highest concentration of 1000 μg·mL-1 without any obvious effect on AFB1 production at all concentrations used (0-1000 μg·mL-1) [78].

Anti-cancer activity

An investigation has shown that the water fraction (EW), the remaining water phase from the methanol extract of E. sinica after fractionation with ethyl acetate and butanol, possesses significant antitumor activity in BDF1 mice containing B16-F10 melanoma cells. Administration at 30 mg·kg-1·d-1 showed comparable inhibitory activity on the growth of the tumor in vivo. The in vitro antitumor activity is due to its anti- angiogenic and anti-invasion effects. At doses up to 30 μg·mL-1, a non-cytotoxic concentration, EW inhibits tube formation induced by human umbilical vein endothelial cells and the invasion of B16F10 melanoma cells through a matrix membrane by more than 90% [79].

A study has reported that herbacetin (30), the aglycon of herbacetin 7-O-neohesperidoside (42) isolated from Ephedra plants, has antiproliferative and analgesic effects [80]. Another study has shown that it could also suppress the HGF-induced motility of human breast cancer MDAMB-231 cells [81]. The mechanism of this inhibitory action is through inhibiting tyrosine phosphorylation of c-Met and the PI3K/Akt pathway. Additionally, the herbacetin (30) can directly inhibit the tyrosine kinase activity of c-Met [51, 82]. To further investigate the mechanism of ephedra inhibiting the phosphorylation of Met, another study has found that Ephedra could promote HGF- stimulated MET and p-MET endocytosis followed by its downregulation in an NSCLC cell line. The degradation of MET likely occurrs in the late endosome pathway [83].

The preparation method of ephedrine alkaloids-free Ephedra Herb (EFE) extracts has been established. The EFE extracts have anti-proliferative effects against the H1975 non-small cell lung cancer (NSCLC) cell line [84]. Moreover, the anti- proliferative effects arecomparable to that of the E. herb extract. Therefore, the EFE, a new herbal medicine with reduced side effects and retained anticancer effects, may have great potential for development.

Additionally, a study has reported that the methanol extracts from E. herb has inhibitory effects on the X-linked inhibitor of apoptosis protein (XIAP). An in vitro fluorescence polarization assay and a protein fragment complementation analysis have confirmed that the extracts of Ephedra contain an inhibitory component for XIAP. Moreover, silica gel column chromatography and precipitation from methanol and chloroform mixtures have confirmed that the active ingredients are oligomeric proanthocyanidins. The inhibitory activity of oligomeric proanthocyanidins has been evaluated, with an IC50 value of 27.3 μg·mL-1 through in vitro FP assay and protein fragment complementation analysis [85].

Antioxidant and hepatoprotective activity

As early as 1985, feruloylhistamine (5), an imidazole alkaloid, was isolated from underground part of Ephedra plants (Ephedraceae). A series of feruloylhistamine analogs were also prepared. The study found that the feruloylhistamine analogs exhibited antihepatotoxic actions [29].

The phenolic and flavonoid constituents from the E. alata plant show an antioxidant effect [86]. As a natural source of potent antioxidants, the constituents could prevent many diseases when used in food, cosmetics, and pharmaceutical products [87].

An in vitro and in vivo study has revealed that the E. pachyclada extracts possess significant protective effects on primary hepatocytes against carbon tetrachloride damage. Inflammation and oxidative stress are the major causes of liver disease. E. pachyclada has anti-inflammatory and antioxidant activities. The antioxidant activity of the E. pachyclada extracts was measured in vitro by 2, 2'- diphenyl-1-picrylhydrazyl (DPPH) and β-carotene bleaching assays. The DPPH scavenging activity of E. pachyclada extracts showed an IC50 value of 55.53 ± 0.5 μg·mL-1. The hepatoprotective effects of E. pachyclada extracts were also examined in vivo on mouse models of carbon tetrachloride (CCL4)-induced chronic and acute liver failure. These results have demonstrated that the pathological indexes of hepatic injury, including aspartae aminotransferase (AST) and alanine aminotransferase (ALT), are significantly reduced in CCL4+ low/high E. pachyclada groups. In addition, the pathological examination showed that hepatic injuries, including inflammation, necrosis and hepatitis, are partially healed with the treatment of E. pachyclada extracts [88]. Therefore, the hepatoprotective mechanism of E. pachyclada is to inhibit oxidative stress and inflammation.

In another D-galactosamine and lipopolysaccharide (LPS)- induced hepatitis model, the hepatoprotective effects of Ephedra extracts have been evaluated [89-90]. The Ephedra extracts markedly alleviates hepatocyte apoptosis and inflammatory factor infiltration by reducing of serum alanine aminotransferase (ALT) and total bilirubin (T. Bil) activity, levels of TNF-α, and the activities of caspase- 8, 9, and 3.

A recent study has found that ephedra non-alkaloids have therapeutic potential for the treatment of hyperlipidemia in diet-induced mice [91-92]. These non-alkaloids can improve lipid metabolism. They may prevent free radical generation and support recuperation of liver function. What is more, they are relatively safe for use under the maximum tolerated dose.

Antiviral activity

E. herb extracts can induce the replication of latent human immunodeficiency virus type 1 (HIV-1) in latently infected U1 cells in vitro, through NF-κB activation. The ultimate goal is to eliminate the persistent viral reservoirs in individuals infected with HIV-1. NF-κB is an inducible cellular transcription factor that regulates a wide variety of cellular and viral gene expression. The E. herb extracts can efficiently induce NF-κB nuclear translocation and activate the NF-κB promoter [93].

A study has confirmed that ephedrine alkaloids-free Ephedra Herb (EFE) extracts have anti-influenza virus activity by showing inhibition of MDCK cell infected with influenza virus A/WSN/33 (H1N1) [81]. The IC50 values of Ephedra Herb extract and EFE are 8.6 and 8.3 μg·mL-1, respectively. The safety assessment of EFE extracts suggests that it is safer than Ephedra Herb extract itself. EFE could be a safer alternative to Ephedra Herb, but further study is necessary.

Miscellaneous biological activities

Zhai et al have examined the effects of E. sinica on the treatment of bleomycin-induced rat idiopathic pulmonary fibrosis. Pulmonary fibrosis is characterized by early lung injury followed by fibrosis. E. sinica can significantly reduce alveolitis and pulmonary fibrosis grades [94-95]. E. sinica has been used to treat pulmonary fibrosis in the clinic, suggesting that traditional Chinese medicine had a major impact on idiopathic pulmonary fibrosis.

The hydro-alcoholic extract from the stems of E. pachyclada has been shown to be effective in experimentally healing rat ulcers [96]. E. pachyclada, is frequently cited by Kerman people as an active agent against gastrointestinal disorders.

As activators of transient receptor potential vanilloid 1 (TRPV1), a pain receptor, the E. Herb extract has analgesic effects [97-98]. However, ephedrine does not show such effects.

2, 3, 5, 6-Tetramethylpyrazine (TMP) (27) isolated from E. sinica has been evaluated for its depigmenting effect in a UVA-induced melanoma/keratinocytes co-culture system. TMP at a 100 μmol·L-1 concentration significantly decreased the expression of tyrosinase-related protein 1 (TRP1) and microphthalmia-associated transcription factor (MITF) levels. Cytokines, such as TNF-α, IL-1β, IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF), were significantly decreased with TMP treatment [99]. TMP could be used as a possible drug candidate to improve pigmentation of the skin.

Additionally, the ephedrannins A (72) and B (73) isolated from E. sinica roots exhibit significant inhibitory activity on melanogenesis in B16F10 melanoma cells. These compounds inhibit the expression of the tyrosinase gene in a dose-dependent manner. In addition, the inhibition by ephedrannin B (72) is more effective than that of ephedrannin A (73) [100]. Ephedrannin B can be a better candidate for whitening the skin.

Conclusions and Future Perspectives

In this review, we summarize the chemical components isolated from the genus Ephedra and their pharmacological activities. One hundred and forty-five chemicals belonging to the groups of alkaloids, flavonoids, polysaccharides, tannins and others have been isolated from the genus Ephedra. Additionally, Ephedra species have anti-inflammatory, anti-tumor, antioxidant, hepatoprotective, antibacterial, and antifungal activities.

We need to do more research on the pharmacology and phytochemistry of Ephedra species in the future. First, ephedra non-alkaloids, as a new herbal medicine with reduced side effects and retained anticancer and analgesia effects, have great potential for development. However, the mechanism of ephedra polysaccharide in the treatment of hyperlipidemia needs further study. Second, the pharmacological activities of more than twenty medicinal plants of genus Ephedra have been reported, but many other species of the genus Ephedra have not been studied for their chemical compositions and pharmacological activities. Therefore, further study on these species is needed. Third, although the ephedra polysaccharide has anti-inflammatory, anti-complement and immunosuppression effects, the relationship between the ephedra polysaccharide structure and its pharmacological activity needs to be further studied.

The active components of E. sinica have been identified, which play a guiding role in the quality control of E. sinica. The aforementioned pharmacological experiments on the mechanisms of action of E. sinica, can provide guidance for the clinical application of E. sinica.

References
[1]
D'Auria M, Emanuele L, Racioppi R. Natural product research: Formerly natural product letters FT-ICR-MS analysis of lignin FT-ICR-MS analysis of lignin[J]. Nat Prod Res, 2012, 26(15): 1368-1374. DOI:10.1080/14786419.2011.586947
[2]
Xie M, Yang Y, Wang B, et al. Interdisciplinary investigation on ancient Ephedra twigs from Gumugou Cemetery (3800 B.P.) in Xinjiang region, northwest China[J]. Micros Res Techniq, 2013, 76(7): 663-672. DOI:10.1002/jemt.v76.7
[3]
Kilpatrick K, Pajak A, Hagel JM, et al. Characterization of aromatic aminotransferases from Ephedra sinica Stapf[J]. Amino Acids, 2016, 48(5): 1209-1220. DOI:10.1007/s00726-015-2156-1
[4]
Pawar RS, Grundel E. Overview of regulation of dietary supplements in the USA and issues of adulteration with phenethylamines (PEAs)[J]. Drug Test Anal, 2016, 9(3): 500-517.
[5]
Yuliana ND, Jahangir M, Korthout H, et al. Comprehensive review on herbal medicine for energy intake suppression[J]. Obes Rev, 2011, 12(7): 499-514. DOI:10.1111/obr.2011.12.issue-7
[6]
Soni MG, Carabin IG, Griffiths JC, et al. Safety of ephedra: lessons learned[J]. Toxicol Let, 2004, 150(1): 97-110. DOI:10.1016/j.toxlet.2003.07.006
[7]
Mehendale SR, Bauer BA, Yuan CS. Ephedra-containing dietary supplements in the US versus ephedra as a Chinese medicine[J]. Am J Chin Med, 2004, 32(1): 1-10. DOI:10.1142/S0192415X04001680
[8]
Ibragic S, Sofić E. Chemical composition of various Ephedra species[J]. Bosnian J Basic Med Sci, 2015, 15(3): 21-27.
[9]
Lee MR. The history of Ephedra (ma-huang)[J]. J Royal Coll Physic Edinburgh, 2011, 41(1): 78-84. DOI:10.4997/JRCPE
[10]
Abourashed EA, El-Alfy AT, Khan IA, et al. Ephedra in perspective-a current review[J]. Phytother Res, 2003, 17(7): 703-712. DOI:10.1002/(ISSN)1099-1573
[11]
Scheindlin S. Ephedra: once a boon, now a bane[J]. Mol Intervent, 2003, 3(7): 358-360. DOI:10.1124/mi.3.7.358
[12]
Yang Y, Wang Q. The earliest fleshy cone of Ephedra from the early cretaceous Yixian Formation of northeast China[J]. PLoS One, 2013, 8(1): e53652. DOI:10.1371/journal.pone.0053652
[13]
Wu H, Ma Z, Wang MM, et al. A high frequency of allopolyploid speciation in the gymnospermous genus Ephedra and its possible association with some biological and ecological features[J]. Mol Ecol, 2016, 25(5): 1192-1210. DOI:10.1111/mec.2016.25.issue-5
[14]
Caveney S, Charlet DA, Freitag H, et al. New observations on the secondary chemistry of world Ephedra (Ephedraceae)[J]. Am J Bot, 2001, 88(7): 1199-1208. DOI:10.2307/3558330
[15]
Orejola J, Matsuo Y, Saito Y, et al. Characterization of proanthocyanidin oligomers of Ephedra sinica[J]. Molecules, 2017, 22(8).
[16]
Xia Y, Kuang H, Yang B, et al. Optimum extraction of acidic polysaccharides from the stems of Ephedra sinica Stapf by Box-Behnken statistical design and its anti-complement activity[J]. Carbohydrate Polymers, 2011, 84(1): 282-291. DOI:10.1016/j.carbpol.2010.11.035
[17]
Kasahara Y, Shinomiya N, Konno C. Structure f mahuannin C, a hypotensive principle of Ephedra roots[J]. Heterocycles, 1983, 20(9): 1741-1744. DOI:10.3987/R-1983-09-1741
[18]
Xia YG, Liang J, Yang BY, et al. Structural studies of an arabinan from the stems of Ephedra sinica by methylation analysis and 1D and 2D NMR spectroscopy[J]. Carbohydr Polym, 2015, 121: 449-456. DOI:10.1016/j.carbpol.2014.12.058
[19]
Wang Q, Shu Z, Xing N, et al. A pure polysaccharide from Ephedra sinica treating on arthritis and inhibiting cytokines expression[J]. Int J Biol Macromol, 2016, 86: 177-188. DOI:10.1016/j.ijbiomac.2016.01.010
[20]
Kuang H, Xia Y, Liang J, et al. Structural characteristics of a hyperbranched acidic polysaccharide from the stems of Ephedra sinica and its effect on T-cell subsets and their cytokines in DTH mice[J]. Carbohydr Polym, 2011, 86(4): 1705-1711. DOI:10.1016/j.carbpol.2011.07.001
[21]
Xia YG, Wang QH, Liang J, et al. Development and application of a rapid and efficient CZE method coupled with correction factors for determination of monosaccharide composition of acidic hetero-polysaccharides from Ephedra sinica[J]. Phytocheml Anal, 2015, 22(2): 103-111.
[22]
Kuang H, Xia Y, Liang J, et al. Fast classification and compositional analysis of polysaccharides from TCMs by ultra-performance liquid chromatography coupled with multivariate analysis[J]. Carbohydr Polym, 2011, 84(4): 1258-1266. DOI:10.1016/j.carbpol.2011.01.014
[23]
Xia YG, Liang J, Yang BY, et al. Identification of two cold water-soluble polysaccharides from the stems of Ephedra sinica Stapf[J]. Chin Med, 2010, 1(3): 63-68. DOI:10.4236/cm.2010.13013
[24]
Liang J, Sun LM, Xia YG, et al. Analysis of monosaccharide compositions of Ephedrae Radix et Rhizoma polysaccharide based on UPLC-MS/MS[J]. Chin J Exp Tradit Med Form, 2017, 23(7): 73-78.
[25]
Konno C, Mizuno T, Hikino H. Isolation and hypoglycemic activity of ephedrans A, B, C, D and E, glycans of Ephedra distachya herbs[J]. Planta Med, 1985, 51(2): 162-163. DOI:10.1055/s-2007-969437
[26]
Kurosawa W, Kan T, Fukuyama T. Stereocontrolled total synthesis of (-)-ephedradine A (orantine)[J]. J Am Chem Soc, 2003, 125(27): 8112-8113. DOI:10.1021/ja036011k
[27]
Zhu J, Hesse M. The spermine alkaloids of Chaenorhinum minus[J]. Planta Med, 1988, 54(5): 430-433. DOI:10.1055/s-2006-962490
[28]
Nezbedová L, Hesse M, Drandarov K, et al. Dihydroxyverbacine is the terminal precursor in the biosynthesis of aphelandrine and orantine[J]. Tetrahedr Lett, 2000, 41(41): 7859-7862. DOI:10.1016/S0040-4039(00)01392-7
[29]
Hikino H, Kiso Y, Ogata M, et al. Pharmacological actions of analogues of feruloylhistamine, an imidazole alkaloid of Ephedra roots[J]. Planta Med, 1984, 50(6): 478-480. DOI:10.1055/s-2007-969777
[30]
Krizevski RB, Einat, Shalit O, Sitrit Y, et al. Composition and stereochemistry of ephedrine alkaloids accumulation in Ephedra sinica Stapf[J]. Phytochemistry, 2010, 71(9): 895-903.
[31]
Ballero M, Foddis C, Sanna C, et al. Pharmacological activities on Ephedra nebrodensis Tineo[J]. Nat Prod Res, 2010, 24(12): 1115-1124. DOI:10.1080/14786410802680902
[32]
Aghdasi M, Bojnoordi MM, Mianabadi M, et al. Chemical components of the Ephedra major from Iran[J]. Nat Prod Res, 2016, 30(3): 1-3.
[33]
Groves RA, Hagel JM, Zhang Y, et al. Transcriptome profiling of Khat (Catha edulis) and Ephedra sinica reveals gene candidates potentially involved in amphetamine-type alkaloid biosynthesis[J]. PLoS One, 2015, 10(3): e0119701. DOI:10.1371/journal.pone.0119701
[34]
Hikino H, Konno C, Takata H, et al. Antiinflammatory principle of Ephedra herbs[J]. Chem Pharm Bul, 1980, 28(10): 2900-2904. DOI:10.1248/cpb.28.2900
[35]
Krizevski R, Bar E, Shalit OR, et al. Benzaldehyde is a precursor of phenylpropylamino alkaloids as revealed by targeted metabolic profiling and comparative biochemical analyses in Ephedra spp.[J]. Phytochemistry, 2012, 81(5): 71-79.
[36]
Cheng DL, Wang DM, li S. A minor alkaloid from the extract of Ephedra Herbs[J]. Chem Res Chin Univ, 1985, 6(7): 609-612.
[37]
Abdel-Kader MS, Kassem FF, Abdallah RM. Two alkaloids from Ephedra aphylla growing in Egypt[J]. Nat Prod Sci, 2003, 9(2): 52-57.
[38]
Zhang D, Deng AJ, Ma L, et al. Phenylpropanoids from the stems of Ephedra sinica[J]. J Asian Nat Prod Res, 2016, 18(3): 260-267. DOI:10.1080/10286020.2015.1070831
[39]
Alkhalil S, Alkofahi A, Eleisawi D, et al. Transtorine, a new quinoline alkaloid from Ephedra transitoria[J]. J Nat Prod, 1998, 61(2): 262-265. DOI:10.1021/np9702998
[40]
Starratt AN, Caveney S. Quinoline-2-carboxylic acids from Ephedra species[J]. Phytochemistry, 1996, 42(5): 1477-1478. DOI:10.1016/0031-9422(96)00126-4
[41]
Nawwar MAM, Barakat HH, Buddrust J, et al. Alkaloidal, lignan and phenolic constituents of Ephedra alata[J]. Phytochemistry, 1985, 24(4): 878-879. DOI:10.1016/S0031-9422(00)84920-1
[42]
Hussein SAM, Barakat HH, Nawar MAM, et al. Flavonoids from Ephedra aphylla[J]. Phytochemistry, 1997, 45(45): 1529-1532.
[43]
Starratt AN, Caveney S. Four cyclopropane amino acids from Ephedra[J]. Phytochemistry, 1995, 40(2): 479-481. DOI:10.1016/0031-9422(95)00342-5
[44]
Tamada M, Endo K, Hikino H. Maokonine, hypertensive principle of Ephedra roots[J]. Planta Med, 1978, 34(3): 291-293.
[45]
Zhao W, Deng AJ, Du GH, et al. Chemical constituents of the stems of Ephedra sinica[J]. J Asian Nat Prod Res, 2009, 11(2): 168-171. DOI:10.1080/10286020802573552
[46]
Khan IA, Abourashed EA. Leung's Encyclopedia of Common Natural Ingredients[M]. 2010.
[47]
Chen AL, Stuart EH, Chen KK. The occurrence of methylbenzylamine in the extract of Ma Huang[J]. J Pharm Sci, 1931, 20(4): 339-345.
[48]
Purev O, Pospíšil F, Motl O. FPaOM: Flavonoids from Ephedra sinica Stapf[J]. Collect Czech Chem C, 1988, 53(12): 3193-3196. DOI:10.1135/cccc19883193
[49]
Tao HM, Zhu QH, Liu YH. Flavonoids from roots of Ephedra sinica[J]. Chin Tradit Herb Drugs, 2011, 42(9): 1678-1682.
[50]
Nawwar MAM, El-Sissi HI, Barakat HH. Flavonoid constituents of Ephedra alata[J]. Phytochemistry, 1984, 23(12): 2937-2939. DOI:10.1016/0031-9422(84)83045-9
[51]
Amakura Y, Yoshimura M, Yamakami S, et al. Characterization of phenolic constituents from Ephedra herb extract[J]. Molecules, 2013, 18(5): 5326-5334. DOI:10.3390/molecules18055326
[52]
Villalobos A. Compositions and methods for enhancing weight-loss by cyclical administration of compounds: US, 11/960696 [P]. 2011-07-12.
[53]
Bouchard NC, Howland MA, Greller HA, et al. Ischemic stroke associated with use of an Ephedra-free dietary supplement containing synephrine[J]. Mayo Clin Proc, 2005, 80(4): 541-545. DOI:10.4065/80.4.541
[54]
Cottiglia F, Bonsignore L, Casu L, et al. Phenolic constituents from Ephedra nebrodensis[J]. Nat Prod Res, 2005, 19(2): 117-123. DOI:10.1080/14786410410001704714
[55]
Friedrich H, Wiedemeyer H. Die gerbstoffbildner in Ephedra helvetica[J]. Planta Med, 1976, 30(6): 163-173. DOI:10.1055/s-0028-1097713
[56]
Porter PL, Wallace JW. C-glycosylflavones from species of Ephedra[J]. Biochem Syst Ecol, 1988, 16(3): 261-262. DOI:10.1016/0305-1978(88)90003-8
[57]
Wallace JW. C-glycosylflavones in the Gnetopsida: A preliminary report[J]. Am J Bot, 1979, 66(3): 343-346. DOI:10.1002/ajb2.1979.66.issue-3
[58]
Ohba S, Yoshida K, Kondo T. Swertisin dihydrate[J]. Acta Crystallogr C, 2004, 60(12): o893-o896. DOI:10.1107/S0108270104028355
[59]
Oshima N, Maruyama T, Yamashita T, et al. Two flavone C-glycosides as quality control markers for the manufacturing process of ephedrine alkaloids-free Ephedra herb extract (EFE) as a crude drug preparation[J]. J Nat Med, 2018, 72(1): 73-79. DOI:10.1007/s11418-017-1111-8
[60]
Tao H, Wang L, Cui Z, et al. Dimeric proanthocyanidins from the roots of Ephedra sinica[J]. Planta Med, 2008, 74(15): 1823-1825. DOI:10.1055/s-0028-1088321
[61]
Iksoo K, Youngjun P, Sungjin Y, et al. Ephedrannin A and B from roots of Ephedra sinica inhibit lipopolysaccharide-induced inflammatory mediators by suppressing nuclear factor-κB activation in RAW 264.7 macrophages[J]. Int Immunopharmacol, 2010, 10(12): 1616-1625. DOI:10.1016/j.intimp.2010.09.019
[62]
Hikino H, Shimoyama N, Kasahara Y, et al. Structures of mahuannins A and B, hypotensive pronciples of Ephedra roots[J]. Heterocycles, 1982, 19(19): 97-105.
[63]
Hikino H, Kasahara Y. Structure of mahuannin D, a hypotensive pronciple of Ephedra roots[J]. Heterocycles, 1983, 20(10): 873-876.
[64]
Tao H, Wang L, Cui Z, et al. Study on chemical constituents of root of Ephedra sinica[J]. Chin Tradit Herb Drugs, 2010, 41(4): 533-536.
[65]
Zang X, Shang M, Xu F, et al. A-type proanthocyanidins from the stems of Ephedra sinica (Ephedraceae) and their antimicrobial activities[J]. Molecules, 2013, 18(5): 5172-5189. DOI:10.3390/molecules18055172
[66]
Yang YF, Yi LU, Gao-Feng WU, et al. Chemical constituents of Ephedra root[J]. Chin Tradit Patent Med, 2010, 32(10): 1758-1760.
[67]
Kallassy H, Fayyadkazan M, Makki R, et al. Chemical composition and antioxidant, anti-inflammatory, and antiproliferative activities of Lebanese Ephedra campylopoda plant[J]. Med Sci Monit Basic Res, 2017, 23: 313-325. DOI:10.12659/MSMBR.905056
[68]
Chumbalov TK, Chekmeneva LN, Polyakov VV. Phenolic acids of Ephedra equisetina[J]. Chem Nat Compd, 1977, 13(2): 238-239. DOI:10.1007/BF00563959
[69]
Lee CH, Lee HS. Growth inhibiting activity of quinaldic acid isolated from Ephedra pachyclada against intestinal bacteria[J]. J Korean Soc Appl Biol Chem, 2009, 52(4): 331-335. DOI:10.3839/jksabc
[70]
Kasahara Y, Hikino H, Tsurufuji S, et al. Antiinflammatory actions of ephedrines in acute inflammations1[J]. Planta Med, 1985, 51(4): 325-331. DOI:10.1055/s-2007-969503
[71]
Saito SY, Maruyama Y, Kamiyama S, et al. Ephedrae herba in Mao-Bushi-Saishin-To inhibits IgE-mediated histamine release and increases cAMP content in RBL-2H3 cells[J]. J Pharmacol Sci, 2004, 95(1): 41-46. DOI:10.1254/jphs.95.41
[72]
Aoki K, Yamakuni T, Yoshida M, et al. Ephedorae herba decreases lipopolysaccharide-induced cyclooxgenase-2 protein expression and NF-kappaB-dependent transcription in C6 rat glioma cells[J]. J Pharmacol Sci, 2005, 98(3): 327. DOI:10.1254/jphs.SC0050118
[73]
Yeom MJ, Lee HC, Kim GH, et al. Anti-arthritic effects of Ephedra sinica STAPF herb-acupuncture: inhibition of lipopolysaccharide-induced inflammation and adjuvant-induced polyarthritis[J]. J Pharmacol Sci, 2006, 100(1): 41-48. DOI:10.1254/jphs.FP0050637
[74]
Li L, Li J, Yue Z, et al. Ephedra sinica inhibits complement activation and improves the motor functions after spinal cord injury in rats[J]. Brain Res Bull, 2009, 78(5): 261-266.
[75]
Zuo S, Li W, Li Q, et al. Protective effects of Ephedra sinica extract on blood-brain barrier integrity and neurological function correlate with complement C3 reduction after subarachnoid hemorrhage in rats[J]. Neurosc Lett, 2015, 609: 216-222. DOI:10.1016/j.neulet.2015.10.056
[76]
Khan A, Jan G, Khan A, et al. In vitro antioxidant and antimicrobial activities of Ephedra gerardiana (root and stem) crude extract and fractions[J]. Evid-based Compl Alt Med, eCAM, 2017, 2017: 6.
[77]
Parsaeimehr A, Sargsyan E, Javidnia K. A comparative study of the antibacterial, antifungal and antioxidant activity and total content of phenolic compounds of cell cultures and wild plants of three endemic species of Ephedra[J]. Molecules, 2010, 15(3): 1668-1678. DOI:10.3390/molecules15031668
[78]
Bagheri-Gavkosh S, Bigdeli M, Shams-Ghahfarokhi M, et al. Inhibitory effects of Ephedra major Host on Aspergillus parasiticus growth and aflatoxin production[J]. Mycopathologia, 2009, 168(5): 249-255. DOI:10.1007/s11046-009-9220-x
[79]
Nam NH, Lee CW, Hong DH, et al. Antiinvasive, antiangiogenic and antitumour activity of Ephedra sinica extract[J]. Phytothe Res, 2003, 17(1): 70-76. DOI:10.1002/ptr.901
[80]
Oshima N. Efficient preparation of Ephedrine alkaloids-free Ephedra herb extract and its antitumor effect and putative marker compound[J]. Yakugaku Zasshi, 2017, 137(2): 173-177. DOI:10.1248/yakushi.16-00233-3
[81]
Hyuga S, Hyuga M, Oshima N, et al. Ephedrine alkaloids-free Ephedra herb extract: a safer alternative to ephedra with comparable analgesic, anticancer, and anti-influenza activities[J]. J Nat Med, 2016, 70(3): 571-583. DOI:10.1007/s11418-016-0979-z
[82]
Hyuga S, Hyuga M, Yoshimura M, et al. Herbacetin, a constituent of ephedrae herba, suppresses the HGF-induced motility of human breast cancer MDA-MB-231 cells by inhibiting c-Met and Akt phosphorylation[J]. Planta Med, 2013, 79(16): 1525-1530. DOI:10.1055/s-00000058
[83]
Nishimura Y, Hyuga S, Takiguchi S, et al. Ephedrae herba stimulates hepatocyte growth factor-induced MET endocytosis and downregulation via early/late endocytic pathways in gefitinib-resistant human lung cancer cells[J]. Int J Oncol, 2016, 48(5): 1895-1906. DOI:10.3892/ijo.2016.3426
[84]
Oshima N, Yamashita T, Hyuga S, et al. Efficiently prepared ephedrine alkaloids-free Ephedra herb extract: a putative marker and antiproliferative effects[J]. J Nat Med, 2016, 70(3): 554-562. DOI:10.1007/s11418-016-0977-1
[85]
Schäfer S, Salcher S, Seiter M, et al. Characterization of the XIAP-inhibiting proanthocyanidin fraction of the aerial parts of Ephedra sinica[J]. Planta Med, 2016, 82(11-12): 973-985.
[86]
Alrimawi F, Abulafi S, Abbadi J, et al. Analysis of phenolic and flavonoids of wild Ephedra alata plant extracts by LC/PDA and LC/MS and their antioxidant activity[J]. Afr J Tradit Compl Alt Med, 2017, 14(2): 130-141. DOI:10.21010/ajtcam
[87]
Kittana N, Aburass H, Sabra R, et al. Topical aqueous extract of Ephedra alata can improve wound healing in an animal model[J]. Chin J Traumatol, 2017, 20(2): 108-113. DOI:10.1016/j.cjtee.2016.10.004
[88]
Ghasemi M, Azarnia M, Jamali M, et al. Protective effects of Ephedra pachyclada extract on mouse models of carbon tetrachloride- induced chronic and acute liver failure[J]. Tissue Cell, 2014, 46(1): 78-85. DOI:10.1016/j.tice.2013.11.005
[89]
Yamada I, Goto T, Takeuchi S, et al. Mao (Ephedra sinica Stapf) protects against-galactosamine and lipopolysaccharide- induced hepatic failure[J]. Cytokine, 2008, 41(3): 293-301. DOI:10.1016/j.cyto.2007.12.003
[90]
Han Y, Zhu JF, Wu ZP. Ephedra protects rats against acute liver failure induced by D-galactosamine and lipopolysaccharide[J]. Chin J Hepatol, 2016, 24(2): 127-129.
[91]
Fan Y, Jingjing LI, Yin Q, et al. Effect of extractions from Ephedra sinica Stapf on hyperlipidemia in mice[J]. Exp Ther Med, 2015, 9(2): 619-625. DOI:10.3892/etm.2014.2117
[92]
Song M, Jaeyoung UM, Jang H, et al. Beneficial effect of dietary Ephedra sinica on obesity and glucose intolerance in high-fat diet-fed mice[J]. Exp Ther Med, 2012, 3(4): 707-712. DOI:10.3892/etm.2012.462
[93]
Murakami T, Harada H, Suico MA, et al. Ephedrae herba, a component of Japanese herbal medicine Mao-to, efficiently activates the replication of latent human immunodeficiency virus type 1 (HIV-1) in a monocytic cell line[J]. Biol Pharm Bull, 2008, 31(12): 2334-2337. DOI:10.1248/bpb.31.2334
[94]
Zhai HQ, Hhang JR, Gao MC, et al. Comparative study between Ephedra sinica Stapf and Fructus Schisandrae Chinensis on ET-1 and 6-keto-prostaglandin F1α in rats with idiopathic pulmonary fibrosis[J]. Genet Mol Res, 2014, 13(2): 3761-3771. DOI:10.4238/2014.May.13.3
[95]
Zhai HQ, Zhang SF, Gao MC, et al. Effects of Herba Ephedra Sinicae and Fructus Schisandrae Chinensis on pathology of rats with bleomycin A5-induced idiopathic pulmonary fibrosis][J]. J Chin Integr Med, 2011, 9(5): 553-557. DOI:10.3736/jcim
[96]
Pirbalouti AG, Amirmohammadi M, Azizi S, et al. Healing effect of hydro-alcoholic extract of Ephedra pachyclada Boiss. in experimental gastric ulcer in rat[J]. Acta Polon Pharm, 1900, 70(6): 1003-1009.
[97]
Kobayashi Y. Analgesic effects and side effects of Ephedra Herb extract and ephedrine alkaloids-free Ephedra herb extract[J]. Yakugaku Zasshi, 2017, 137(2): 187-194. DOI:10.1248/yakushi.16-00233-5
[98]
Nakamori S, Takahashi J, Hyuga S, et al. Correction to: Ephedra herb extract activates/desensitizes transient receptor potential vanilloid 1 and reduces capsaicin-induced pain[J]. J Nat Med, 2016, 71(1): 1-9.
[99]
Yeom GGM, Min S. Corrigendum to 2, 3, 5, 6-tetramethyl- pyrazine of Ephedra sinica regulates melanogenesis and inflammation in a UVA-induced melanoma/keratinocytes co-culture system[J]. Int Immunopharmacol, 2014, 19(1): 191-191. DOI:10.1016/j.intimp.2014.02.008
[100]
Kim IS, Yoon SJ, Park YJ, et al. Inhibitory effect of ephedrannins A and B from roots of Ephedra sinica Stapf on melanogenesis[J]. Biochim Biophys Acta, 2015, 1850(7): 1389-1396. DOI:10.1016/j.bbagen.2015.04.001