Chinese Herbal Medicine for Hyperlipidaemia: A ...

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REVIEW ARTICLE

Chinese Herbal Medicine for Hyperlipidaemia: A Review Based on Data Mining from 1990 to 2016 Liang Daia,b, Aiping Lua,b,*, Linda L.D. Zhonga,b,*, Guang Zheng1c and Zhaoxiang Bian2a,b a

School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; bHong Kong Chinese Medicine Clinical Study Centre, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; cSchool of Information Science and Engineering, Lanzhou University, Lanzhou, China Abstract: Background: Many studies have shown that the reduction of low density lipoprotein (LDLC) levels provides cardiovascular protection; therefore LDL-C is considered to be a core therapeutic target in anti-hyperlipidaemia treatment. However, the LDL-C goal attainment is often not satisfied in China with conventional lipid-lowering agents. Many patients seek help from Chinese Herbal Medicine (CHM). To further understand the current use of CHM in hyperlipidaemia, we conducted a review based on a systematic literature search and data mining.

ARTICLE HISTORY Received: April 06, 2017 Revised: May 06, 2017 Accepted: May 17, 2017 DOI: 10.2174/1570161115666170713163127

Methods: We comprehensively searched MEDLINE, EBSCO, Cochrane Library, EMBASE, Chinese Biomedical Literature Database (CBM), Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI) and Wanfang database to identify potentially relevant articles. We included literatures that met the following criteria: (1) randomized or non-randomized controlled trials; (2) observational clinical trials; (3) case series or case reports. In order to enrich the systematic literature searching and provide the quantitative relationship between relative items and the treatment of hyperlipidaemia, the data mining was also conducted by filtering the biomedical literature on hyperlipidaemia in SinoMed and other available databases like VIP and CNKI. Results: In summary, 282 records of CHM on hyperlipidaemia were captured and analysed. The top used single herb was Radix Salviae Miltiorrhizae. The most frequently used formula was Xuefuzhuyu Decoction. The most used herbs in clinical practice have some pharmacological evidences. The mechanisms are different, but could be classified into three categories: inhibiting synthesis, increasing decomposition and reducing absorption. Conclusion: CHM shows positive effect in the treatment of hyperlipidaemia and has the potential to be used in combination with conventional drugs. However, their use should be demonstrated in highquality clinical trials and clinicians should pay attention to potential herb-drug interactions.

Keywords: Hyperlipidaemia, Chinese Herbal Medicine, Traditional Chinese Medicine, pharmacological mechanism, data mining. 1. INTRODUCTION How to control blood lipid levels has been discussed for more than one hundred years in clinical and scientific researches. Based on late epidemiological research, the prevalence of hyperlipidaemia in China was reported as 34% when defined the criteria for higher total cholesterol (TC), higher low density lipoprotein (LDL-C), lower high density lipoprotein (HDL-C) and higher triglyceride (TG) 6.22 mmol/L, 4.14 mmol/L, 1.04 mmol/L and 2.26 mmol/L, respectively [1]. However, if relative more strict major risk factors for the development and progression of atherosclerosis and index was selected (TC 5.2 mmol/L, LDL-C 3.4 mmol/L, HDL-C 1 *Address correspondence to these authors at the School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Tel: +852-3411-6523; Fax: +852-3411-2929; E-mail: [email protected]; [email protected] 1570-1611/17 $58.00+.00

mmol/L or TG 1.7 mmol/L), the percentage would be raised as higher as 49.3% [2]. Hyperlipidaemia, especially elevated LDL-C, has been demonstrated to be one of the cardiovascular diseases (CVD) [3-6]. A number of studies have illustrated that reducing the serum level of LDL-C could stabilize or degrade the pathological change of atherosclerosis, as well as decrease the morbidity and mortality of CVD [3-6]. Therefore, LDL-C is considered to be the core therapeutic target. Nowadays, major conventional lipid-lowering drugs contain statins, fibrates, bile acid sequestrants, niacin, selective cholesterol absorption inhibitors and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [5]. Among these agents, statins are the most utilized drug in clinical practice. Recent research reported that 88.9% of Chinese population with lipid-lowering medications used statins [7]. However, © 2017 Bentham Science Publishers

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only 61.5% population reached the therapeutic goal of LDLC, which was unsatisfactory [7]. Moreover, this result was based on relative looser standard according to 2007 Clinical guidelines on hyperlipidaemia in China, which meant that the goal attainment would be lower if utilizing current criteria [6]. The unsatisfied goal attainment may result from various reasons including higher adverse events and increasing economy burden. Therefore, in order to elevate the goal attainment, seeking help from Traditional Chinese Medicine (TCM), especially Chinese Herbal Medicine (CHM), is a common choice for Chinese patients.

Dai et al.

We aimed to comprehensively investigate the current clinical studies of CHM for hyperlipidaemia. Therefore, the following styles of clinical trial were included: (1) randomized or non-randomized controlled trials; (2) observational clinical trials; (3) case series or case reports. In addition, for the intervention methods, we also desired to acquire all forms of herbal treatment. Thus, the following interventions were included: single herb, classical formulas, self-designed formulas, herb-derived products, and combination products. The process of literature searching was presented in Fig. (1).

TCM is a representative medical system of complementary and alternative medicine, and has been utilized for thousands of years in China. According to TCM theory, the basic pathogenesis of hyperlipidaemia is considered to be phlegmdampness stagnation and blood vessel obstruction by phlegm and blood stasis, which could be resulted from various internal and external reasons including deficiency of spleen, stagnation of liver qi or over intake of greasy and surfeit flavour. The related viscera in Chinese Medicine include Liver, Spleen, Kidney and Triple Energizers. On the foundation of its pathogenesis, the vital intervention principle of hyperlipidaemia is promoting blood circulation to remove blood stasis and promoting diuresis to eliminate dampness [8, 9]. Not only ancient classics hint that TCM interventions are beneficial to the management of hyperlipidaemia, but also modern scientific evidences have reported the positive efficacy [10, 11]. Currently, there are more than 50 kinds of Chinese patent medicine for hyperlipidaemia which have been approved by State Food and Drug Administration of China (SFDA). However, there is no sufficient information about the details of TCM formula or single herb which had benefits for hyperlipidaemia and how to apply these in the clinical practice. Data mining, also called knowledge discover in database (KDD), is a process which acquires connotative, unknown and potentially valuable information from mass data [12]. It could comprehensively analyse available data and obtain reliable results so that this technique has already been utilized in summarizing experiences of distinguished veteran doctors of TCM [13-15]. On the foundation of previous experience, we attempted to use systematic literature searching combined with data mining technique to summarize the most common used herbs in clinical practice, and then to discuss the scientific foundation so as to provide better understanding of CHM for hyperlipidaemia. 2. METHODS 2.1. Systematic Literature Searching Strategy We comprehensively searched MEDLINE, EBSCO, Cochrane Library, EMBASE, Chinese Biomedical Literature Database (CBM), Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI) and Wanfang database and collected the data from January 1990 to September 2016. The following searching strategy was applied: “(((((((herb) OR herbal medicine) OR traditional Chinese medicine) OR Chinese medicine) OR complementary medicine) OR naturopathy)) AND ((hyperlipidaemia) OR hypercholesterolemia)”.

Fig. (1). Flowchart of literature selection logistics.

2.2. Data Mining Process The data mining was conducted by filtering the biomedical literature on hyperlipidaemia in SinoMed (http://www.sinomed.ac.cn/) and other available databases like VIP and CNKI on Sep. 30, 2016. The same searching strategy above was used. Then, we filtered the downloaded literature data base with TCM keywords including CHM, Chinese patent medicine and TCM pattern. We used a wheel-shaped network to indicate the association between different TCM keywords and hyperlipidaemia. The wheelshaped network was a visualized graph which could exhibit the frequencies and correlations among the same categories [16]. For the results from data mining, the following variables were extracted: TCM patterns, TCM treatment principles, CHM including all used herbs, fundamental decoctions, and patent medicines. The results were good supplement for literature review, which would provide the quantitative relationship between relative items and the treatment of hyperlipidaemia. All Chinese-to-English translations were conducted primarily from the “World Health Organization (WHO) Evidence-Based Complementary and Alternative Medicine International Standard Terminologies on Traditional Medicine in the Western Pacific Region” [17].

Chinese Herbal Medicine for Hyperlipidaemia

3. RESULTS 3.1. Summary of all the Results Totally, we accessed 2684 records based on our search criteria, of which 2318 were excluded for reasons of irrelevance and 56 were duplicate records. The full text of 310 articles was retrieved for detailed assessment, of which 10 were animal experiments and 18 applied TCM external interventions. In summary, 282 records of CHM on hyperlipidaemia were captured and analysed. Based on these literatures, the five most combined diseases with hyperlipidaemia were hypertension, diabetes, coronary heart disease (CHD), atherosclerosis and obesity (Fig. 2). Table 1 presented the top ten most utilized herbs and their actions based on TCM theory. The top ten single herbs successively were Radix Salviae Miltiorrhizae (Danshen), Fructus Crataegi (Shanzha), Rhizoma Alismatis (Zexie), Radix Angelicae Sinensis (Danggui), Radix Astragali (Huangqi), Flos Carthami (Honghua), Rhizoma Chuanxiong (Chuanxiong), Radix Et Rhizoma Rhei (Dahuang), Radix Polygoni Multiflori (Heshouwu), and Rhizoma Pinelliae (Banxia). The possible active components, hypolipidaemic effects and possible mechanisms were summarized in Table 2. Table 3 showed the five most frequently used formulas and their compositions. Xuefuzhuyu Decoction was the most commonly utilized fundamental formula, followed by Jiangzhi Decoction, Buyanghuanwu Decoction, Wendan Decoction, and Erchen Decoction. According to the summary of frequently used herbs and formulas, it was distinct that the frequently used herbs were consistent with the mostly utilized Chinese herbal formulas. 3.2. Studies of Single Herbs 3.2.1. Radix Salviae Miltiorrhizae (Danshen) Radix Salviae Miltiorrhizae, which is a commonly used TCM herb in management of CVD, is derived from the root and rhizome of Salviae miltiorrhiza Bunge. Based on TCM

Fig. (2). Five most combined diseases with hyperlipidaemia.

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theory, the basic action of Radix Salviae Miltiorrhizae is promoting blood circulation to remove blood stasis [18]. The active components could be divided into two categories, lipophilic and hydrophilic. Lipophilic components mainly include tanshinone class (adjacent quinoid type) and ketone class (adjacent hydroxyl quinoid type), while tanshinol and salvianolic acid class are two major categories of hydrophilic compounds. According to past researches, the lipid-lowering effects of both categories have been demonstrated. And the principal mechanisms involve the anti-oxidative effect and lipid metabolism regulation. To be specific, among the lipophilic components, tanshinone IIA is the most well studied compound. Recent study has reported that the tanshinone IIA sulfonate intravenous injection (80 mg dissolved in 250 mL 0.9% normal saline) could significantly reduce the levels of serum TC, TG and LDL-C in patients with diabetes mellitus [19]. In animal models, there have also been increasing evidences illustrated the effect of tanshinone IIA. Chen et al. found that oral administration of tanshinone IIA (3-30 mg/kg) could greatly inhibited the formation of atherosclerotic lesions in highlipid diet feeding hyperlipidaemic rabbits, which may relate to the reduced oxidative stress resulted from decreasing oxidized low density lipoprotein (oxLDL) production and enhancing activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) [20]. Additionally, in high-fat diet feeding rat model, 1.2 ml of sodium tanshinone IIA sulfonate at a dose of 10 mg/kg by daily intraperitoneal administration could regulate the expression of proteins related to the metabolism of lipid such as microRNA (miR)-33a and sterol regulatory element-binding protein 2 (SREBP-2)/PCSK9 signalling pathway proteins, thereby attenuate lipid deposition in the liver and regulate the intake and efflux of cholesterol [21, 22]. For the hydrophilic components, on the other hand, in an ovariectomized hyperlipidaemic rat model, the aqueous extract of Radix Salviae Miltiorrhizae (600 mg/kg/day, 12 weeks) could result in a decline of TC and LDL-C [23]. Salvianolic acid A and salvianolic acid B, among the hydrophilic compounds, are the most-well explored. In high-fat diet-fed and streptozotocin-induced diabetic rats, oral administration of salvianolic acid A at 0.3 mg/kg twice a day for 16 weeks could significantly reduce


Table 1.

Dai et al.

TCM Action and clinical applications of the ten most frequently used herbs for hyperlipidaemia.

Chinese Name Danshen

Shanzha

Latin Name Radix Salviae Miltiorrhizae

Percentage Among Top Ten Herbs 17.3%

Action Promote blood circulation to remove blood stasis; cool the blood to relieve carbuncle; remove annoyance and tranquilize the mind

Clinical Applications 1. Blood-stasis syndrome 2. Breast abscess with swelling and pain 3. Restlessness and insomnia

Promote digestion and relieve dyspepsia; invigorate blood and disperse blood-stasis

1. Indigestion

9.2%

Promote diuresis to drain dampness; expel heat

Dysuria, oedema, diarrhoea, dizziness due to retention of phlegm, leukorrhea, heat stranguria with astringent pain in urination

8.7%

Tonify blood, activate blood, regulate menstruation to relieve pain, moisten the bowels to relieve constipation

Fructus Crataegi

15.7%

Zexie

Rhizoma Alismatis

Danggui

Radix Angelicae Sinensis

2. Postpartum lochiorrhea and abdominal pain with blood-stasis

1. Blood deficiency syndrome 2. Irregular menstruation, amenorrhea and menorrhagia 3. Abdominal pain due to deficiency-cold; injuries from falls; carbuncles, ulcers and sores; arthralgia due to wind-cold 4. Constipation due to blood deficiency with intestinal dryness

Huangqi

Radix Astragali

8.5%

Tonify qi and raise yang; strengthen the defensive and superficial; induce diuresis to alleviate oedema; expel toxin and promote tissue regeneration

1. Spleen qi deficiency syndrome, syndrome of sinking of middle qi 2. Lung qi deficiency syndrome, spontaneous sweating due to qi deficiency 3. Oedema due to qi deficiency 4. Deficiency syndrome of qi and blood, unruptured ulcers or unhealed ulcers after rupture

Honghua

Flos Carthami

8.5%

Promote blood circulation to promote menstruation; remove blood stasis and alleviate pain

1. Blood-stasis syndrome 2. Chest and hypochondriac pain and mass 3. Trauma pain and pains in joints 4. Stagnation of heat and blood stasis

Chuanxiong

Dahuang

Rhizoma Chuanxiong

8.4%

Radix Et Rhizoma Rhei

8.1%

Activate blood and move qi; expel wind and alleviate pain

1. Stagnation of blood and qi

Remove stagnation by purgation; clear heat and discharge fire; cold blood and remove toxin; active blood and remove blood stasis; clear and purge damp-heat

1. Stagnation in the stomach and intestine and obstruction of the bowels

2. Headache and bi-syndrome pain of wind and dampness

2. Excess fire 3. Pyocutaneous disease due to toxic heat, burn and scald 4. Blood stasis 5. Jaundice of damp-heat and stranguria

Heshouwu

Radix Polygoni Multiflori

8.1%

Tonify the liver and kidney; replenish essence and blood; blacken hairs; strengthen tendons and bones

1. Dizziness, blurred vision, early graying of hair, limpness of loins and knees, spermatorrhea and leukorrhea due to deficiency of essence and blood 2. Chronic malaria, scrofula, abscesses, constipation due to intestinal dryness

Banxia

Rhizoma Pinelliae

7.6%

Dry dampness and remove phlegm; suppress adverse rise of qi to stop vomiting; relieve stuffiness and dissipate nodulation; relieve swelling and pain

1. Damp-phlegm syndrome 2. Adverse rise of stomach qi manifested as nausea and vomiting 3. Chest and epigastric fullness and distress, globus hystericus, goiter, subcutaneous nodule 4. Large carbuncle, mammary sore, bite by poisonous snake


Table 2.


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Possible active components, hypolipidaemic effects and mechanisms of the ten most frequently used herbs for hyperlipidaemia.

Chinese Name

Latin Name

Danshen

Radix Salviae Miltiorrhizae

Possible Active Components

Hypolipidemic Effects

Tanshinone IIA

TC, TG, LDL-C

1. Reducing oxidative stress 2. Regulating the expression and function of key proteins involving in the lipid metabolism

Salvianolic acid A Salvianolic acid B

Shanzha

Possible Mechanisms

Fructus Crataegi

Flavonoids Triterpenic acids (oleanolic acid and ursolic acid)

TC, TG, LDL-C

Rhizoma Alismatis

Triterpenoids

TC, TG, LDL-C

Danggui

Radix Angelicae Sinensis

Volatile oil Polysaccharide

TC, TG, LDL-C

1. Regulate inflammatory cytokine responses

Huangqi

Radix Astragali

Saponins

TC, TG, LDL-C

1. Inhibiting cholesterol absorption

Polysaccharides

HDL-C

Zexie

HDL-C

HDL-C

1. Regulate the inflammatory cytokine responses 2. Decreasing the absorption of cholesterol 1. Reducing liver synthesis of cholesterol 2. Intervention on Lyso PCs

2. Increasing hepatic cholesterol synthesis 3. Regulating gene expression of cholesterol-7-hydroxylase LDL-receptor and HMG-CoA reductase

Honghua

Flos Carthami

Safflower yellow

TC, TG, LDL-C HDL-C

Chuanxiong

Dahuang

1. Regulation of MDA 2. Inhibition of the biosynthesis of intracellular cholesterol

Rhizoma Chuanxiong

Ligustrazine

TC, TG, LDL-C

1. Alleviating of oxidative stress

Ferulic acid

HDL-C

2. Regulating cytokine response

Radix Et Rhizoma Rhei

Anthraquinone (rhein and danthron)

TC, LDL-C

1. Suppressing the expression of lipid synthesis related gene, including SREBP-1c and fatty acid synthetase 2. Regulating inflammatory cytokine responses

Heshouwu

Banxia

Radix Polygoni Multiflori

Rhizoma Pinelliae

Stilbene glucoside

TC, TG, LDL-C

1. Suppressing of lipid peroxidation

Anthraquinones (emodin and physcion)

HDL-C

2. Regulating the activity of key proteins involving in the lipid metabolism

fatty acids (palmitic acid, linoleic acid, oleic acid)

TG

1. Inhibiting TNF--induced nuclear factor B (NF-b) activation 2. Activating PPAR and PPAR

Table 3.

Top five most frequently used Chinese herbal formula for hyperlipidaemia.

Formulae Name Xuefuzhuyu Decoction

Ingredients

TCM Pattern

Semen Persicae (Taoren)

Qi stagnation and blood stasis

Flos Carthami (Honghua)

Percentage Among Top Five Formula 30.8%

Action Activate blood, remove stasis, circulate qi and relieve pain

Radix Angelicae Sinensis (Danggui) Radix Rehmanniae (Shengdi) Rhizoma Chuanxiong (Chuanxiong) Radix Paeoniae Rubra (Chishao) Radix Achyranthis Bidentatae (Niuxi) Radix Platycodi (Jiegeng) Radix Bupleuri (Chaihu) Fructus Aurantii (Zhiqiao) Radix Glycyrrhizae (Gancao) Table (3) contd….


Formulae Name Jiangzhi Decoction

Dai et al.

Percentage Among Top Five Formula

Action

Ingredients

TCM Pattern

Fructus Lycii (Gouqizi)

Liver-kidney yin deficiency

26.6%

Tonify yin and remove stasis

Qi deficiency with blood stasis

18.2%

Tonify qi, activate blood and dredge collaterals

Internal harassment of phlegm-heat

13.1%

Regulate qi, remove phlegm, clear gallbladder heat and harmonize stomach

Phlegm-dampness pattern

11.2%

Dry dampness and remove phlegm, regulate qi and harmonize the middle energizer

Radix Polygoni Multiflori (Heshouwu) Semen Cassiae (Juemingzi) Fructus Crataegi (Shanzha) Radix Salviae Miltiorrhizae (Danshen)

Buyanghuanwu Decoction

Radix Astragali (Huangqi) Radix Angelicae Sinensis (Danggui) Radix Paeoniae Rubra (Chishao) Lumbricus (Dilong) Rhizoma Chuanxiong (Chuanxiong) Flos Carthami (Honghua) Semen Persicae (Taoren)

Wendan Decoction

Rhizoma Pinelliae (Banxia) Pericarpium Citri Reticulatae (Juhong) Poria (Fulin) Radix Glycyrrhizae Praeparata (Zhigancao) Rhizoma Zingiberis Recens (Shengjiang) Caulis Bambusae In Taenia (Zhuru) Fructus Aurantii Immaturus (Zhishi) Fructus Ziziphi Jujubae (Dazao)

Erchen Decoction

Rhizoma Pinelliae (Banxia) Pericarpium Citri Reticulatae (Juhong) Poria (Fulin) Radix Glycyrrhizae Praeparata (Zhigancao) Rhizoma Zingiberis Recens (Shengjiang) Fructus Mume (Wumei)

the serum levels of TG, TC and LDL-C, and also prevent the pathological progression of hepatic fibrosis. The action may result from the anti-oxidative effect of salvianolic acid A [24]. Similarly, salvianolic acid B (100 mg/kg/day) administration by gavage for 8 weeks in high-fat diet-induced obesity mice could decrease the body weight and the serum levels of TG and TC. This effect may relate to its actions on key proteins of lipid metabolism like peroxisome proliferatoractivated receptor gamma (PPAR), CCAAT/enhancer binding protein (C/EBP), GATA binding protein 2 and 3 (GATA 2, GATA 3) [25]. In addition, Wang et al. has reported that salvianolic acid B could protect human aortic endothelial cells (HAECs) from oxidative injury-mediated cell death via inhibition of reactive oxygen species (ROS) production [26]. Generally speaking, oral administration of Radix Salviae Miltiorrhizae product is safe and well-tolerated. However, long-term usage may also lead to adverse events including

abdominal discomfort and poor appetite. Besides, it may also increase the bleeding risk when utilized in combination with aspirin and warfarin [27]. 3.2.2. Fructus Crataegi (Shanzha) Fructus Crataegi is the dried ripe fruit of Crataegus pinnatifida Bunge. var. major N.E.Br. (Rosaceae) or Crataegus pinnatifida Bunge. (Rosaceae). In general, Fructus Crataegi is a kind of herbs used to help digestion. However, it is also armed with the actions of improving blood circulation and dispelling stasis [18]. In patients of hyperlipidaemia, the serum levels of TC, TG and LDL-C were reported to experience an obvious decrease after taking the water extraction of Fructus Crataegi orally at the dosage of 3.6 g/day for 3 months [28]. Unsurprisingly, the hypolipidaemic effect of Fructus Crataegi has been repeated in animal models. In hamster


dyslipidaemia model induced by high-fat diet, oral administration of Fructus Crataegi (250 mg/kg, three time a day for 7 days) could significant decrease the serum levels of TC, TG and LDL-C, while increase the level of HDL-C [29]. Modern researches have reported that the hypolipidaemic effect of Fructus Crataegi is mainly originated from actions of flavonoids and triterpenic acids [30]. Zhang et al. has illustrated that oral intake of the aqueous extract of Fructus Crataegi (288 mg/kg/day, 4 weeks), rich in flavonoids such as chlorogenic acid, procyanidin B2, ()-epicatechin, rutin and isoquercitrin, could regulate the inflammatory cytokine responses, then consequently improve the serum lipid profile and protect endothelium in atherosclerosis rats [31]. Besides, the study conducted by Lin et al. has also proven that oral administration of triterpenic acids (oleanolic acid and ursolic acid) could reduce the serum level of non-HDL-C by decreasing the absorption of cholesterol through inhibiting intestinal acylCoA-cholesterol acyltransferase (ACAT) activity [32]. Although adverse events including mild rash, headache, sweating, dizziness, palpitations, sleepiness, agitation, and gastrointestinal symptoms may appear in utilizing Fructus Crataegi, there was no sufficient data to demonstrate the specific association between the herb and the symptoms [33, 34]. 3.2.3. Rhizoma Alismatis (Zexie) Rhizoma Alismatis is derived from the dried rhizome of Alisma orientale (Sam.) Juzep, which is categorized as herbs of eliminating dampness. The major actions of Rhizoma Alismatis contain promoting diuresis to drain dampness and expelling heat [18]. In healthy controls, it has been reported that the oral administration of powders of Rhizoma Alismatis at dosage of 10 g/day for 2 weeks could result in a decline in TC, TG and LDL-C [35]. In mice fed with high-fat diet, both the water and ethanol extracts of Rhizoma Alismatis could lead to significant decline in serum TG and TC [36, 37]. Besides regulation on lipid profile, Dan et al.’s study has also found that administration of Rhizoma Alismatis (2.26 g/kg/day, 4 weeks) could substantially decrease the mRNA expression of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase, while not affect the expressions of sterol regulatory element binding factor 2 (SREBF2) and cholesterol 7alphahydroxylase (CYP7A1), which means the mechanism of Rhizoma Alismatis may act by reducing the liver synthesis of cholesterol, rather than by elevating the cholesterol catabolism [38]. Currently, triterpenoids are considered to be the main active components of Rhizoma Alismatis. Various categories of triterpenoids isolated from Rhizoma Alismatis have been illustrated the hypolipidaemic effect [39]. Recent research has also discovered that intake of triterpene fraction containing 18 alisol derivatives extracted from Rhizoma Alismatis (180, 360 and 720 mg/kg/day, 4 weeks) could significantly reduce the serum levels of TC and LDL-C, and the potential mechanism may relate to the regulation of lysophosphatidylcholines (Lyso PCs), possibly by increasing of unsaturated Lyso PCs and decreasing of saturated ones [40].


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Hepatotoxicity and nephrotoxicity were reported in treatment with Rhizoma Alismatis [41, 42]. Therefore, it should be careful when applying on specific patients. 3.2.4. Radix Angelicae Sinensis (Danggui) Radix Angelicae Sinensis, derived from Angelica sinensis (Oliv.) Diels, is a well-known material medica in treatment of blood diseases. According to TCM theory, Radix Angelicae Sinensis could tonify and activate blood, thus be suitable for all blood-related patterns [18]. Currently, there is limited data about the hypolipidaemic effect of administration of Radix Angelicae Sinensis alone in patients. However, in animal models, the effect was reported in different components. Angelica sinensis volatile oil contains lipo-soluble components of Radix Angelicae Sinensis and its lipid-lowering effect has been verified in hyperlipidaemia rats. Specifically, intragastric administration of high and moderate dosage of volatile oil (60 and 30 mg/kg/day, 3 weeks) could reduce the serum TC and LDL-C level in hyperlipidaemia. The mechanism may be related to the vascular endothelium protection effect by reducing the level of endothelin-1 and von Willebrand factor [43]. In addition, Angelica sinensis polysaccharide is a kind of water-soluble component, which attracts a lot of research enthusiasm recently. In prediabetic mice induced by feeding high-fat diet, Wang et al. have reported that oral intake of Angelica sinensis polysaccharide (400 mg/kg/day, 4 weeks) could significantly reduce the level of TC and TG. The action may result from the regulation of inflammatory factors such as interleukine-6 (IL-6) and tumour necrosis factor- (TNF-) [44]. Generally, administration of Radix Angelicae Sinensis is safe and well-tolerated. There were few reports described the toxicity of Radix Angelicae Sinensis [45]. 3.2.5. Radix Astragali (Huangqi) Radix Astragali is derived from the dried root of Astragalus propinquus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (Fabaceae) or Astragalus membranaceus (Fish.) Bge. (Fabaceae), which is an important qi-tonifying herb in CHM. The fundamental actions of Radix Astragali are nourishing qi and raising yang [18]. The constituents of Radix Astragali include saponins, polysaccharides and flavonoids. Based on recent researches, the hypolipidaemic effect was observed in saponins and polysaccharides. To be specific, cycloastragenol, a bioactive triterpenoid saponin isolated from Radix Astragali, could reduce cytoplasmic lipid droplet in 3T3-L1 adipocytes [46]. In addition, in rat hyperlipidaemia model, recent research has found that oral administration of astragalus polysaccharides at the dosage of 40 mg and 100 mg/kg/day for 40 days could decrease the serum levels of TC, TG and LDL-C, while increase HDL-C in the meantime [47]. The mechanism of astragalus polysaccharides may be related with the upregulated cholesterol-7-hydroxylase and LDL-receptor gene expressions, while down-regulated HMG-CoA reductase gene expression in the liver, thereby it could inhibit cholesterol absorption and increase hepatic cholesterol synthesis [48].


In general, oral intake of Radix Astragali is safe and well-tolerated. However, dry cough, bradycardia, hypotension and digitalis poisoning were reported in clinical trials regarding the injection of Radix Astragali [49]. 3.2.6. Flos Carthami (Honghua) Flos Carthami, the dried flower of Carthamus tinctorius L., is also widely applied in the treatment of CVD in TCM. The basic functions are activation of blood circulation and prevention of stasis [18]. Recent research has reported that the intravenous injection of Flos Carthami (40 mL dissolved in 250 mL 0.9% normal saline or 5% glucose, once a day for 4 weeks) could reduce the serum levels of TC, TG and LDLC, while elevate the level of HDL-C [50]. The basic researches on hypolipidaemic effect of Flos Carthami were relatively less than other herbs. Research on hyperlipidaemia rats has showed that the water extraction and alcohol extraction of Flos Carthami could both regulate the lipid metabolism. The effect may relate to the regulation of malondialdehyde (MDA) [51, 52]. Safflower yellow is one of the major active components in Flos Carthami. Recent research has demonstrated that intragastric administration of middle and high dosage of safflower yellow (0.5 and 1.0 mg/kg/mouse, for 1 month) could lead to a significant decline in the serum levels of TC, TG and LDL-C in hyperlipidaemic mice [53]. The mechanism was supposed to be associated with inhibition of the biosynthesis of intracellular cholesterol [53]. For the safety concern, few clinical studies reported the side-effects. Skin rash was the only adverse event mentioned in the treatment of safflower yellow [54]. But in the animal studies, the therapeutic dosage was well-tolerated [51, 52]. 3.2.7. Rhizoma Chuanxiong (Chuanxiong) Rhizoma chuanxiong comes from the dried rhizome of Ligusticum chuanxiong Hort. (Umbelliferae), which is also a representative herb for invigorating blood circulation and eliminating stasis in TCM [18]. In rabbit atherosclerosis model induced by high-fat diet, the oral intake of Rhizoma chuanxiong at an equivalent dosage of 30 times that administrated to humans for 91 days could markedly reduce the serum levels of TC and TG while raise the HDL-C level [51, 55]. Ligustrazine, also known as tetramethylpyrazine, is one of the main active ingredients in Rhizoma chuanxiong. Plenty of researches have proven its effects in lipid-lowering and cardiovascular protection [5658]. Specifically, oral administration of ligustrazine at the dosage of 20 and 80 mg/kg/day for 12 weeks could reduce the TG, TC and LDL-C levels in rat atherosclerosis model. Further study found that this effect may be induced by restoring the total antioxidant capacity and SOD1 activity while decreasing the MDA generation by ligustrazine [57]. This phenomenon has also been repeated in rabbit atherosclerosis model, with administration of tetramethylpyrazine at 75 and 150 mg/kg/day for 12 weeks [58]. Besides, ferulic acid is another active compound in Rhizoma chuanxiong. Previous study showed that oral administration of ferulic acid (50 mg/kg/day, 30 days) could significantly decrease the serum levels of TC and LDL-C. The mechanism may relate

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to the regulation of cytokine response like transforming growth factor-beta 1 (TGF-1) [59]. The oral intake of Rhizoma chuanxiong is generally safe. However, there has been reported that Rhizoma chuanxiong may increase the concentration of warfarin when combination, thereby increase the risk of bleeding [60]. 3.2.8. Radix Et Rhizoma Rhei (Dahuang) Rhei Radix et Rhizoma is derived from the root and rhizome of Rheum palmatum L., R. tanguticum Maxim, or R. officinale Baill. Although Rhei Radix et Rhizoma is well noticed with its laxation function, it also possesses the action of activing blood circulation, removing blood stasis, clearing and purging damp-heat [18]. In modern studies, researchers have found that aqueous extraction of Rhei Radix et Rhizoma (50 mg/kg/day, orally for 6 months) could obviously reduce the TC and LDL-C levels in patients with atherosclerosis [61]. Rhein belongs to anthraquinone, which is a main active component of Rhei Radix et Rhizoma. In diet-induced obese mice, Sheng et al. reported that intragastric administration of rhein at dosage of 150 mg/kg/day for 40 day could result in the decrease of serum TC and LDL levels. Further analysis indicated that rhein could suppress the expression of the SREBP-1c in liver, which was a key protein in lipid metabolism [62]. This hypolipidaemic effect has also been demonstrated in mice with diabetic nephropathy, and the mechanism may be related to the down-regulation of TGF- expression [63]. Danthron, another anthraquinone derivative, has also been reported to have potential in regulating lipid metabolism. Zhou et al.’s revealed that it could activate AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in both HepG2 and C2C23 cells, and consequently reduce the lipid synthesis related SREBP1c and fatty acid synthetase gene expressions [64]. Common adverse events reported include vomiting, headache, diarrhoea and abdominal pain, hence clinical application should pay attention to the dosage and course [65]. 3.2.9. Radix Polygoni Multiflori (Heshouwu) Radix Polygoni Multiflori is derived from the dried root tuber of Fallopia multiflora Thunb. (Polygonaceae) and could be used in either raw or prepared pharmaceutical forms. Radix Polygoni Multiflori belongs to the category of blood-tonifying herbs, and has the action of replenishing essence and blood [18]. He et al. have reported that administration of Radix Polygoni Multiflori oral liquid (equivalent to 15 g prepared Radix Polygoni Multiflori/day, 60 days) could significantly lower the levels of TC and TG [66]. Recent research has found that both Radix Polygoni Multiflori and prepared Radix Polygoni Multiflori could regulate the lipid content in liver cell, but prepared Radix Polygoni Multiflori showed stronger effect on lipid metabolism in circulatory system [67]. According to current researches, the possible hypolipidaemic components of Radix Polygoni Multiflori include stilbene glucoside and anthraquinones. In particular, stilbene glucoside is a major component of water extract of Radix Polygoni Multiflori. In hyperlipidaemia rats induced by high-fat diet, oral intake of stilbene glucoside (30


and 60 mg/kg/day, 28 days) could significantly lower the serum levels of TC, TG and LDL-C, but raise HDL-C. The effect may result from the suppression of lipid peroxidation, like increasing the concentration of SOD and nitric oxide (NO), while decreasing MDA [68]. Meanwhile, in vivo study has explored the effect of stilbene glucoside and anthraquinones (emodin and physcion) of Radix Polygoni Multiflori on TC and TG contents of steatosis human liver cell line L02. The results indicated that stilbene glucoside could raise the concentration of CYP7A and then promote the lipolysis of cholesterol, emodin could inhibit HMG-CoA reductase and diacylglycerol acyltransferase 1 (DGAT1) thereby block the synthesis of TC and TG, and physcion could increase the content of hepatic triglyceride lipase (HTGL) then block the synthesis of TG [69]. Hepatotoxicity is the major side-effect of Radix Polygoni Multiflori. However the mechanism and specific components were still not clear. Extra attention should be paid in certain patients when applying [70]. 3.2.10. Rhizoma Pinelliae (Banxia) Rhizoma Pinelliae, the dried tuber of Pinellia ternata (Thunb.) Breit, is commonly used for warming and resolving cold-phlegm [18]. Aqueous extract of Rhizoma Pinelliae has been found to be able to lower the level of TG and suppress the oxidation of fatty acids in obese Zucker rats [71]. In addition, it has also been demonstrated that the water extract could reduce blood viscosity, inhibit aggregation of red blood cells, and increase deformation ability of red blood cells in healthy rats [72]. The detailed mechanism of its hypolipidaemic effect needs further researches. Available research has found that apolar extract from Rhizoma Pinelliae containing fatty acids, such as palmitic acid, linoleic acid, oleic acid, and stearic acid, could inhibit TNF--induced nuclear factor B (NFB) activation and activate PPAR and PPAR, which may contribute to the hypolipidaemic action [73]. Occupational asthma was reported when using Rhizoma Pinelliae in clinical practice [74]. Other adverse events mainly contain gastrointestinal reactions and neurological symptoms. Nephrotoxicity may happen in long-term and over-dosage usage [75]. 4. DISCUSSION Recent meta-analysis has demonstrated that every 1 mmol/L LDL-C reduction with statins therapy could issue a 20-25% reduction in risk for CVD mortality and non-fatal myocardial infarction [76]. However, how to obtain a meaningful reduction of LDL-C is the vital question [3-6]. Since 2013 ACC/AHA guideline suggested that high-intensity statins could be applied initially to obtain a 50% reduction in LDL-C level [3], the debate whether high-intensity statins should be widely used in Chinese population has been emerged [77]. HPS2-THRIVE study showed that Chinese population could achieve a lower LDL-C level than European population by using same statin [78]. In addition, HPS2-THRIVE study reported that the adverse events of statins happened in Chinese population were much higher than European population [78]. Besides, CHILLAS study


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also explained that high-intensity statin did not exhibit more benefit in patients with acute coronary syndrome in China [79]. Therefore, attaining the LDL-C goal with relative low intensive statin combining with other kinds of drugs could be a relatively suitable option for Chinese population, which brings the opportunity for TCM in the management of hyperlipidaemia. As one of the oldest medical systems, TCM has been applied for thousands of years in preventing and treating diseases. In the past two decades, the researches on lipidlowering treatment with CHM have made some progress. Among them, Xuezhikang could be a representative Chinese patent medicine in this area. The lipid-lowering effect of Xuezhikang has been demonstrated in an international multicentre, large scale and randomized controlled clinical trial [80]. However, except for the case of Xuezhikang, there are still some issues which needed to be concerned. Firstly, highquality clinical evidences are lacking. Based on data mining, although the top ten herbs used in hyperlipidaemia treatment have certain pharmacological evidences, the clinical supports are still not enough yet. We cannot deny that there are increasing CHM researches published every year, while the quality is usually not satisfied due to poor design and execution. Secondly, it is generally understood that one herb may have hundreds of components. Thus, it is conceivable that exhaustive understanding of the specific hypolipidaemic mechanism of one herb or even one formula would be a difficult work which may cause obstacles in clinical application. Thirdly, theoretical background of CHM is quite different from conventional agents, and the application of CHM should be on the foundation of TCM theory, namely treatment based on pattern differentiation. Conventional drugs always have explicit indications, for instance, different statins in different dosages have different effect sizes in reducing LDL-C [81]. However, we cannot require that every clinician has a clear understanding of TCM theory. As a consequence, the accuracy of CHM prescription may not be optimal. Except for these issues of TCM itself, more importantly, herb-drug interaction, which could directly influence treatment effect, has raised increasing concern. Recent published literature has already emphasized that there may be serious adverse effects and interactions between conventional agents and TCM [82]. For example, Fermentum Rubrum, also called Hongqu, is a commonly used herb with lipid-lowering effect, which is also considered to be a natural statin because of its pharmacokinetics similar to lovastatin. In addition, lovastatin was reported to have synergistic effect with niacin and may develop adverse events like flushing, pruritus, or rush [83]. Thus, we may conclude that Fermentum Rubrum is possible to have herb-drug interaction with niacin. Besides, herbs with blood-circulation activating property are frequently applied in hyperlipidaemia treatment, and this kind of herbs may also have drug-interaction with western anticoagulants and antiplatelet drugs. It has been reported that the bleeding risk would be higher if conventional anticoagulants and antiplatelet drugs combined with CHM like Radix Salviae Miltiorrhizae [84]. Although there are still insufficient information about the drug-interaction between CHM and western medicines, the potential harm brought by


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Fig. (3). Novel TCM formula for treatment of hyperlipidaemia.

herb-drug interaction should not be underestimated. In clinical practice, doctors should pay enough attention. Our review focused on the single herbs and their active components, it is not difficult to notice that different active components of same herb may aim distinct targets. Therefore, if we follow this fact, we may be able to design an innovative TCM formula which could intervene on multiple targets at the same time and then lead to better therapeutic effect. In general, inhibiting synthesis, increasing decomposition, and reducing absorption are three common methods to lower the level of LDL-C. Hence, if we combine three active components which act on these three mechanisms, this novel TCM formula may able to achieve higher hypolipidaemic efficacy. For example, triterpenoids from Rhizoma Alismatis, tanshinone IIA from Radix Salviae Miltiorrhizae and triterpenic acids from Fructus Crataegi could be a promising combination (Fig. 3). The efficacy and safety of combination of two chemical drugs with different mechanisms have been demonstrated repeatedly in hyperlipidaemia treatment [8587]. The novel TCM formula may also have the potential to achieve the promising efficacy enhancement. Nonetheless, the active components combination still needs to consider issues like drug interaction, efficiency enhancement, and economic cost. In conclusion, CHM shows positive effect on the treatment of hyperlipidaemia and has the potential to be served as an option for combination with statins. However, the usage of CHM combined with conventional lipid-lowering agents should be further explored in high-quality clinical trials, and the potential adverse events caused by the drug-interaction are also worthy of awareness. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST

APL, LZ and ZXB provided critical advice and comments on the manuscript. ZG conducted data mining and data analysis process. All authors read and approved the final manuscript. APL and LZ contributed equally to this paper and should be considered as co-corresponding authors. REFERENCES [1] [2]

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The authors declare no conflict of interest, financial or otherwise.

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All authors participated in design and development of the review. LD reviewed the data and drafted the manuscript.

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