Herbal drugs against cardiovascular disease: traditional medicine and modern development.

Drug Discovery Today Volume 00, Number 00 May 2015

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Herbal drugs against cardiovascular disease: traditional medicine and modern development Q1

Lingjun Li1,3, Xiuwen Zhou1,3, Na Li1, Miao Sun1, Juanxiu Lv1 and Zhice Xu1,2 1

Institute for Fetology, First Hospital of Soochow University, Suzhou 215006, China Center for Perinatal Biology, Division of Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA 2

Herbal products have been used as conventional medicines for thousands of years, particularly in Eastern countries. Thousands of clinical and experimental investigations have focused on the effects and mechanismsof-action of herbal medicine in the treatment of cardiovascular diseases (CVDs). Considering the history of clinical practice and the great potentials of herb medicine and/or its ingredients, a review on this topic would be helpful. This article discusses possible effects of herbal remedies in the prevention and treatment of CVDs. Crucially, we also summarize some underlying pharmacological mechanisms for herb products in cardiovascular regulations, which might provide interesting information for further understanding the effects of herbal medicines, and boost the prospect of new herbal products against CVDs.

Xu received his PhD at the University of Cambridge, UK, with subsequent postdoctoral training at the University of Iowa, USA. After that, he was an assistant professor in the Deptartment of Obstetrics and Gynecology at the School of Medicine, UCLA, and then served as an associate professor and professor at the Center for Perinatal Biology, Loma Linda University, USA. He is currently Professor and Director for the Institute for Fetology at First Hospital of Soochow University, China. His current major research interests focus on adult health and diseases with developmental origins. The institute where he works is leading in the study of cardiovascular diseases with fetal origins in China.

Introduction Herbal drugs have been used as conventional medicines for thousands of years in Eastern Q2 countries. Currently, in almost all major cities in China there are large traditional medicine hospitals where all kinds of herbal medicines are prescribed to thousands of patients daily. Interestingly, herbal medicines have gradually entered Western medical markets as important complementary and alternative remedies during recent decades [1]. In fact, a significant number of approved drug substances have their origins in plants or herbs, including aspirin, digoxin, atropine, reserpine, tetrandrine and amiodarone [2]. A number of herbal medicines or their ingredients, such as ginseng, motherwort, garlic, red yeast rice, Danshen, Ginkgo biloba, tanshinone and ginsenoside, have been used against cardiovascular diseases (CVDs) in clinical work and experimental studies. Such herbal medicines contain analogous bioactive substances of various components including flavones, triterpenic acids and phenol carboxylic acids, which showed positive effects against CVDs. Complicated theories regarding treatment of diseases using herbal medicines are acknowledged. We also note

Corresponding author: Xu, Z. ([email protected]) 3

Authors contributed equally to this work.

1359-6446/ß 2015 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2015.04.009

www.drugdiscoverytoday.com 1 Please cite this article in press as: Li, L. et al. Herbal drugs against cardiovascular disease: traditional medicine and modern development, Drug Discov Today (2015), http://dx.doi.org/ 10.1016/j.drudis.2015.04.009

Reviews KEYNOTE REVIEW

Teaser Traditional herbal medicines have attracted increased attention against cardiovascular diseases with new approaches used in herb investigation and evaluation.

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that there are different views, especially regarding differences between Western and Eastern medical fields, on medical use of herbs, particularly for clinical practice. Recent progress has been made in pharmacological actions as well as systemic or molecular mechanisms using modern evaluation approaches in the study and use of herbal medicines. Based on those clinical and basic science records, this article focuses on the effects and possible mechanisms-of-action of some of the key herbal medicines in the treatment of CVDs. Interestingly, a search of the PubMed database was performed using the key words ‘herbal drug AND cardiovascular disease’, the database indicated that there were at least 609 clinical trials and a total of 3323 publications concerning herbal drugs against CVDs. Those studies provide further comprehensive scientific evidence, views and information on the herbal medicines used for the cardiovascular system. They could also offer interesting and important insight of alternative medicines against CVDs. Thus, this article reviews the critical effects of major herbal medicines that are frequently used in clinical and experimental work in the treatment of various CVDs. In addition, biological and pharmacological mechanisms studied by using modern approaches are discussed. Although there have been over 600 clinical trials in recent history, we would like to suggest that it might be a better idea to consider those data as preliminary results, further studies with modern technology would be beneficial.

The significant effects of major herbal medicines against CVDs Hypertension Hypertension is a worldwide health problem with high morbidity. Without proper treatments, hypertension can lead to other CVDs, including cardiac hypertrophy, atherosclerosis and heart failure (HF). Notably, several common drugs used in the treatment of hypertension originate from plants or herbs, including aspirin (from Salix alba), reserpine (from Rauwolfia serpentia) and tetrandrine (from Stephenia tetradra) [2]. Besides those well known medicines, there are many herbal products and their extracts, such as garlic, Danshen, motherwort, ginseng and hawthorn, that exhibit antihypertensive effects [3]. Danshen. Danshen, Labiatae spp., a dried root of Salvia miltorrhiza, has been demonstrated to be highly effective at ‘activating circulation and dispersing stasis or sludging of blood’ [4]. A recent analysis demonstrated at least nine compounds of Danshen (tanshinone IIA, salvianolic acid B, protocatechuic aldehyde, danshensu, cryptotanshinone, notoginsenoside R1, ginsenoside Rg1, ginsenoside Rb1 and borneol) could modulate 42 genes [e.g. peroxisome proliferator-activated receptor gamma (PPARg), angiotensin-converting enzyme (ACE), KCNJ11, KCNQ1, ABCC8, etc.] related to CVDs including non-insulin-dependent diabetes, coronary heart disease (CHD) and hypertension [5]. The antihypertensive effects of Danshen-based preparations have been proved in a randomized, double-blind, placebo-controlled clinical investigation that showed blood pressure and heart rate were reduced by the drug [6]. Tanshinone II(A), an active ingredient of Danshen, was able to normalize arteriolar diameter, probably because of increased expression and phosphorylation of endothelial nitric oxide synthase (eNOS) [7]. In a clinical investigation of 126 subjects of moderate gestational hypertension, Danshen 2


injection significantly reduced blood rheology indexes (hematocrit, plasma viscosity) [8]. In a study on ovine fetuses in utero during the final third of gestation, intravenous (i.v.) administration of tanshinone IIA into the mothers did not alter the blood values and cardiac enzyme activities in ewes and their fetuses, Q3 whereas fetal systolic pressure (SP) was slightly and significantly increased [9]. In general, Danshen has been considered to have a mild-to-moderate antihypertensive effect, and used for hypertension at early stages. One of the advantages of using Danshen is that doctors and patients can decide to stop using that herbal drug if blood pressure is under the control. Garlic. Garlic, Liliaceae spp. (Allium), has shown its efficiency in reducing blood pressure, including SP and diastolic pressure (DP), in hypertensive patients according to dozens of investigations [10]. In a systematic review and meta-analysis of nine doubleblind trials, with 482 hypertensive individuals on follow-up from 8 to 26 weeks, SP and DP were effectively reduced by garlic preparations [11]. The major bioactive compound of garlic is allicin which plays an important part in decreasing blood pressure [12]. In hypertensive rats garlic could effectively produce hypotensive effects, and reduce circulatory levels of vasoconstrictor thromboxane-B2, prostanoid-E2 and ACE, suggesting that the renin–angiotensin-system (RAS) and the nitric oxide (NO) system might be involved in the antihypertensive effects of garlic [13,14]. In addition, a clinical trial with a relatively small number of subjects showed that treatment with garlic pearls could significantly improve total antioxidants and inhibit oxidative DNA damage in young essential hypertensives [15]. In cultured aortic smooth muscle cells, allyl methyl sulfide (AMS) and diallyl sulfide (DAS) extracted from garlic inhibited angiotensin-II-stimulated cell-cycle progression, migration and generation of reactive oxygen species (ROS) [16], indicating the beneficial effects of garlic against hypertension. To date, garlic treatment has not presented significant adverse reactions other than minor gastrointestinal effects. Hawthorn. Hawthorn, Rosaceae spp. (Crataegus), has a long history in treating chronic HF, and also exhibits therapeutic effects against hypertension. A randomized and double-blind study showed that long-term treatment using hydroalcoholic hawthorn extract could decrease SP and DP in a time-dependent manner in subjects suffering mild primary hypertension [17], as well as significantly reducing DP in patients with diabetes [18]. Hawthorn constituents, especially the hyperoside fraction, could prevent eNOS inhibitor (L-NAME)-mediated hypertension in rats [19]. In an in vitro study with endothelial EA.hy926 cells, the hawthorn extract WS11442 improved sodium permeability on the endothelial surface layer, indicating an endothelial protection effect of hawthorn [20]. Eucommia ulmoides. Eucommia ulmoides, Eucommiaceae spp. (Parabarium Pierre), has been considered as an appropriate alternative intervention for pre-hypertension conditions in recent years. Clinical trials and laboratory investigations showed that an aqueous bark extract of Eucommia standardized to 8% pinoresinol dibeta-D-glucoside (PG) could cause a significant reduction in blood pressure with beta-adrenergic blocking activity [21]. Eucommia lignans could be the effective fraction of the herb in reducing blood pressure. Its antihypertensive effects might be associated with the regulation of pathways of nitric acid and RAS, as well as direct actions on vascular relaxation [22]. E. lignans has

www.drugdiscoverytoday.com Please cite this article in press as: Li, L. et al. Herbal drugs against cardiovascular disease: traditional medicine and modern development, Drug Discov Today (2015), http://dx.doi.org/ 10.1016/j.drudis.2015.04.009

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demonstrated its effects against hypertensive renal injury [23,24] and hypertensive vascular remodeling [24], probably due in part to its inhibition of aldose reductase, a vital target in pathological processes in cardiovascular systems. E. lignans exerted beta-adrenergic blocking activity in vitro [21], and inhibited angiotensin-IIstimulated extracellular matrix biosynthesis in mesangial vessels by suppressing mRNA and protein expression of collagen type I, collagen type III, collagen type IV and fibronectin, as well as inhibiting aldose reductase [25], suggesting possible underlying mechanisms for its antihypertensive effects. Besides the above herb products, many others such as Gynura procumbens, Ligusticum wallichii, Schisandra chinensis, Panax notoginseng, breviscapine and Marrubium vulgare have been investigated for their potential use in hypertension. Some showed promising effects; for example, purified fractions of the leaves of G. procumbens were capable of reducing blood pressure in rats by inhibiting ACE activity, causing vasodilatation [26] and increasing NO production in blood vessels in spontaneously hypertensive rats [27]. In vitro study showed that the vasodilatory effect of G. procumbens could be the result of blocking calcium channels, opening potassium channels and stimulating prostacyclin production [28].

Hyperlipidemia Hyperlipidemia is identified as persistently increased total cholesterol and low-density lipoprotein (LDL) cholesterol, as well as reduced high-density lipoprotein (HDL) cholesterol – usually associated with an increased risk of atherosclerosis and heart disease. Red yeast rice. Red yeast rice, Monascaceae spp. (Monascus Van Tiegham), has been widely used for cardiovascular protection for hundreds of years. A randomized trial demonstrated that red yeast rice caused a significant reduction in total cholesterol and LDL without increasing creatinine phosphokinase or pain levels, indicated an option of treatments for dyslipidemic patients who cannot tolerate statin therapy [29]. Xuezhikang, a preparation of red yeast rice, is popular in treatment of hypolipidemia. In a study of 1145 elderly patients with a history of myocardial infarction (MI), Xuezhikang decreased average total cholesterol and LDL cholesterol levels by 12.1% and 17.7%, respectively, compared with a corresponding reduction of 2.4% and 2.3% in the placebo group [30]. Moreover, red yeast rice contains other bioactive constituents such as beta-sitosterol and capesterol with an inhibitory effect on cholesterol absorption in the gut [31]. Multiple elements in red yeast rice, including unsaturated fatty acids, oleic, linoeic and linolenic acids and vitamin B complex, are considered to be helpful in reducing serum cholesterol levels [32]. Garlic. The effect of garlic on blood lipids was studied in numerous trials with various results. A recent meta-analysis, which comprehensively includes 39 primary trials involving a total of 2298 participants using garlic preparations, suggested that garlic used for longer than 2 months could effectively reduce total serum cholesterol and LDL in the body [33]. In addition, laboratory investigation demonstrated protective effects of garlic oil on cardiac apoptosis in rats fed with high cholesterol diets [34]. Garlic was shown to downregulate gene expression, including PPARg, acetyl CoA carboxylase (ACC), adipose-specific fatty-acid-binding protein and glycerol-3-phosphate dehydrogenase (GPDH) [35]. In general, garlic preparations are considered as an alternative option

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with a higher safety profile than conventional cholesterol-lowering medications for patients with hyperlipidemia [33]. Other herbal products also showed promising antihyperlipidemia effects. Hawthorn and, particularly, its bioactive compounds oleanolic acid and ursolic acid were shown to reduce LDL and verylow-density lipoprotein (VLDL) in hamsters fed with atherogenic diets by inhibiting intestinal cholesterol acyltransferase activity [36]. Triterpenic acid components oleanolic acid and ursolic acid might be the key to the herbal hypocholesterolemic properties.

Coronary heart disease CHD is caused by an imbalance between coronary blood flow and myocardial requirements, which usually results from atherosclerosis or narrowing of the coronary artery. Controlling risk factors such as serum cholesterol and hypertension is one of the most important methods in the prevention of CHD [37]. Meanwhile, cardiac protection by suppressing lipid peroxidation and cardiac apoptosis are crucial as a remedy strategy. Hawthorn. Hawthorn, Rosaceae spp. (Crataegus), was recommended recently for the treatment of stage II chronic HF. Accumulated evidence from in vivo and in vitro studies showed effects of hawthorn against CHD. Its significant efficacy has been demonstrated in the treatment of HF in over 4000 patients where hawthorn extracts improved cardiac efficiency [38]. Standardized hydroalcoholic extracts LI 132 (70% methanol extract, adjusted to a content of 2.2% flavonoids) and WS1 1442 (45% ethanol extract, adjusted to a content of 18.75% oligomeric procyandins) from hawthorn have shown a positive inotropic effect on the contractile force and have been demonstrated to be cardioprotective against ischemic reperfusion injury [39]. Another trial involving a total of 2681 patients with New York Heart Association (NYHA) class II or III HF demonstrated 900 mg WS1 1442 for Q4 24 months reduced sudden cardiac death in patients resulting in Q5 less-compromised left ventricular (LV) function [40]. A variety of studies suggested that multiple effects of hawthorn could contribute to its treatment of CHD. Those effects included antioxidant activity [41], anti-inflammatory effects [42], antiremodeling effects [43], endothelial protective effects [44] and lipid-reducing effects [36]. Danshen. Danshen is used either alone or in combination with other herbal ingredients for coronary artery disease [45]. Danshen dripping pill (DSP), a Danshen-based preparation composed of Salvia miltiorrhiza, P. notoginseng and Dryobalanops camphor, ranks as one of the top over-the-counter herbal medicines in China [46]. In a clinical study, treatment with DSP for 4 weeks improved symptoms in the patients, significantly reducing angina pectoris and improving the ST-T period in electrocardiography [47]. Experimental studies and clinical trials demonstrated that tanshinone IIA, a unique ingredient of Danshen, had the potential to prevent atherogenesis and stabilize atherosclerotic plaques, which was related to its antioxidant and anti-inflammatory actions, such as inhibiting LDL oxidation, proinflammatory cytokine expression, monocyte adhesion to endothelium, smooth muscle cell migration and proliferation, macrophage cholesterol accumulation and platelet aggregation [48]. Danshen hydrophilic extracts could significantly reduce serum levels of endothelial biomarkers such as vascular cell adhesion molecule (VCAM)-1 and von Willebrand factor (vWF) in diabetic patients with CHD [49]. In






addition, Danshen extracts showed cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury and hypertrophy. In rat models, Danshen extracts were observed to inhibit apoptosis in cardiomyocytes after MI/R injury by activating the Akt/eNOS signaling pathway [50], and reducing myocardial contraction by inhibiting L-type Ca2+ channels [51]. Red yeast rice. Red yeast rice, containing monacolin K (lovastatin), an agent capable of reducing lipid, has been suggested to be effective in reducing morbidity and mortality caused by CHD. In a 4.5 year investigation of Xuezhikang (a popular red yeast rice medicine) in 2704 hypertensive patients with previous MI, results demonstrated a 43% reduction of CHD risk and a 30% decrease of death risk from CHD by Xuezhikang therapy, indicating that red yeast rice therapy could effectively reduce cardiovascular events and all-cause death in the elderly hypertensive patients with previous MI [52]. Those cardiovascular protective effects might be linked to inhibit the homocysteine-induced ROS formation, nuclear factor kB (NF-kB) activation and VCAM-1 expression [53]. Ginseng. Ginseng, the root of Panax ginseng C.A. Mayer, Araliaceae spp. (panax), contains a complicated mixture of active ingredients: ginsenoside predominates. More than 200 ginsenosides have been isolated, including Rb1, Rb2, Rc, Rd, Re, Rg1, Rg3, Rh1 and Rh2 elements [54]. Hundreds of randomly controlled trials reported that ginseng-based medicines could relieve the symptoms of ischemic heart disease. A recent meta-analysis of 18 eligible studies with 1549 participants found that ginseng-based medicines were effective for angina pectoris in symptomatic improvement and in electrocardiogram improvement [55]. Another study on 116 patients with coronary angina pectoris showed greater improvement by ginseng-based prescription (composed of Radix ginseng, P. notoginseng and succinum) in terms of electrocardiogram results, general symptoms and nailfold microcirculation [56]. The protective effects of ginseng, demonstrated by several studies, depended on antioxidant properties of the components used [57,58]. Recently, Kim and Lee [59] suggested that total ginsenosides, panaxatriol especially, provided useful protection against MI/R injury. Ginsenosides have similar molecular structures to cardiac glycosides. They were able to couple with the a subunit of Na+–K+-ATPase, enhancing cardiac contractility and ameliorating heart dysfunctions [60]. Ginsenosides increased coronary perfusion flow in a dose-dependent manner. Rb1, as well as Rc and Re, could inhibit vascular dysfunction in the porcine coronary arteries [61]. Notably, not all ginsenosides exhibit cardiotonic actions; and such effects depend on whether the sugar moieties are attached to the C3, C6 or C20 position of the steroidlike structure [62]. Because the transcriptomes of P. ginseng and the genes involved in ginsenoside biosynthesis have been identified recently, it is expected that gene functions in pharmacology will be determined in the near future [63]. Several studies suggested other herbal products with promising effects against CVDs. Leonurin (4-guanidino-n-butyl syringate), isolated from motherwort, showed protective effects on the myocardium of rats with ischemia-induced damage by reducing lipid peroxidation and myocardial apoptosis [64]. A randomized and controlled clinical study demonstrated that after treatment with berberine the symptoms were improved in the patients suffering chronic congestive HF, including an increase in LV ejection fraction and exercise capacity, and improvement of the 4


Dyspnea–Fatigue Index [65]. G. biloba was shown to produce a concentration-dependent increase in coronary flow in the cardiovascular system [66].

Hyocardial hypertrophy

Q10

Elevated blood pressure could result in cardiac hypertrophy. Over long periods, irreversible changes in the LV wall could become harder, thinner and weaker, resulting in a larger LV volume, and ultimately leading to cardiac insufficiency. Remedies for hyocar- Q11 dial hypertrophy require a chronic treatment for reducing the risks such as elevated blood pressure and atherosclerosis. Several herbal medicines have been suggested with those kinds of therapeutic potential. Danshen. For effects of Danshen on hyocardial hypertrophy, a Q10 previous study demonstrated that tanshinone IIA could inhibit LV hypertrophy in hypertensive rats [67]. This effect could be related to downregulating myocardial angiotensin II and expression of ACE as well as angiotensin II receptors in hypertensive rats. By contrast, angiotensin (I–VII) and ACE2 concentrations were increased in the myocardial cells [68]. It is known that either reducing ACE or increasing of angiotensin (I–VII) and ACE2 would be beneficial to cardiovascular systems. Previous studies also indicated that Danshen could improve heart functions by enhancing myocardial contractility and deposition, limiting apoptosis in cardiomyocytes and suppressing oxidative damage by decreasing malondialdehyde (MDA) and increased activity of superoxide dismutase (SOD) [69]. Ginseng. For determination of effects of ginseng against LV hypertrophy, Ginsenoside Rg1 (ginseng constituent) was found to prevent transverse aortic constriction-induced LV hypertrophy and cardiac dysfunction by inhibiting fibrosis and enhancing angiogenesis, associated with phospho-Akt activation and p38 mitogen-activated protein kinase (MAPK) inhibition [70]. All gin- Q10 senosides could inhibit right ventricular hypertrophy induced by monocrotaline in rats [71], indicating their potential against ventricular hypertrophy. Previous studies also showed cardiac effects of the ingredients from P. ginseng and Radix aconiti lateralis preparata, by blocking sodium channels, and partial inhibition of the Na+ currents by ginsenoside 20(S)-Rg3 [72]. These studies suggested that the changes in the ion channel activity by the herb might affect smooth muscle cells in the left ventricle and cardiac functions. Hawthorn. Hawthorn preparations showed the effects in treatment and prevention of hyocardial hypertrophy as well as Q10 their effects against hypertension and hyperlipidemia mentioned above. Hawthorn preparation WS1 1442 was used in the experimental rats for testing its potential in the treatment of hyocardial Q11 hypertrophy. The data showed that WS1 1442 could prevent remodeling in the left ventricle associated with a significant reduction of LV volumes in the rats [73].

Stroke Stroke is one of leading causes of mortality. It is reported that 85% of strokes are due to vascular occlusions (ischemic stroke), whereas 15% are primary intracerebral hemorrhage (hemorrhagic stroke) [74]. Ischemic stroke is complex and multiple factors are involved, including energy failure, increased intracellular calcium levels, platelet aggregation, production of ROS, disruption of the


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blood–brain barrier, inflammation, and so on. Not only ischemic insults but also reperfusion processes cause tissue damage, inducing inflammatory responses that produce additional injury to the cerebral microcirculation and adjacent brain tissue [75]. The majority of stroke cases showed a slow evolution of brain injury that occurred over a period of hours-to-days following the attack [74]. This period is the therapeutic window to inhibit the progression of tissue damage after ischemia and reperfusion. However, few treatment options are available to minimize tissue death following a stroke. Currently, calcium channel blockers such as nimodipine and flunarazine have been used for the treatment of stroke [76] with limited effects [74]. Thus, alternative remedies using herbal medicines have become rational to be a common choice in those treatments in many regions. Danshen. Danshen is often used for cerebrovascular diseases, especially for stroke, based on experimental and clinical work [77]. In a clinical investigation on the patients with acute cerebral infarction, administration of salvianolate (Danshen preparation) within 72 h of the event showed a relief effect in the patients, indicating protective influence on the brain from injury [78]. The efficiency of DSP for prevention of secondary stroke was evaluated in patients with ischemic cerebrovascular disease. A total of 106 patients with ischemic stroke or transient ischemic attack (TIA) were enrolled. The results showed that the recurrence in the patients taking DSP was significantly less than that in the control. Moreover, levels of blood C-reactive protein were significantly decreased in the patients administered with DSP. These data indicated that Danshen or the ingredients might be able to reduce risks for stroke and/or TIA recurrence, and these types of effects might be associated with its anti-inflammatory mechanisms [79]. Tetramethylpyrazine. Tetramethylpyrazine has shown promising results in the treatment of patients with cerebrovascular ischemic diseases. The anti-inflammatory and neuroprotective effects were suggested to have a crucial role in the therapeutic effects for ischemic stroke. It was shown that tetramethylpyrazine attenuated proinflammatory mediators induced by amyloid b and interferon (IFN)-g in brain microglia in rats [80]. In addition, attenuation of the major cellular inflammatory responses via Q12 targeting of macrophages and microglia by elevating Nrf2/HO-1 Q13 expression might contribute to TMP-mediated neuroprotection against cerebral ischemia [81]. P. notoginseng. P. notoginseng, Araliaceae spp. (Panax Linn), is used for stroke, not only as a traditional medicine against ischemic stroke but also as a treatment in acute spontaneous intracerebral hemorrhage (ICH). A multicenter, double-blinded, randomized clinical trial showed that treatment with sanchitongshu capsule as a complementary medicine to aspirin significantly ameliorated neurological deficit (increased European Stroke Scale score) and activities of daily living (increased Bathel index score) [82]. In addition, Xueshuantong injection (a traditional herbal prescription) reduced inflammatory responses, including leukocytes, neutrophil percentage, C-reactive protein values and increased hematoma absorption, which significantly improved recovery of neurological functions such as decrease in NIH Stroke Scale score and hematoma volume [83]. The neuroprotective effect might also result from the effects of P. notoginseng against ROS accumulation, reducing H2O2 or oxygen/glucose deprivation/reoxygenationinduced cell damage.

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G. biloba. In recent clinical and experimental studies, G. biloba was reported to have potential in medical protection of the brain against ischemic injury, cerebrovascular insufficiency, dementia and Alzheimer’s disease [84]. LI 1370 is one of the extracts from G. biloba. In a placebo-controlled, double-blind trial on LI 1370 in 90 outpatients with cerebral insufficiency over a period of 12 weeks, improvement of clinical conditions in the patients were observed following 6 weeks of treatment [85], indicating possible influence of G. biloba against cerebrovascular insufficiency, which is worthy of further investigation regarding the protective effects and possible underlying mechanisms. Notably, although almost all herbal medicines mentioned above have been used for decades or hundreds of years in thousands of people with promising effects as suggested, standard research with modern scientific approaches on medical potentials of those herbs has only started in recent decades for most herbal medicines (some listed in Table 1). In reviewing those published trials, we note that the number of patients or experimental subjects in the clinical trials can be small or not. If it was a small number then that might cause concerns for the conclusions. Therefore, further testing or trials with larger samples should be recommended for future clinical research for the related herbal drugs. However, owing to a number of advantages of those natural products against CVDs, a rapid development of using herbal products in the prevention and treatments of CVDs should be expected based on a rapid increase of scientific investigations in the laboratory and the clinic. The following section focuses on recent progress in the study of possible mechanisms of the herbal medicines against CVDs.

Mechanisms of herbal medicines in regulation of the cardiovascular system Regulation of cardiac inotropic and vascular functions Ion channels. Cardiac cellular action potentials are generated from coordinated activation of a number of ion channels with closely related functions and localization. Dysfunction in channel activity or localization can disrupt action potential conduction, resulting in arrhythmia. Recently, tanshinone IIA was found to be able to affect ion channel currents on cardiovascular cells. For example, tanshinone IIA directly and specifically activated human cardiac KCNQ1/KCNE1 (IKs) potassium channels in embryonic kidney293 (HEK293) cells, and inhibited L-type Ca2+ in guinea pig ventricular myocytes [86]. Tanshinone IIA was also shown to alter hyperpolarization-activated cyclic nucleotide-gated (HCN) channels by selectively enhancing instantaneous currents (HCN2 channels), resulting in a corresponding increment of minimum open probabilities, slowing channel activation and deactivation processes rather than voltage-dependent currents [87]. Besides tanshinone IIA, the other two lipophilic components of Danshen: dihydrotanshinone [88] and cryptotanshinone [89], were demonstrated for their vasorelaxant effects by inhibiting Ca2+ influx in the vascular smooth muscle cells (VSMCs) via the unique signaling pathway, independent of endothelium, muscarinic receptors, beta-adrenoceptors, adenylyl cyclase and guanylyl cyclase. These data suggested there might be important mechanisms underlying antiarrhythmia and anti-ischemia activity of Danshen.






TABLE 1

Clinical investigations of herbal drugs against cardiovascular disease Herbal drug

Clinical use

Pharmacological effects

Garlic

Hypertension

# SBP, # DBP

210

[154]

Danshen

Moderate gestational hypertension

# HCT, # BV, # PV

126

[8]

Red yeast rice Reviews KEYNOTE REVIEW

Hawthorn

Number of subjects

Refs

Hyperlipidemia

# Total cholesterol, # LDL

1145

[30]

Coronary heart disease

# Coronary events # Death from coronary heart disease

2704

[52]

Primary mild hypertension

# SBP, # DBP

92

[155]

Coronary heart disease

# Cardiac mortality

Ginkgo biloba

Cerebral insufficiency

Improvement of memory

90

[156]

Panax notoginseng

Spontaneous intracerebral hemorrhage

# # # "

63

[83]

Ischemic stroke

" Score of ESS " Score of BI

140

[82]

Acute coronary syndrome

Ameliorates inflammation following percutaneous coronary intervention

130

[157]

Chronic congestive heart failure

" LVEF, exercise capacity and Dyspnea-Fatigue Index, # frequency of VPCs

146

[65]

Acute coronary syndrome

Preventing coronary thrombosis after PCI

80

[158]

Myocardial infarction

# Attack of angina pectoris, # LPO, " SOD

59

[159]

Berberine

Tetramethylpyrazine

NIHSS score Hematoma volume Inflammatory responses Hematoma absorption

2681

[40]

Abbreviations: HCT, hematokrit; BV, blood relative viscosity; PV, plasma viscosity; ESS, The European Stroke Scale; BI, Barthel Index; VPCs, ventricular premature complexes; PCI, percutaneous coronary intervention; LPO, lipoperoxides; SOD, superoxide dismutase; #, reduce; ", increase.

Similar to Danshen, 1,5-dihydroxy-2,3-dimethoxy-xanthone isolated from Halenia elliptica was found to be able to open potassium channels and inhibit Ca2+ influx through L-type voltageoperated Ca2+ channels and intracellular Ca2+ stores, resulting in relaxing coronary arteries in rats [90]. Different herbs or herbal extracts might act at various ion channels on cells. Paeoniflorin, allitridi and changrolin could block Na+ and Ca2+ channels, as well as K+ channels, contributing to alleviation of arrhythmia [91–93] Q14 (Fig. 1). By contrast, some adverse drug reactions of herbs were reported to be associated with changes in activity of ion channels. Shuanghuang-lian, Qing-kai-ling and Yin-zhi-huang, three herbal intravenous injections, were found to have pro-arrhythmic risk, which mainly resulted from inhibiting Na+ currents and L-type Ca2+ currents [94]. Nitric oxide pathway. Endothelium-delivered NO is one of the most important factors in the regulation of vascular tone. NO, generated by eNOS, is a potent vasodilator via stimulation of soluble guanylate cyclase (sGC). This enzyme catalyzes the conversion of GTP to cGMP, resulting in relaxation of vascular smooth muscle. eNOS is reported to be activated by Akt-dependent phosphorylation of eNOS at Ser1179 [95] to exert the properties of antiatherosclerosis, including inhibition of smooth muscle cell proliferation, platelet aggregation, leukocyte adhesion and expression of atherosclerosis-related genes [96]. Therefore, the NO/cGMP or phosphoinositide 3 kinase (PI3K)/Akt/eNOS pathways might be likely to be involved in the regulation of cardiovascular functions and blood pressure. Some herbs, including Cistanche tubulosa, Sophora flavescens and P. notoginseng, have been demonstrated to be capable of increasing endothelial-dependent vascular dilatation, probably via the 6

pathway of elevating cGMP or NO levels in arterial rings [97– 99]. To take gomisin J contained in S. chinensis as an example, this ingredient could enhance phosphorylation of eNOS and subsequently increase NO production [100]. There are other medicinal herbs that affect or decrease blood pressure independently of endothelium functions. For example, ethanol extract of Aspidosperma subincanum (EEAS) is one. In the determination of vasodilator effects of EEAS in isolated pre-contracted rat aortas, the sGC/cGMP and AC/cAMP pathways, as well as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activation, were found to be likely to be involved in vasorelaxation [101]. Modulating of vascular tone through the NO pathway for the herbs is shown in Fig. 1. Smooth muscle cell proliferation and migration. VSMCs are the main cellular components of the arterial wall. The proliferation of VSMCs induced by injury of arteries is a major etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis. Platelet-derived growth factor (PDGF), released from VSMCs, vascular endothelial cells, platelets or macrophages in the injured vascular walls, can stimulate growth of cells and induce migration of VSMCs [102,103]. The PDGF-induced mitogenesis signaling pathway has been characterized. Binding of PDGF to its receptors induces phosphorylation of PDGF-Rb tyrosine residues, leading to the activation of phospholipase C (PLC)g1, PI3K, Ras/Raf, subsequently coupled to activation of MAPK that is also known as extracellular signal-regulated kinase (ERK) [104]. In those signaling pathways, the expression of certain genes or proteins involved in PDGF-induced proliferation has been shown to be affected by several herbs with antiproliferative and antirestenosis properties.


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Schisandra chinensis Panax notoginseng

PI3K-Akt-eNOS Nitric oxide

Salvia miltiorrhiza Halenia elliptica Paeoniflorin Tetrandrine

GC-cGMP

L-Ca

Kv

Astragaloside IV Ligusticum chuanxiong Hort Tetramethylpyrazine

KATP

Rhododendron simsii Planch Tetramethylpyrazine

Kca

Paeoniflorin Changrolin Panax Ginseng

Direct stimulatory modification

Aspidosperma subincanum

[Ca2+]i ↓

Aralia elata

Salvia miltiorrhiza Halenia elliptica Ligusticum wallichii Allitridi

AC-cAMP


Schisandra chinensis Cistanche tubulosa Sophora flavescens Cynanchum wilfordii Ligusticum chuanxiong Hort

K+ ↑

Vasorelaxation

Hypertension Atherosclerosis Arrhythmia

Na+ ↓ Direct inhibitory modification

Multistep stimulatory modification Drug Discovery Today

FIGURE 1

The effects of herbs on vasodilatation via modulating ion channels and the nitric oxide (NO)/cGMP pathway in the cardiovascular system. Relaxation of vessels or attenuation of vasoconstriction is crucial in the treatment of hypertension, atherosclerosis and arrhythmia.

The antiproliferative effect of berberine, a well-known component of Coptis chinensis, has been demonstrated in VSMCs. Berberine could suppress phosphorylation of Akt induced by angiotensin Q15 II [105], mitogen-activation protein kinase kinase (MEK)1/2 and Q16 ERK1/2 in the injury model [106]. The finding from Liang et al. indicated that berberine could inhibit PDGF-induced VSMC growth via activation of AMP-mediated protein kinase (AMPK)/ p53/p21Cip1 signaling, while inactivating Ras/Rac1/cyclin D/Cdks and suppressing PDGF-stimulated migration via inhibition of Rac1 and Cdc42 [107]. Esculetin was shown to suppress p42/44 MAPK activation, PI3K activation, as well as NF-kB and activity protein (AP)-1 activation Q17 [108]. Corynoxeine could act as a potent ERK1/2 inhibitor [109]. Protocatechuic aldehyde was demonstrated to downregulate the phosphatidylinositol of the PI3K/Akt and MAPK pathway [110]. Baicalin was found to be able to inhibit cyclin E/CDK2 activation and increase p27 accumulation via blockade of the PDGFRb/ERK1/ 2 signaling cascade [111]. Together, accumulated evidence strongly indicates that herbal ingredients might act at multiple levels on multiple signaling pathways to affect cellular development or activation in cardiovascular systems (Fig. 2). Some of those signal sites and pathways could be interesting targets for development of new drugs or therapies against CVDs (Fig. 3).

Resistance to cell damage Oxidative stress. Oxidative stress is defined as the imbalanced redox state in which pro-oxidants overwhelm antioxidant

capacity, resulting in an increased production of ROS. Reperfusion of the ischemic myocardium is accompanied by generation of reactive ROS that can cause vascular and microvascular injury, endothelial cell dysfunction, myocyte edema, myocyte apoptosis/ necrosis and cardiac contractile dysfunction [112,113]. Moreover, ROS has been implicated in the pathogenesis of virtually every stage of formation for vascular lesions in atherosclerosis. Notably, several herbal medicines have been indicated for their effects on cardiovascular systems related to ROS pathways. Uncontrolled ROS production increases oxidative stress and activates key transcription factors, including NF-kB, in regulating gene expression for proinflammatory and adhesion molecules [114]. Lipid oxidation induced by ROS can also amplify foam cell formation through oxLDL uptake [115]. Clinical and laboratory studies on herbal medicines paid special attention to ROS-pathway-mediated injury in CVDs. The diagnostic marker enzymes aminotransferase (AST), lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) serve as a sensitive index in assessing the degree of ROS-induced injury. Glutathione (GSH), lipid peroxidation (LPO), MDA and activity of antioxidant enzymes, including SOD, catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) in tissues, were commonly determined as antioxidant biomolecules. There are numerous reports demonstrating that tanshinone IIA presented antioxidant properties, preventing the oxidation of LDL [116], rescuing PC-12 cells from hypoxia [117] and reducing cellular damage caused by free radicals [118]. Tanshinone IIA




Angll, PDGF

Baicalin

EGF-R

Esculetin Protocatechuic aldehyde

PLCγ

PI3K


Ras

Berberine

Akt Raf

↑ [AMP]/ATP

FoxO1/3 MEK 1/2 Berberine

AMPK

ERK1/2, MAPK

p53/p21

Berberine

Rac1

Cyclin D/Cdks

Direct stimulatory modification

Egr-1, c-Fos, Elk-1....

Direct inhibitory modification

Esculetin Corynoxeine Triptolide Ginseng Berberine

Atherosclerosis Restenosis Arrhythmia Multistep stimulatory modification

Drug Discovery Today

FIGURE 2

Schematic representation of effects of herbs on the smooth-muscle-cell-proliferation signaling pathway. Activation of p53 via phosphoinositide 3-kinase (PI3K)/ Q24 protein kinase B (Akt) or AMP-activated protein kinase (AMPK), or inhibition of Rac1/cyclin D directly, could cause G0/G1 arrest of cells. In addition, mitogenesis Q25 could be suppressed via the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) cascade. The antiproliferative effects of herbs could be used to treat atherosclerosis, restenosis and/or arrhythmia.

was found capable of protecting cultured macrophages from H2O2induced cell death, and this cellular protection was mediated in a large part by induction of glutathione peroxidase gene expression and activity [119]. Co-administration of G. biloba phytosomes and Ocimum sanctum extract could restore the isoproterenol-decreased activities of AST, LDH, CPK, SOD, CAT, GPx and GR, as well as levels of GSH and LPO in the heart, indicating their cardiac-protective properties [120]. The flavones from Abacopteris penangiana were suggested to have similar vascular regulatory functions. One previous study demonstrated that flavones could scavenge free radicals [121], inhibit LPO and enhance activity of SOD, CAT, GPx and paraoxonase (PON)-1 [122]. Other candidates from herbs with similar underlying mechanisms related to elevating SOD or reducing MDA include flavonoids from Inula britannica [123], hydroxysafflor yellow A [124] and farrerol [125]. Andrographolide was shown to have protective effects on cardiomyocytes against hypoxia/ Q18 reoxygenation injury via activating promoters of gamma-glutamate cysteine ligase catalytic subunit and modifier subunit, and subsequently upregulating GSH [126]. In brief, because ROS signals are a major contributor to injury occurring in the cardiovascular system, the potentials for herbs targeting at various sites and molecules in ROS pathways has become increasingly interesting in the investigation of natural products against CVDs. Apoptosis. Apoptosis of VSMCs is physiological, in vessel remodeling, and pathological, in development of diseases such as atherosclerosis, arterial aneurysm formation, myocardial infarction, diabetic cardiomyopathy and end-stage congestive HF 8

[127,128]. Apoptosis is a form of programmed cell death that could be mediated by death receptors in the plasma membrane, as well as mitochondria and the endoplasmic reticulum [129]. Apoptosis of cardiac myocytes is activated by various stressors, including cytokines [130], oxidative stress [131] and DNA damage [132]. A number of studies have demonstrated that inhibition of apoptosis is an effective cardioprotective approach in prevention of the development of HF. Modern scientific approaches have provided opportunities to study the effects of herbal medicines related to apoptosis in prevention or treatment of CVDs [133–136]. Much research has demonstrated that a number of herbs or their extracts have cardioprotective effects by inhibiting apoptosis. The ethanol extract of epimedium could attenuate myocardial apoptosis in rats with congestive HF via regulating Bcl-2/Bax axle [133]. Breviscapine markedly inhibited activation of caspase-3 and upregulated expression of Bcl-2 to exert protective effects on cerebral ischemic damage [134]. Danggui, either pre-treatment or posttreatment, greatly attenuated the angiotensin-II-induced apoptosis in cardiomyoblast cells by inhibiting c-Jun N-terminal kinase (JNK) and PI3K [135]. Farrerol prevented H2O2-induced apoptosis in human endothelium-derived EA.hy926 cells via the decreased expression of Bax, cleaved caspase-3 and phospho-p38 MAPK, while increasing expression of Bcl-2 mRNA [125]. The cardioprotective effect of a novel drug of leonurine, 3,5-dimethoxy-4-(3-(2carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidinobutyl ester, was demonstrated to inhibit hypoxia-induced cardiac myocyte apoptosis partly via modulating the PI3K/Akt pathway [136].


DRUDIS 1615 1–13 Drug Discovery Today Volume 00, Number 00 May 2015

REVIEWS

Survival factors, growth factors Danggui

TNF-α

Hirsutine

FasL

Fas

Procaspase-3

JNK

Caspase-8

Akt

Leonurine

Bad

Epimedium Breviscapine Farrerol Leonurine Hirsutine

Bcl-2

Bax

Apoptosis

P Caspase-3

p38

C-JUN

Atherosclerosis Hypertension Cardiomyopathy Myocardial ischemiareperfusion injury Arrhythmia

C-FOS

Breviscapine Farrerol Leonurine Hirsutine Bacopa monniera Direct stimulatory modification

Direct inhibitory modification

Multistep stimulatory modification

Drug Discovery Today

FIGURE 3

Q26 Regulation of cardiomyocyte apoptosis. This figure details the mechanisms by which apoptosis can be regulated by herbs. Apoptosis pathways are initiated by Q27 growth factors, mitochondrial stress (e.g. oxidants) or endoplasmic reticulum (ER) stress (e.g. depletion of ER Ca2+). The apoptosis could be downregulated at several levels by herbs such as Danggui, hirsutine and breviscapine to protect myocytes and prevent the development of atherosclerosis, hypertension and cardiomyopathy.

Inflammation. CVDs are often associated with metabolic disorders such as insulin resistance and obesity [137]. Emerging clinical and experimental evidence suggest that inflammation participates in the pathogenesis of several major cardio-metabolic disorders, including atherosclerosis, insulin resistance and aortic valve disease [138,139]. A proinflammatory subset of monocytes and macrophages could importantly contribute to pathological processes in cardio-metabolic organs [137]. Thus, controlling proinflammatory molecules or pathways by herbs or their ingredients could attenuate processing of such diseases. Diabetic chronic hyperglycemia in patients with diabetes mellitus induces loss of vascular homeostasis, commonly referred to as endothelial dysfunction. It is reported that scutellarin was able to inhibit the activation of NF-kB induced by high glucose in human endothelial cells (ECV304) and decrease serum levels of monocyte chemoattractant protein-1 significantly in alloxan-induced diabetic mice, suggesting scutellarin has anti-inflammation effects that could offer protection against hyperglycemia-induced vascular inflammatory in vitro and in vivo [140]. Glycosylated serum protein (GSP), local myocardial angiotensin II, myocardial gene expression and activity of chymase were significantly decreased in diabetic hamsters after the treatment with Astragalus polysaccharides compared with the control, indicating that Astragalus polysaccharides could inhibit the local chymase/angiotensin II system in diabetic cardiomyopathy [141]. Radix astragali was shown to attenuate the elevated levels of the Th1 cytokines [IFN-g and

interleukin (IL)-2] significantly, and increase the Th2 cytokines (IL-4 and IL-10) in autoimmune myocarditis [142]. Similarly, astragaloside IV attenuated inflammatory cytokines by inhibiting Toll-like receptor (TLR)4/NF-kB signaling pathway in isoproterenol-induced myocardial hypertrophy [143]. Future investigations will continue to focus on anti-inflammation effects of herbal medicines against CVDs, and pay special attention to interactions between systemic and local immune systems and the cardiovascular system.

Herb–drug interactions Concomitant use of herbal medicines and/or natural products and Western medicines is a growing new trend in the fight against major chronic diseases, thereby enhancing possibilities of clinically significant herb–drug interactions. Herb–drug interactions can lead to pharmacokinetic modulation of drug metabolizing enzymes and active transporters in the gastrointestinal epithelium and the liver, which can result in beneficial or toxic effects.

Beneficial effects Butylidenephthalide is a major active constituent of Ligusticum chuanxiong that can interact with the nitric oxide donor sodium nitroprusside (SNP); the compounds can interact synergistically to enhance the effectiveness of SNP in producing relaxation of vas- Q19 cular tone induced by Ca2+ sensitization [144]. Huang-Lian-Jie-DuTang (HLJDT), an aqueous extract of Rhizoma coptidis, Radix



PI3K



scutellariae, Cortex phellodendri and Fructus gardeniae (3:2:2:3), is an important multi-herb remedy in traditional herbal medicine. In vivo brain concentrations of nimodipine could be significantly increased when rats were pre-treated with HLJDT. HLJDT-treated samples could increase accumulation of nimodipine in primary cultured rat brain microvessel endothelial cells (rBMECs), and decrease expression of P-glycoprotein in rBMECs [145]. In vivo and in vitro experimental findings indicated that HLJDT pre-treatment could alter the transport of nimodipine across the blood– brain barrier. Demethylbellidifolin could prevent nitroglycerin tolerance by increasing aldehyde dehydrogenase 2 activity, which is responsible for nitroglycerin bioactivation [146]. Doxorubicin (DOX) is a highly effective antineoplastic agent. It is commonly used to treat a variety of cancers, including acute leukemia, lymphomas and solid tumors [147]. However, DOX-induced apoptosis in cardiomyocytes could lead to irreversible degenerative cardiomyopathy and HF, which limit the clinical application of DOX. DOX-induced cardiotoxicity can be primarily mediated by generation of ROS in cardiomyocytes and increased oxidative stress in the cardiomyocyte mitochondria [148,149]. There are many herbs reported to show a protective effect against DOX-induced apoptosis and ROS production, including Astragalus, leonurine, naringenin-7-O-glucoside and P. notoginseng saponins [150].

Side effects Equally important, when co-administered with drugs, many herbs could reduce the effectiveness of the drug or sometimes cause toxic adverse effects, such as ginkgo, St John’s wort (Hypericum perforatum), garlic and Danshen [151]. As introduced above, ginkgo is believed to be a common traditional medicine against CVDs. Warfarin is an anticoagulant normally used to prevent blood clots in vessels. A case of intracerebral hemorrhage attributed to concurrent use of ginkgo and warfarin was reported [152]. Ginkgo extract could attenuate warfarin-mediated anticoagulation in mice, by inducing hepatic metabolizing enzyme cytochrome P450 (CYP) [153]. Whether this also applies to humans needs to be confirmed in clinical trials. There are still some conflicting conclusions about the interplay between herbs and drugs in different reports. Owing to various components of herbs and different types of preparations (e.g. aqueous extract or alcoholic


extract), further research in the area of herb–drug interactions, especially in vivo, are needed.

Concluding remarks Despite there being many endless debates around Western medicine and traditional herbal medicine used in medical markets, traditional medical practice is continuously growing in modern societies. As mentioned above, in almost all modern major cities in China, millions of patients and their doctors in large and small, public and private, traditional medical hospitals and/or clinics choose herbal remedies. As a result of the introduction of modern scientific examination and evaluation approaches into herbal medicine fields, new knowledge and information regarding effects and mechanisms of action of herbs against CVDs have been revealed over the past two decades. The sustainable growth will be seen in the next decade. Thus, research data regarding impact of herbs or their ingredients on biosignals in ion channel activities, NO pathways, cellular growth and death, as well as inflammation, should attract considerable attention for experimental and clinical studies. The information generated from such work would contribute significantly to new insights for medical practice and the pharmaceutical industry. Although this article reviewed the herbal medicines used against CVD by reviewing published clinical trials and laboratory research, some of the clinical trials might only provide limited information as a result of sample size that might be small. We would like to suggest readers pay special attention to that concern, and treat those reported data as preliminary work in the evaluation of the herbal drugs used for CVDs. In addition, following more laboratory findings and preliminary data from those clinical trials, it is rational to develop more-advanced experiments and trials in the field.

Conflicts of interest The authors declare no conflicts of interest.

Acknowledgments Supported by grants: 2012CB947600, 2013BAI04B05, NSFC Q20 (81070540, 81320108006 and 81370719) and Jiangsu Province’s Key Discipline/Laboratory of Fetal Medicine and Human Assisted Reproduction.

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