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Chinese Journal of Natural Medicines 2020, 18(12): 907-915

doi: 10.1016/S1875-5364(20)60034-6

•Research article•

The cardiovascular protective effect and mechanism of

calycosin and its derivatives
PAN Li1, ZHANG Xuan-Fen2*, WEI Wan-Sheng1, ZHANG Jing1, LI Zhen-Zhen1
1
Department of Cardiopulmonary Bypass, Lanzhou University Second Hospital, Lanzhou 730000, China;
2
Department of Orthopaedic Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China
Available online 20 Dec., 2020

[ABSTRACT] Cardiovascular disease is the main cause of mortality and morbidity in the world, especially in developing countries.
Drug therapy is one of the main ways to treat cardiovascular diseases. Among them, great progress has been made in the treatment of
cardiovascular diseases with traditional Chinese medicine. In terms of experimental research, the mechanism of traditional Chinese
medicine in the treatment of cardiovascular diseases has been thoroughly discussed in vitro and in vivo. In terms of clinical treatment,
traditional Chinese medicine with flavonoids, saponins and alkaloids as the main effective components has a definite effect on the
treatment of cardiovascular diseases such as arrhythmia, myocardial ischemia, angina pectoris and myocardial infarction, with high
safety and good application prospects. With the further research on the effective ingredients, mechanism and adverse reactions of tradi-
tional Chinese medicine, it will be beneficial to the effectiveness of traditional Chinese medicine, reduce side effects and promote the
modernization of traditional Chinese medicine. Calycosin and its derivatives, the main bioactive flavonoids in Astragalus mem-
branaceus have multiple biological effects, such as antioxidant, pro-angiogenesis, anti-tumour, and anti-inflammatory effects. Based
on the above biological effects, calycosin has been shown to have good potential for cardiovascular protection. The potent antioxidant
effect of calycosin may play an important role in the cardiovascular protective potential. For injured cardiac myocytes, calycosin and
its derivatives can alleviate the cell damage mainly marked by the release of myocardial enzymes and reduce the death level of cardiac
myocytes mainly characterized by apoptosis through various mechanisms. For vascular endothelial cells, calycosin also has multiple
effects and multiple mechanisms, such as promoting vascular endothelial cell proliferation, exerting vasodilating effect and directly af-
fecting the synthesis function of endothelial cells. The present review will address the bioactivity of calycosin in cardiovascular dis-
eases such as protective effects on cardiac myocytes and vascular endothelial cells and elucidate main mechanism of calycosin and its
derivatives to exert the above biological effects.
[KEY WORDS] Cardiovascular disease; Calycosin; Cadiac myocytes; Vascular endothelial cells; Protective effect
[CLC Number] R965 [Document code] A [Article ID] 2095-6975(2020)12-0907-09

Introduction cigarette smoking, and insufficient regular exercise are estab-

lished primary causal factors of CVD [5]. Over 95% of all
Cardiovascular disease (CVD) is one of the leading
CVD deaths are attributable to 6 conditions: ischemic heart
cause of death worldwide, especially in developing countries,
disease (IHD), stroke, hypertensive heart disease (which ulti-
where the prevalence has increased significantly [1]. The glob-
al number of deaths from CVD has increased during the past mately results in heart failure), cardiomyopathy, rheumatic
decade by 12.5% [2]. Between 1990 and 2020, the burden of heart disease (RHD), and atrial fibrillation (AF) [4, 6, 7]. The
CVD in the developing countries is growing [3]. These treatment methods of CVD mentioned above generally in-
changes are driven by population growth and aging popula- clude drug therapy, interventional methods and surgical
tions, with the largest number occurring in countries of South techniques that improve the health of patients from different
and East Asia because of their large and growing popul- perspectives and mechanisms [8]. Among them, drug therapy
ations [4]. Elevated blood lipid levels, hypertension, elevated is one of the main ways to treat CVD. In recent years, with
blood glucose levels, overweight, unhealthy dietary habits, the wide application of high and new technologies and bio-
technology in drug research, natural medicines show great
potential in the application and discovery of cardiovascular
[Received on] 20-May-2020
[*Corresponding author] E-mail: zhxf9304@126.com drugs [9].
These authors have no conflict of interest to declare. Astragalus membranaceus has been widely studied and

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has been shown to have important pharmacological effects, factors, including dysfunction of oxidases, such as xanthinox-
such as protecting injured myocardium, inhibiting ventricular idase and nicotinamide adenine dinucleotide phosphate
remodelling and regulating blood pressure [10]. However, the (NADPH), transport dysregulation in mitochondria, micro-
components of Astragalus membranaceus are complex and somes and/or the nucleus, neutrophil activation, arachidonic
varied and more than 200 compounds have been identified acid metabolism, and auto-oxidation of catecholamines,
from Astragalus membranaceus [11]. The major active ex- flavonoids, quinones, and proteins, etc. [24]. Mitochondria are
tracts include flavonoids, triterpene saponins and polysac- considered the main source of ROS production in high-meta-
charides [11, 12]. Astragalus membranaceus are a rich source of bolic organs such as the heart. Mitochondrial calcium activ-
flavonoids. Studies have shown that flavonoids from As- ates the dehydrogenases in the Krebs cycle involved in oxid-
tragalus membranaceus have multiple physiological effects, ative phosphorylation and maintains a low level of nicotinam-
such as antioxidant, antitumor, anti-inflammatory, anti-osteo- ide adenine dinucleotide (NADH) accumulation, thus contrib-
porotic effects, and so on [13]. Especially, flavonoids that serve uting to cellular energy balance and maintaining adequate
as potent antioxidants can inhibit the production of reactive cardiac function [25]. In cardiac diseases, especially in heart
oxygen species (ROS) and free radicals that are responsible failure, this process is disrupted, and mitochondrial Ca2+ up-
for many human diseases [14]. take disorders eventually lead to NADPH oxidation and ROS
Currently, exploring the pharmacological effects of a production and accumulation [26, 27]. In addition, ROS can also
single bioactive component for the treatment of cardiovascu- be produced through the metabolism of drugs and exogenous
lar diseases and validating the specific therapeutic target are substances, such as anticancer drugs, among which doxorubi-
hot research topics. Calycosin and its derivatives are the main cin, which is related to the development of cardiomyopathy,
bioactive flavonoids in Astragalus membranaceus [15]. Stud- is the most representative [28]. Oxidative stress is an import-
ies have confirmed that calycosin has multiple biological ef- ant common mechanism of myocardial injury caused by vari-
fects, such as antioxidant [16], pro-angiogenesis [17], anti-tu- ous aetiologies, such as hypertension, hyperglycaemia,
mour [18], and anti-inflammatory [19, 20] effects. Based on the ischaemia-reperfusion injury, and chemotherapy drugs, and is
above biological effects, current research has been increas- closely related to the subsequent occurrence and develop-
ingly focused on the protective effects of calycosin on cells ment of cardiac failure. Abnormally elevated ROS can cause
and organs. For example, a recent study showed that calycos- many negative effects on cardiac function [29]. In myocardial
in has a protective effect against high-fat diet-induced liver tissues, ROS directly damages the electrophysiology and con-
damage [21]. In the nervous system, calycosin can activate the tractile structure of myocardial cells by modifying the core
transient receptor potential canonical 6 (TRPC6) pathway and proteins of the excitation-contraction coupling mechanism,
other protective proteins to alleviate cerebral ischaemia- including L-type calcium channels, sodium channels, potassi-
reperfusion injury and other injuries [22]. Furthermore, the pro- um channels and sodium/calcium exchangers, and causes an
tective effect of calycosin on the cardiovascular system has energy deficiency in cardiac myocytes by affecting the func-
also received attention. It has been shown, preliminarily, that tion of proteins involved in energy metabolism [23]. ROS leads
calycosin can antagonize hypoxic injury in myocardial to the activation of multiple signalling pathways related to
ischaemia and increase the myocardial survival rate. cell death, cardiac fibroblast proliferation, matrix metallopro-
However, existing studies have only focused on the prelimin- teinase activation, mitochondrial deoxyribonucleic acid
ary role of calycosin in ischaemic diseases, myocardial hy- (DNA) damage, mitochondrial dysfunction, impaired calci-
pertrophy and viral myocarditis, while comprehensive and in- um regulation and cardiac hypertrophy [30-33]. These effects
depth experimental studies have not been carried out to elu- eventually lead to abnormal adaptive myocardial remodel-
cidate its molecular mechanism and determine its effects on ling and cardiac dysfunction [34]. In addition, recent studies
other types of myocardial damage. have proposed that ROS can directly modify micro ribonuc-
In recent years, studies on the effects of calycosin on the leic acid (microRNA), leading to changes in protein expres-
cardiovascular system have been carried out, and calycosin sion levels and the disruption of downstream gene regulation
has been shown to have good potential for cardiovascular in corresponding tissues, thus leading to proteome remodel-
protection. Therefore, this review focuses on the bioactivity ling and metabolic changes in cardiac tissues [35-37]. In addi-
of calycosin in cardiovascular diseases and reviews previous tion to abnormally regulating related biomolecules and sig-
studies of calycosin to provide a theoretical basis for further naling pathways, ROS can also trigger cascade reactions of
research and clinical application. oxidative stress and expand the oxidative stress injury men-
tioned above, through producing other types of bioactive mo-
The cardiovascular protective effects of calycosin
lecules (aldehydes), ROS induced ROS release and ROS me-
and its derivatives
diated paracrine signals [36, 38].
The antioxidant effects of calycosin and its derivatives The abnormal increase in ROS and clearance barriers are
Oxidative stress is an unbalanced state of ROS produc- the main factors of oxidative stress injury, while flavonoids
tion and abnormal regulation of the endogenous antioxidant have been shown to be the main effective components in As-
mechanism [23]. ROS production is affected by multiple tragalus membranaceus responsible for antioxidation and

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free radical elimination [12]. Recently, studies have adopted have a common basis of cell damage, such as oxidative stress
electron spin resonance, chemiluminescence and other meth- in cardiomyocytes or endothelial cells, substrate metabolism
ods to test the bioactivity of anti-superoxide anion radicals in and energy consumption, cell survival and apoptosis, and
a few major types of flavonoids. Studies have shown that the autophagy [45]. Therefore, the treatment of cardiovascular dis-
antioxidant activity of different flavonoids by the order of eases mainly includes two directions: intervention for the ae-
strength is quercetin > kaempferol > isorhamnetin > isoquer- tiologies of cardiovascular diseases and protective measures
citrin > rutin > calycosin > vitamin C > (3R)-8, 2′-dihydroxy for the injury effects (organ level, cellular level or molecular
7, 4′-dimethoxyisoflavanone > formononetin > ononin > 2′, 4′- level). Based on the multiple biological effects of calycosin
dimethoxy-3′-hydroxyl-isoflavanone-6-O-β-glucoside > (6- and its derivatives, the protective effect of calycosin on cardi-
aR, 11aR)-10-hydroxyl-3, 9-dimethylnissolin > (6aR, 11aR) ovascular cells has been studied.
9, 10-dimethylnissolin-3-O-β-D-glycoside [39]. These results In vitro effects
suggest that calycosin has relatively strong antioxidant activ- For in vitro cardiomyocytes affected by different injury
ity and is also superior to standard antioxidant vitamin C. Re- factors (H2O2, hypoglycaemia, hypoxia, and viruses, etc.), ca-
cent studies have more accurately discriminated, from the lycosin and its derivatives exhibit a common effect, that is, to
perspective of quantum chemistry, the antioxidant activity of reduce cell damage, predominantly indicated by the release of
four major flavonoids, from which it was confirmed that the myocardial enzymes, and to reduce apoptosis-dominated car-
antioxidant activity of calycosin is stronger than that of three diomyocyte death levels; furthermore, calycosin may play an
other antioxidants (calycosin > calycosin-7-glucoside > for- anti-injury role through multiple mechanisms. For example,
mononetin > ononin) [15]. The antioxidant bioactivity of calyc- in H9C2 cells under hypoxic and hypoglycaemic conditions,
osin is related to its chemical structure. The C-ring Δ2, 3- pretreatment with calycosin can reduce the released level of
double bond and 4-carbonyl group in calycosin are all bioact- the cell damage indicator lactate dehydrogenase (LDH)
ive antioxidant groups. They can remove oxidative free radic- (Table 1), improve the cell survival rate, and increase the pro-
als, reduce malondialdehyde (MDA) (lipid peroxidation tein expression levels of phosphorylated Akt/PI3K, Nrf-l, Nrf-
product), protein carbonyl (amino acid oxidation product) and 2, and HO-1, which suggests that the myocardial protective
ROS levels, and increase superoxide dismutase (SOD), effect of calycosin in this process is related to the direct activ-
catalase and glutathione peroxidase (GSH-Px) levels. It can ation of the PI3K/Akt and Nrf-2/HO-1 pathways [44]. In addi-
also enter the lipid bilayer of biological membranes to ameli- tion, these pathways are important in cell proliferation and in
orate lipid peroxidation induced by free radicals [40]. Further the balance of oxidation and antioxidation. In another study,
studies suggest that calycosin may stabilize the membrane the cellular protective effect of calycosin is considered to be
structure and enhance membrane integrity, which can reduce related to its phytoestrogen-like effects and the study first
the lipid fluidity of the cell membrane and hinder the diffu- demonstrates that calycosin can inhibit the oxidative stress-
sion of free radicals, thereby reducing oxidative damage in induced apoptosis of cardiac muscle cells (H9C2 cells) in
cells [19, 41]. Using biological experiments, it was also shown vitro and the protective effect on the heart occur through oes-
that calycosin has a good antioxidant effect and that its cellu- trogen receptor α (ERα) binding to ERβ and upregulating its
lar protective effect in multiple pathological states is mainly expression, thereby activating the Akt signalling pathway [46].
antioxidative. Li et al. showed that calycosin has a signific- For infective myocardial injury, calycosin can inhibit cox-
ant inhibitory effect on H2O2-induced oxidative stress in hu- sackie virus replication in African green monkey kidney het-
man liver parenchymal cells and can significantly alleviate eroploid cell (Vero cells), and its antiviral activity and spe-
oxidative damage in hepatic cells [42]. Recent studies on the cificity are all superior to the traditional antiviral drug rib-
neuronal protective effects of calycosin indicate that calycos- avirin (antiviral activity analysis showed that its half-maxim-
in can alleviate oxidative stress and the inflammatory re- al inhibition (IC50) was 25 μg·mL−1 and that the ratio of cyto-
sponse of neurons in the hippocampus of a mouse model of toxicity to antiviral activity was 5.7), suggesting that it plays
Alzheimer′s disease by activating the protein kinase C path- a role in cell protection through direct antiviral effects [47].
way, thereby improving cognitive function [43]. In addition, in In vivo effects
myocardial injury caused by ischaemia and hypoxia, calycos- In recent years, to further explore the myocardial protect-
in can activate the Akt/PI3K and Nrf2/HO-1 signalling path- ive effect and mechanism of calycosin, increasingly more in
ways, with myocardial protective effects; these pathways are vivo experiments have provided more accurate and reliable
important in organism oxidation and antioxidative regula- evidence from different aspects.
tion [44]. Therefore, the antioxidative activity of calycosin may Myocardial ischaemia-reperfusion injury is the main
play an important role in its cardioprotective potential. pathological of ischaemic heart disease develops and is asso-
The protective effects of calycosin and its derivatives on car- ciated with the development of myocyte necrosis, arrhythmia,
diac myocytes myocardial stunning, endothelial dysfunction, and microvas-
Cardiovascular diseases are a large group of patho- cular complications, etc [48-50]. Calycosin has been shown to
physiological states with multiple risk factors and aetiologies, have a good protective effect on ischaemic and reperfused
but at the cellular level, various cardiovascular diseases often myocardium: On the one hand, calycosin can improve cardi-

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Table 1 In vitro myocardial protective effects of calycosin and its derivatives

Cardiac
Chemical Drug administration Signalling
injury Cell type In vitro effect References
components method pathway
inducer
Cardiomyocyte
5, 10, 20 μmol·L−1
apoptosis ↓ Akt signalling
Calycosin H2O2 pretreatment for 24 H9C2 cells [46]
ERα/β expression pathway
hours
levels ↑Akt↑
Calycosin -7-O- African green monkey
Coxsackie
β-D- 25 μg·mL−1 kidney heteroploid Virus replication ↓ [47]
virus B3
glucopyranoside cells (Vero cells)
LDH↓
−1
Hypoglycae 0.01,0.1,1,10 μmol·L Cell survival rate↑ PI3K/Akt signalling
Calycosin mia and pretreatment H9C2 cells Phosphorylated Akt, pathwayNrf2/HO-1 [44]
hypoxia for 2 hours PI3K proteins↑ signalling pathway
Nrf2, HO-1 proteins↑

ac function after ischaemia. For example, it increases the (CCGR) treatment increased myocardial contractile force and
ejection fraction (EF), fractional shortening (FS), and left cardiac EF. In addition, the progression of heart failure in in-
ventricular end systolic pressure (LVESP) and decreases left fected mice was inhibited by increasing the systolic ventricu-
ventricular end diastolic pressure (LVEDP) (Table 2). Fur- lar septal thickness, left ventricular posterior wall thickness
thermore, it can induce the expression of vascular endothelial and left ventricular volume. Overall, the symptoms of viral
growth factor (VEGF) and CD31 and promote the angiogen- myocarditis were reduced, and the survival rate was im-
esis of ischaemic myocardium [51]. On the other hand, oxidat- proved (77.7% in the treatment group and 44.4% in the non-
ive stress is an important mechanism for myocardial treatment group). This study further suggested that CCGR
ischaemia-reperfusion injury. Calycosin can significantly re- could play a protective role in myocardial tissue in viral
duce the level of MDA, the lipid oxidation product of the cell myocarditis by significantly reducing viral titres, reducing
membrane. It also increases the level of the protective antiox- myocardial cell oedema and inhibiting myocardial cell nec-
idant product SOD, thus inhibiting the release of myocardial rosis and monocyte infiltration caused by viral infection [47].
enzymes including creatine kinase (CK) and LDH, etc [52-54]. The protective effects of calycosin and its derivatives on vas-
The P13K/Akt signalling pathway is considered an important cular endothelial cells
pathway involved in the regulation of cardiomyocyte apop- The influence of calycosin on vascular endothelial cells
tosis and myocardium tissue protection. In addition, calycos- has multiple effects and multiple mechanisms. First, calycos-
in can increase the protein phosphorylation level of P13K and in, as a phytoestrogen, can bind to ER-positive cells in the
Akt during ischaemia-reperfusion injury, suggesting that ca- vascular endothelium and exert its role as a selective oestro-
lycosin may exert a myocardial protective effect through ac- gen receptor modulator (SERM) by increasing ERK1/2 phos-
tivating the P13K/Akt signalling pathway in ischaemia-reper- phorylation and activating the MAPK signalling pathway,
fusion injury [52]. thereby promoting vascular endothelial cell proliferation [57].
In addition to its protective effect on acute ischaemic in- Second, calycosin can interfere with ion channels. It has been
jury, calycosin also has a protective effect on some maladapt- shown that calycosin has a vasodilating effect, which is not
ive changes in myocardial tissue. In a mouse model of endothelium-dependent and independent of intracellular cal-
myocardial hypertrophy constructed by isoproterenol induc- cium ion release. Calycosin is a non-competitive calcium
tion and aortic constriction, calycosin significantly reduced channel blocker that primarily blocks voltage-gated calcium
markers of cardiac hypertrophy (atrial natriuretic peptide and ion channels and receptor-gated calcium channels [58]. Tse-
myosin heavy chain-β) and inhibited myocardial remodelling. ng [59] et al. demonstrated that calycosin could activate the
Additionally, the activation of the mitogen-activated protein large-conductance Ca2+-activated K+ (BKCa) channels of hu-
kinase (MAPK) and AKT signalling pathways in mouse man umbilical vein endothelial cells, thereby increasing the
myocardium tissue was significantly attenuated, suggesting hyperpolarization of endothelial cells and the production of
that calycosin may reduce cardiac hypertrophy induced by nitric oxide and mediating endothelium-dependent vasodila-
isoproterenol or aortic coarctation by inhibiting AKT/GSK3β tion. In addition, calycosin also has protective effects on en-
and extracellular signal-regulated kinase (ERK) signalling [55]. dothelial cell injury induced by various factors. For en-
For infective myocardial injury, calycosin showed mul- dothelial cell injury induced by bacterial endotoxin, calycos-
tiple positive effects, such as anti-viral, anti-apoptosis and in can increase the production of nitric oxide, reduce phos-
anti-inflammatory properties. In a mouse model of coxsackie phorylated myosin light chain, reduce Rho/Rock signalling
virus B3 infection, calycosin-7-O-β-D-glucopyranoside pathway activation-induced cytoskeleton remodelling by in-

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Table 2 In vivo myocardial protective effects of calycosin and its derivatives

Chemical Drug administration Signalling
Dose Animal Model Protective effects References
components methods pathway
Isoproterenol- MPO↓ (Neutrophils seepage
40 mg·kg−1·d−1
Intraperitoneal −1 induced myocardial reduction)
Calycosin 1 t·d , [53]
injection infarction mouse MDA↓ (Lipid peroxidation
3 days
model attenuation)
0.5 mg·kg−1
1 mg·kg−1
Intraperitoneal 2 mg·kg−1 myocardial Cardiac function↑
Calycosin [51]
injection 4 mg·kg−1 ischaemia rat model VEGF expression↑
1 t·d−1,
28 days
30 mg·kg−1 Cardiac function↑
(high dose) Myocardial Area of myocardial infarction ↓
Calycosin-7-O-β-d Intravenous 15 mg·kg−1 ischaemia- CK, LDH, MDA↓ PI3K/Akt signalling
[52]
glucoside injection (low dose) reperfusion rat SOD↑ pathway
pretreatment model caspase-3, caspase-9↓
once phosphorylated PI3K p85/Akt↑
24 mg·kg−1 Coxsackie virus B3 Survival rate, cardiac function↑
Calycosin-7-O-β-
Intragastric gavage 1 t·d−1, viral myocarditis Mononuclear cell infiltration, [47]
D-glucopyranoside
14 days mouse model Virus replication↓
0.1 μmol·L−1 CK, LDH↓
Ex vivo cardiac
pretreatment SOD, SDH↑
ischaemia-
Calycosin Ex vivo perfusion continuous MDA↓ [54]
reperfusion rat
perfusion Nrf-2/HO-1↓
model
for 10 min p-Akt/Akt, p-ERK/ERK↓
Isoproterenol
Cardiac function↑
intraperitoneal
−1 Marker of myocardial Akt/GSK3β
50 mg·kg injection and aorta
hypertrophy↓ signalling pathway
Calycosin Intragastric gavage 1 t·d−1, constriction [55]
p-Akt/Akt↓ ERK signalling
14 days myocardial
p-GSK3β/GSK3β↓ pathway
hypertrophy mouse
p-ERK/ERK↓
model
Abdominal aorta
1 mg·kg−1·d−1 constrictive pressure Cardiac function↑
Intraperitoneal JAK/STAT
Calycosin 1 t·d−1, overload rat model JAK1, STAT3 protein [56]
injection signalling pathway
7 weeks of myocardial expression↓
hypertrophy

hibiting the AKT signalling pathway, and exert protective ef- In addition to these protective effects on endothelial
fects on endothelial cells [60]. Calycosin can also reduce the cells, calycosin can also directly affect endothelial cells
cytotoxicity and apoptosis of human umbilical vein en- (Fig.1). Calycosin-7-glucoside has therapeutic effect on an-
dothelial cells induced by vascular endothelial growth factor giotensin II (Ang II)-induced renin-angiotensin-aldosterone
receptor (VEGFR) tyrosine kinase inhibitor II (VRI), which system (RAAS) disorder in human umbilical vein endothelial
is related to the activation of the PI3K/Akt/Bad and cells by down-regulation of angiotensin-converting enzyme
BRAF/MEK1/2/ERK1/2 signalling pathways [61]. However, (ACE) expression and increased ACE2 expression [64]. Calyc-
for human umbilical vein endothelial cell apoptosis induced osin can inhibit the synthesis of Ang II-induced thromboxane
by glycation end products, calycosin can directly increase A2 (TXA2) and prostacyclin (PGI2) in endothelial cells and
the expression of anti-apoptotic protein Bcl-2 and simu- reduce Ang II-induced endothelial cell injury. In addition, ca-
ltaneously reduce the expression levels of pro-apoptotic pro- lycosin can inhibit the secretion and expression levels of
teins Bax and Bad, thereby inhibiting endothelial cell apop- endothelial cell inflammatory factors induced by tumor
tosis [62, 63]. necrosis factor-α (TNF-α), such as intercellular adhesion

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molecule-1 (ICAM-1) and its receptor lymphocyte function- The effect on platelet
associated antigen 1 (LFA-1), thus protecting endothelial Ischemic heart disease and thromboembolic disease are
cells [65, 66]. common types of cardiovascular diseases. Platelets play a
The relation of calycosin and its derivatives to inflammation crucial role in the development of these diseases by particip-
The pathophysiological mechanism of many cardiovas- ating in thromboembolism development [71]. Thus, anti-plate-
cular diseases is closely related to the inflammatory response. let is often a crucial part of cardiovascular disease therapy [72].
Previous studies have shown that the inflammatory response Studies have shown that calycosin and its derivatives are the
plays an important role in the occurrence and progression of main active ingredients in many traditional Chinese medicine
cardiovascular diseases [67]. In recent years, it has been found compounds widely used in cardiovascular diseases [73-76]. For
that calycosin and its derivatives have potential anti-inflam- example, calycosin-7-O-β-D-glucoside as one of main active
matory effects. Recent studies have revealed that the inhibi- ingredients of BuyangHuanwu decoction (BHD) can inhibit
tion of the NF-κB signalling pathway may be the main mech- adenosine diphosphate (ADP)-induced platelet aggregation in
anism of calycosin’s anti-inflammatory effects [68, 69]. By in- vitro [73]. In addition, the core bioactive components of com-
hibiting the expression of NF-κB and MAPK signalling path- pound xueshuantong capsule (CXC) act on different aspects
way-related proteins, calycosin-7-glucoside can reduce the of the vascular system to promote blood circulation. Among
production of pro-inflammatory factors including Prostagl- them, calycosin-7-O-β-D-glucoside has been proved to
andin E2 (PGE2), TNF-α, interleukin-1β (IL-1β) and inter- mainly affect extrinsic clotting activity and to have negative
leukin-6 (IL-6) in endotoxin-induced macrophagocytes and effects on red blood cell (RBC) aggregation, RBC deformab-
inhibit the mRNA expression levels of inflammatory mediat- ility, intrinsic clotting activity and platelet aggregation [74].
ors inducible Nitric Oxide Synthase (iNOS) and cyclooxy- Although the above studies reveal the effect of calycosin on
genase-2 (COX-2) [70]. However, studies on the anti-inflam- vascular system, the mechanism underlying it functional
matory effects of calycosin mainly focus on the diseases of activity requires further systematic research.
the haematologic system, immune system and neurological
Conclusion
system. There is no definitive research on the effects of ca-
lycosin on the inflammatory response in cardiovascular dis- Calycosin is characterized by low toxicity and diverse
eases. biological effects [77] and is a monomer compound with a

VEGF
VEGFR

Calycosin

E
AG
VRI P PI3K
Raf
RA

P Calyco
sin
GE

gⅡ eNOS↑
An P AKT P MEK

Oxidative stress NO↑

Bad P ERK K+ BKCa
P

TXA2↑

PGI2↑ n
cosi
Caly
Cal
yco
sin
Bal-2↓
Bad, Bax↑
Calycosin

Ca2+
Apoptosis

Proliferation Vasodilation
angiogenesis

Fig. 1 Schematic chart of the effects and mechanisms of calycosin on vascular endothelial cells

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Cite this article as: PAN Li, ZHANG Xuan-Fen, WEI Wan-Sheng, ZHANG Jing, LI Zhen-Zhen. The cardiovascular protect-
ive effect and mechanism of calycosin and its derivatives [J]. Chin J Nat Med, 2020, 18(12): 907-915.

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