(CM) Fphar 11 570867

REVIEW
published: 14 January 2021

doi: 10.3389/fphar.2020.570867
Saponins in Chinese Herbal Medicine

Exerts Protection in Myocardial
Ischemia–Reperfusion Injury: Possible
Mechanism and Target Analysis
Ruiying Wang 1,2,3,4,5, Min Wang 1,2,3,4,5, Jiahui Zhou 1,2,3,4,5, Daoshun Wu 1,2,3,4,5,
Jingxue Ye 1, Guibo Sun 1,2,3,4,5* and Xiaobo Sun 1,2,3,4,5*
1
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing,
China, 2Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational
Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences,
Beijing, China, 3Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of
Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing, China, 4Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glycolipid Metabolic Disorders, State
Administration of Traditional Chinese Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and
Chinese Academy of Medical Sciences, Beijing, China, 5Key Laboratory of New Drug Discovery Based on Classic Chinese
Edited by: Medicine Prescription, Chinese Academy of Medical Sciences, Beijing, China
Da-zhuo Shi,
China Academy of Chinese Medical
Sciences, China Myocardial ischemia is a high-risk disease among middle-aged and senior individuals. After
Reviewed by: thrombolytic therapy, heart tissue can potentially suffer further damage, which is called
Jun Peng, myocardial ischemia-reperfusion injury (MIRI). At present, the treatment methods and
Fujian University of Traditional Chinese
drugs for MIRI are scarce and cannot meet the current clinical needs. The mechanism of
Medicine, China
Lanping Guo, MIRI involves the interaction of multiple factors, and the current research hotspots mainly
China Academy of Chinese Medical include oxidative stress, inflammation, calcium overload, energy metabolism disorders,
Sciences, China
pyroptosis, and ferroptosis. Traditional Chinese medicine (TCM) has multiple targets and
*Correspondence:
Guibo Sun
few toxic side effects; clinical preparations containing Panax ginseng C. A. Mey., Panax
[email protected] notoginseng (Burk.) F. H. Chen, Aralia chinensis L., cardioprotection, and other Chinese
Xiaobo Sun
herbal medicines have been used to treat patients with coronary heart disease, angina
[email protected]
pectoris, and other cardiovascular diseases. Studies have shown that saponins are the
Specialty section: main active substances in TCMs containing Panax ginseng C. A. Mey., Panax notoginseng
This article was submitted to (Burk.) F. H. Chen, Aralia chinensis L., and Radix astragali. In the present review, we sorted
Ethnopharmacology,
a section of the journal the saponin components with anti-MIRI effects and their regulatory mechanisms. Each
Frontiers in Pharmacology saponin can play a cardioprotective role via multiple mechanisms, and the signaling
Received: 09 June 2020 pathways involved in different saponins are not the same. We found that more active
Accepted: 28 October 2020
saponins in Panax ginseng C. A. Mey. are mainly dammar-type structures and have a
Published: 14 January 2021
strong regulatory effect on energy metabolism. The highly active saponin components of
Citation:
Wang R, Wang M, Zhou J, Wu D, Ye J, Aralia chinensis L. are oleanolic acid structures, which have significant regulatory effects on
Sun G and Sun X (2021) Saponins in calcium homeostasis. Therefore, saponins in Chinese herbal medicine provide a broad
Chinese Herbal Medicine Exerts
Protection in Myocardial application prospect for the development of highly effective and low-toxicity anti-
Ischemia–Reperfusion Injury: Possible MIRI drugs.
Mechanism and Target Analysis.
Front. Pharmacol. 11:570867. Keywords: saponins, traditional Chinese medicine, myocardial ischemia-reperfusion injury, mechanism,
doi: 10.3389/fphar.2020.570867 ginsenosides, aralia saponins
Frontiers in Pharmacology | www.frontiersin.org 1 January 2021 | Volume 11 | Article 570867

Wang et al. Saponins Protect Against MIRI
INTRODUCTION MECHANISMS OF MYOCARDIAL

ISCHEMIA–REPERFUSION INJURY
To date, revascularization, such as thrombolysis, is an
effective method for the treatment of ischemic Oxidative Stress and Myocardial
cardiomyopathy in patients with acute myocardial Ischemia–Reperfusion Injury
infarction (Yang et al., 2018). However, reperfusion can MIRI is accompanied by an excess of oxygen free radicals, and
still cause other damage to the myocardium, which greatly reactive oxygen species (ROS) are the main driving forces for
reduces the advantages of reperfusion therapy (Bell and reperfusion injury (Zhou et al., 2015). ROS and cellular redox
Yellon, 2011). Therefore, myocardial ischemia-reperfusion states regulate many critical cellular activities. In presence of
injury (MIRI) is a current clinical problem that needs urgent sufficient oxygen supply, ROS and endogenous antioxidants
attention. MIRI involves a variety of classical mechanisms, maintain balance to protect essential activities in the cell
including oxidative stress, inflammation, calcium overload, (Cadenas, 2018). MIRI damages the cellular antioxidant
and mitochondrial damage (Turer and Hill, 2010). In recent system and promotes oxidative damage. After reperfusion, the
years, there has been an increasing number of studies on cell generation of excessive ROS, notably hydroxyl radicals, may
pyroptosis, ferroptosis, and autophagy during MIRI (Jia et al., cause the oxidation of proteins, lipids and nucleic acids
2019; Li C. Y. et al., 2020). Over the past three decades, (Dongo et al., 2011). This further leads to changes in protein
methods to reduce MIRI have been in development and have function, membrane damage, gene mutations, and metabolic
been used in clinical treatments (Garcia-Dorado et al., 2014). disorders, which generates oxidative stress. Superoxide anion
The treatment methods mainly include non-pharmacological (O2−), hydroxyl radical (OH−), and hydrogen peroxide (H2O2),
interventions (ischemic pre-conditioning) and which are the culprits responsible for inducing oxidative stress in
pharmaceutical treatments (Ibanez et al., 2015). At the vascular wall, are mainly produced through xanthine oxidase,
present, several drugs are effective in MIRI animal models, NADPH oxidase, endothelial nitric oxide synthase, and other
but their clinical use is not ideal, which may be due to the enzyme systems (Zhou et al., 2015). In other words, a close
complex pathological mechanism of MIRI. connection exists between endothelial cells and ROS injury. The
Traditional Chinese medicines (TCM) has a holistic treatment enhancement of endogenous antioxidant activity and the
concept, and has the advantages of multiple targets, multiple intervention of exogenous antioxidants can effectively inhibit
links, and multiple approaches. In the field of TCM, the etiology oxidative stress and reduce damage to cells (Matsushima et al.,
of MIRI involves deficiency of qi, blood stasis, and phlegm. The 2014; Zhao D. et al., 2017). Therefore, researchers have screened
clinical treatment is often based on TCM and compound several natural compounds with antioxidant activity, such as
preparations with the effects of replenishing qi and araloside C, dioscin, etlatoside C, ginsenoside Rb3, and
nourishing yin, warming the heart, promoting blood ginsenoside Rg3 (Xia et al., 2011; Wang M. et al., 2015),
circulation and removing blood stasis, and expelling phlegm which are expected to protect the heart by inhibiting oxidative
(Liu et al., 2013). TCM containing a large amount of saponins stress.
include Panax ginseng C. A. Mey., Panax notoginseng (Burk.)
F.H. Chen, Panax quinquefolium L., Aralia chinensis L., and
Radix astragali (Tu et al., 2013; Aravinthan et al., 2015; Wang H. Inflammatory Response and Myocardial
W. et al., 2018). In recent years, many studies have shown that Ischemia–Reperfusion Injury
the saponins extracted from TCM has great anti-MIRI effects in The inflammatory response activates during myocardial ischemia
vivo and in vitro; their mechanisms are diverse and mainly and is significantly aggravated during reperfusion (Vinten-
involve regulating energy metabolism and calcium homeostasis, Johansen et al., 2007). The adhesion and infiltration of
and inhibiting oxidative stress and inflammation (Zhu et al., neutrophils are the main pathological changes of coronary
2017; Wang et al., 2019). Saponins mainly include four-ring arteries after MIRI. After MIRI, the metabolism of arachidonic
triterpene saponins and five-ring triterpene saponins. Among acid on the myocardial cell membrane increases, which leading
the tetracyclic triterpene type saponins, dammarane-type the production of large amounts of leukotrienes, prostaglandins,
saponins have been studied in-depth, while among the and thromboxane A2 (Boag et al., 2017). And then the expression
pentacyclic triterpene-type saponins oleanane-type saponins of special adhesion molecules on the surface of microvascular
are most widely distributed and studied (Leo et al., 2007; Hu endothelial cells or leukocytes increases, which promotes the
et al., 2010; Shin et al., 2015; Zebiri et al., 2016). Each saponin chemotaxis, adhesion and aggregation of neutrophils, increases
also has its unique protection mechanism for MIRI due to its the blood flow resistance of microvascular, and even causes no-
structural specificity. reflow phenomenon, aggravating myocardial ischemic damage
In this review, we discuss the classic mechanisms of MIRI and (Arslan et al., 2008). Neutrophils adhere to the endothelial cells of
a few emerging regulatory mechanisms (Figure 1). Based on the the blood vessel wall under the guidance of adhesion molecules
significant anti-MIRI effect of saponins, we classified and and then migrate to the myocardial tissue (Moos and Funk,
summarized the saponins with cardioprotective effects and 2008). During MIRI, the levels of inflammatory factors, including
analyzed their cardioprotective mechanisms. This review aims tumor necrosis factor-α (TNF-α) and IL-1, significantly increase
to provide potential treatment strategies and drug candidates in the myocardial tissue causing myocardial damage. Anti-
for MIRI. inflammatory factors and pro-inflammatory factors co-exist

FIGURE 1 | Graphical summary of MIRI mechanism.
during MIRI, and generally, the pro-inflammatory factors are effects (Vinten-Johansen et al., 2007; Sandanger et al., 2016).
more dominant (Singhal et al., 2010). Some natural saponins, such as celastrol, ginsenoside Rb1, and
Endothelial cells are closely related to inflammation, and ginsenoside Rb3, can reduce MIRI by inhibiting inflammation
endothelial dysfunction and microcirculation injury are and restoring endothelial cell function (Wang Y. et al., 2015; Li
important bases of MIRI. Studies have found that endothelial et al., 2017).
cells are more vulnerable to damage than cardiomyocytes during
reperfusion, whereas cardiomyocytes are more vulnerable to
damage during the ischemic phase (Singhal et al., 2010; Calcium Overload and Myocardial
Schanze et al., 2019). Therefore, coronary endothelial cells are Ischemia–Reperfusion Injury
critical mediators of myocardial dysfunction post MIRI. As the second messenger in the cell, Ca2+ can maintain
Autophagy of endothelial cells would cause structural and cardiomyocyte function, proliferation, division, energy
functional damage that hinders the blood flow to increase metabolism and other important processes (Verkhratsky and
MIRI (Raivio et al., 2009; Russo et al., 2017). The mechanism Parpura, 2014). During myocardial ischemia, ATP production
of endothelial cells involved in MIRI may be related to the decreases, resulting in decreased sarco-endoplasmic reticulum
AMPK/mTOR and nuclear factor κB (NF-κB)-p65-Beclin1 Ca2+ ATPase (SERCA) activity (Zhu et al., 2017). Thus,
pathways (Moos and Funk, 2008; Singhal et al., 2010). The intracellular calcium transport is impaired, causing calcium
role of NOD-like receptors (NLRs) with a pyrin domain 3 overload. On reperfusion, ROS damage the cell membrane,
(NLRP3) inflammasome in MIRI is a current hot topic. leading to extracellular Ca2+ influx; NCX transports Ca2+ into
NLRP3 can be combined with caspase-1 and ASC to form the the cells and discharges a large amount of Na+ in the cell,
NLRP3 inflammasome, which requires NF-κB activation (Wang exacerbating calcium overload (Ohtsuka et al., 2004).
Y. et al., 2015; Li et al., 2017). Recent research on the role of NOD- Intracellular Ca2+ regulates the contractile and diastolic
like receptor (NLR) with a pyrin domain 3 (NLRP3) function of cardiomyocytes and plays an essential role in
inflammasome in MIRI is a hot topic. NLRP3 can be excitation-contraction coupling (MacLennan and Kranias,
combined with caspase-1 and ASC to form the NLRP3 2003). The action potential triggers a small amount of Ca2+ to
inflammasome, which requires NF-κB activation (Sandanger enter the cell through L-type calcium channels (LTCC), and a
et al., 2016). NLRP3 inflammatory bodies promote the large amount of Ca2+ is released from the sarcoplasmic reticulum
increase in IL-1β levels, triggering downstream inflammatory (SR) through ryanodine receptor 2 (RyR2). Then, calcium and
responses, including leukocyte recruitment and activation. troponin C combine to cause myocardial cell contraction
Studies have shown that during the MIRI process, the (Grueter et al., 2007). SERCA can retake the intracellular Ca2+
activation of NLRP3 inflammatory bodies has cardioprotective to the SR, while NCX in the cell membrane can export Ca2+ from

the cells, leading to relaxation of the cardiomyocytes (Fang et al., mitochondrial permeability transition pores (MPTP) opening
2016). Therefore, the intracellular calcium level affects the (Paradies et al., 2018). Therefore, MIRI causes energy
excitability degree and relaxation rate of cardiomyocytes. The metabolism disorders, and MPTP opening further promotes
occurrence of calcium overload is bound to have a non-negligible cardiomyocyte apoptosis and necrosis (Ong et al., 2015). In
effect on the contraction and relaxation of cardiomyocytes (Li the meantime, pathways, including glycogen synthesis kinase
et al., 2013). Calcium overload is closely related to oxidative 3β (GSK-3β) pathway, protein kinase C (PKC) pathway, signal
stress, and inflammatory response and these factors together transducer and activator of transcription 3 (STAT3) pathway and
promote MIRI process (Verkhratsky and Parpura, 2014). apoptosis signaling pathway, are activated successively
Therefore, inhibiting calcium overload is an effective method (Makhdoumi et al., 2016; Lesnefsky et al., 2017). These
to reduce heart damage during MIRI. Some natural ingredients, pathways further affect the function of mitochondria, either
such as ginsenoside Re, ginsenoside Rb1, Elatoside C and promoting or inhibiting cardiomyocyte apoptosis (Zheng et al.,
Araloside C, can promote the restoration of calcium 2017). Saponins, such as Araloside C, astragaloside IV, dioscin,
homeostasis and thus play a cardioprotective role (Wang et al., ginsenoside Rb1, ginsenoside Rd, ginsenoside Rg1 and
2014; Wang M. et al., 2015). notoginsenoside R1, can reduce MIRI by regulating
mitochondrial function (Wang et al., 2012; Li et al., 2018).
Mitochondrial autophagy is a process that selectively removes
Energy Metabolism Disorder and damaged mitochondria to reduce cell damage. During MIRI,
Myocardial Ischemia–Reperfusion Injury PTEN induces mitochondrial autophagy through pathways such
In the early stage of myocardial ischemia, because the oxygenated as putative kinase 1 (PINK1)/Parkin, BNIP3/NIX, and FUNDC1
hemoglobin in the ischemic tissue is consumed, the energy signaling pathway (Ney, 2015). Moderate mitochondrial
metabolism changes from aerobic oxidation of mitochondria autophagy has a protective effect on the maintenance of
to glycolysis (Cui et al., 2017; Alegre et al., 2020). So, ATP mitochondrial membrane potential and the normal structure
produced by glycolysis becomes dominating source of energy and function of cell membranes, thereby reducing MIRI. In
to the maintenance of myocardial cell survival. The enhancement contrast, mitochondrial dysfunction leads to impaired
of glycolysis induces the intracellular lactate increase, autophagy function, insufficient clearance, or excessive
intracellular pH drops, which leading the calcium overload activation of mitochondrial autophagy, which can increase
process is aggravated. In addition, the level of fatty acid MIRI (Shirakabe et al., 2016; Tong and Sadoshima, 2016).
oxidation and metabolism after MIRI significantly exceeds the Exploring mitochondrial autophagy and its regulatory
level before ischemia, which slows the recovery of heart function mechanism during MIRI may help to understand the
(Li et al., 2018; Tian et al., 2019). The main reason is that fatty acid relationship between mitochondrial autophagy and MIRI, and
β oxidation accelerates and ATP production increases, but provide new ideas for the clinical treatment of MIRI.
oxygen consumption also increases (Lesnefsky et al., 2017).
To improve myocardial metabolism during MIRI, it is mainly
to promote glucose metabolism and inhibit fatty acid metabolism. microRNA and Myocardial
Optimizing energy metabolism is only a cytoprotective measure, Ischemia–Reperfusion Injury
and the therapeutic effect is limited. The treatment purpose of In recent years, the application of microRNA (miRNA) and long
improving energy metabolism is to prolong the process of noncoding RNAs (lncRNA) in MIRI treatment has increasingly
ischemic myocardial necrosis, buy precious time for become a research focus. miRNA is an endogenous, single-
myocardial revascularization therapy, and promote the stranded, non-coding, small regulatory RNA in a variety of
recovery of heart function (Paradies et al., 2018). Because eukaryotic cells (Diaz et al., 2017). Studies have shown that
metabolic drugs have no obvious hemodynamic effects, it is miR-1275, miR-133, miR-148a and miR-324 interfere with the
recommended to use them in combination with β-receptor process of MIRI by inhibiting myocardial cell apoptosis, reducing
blockers. At present, there are many studies on trimetazidine myocardial inflammation, and promoting angiogenesis (Dai
and niacin, but the research progress is relatively slow due to et al., 2020; Jiang et al., 2020; Zong and Wang, 2020). lncRNA
some side effects (Wu et al., 2018). The saponins in natural is a heterogeneous non-coding RNA that can directly regulate the
products are safer to be used as medicines, and have the transcription of target genes and the degradation of proteins
advantage of multiple targets. It is worth carefully exploring (Ruan et al., 2019). lncRNA has the function of competing or
the effective ingredients of anti-MIRI. Studies have shown that cooperating with endogenous RNA, which can promote or inhibit
ginsenosides including total ginsenosides, ginsenoside Rg1, the degradation of target gene mRNA by miRNA, thereby
ginsenoside Rb1 have a significant effect on energy regulating the expression of target gene mRNA and its protein
metabolism (Cui et al., 2017; Li et al., 2018). (Xiong et al., 2019). The main functions of lncRNA include
Mitochondria are the main organelles that produce ATP. regulating gene methylation, transcription activation, and
Cardiomyocytes need to consume large amounts of ATP to binding to mRNA and miRNA to affect the translation
maintain normal function. Oxygen is required for process (Pei et al., 2020). At present, most researches focus on
mitochondrial energy production (Alam et al., 2015). But the mechanism of lncRNA regulating miRNA. But miRNA can
during MIRI, the levels of oxygen reduce but those of ROS also regulate lncRNA. lncRNA and miRNA mainly regulate and
increase, which result in reduced ATP synthesis and treat MIRI through mechanisms such as oxidative stress,

inflammatory infiltration, mitochondrial dysfunction, autophagy, However, although ferroptosis is closely related to MIRI, its
and apoptosis (Ruan et al., 2019; Pei et al., 2020). To clarify the precise molecular mechanism and biological function are not
complex and delicate regulatory network of lncRNA-miRNA- yet fully elucidated. Research on its mechanism is expected to
mRNA is important for revealing the interaction between RNA provide new insights for MIRI treatment.
molecules (Xiong et al., 2019). The role and interpretation of the
complex molecular network regulation between its functions is of
vital importance, providing new therapeutic targets for the Interaction Among Myocardial
treatment of MIRI. Ischemia–Reperfusion Injury Mechanisms
Due to ischemia and hypoxia of myocardial tissue, energy
metabolism disorder is the initiation of MIRI (Lesnefsky et al.,
Pyrocytosis and Myocardial 2017). In addition, the ischemic and hypoxic environment creates a
Ischemia–Reperfusion Injury certain material basis for the formation of oxygen free radicals
Pyroptosis is a new form of programmed cell death that is (Chen and Chow, 2005). With the massive formation of oxygen
accompanied by inflammatory reactions (Bergsbaken et al., 2009). free radicals, it directly or indirectly leads to calcium overload in
It is characterized by morphological necrosis and apoptosis. myocardial cells. Calcium overload can cause damage to
However, its features are entirely different, for example, nuclear mitochondrial structure and function under the joint
shrinkage, DNA breakage, and a large number of 1–2 nm-diameter participation of inflammatory (Verkhratsky and Parpura, 2014).
holes on the cell membrane are observed (Jia et al., 2019). Pyroptosis Calcium overload and mitochondrial dysfunction are mutually
mainly depends on caspase-1 and is accompanied by an causal, forming a vicious circle, and ultimately leading to
inflammatory cascade. During MIRI, ASC combines with pro- irreversible damage to cardiomyocytes. During the MIRI,
caspase-1 to form a multi-protein complex that activates caspase- pyroptosis is accompanied by inflammation, and ferroptosis is
1, which in turn induces the activation of IL-1β and IL-18, recruits related to apoptosis caused by ERS (Toldo et al., 2018; Li W. et al.,
more inflammatory factors, and expands the inflammatory response 2020). In addition, miRNA can regulate the expression of genes
(Toldo et al., 2018; Wang Z. et al., 2018). NLRP3 is also an important related to oxidative stress, inflammation, energy metabolism
factor that initiates cell pyroptosis and mediates the production of disorder, apoptosis, and calcium overload. Therefore, the
IL-1β and IL-18. In the early stage of MIRI, NLRP3 inflammation is mechanism of MIRI involves multiple factors and multiple
activated before apoptosis, indicating its participation in the levels, and these factors are interrelated and synergistic, which
pathological process of MIRI, and therefore it may be considered together lead to serious myocardial tissue damage.
a marker of early MIRI (Allam et al., 2014; Qiu et al., 2017;
Yumnamcha et al., 2019). Hence, understanding the specific role
of NLRP3, ASC, procaspase-1/caspase-1, IL-1b/18, and other SAPONINS IN THE TREATMENT OF
proteins related to the pyroptosis signaling pathway in MIRI is MYOCARDIAL ISCHEMIA–REPERFUSION
essential to develop targeted cell pyroptosis and provide new ideas
for MIRI prevention in the future (Yang et al., 2018; Wu et al., 2019).
INJURY
Protective Mechanism of Saponins From
Ferroptosis and Myocardial Ginseng Against Myocardial
Ischemia–Reperfusion Injury Ischemia–Reperfusion Injury
Ferroptosis is a new form of cell death caused by MIRI (Baba Ginsenosides are essential bioactive ingredients of Araliaceae plants,
et al., 2018). It is characterized by the generation of ROS through such as Panax ginseng C. A. Mey., Panax notoginseng (Burk.) F. H.
the reaction of ferritin, which causes the accumulation of lipid Chen, and Panax quinquefolium L., as well as Cucurbitaceae plants
peroxides and manifests in iron ion accumulation, increased lipid such as Gynostemma pentaphyllum (Thunb) Makino (Hu et al., 2010;
peroxidation levels, smaller mitochondria, and increased Shin et al., 2015). Panax ginseng C. A. Mey. and Panax notoginseng
mitochondrial membrane density (Xie et al., 2016; Fang et al., (Burk.) F. H. Chen are the two main plant sources of ginsenosides.
2019). Due to its iron-dependent characteristics, ferroptosis is Among them, authentic Panax ginseng C. A. Mey. is mainly
genetically and biochemically different from other forms of cell distributed in Southwest China, East Asia and North America, and
death. Inhibitors of apoptosis, pyroptosis, and autophagy cannot authentic Panax notoginseng (Burk.) F. H. Chen is mainly distributed
prevent the occurrence of ferroptosis, but iron-chelating agents in Southwest China. Although the proportion of ginsenosides in these
can inhibit cell ferroptosis (Baba et al., 2018; Yumnamcha et al., Chinese herbal medicines varies, all of them are excellent TCMs for
2019). Ferroptosis-induced ERS leads to apoptosis, which is anti-tumor, anti-oxidation, anti-aging, anti-fatigue, regulating blood
closely related to MIRI; ferroptosis induces an unfolded sugar balance, improving cardiovascular and cerebrovascular, and
protein response during ERS and subsequently activates the enhancing immunity (Chen et al., 2011; Wang et al., 2012).
PERK-eIF2α-ATF4-CHOP signaling pathway, leading to Xuesaitong, the main active ingredient of Panax notoginseng
apoptosis, which plays a vital role in the process of MIRI saponins, is currently used in the clinical treatment of
(Peng et al., 2020). Moreover, p53 upregulates apoptosis cardiovascular and cerebrovascular diseases and activates blood
regulators and participates in the synergy between ferroptosis circulation, alleviates blood stasis, and expands blood vessels (Li
and apoptosis (Chen et al., 2019; Sumneang et al., 2020). et al., 2019). Studies show that Xuesaitong injection can reduce

MIRI by promoting pyruvate dehydrogenase-mediated aerobic triterpene saponins, flavonoids, coumarins, and alkaloids, of which
metabolism (Zhao X. et al., 2017). Ginseng total saponins can also saponins are its main active ingredient (Wang R. et al., 2018). Current
enhance myocardial energy metabolism by regulating the tricarboxylic research shows that Aralia saponins can regulate the cardiovascular
acid cycle pathway as well as reduce MIRI by inhibiting inflammation system and possess anti-tumor and anti-inflammatory effects (Yan
and oxidative damage (Wang et al., 2012). Panax notoginseng et al., 2015). The total saponin of Aralia elata constitute the main
saponins were found to have a protective effect against rat MIRI component of the Longya Guanxinkang capsule, which functions to
and cardiomyocyte hypoxia-reoxygenation (HR) by regulating nourish qi, promote blood circulation, reduce blood stasis, and relieve
autophagy and apoptosis via the HIF-1α/BNIP3 and PI3K/Akt pain; it is suitable for treating coronary heart disease, angina pectoris
pathways (Chen et al., 2011) (Table 1). with qi deficiency, and blood stasis syndrome (Wang R. et al., 2018). In
Ginsenosides, such as ginsenoside Rb1, ginsenoside Rg1, addition, Aralia Xinmaitong capsules, developed with total saponins
ginsenoside Rb3, ginsenoside Rg3, ginsenoside Rd, and of Aralia elata as ingredients, have obtained drug clinical research
ginsenoside Re, are mainly dammarane-type structures, with approval for the treatment of angina pectoris caused by qi deficiency
different types and positions of glycosides that result in unique and blood stasis (Wang M. et al., 2015). Our team has previously
physicochemical and biological activities (Aravinthan et al., 2015; proved that total saponins of Aralia elata (Miq) Seem. protects against
Liu X.-W. et al., 2019) (Figure 2). Ginsenoside Rb1, a common MIRI by suppressing ERS-related apoptosis and calcium overload via
saponin in Panax ginseng C. A. Mey., Panax notoginseng (Burk.) F. H. the PKCε-dependent signaling pathway (Wang R. et al., 2018). Total
Chen, and Panax quinquefolium L., has an excellent therap effect on saponins of A. taibaiensis also showed a protective effect against MIRI
MIRI in vivo and ex vivo, mainly by inhibiting apoptosis pathways (in vivo) and HR (in vitro), and the protective mechanism was
and activating mTOR phosphorylation (Li C. Y. et al., 2020). associated with AMPK pathway-related apoptosis (Yan et al., 2015).
Moreover, ginsenoside Rb1 as well as ginsenoside Rg1, improved After screening a large number of saponin components, three
heart function by improving energy metabolism via the RhoA components with strong anti-MIRI activity were identified: elatoside
signaling pathway, which is similar to the cardiac regulation by C, araloside C, and calenduloside E (Table 2). The chemical structures
ginseng total saponins (Cui et al., 2017). Ginsenoside Rg1 also of these saponins have oleanolic acid configurations (Figure 4).
protected H9c2 cardiomyocytes by inhibiting apoptosis, or Calenduloside E contains fewer glycosidic bonds than elatoside C
activating the PI3K/AKT/mTOR pathway (Deng et al., 2015; Li and araloside C, which results in its marginal inferior solubility and
et al., 2018; Qin et al., 2018; Yuan et al., 2019). In addition, different biological activities. Further, calenduloside E reportedly
ginsenoside Rd restored mitochondrial damage and inhibited reduced H2O2-induced H9c2 cardiomyocyte injury by inhibiting
oxidative stress by activating the Akt/GSK-3β and Nrf2/HO-1 oxidative stress, apoptosis, and calcium overload (Tian et al., 2017).
signaling pathways (Wang et al., 2013; He et al., 2014; Yu et al., Elatoside C protected against rat global MIRI by attenuating oxidative
2016c). Notoginsenoside R1 reduced MIRI by preventing energy stress and calcium overload via PI3K/Akt and JAK2/STAT3 signaling
metabolism disorder and ERS, which was related to the ROCK and pathway activation and MPTP inhibition (Wang M. et al., 2015).
NF-κB signaling pathways. Araloside C reduced oxidative stress, ERS, and calcium overload by
In summary, total ginsenoside as well as ginsenoside monomer regulating Hsp90, and improved mitochondrial function and AMPK
components can significantly reduce MIRI and HR damage. The activation, which were dedicated to alleviating rat global MIRI and
specific regulatory mechanisms of ginsenosides mainly reduce H9c2 cardiomyocyte HR damage (Wang et al., 2017; Du et al., 2018;
energy metabolism disorders, inhibit oxidative stress and Wang et al., 2019).
inflammatory response, and reduce cardiomyocyte apoptosis (Li In short, Aralia saponins have an excellent effect on the
et al., 2016; Zhang et al., 2016). Notably, the regulation of energy treatment of coronary heart disease and angina pectoris (Wang
metabolism by ginsenosides, mainly through the Akt/GSK-3β and R. et al., 2018). Current studies have shown that the cardioprotective
RhoA/ROCK signaling and mitochondrial autophagy pathways, is effect of Aralia saponins is mainly through inhibition of calcium
particularly significant and coincides with the significance of overload, oxidative stress and ER stress-related apoptosis. Aralia
ginseng’s TCM guidance (Figure 3). Various ginsenosides can saponins showed a significant role in maintaining calcium
protect against MIRI through the regulation of different signaling homeostasis, primarily by activating HSP90, PKCε and JAK2/
pathways. The clinical efficacy of ginsenosides also encourages STAT3 signaling pathways, inhibiting MPTP opening (Wang
researchers to further explore the mechanism underlying the et al., 2014; Wang M. et al., 2015; Du et al., 2018) (Figure 3).
treatment of cardiovascular diseases, provide a theoretical basis However, the current research on MIRI protective mechanism of
for their clinical application, and expand ginseng indications. Aralia saponins is not deep enough, and some data on animals in
vivo experiments and clinical studies are insufficient.
Protective Mechanism of Saponins From
Aralia Against Myocardial Protective Mechanism of Other Saponins
Ischemia–Reperfusion Injury Against Myocardial Ischemia–Reperfusion
Aralia chinensis L. is an edible Araliaceae plant with medicinal Injury
value, including Aralia elata (Miq) Seem. and Aralia taibaiensis In addition to ginsenosides and aralia saponins, other saponins
(Wang et al., 2014). Aralia elata (Miq) Seem. is mainly distribution also possess anti-MIRI activity (Table 3). Since each saponin has
in Northeast China, North Korea, Japan and Russia, and Aralia a different chemical structure, its characteristic cardiac protection
taibaiensis is distribution in Midwest China. It contains several mechanism also differs. Radix Astragali is a known TCM for

TABLE 1 | Anti-MIRI effects of saponins from ginseng.
Compound Major plant Geographical Dose/ Models Mechanism

source distribution concentration
of plants
Ginseng total Panax ginseng C. A. Mey Southwest China, East 100, 200 mg/kg, i.g. Guinea pig MIRI model (in vivo) Anti-oxidative and anti-inflammatory
saponins Asia and North America (Aravinthan et al., 2015) properties by reducing inflammatory
cytokines and NF-kB
50 mg/L for 60 min Rat global MIRI model (ex vivo) Modulating TCA cycle protein
(Wang et al., 2012) expression to enhance cardiac energy
metabolism; reducing oxidative stress
Panax notoginseng Panax notoginseng Southwest China 200, 500 μg/ml Neonatal rat MIRI model (in vitro) Inhibiting oxidative stress via MiR-
saponins (Burk.) F. H. Chen (Wang et al., 2019) 30c-5p
30, 60 mg/kg, i.p. Rat MIRI model (in vivo) (Liu X.- Regulating the HIF-1a/BNIP3 pathway
W. et al., 2019) of autophagy
30, 60 mg/kg, i.g.; Rat MIRI model (in vivo); H9c2 Inhibiting apoptosis by activating PI3K/
0.05, 0.25, cardiomyocytes HR model Akt pathway
2.25 mg/ml (in vitro) (Chen et al., 2011)
Gypenoside Panax notoginseng Southwest China; East 50, 100, Rat MIRI model (in vivo); H9c2 Inhibiting ER-stress and apoptosis via
(Burk.) F. H. Chen; Asia and Southeast Asia 200 mg/kg, i.g.; 5, cardiomyocytes HR model CHOP pathway and PI3K/Akt
Gynostemma 10, 20 μM (in vitro) (Yu et al., 2016a; Yu pathway; inhibiting NF-kB p65
pentaphyllum et al., 2016b) activation via MAPK signaling pathway
(Thunb.) Mak 100 mg/kg, i.g. (in Rat MIRI model (in vivo); H9c2 Suppressing miR-143-3p level via the
vivo); 10, 20 μM cardiomyocytes HR model activation of AMPK/Foxo1 signaling
(in vitro) (in vitro) (Chang et al., 2020) pathway
Ginsenoside Rb1 Panax ginseng C. A. Southwest China, East 40 mg/kg, i.g. Rat MIRI model (in vivo) (Xia et al., Enhancing eNOS expression and NO
Mey.; Panax notoginseng Asia and North America; 2011; Li et al., 2016) content and inhibiting p38-MAPK
(Burk.) F. H. Chen Southwest China signaling pathway
20, 40, 80 mg/kg, Rat global MIRI model (ex vivo); Activating mTOR signal pathway
i.g.; 1, 5, 10, 20 μM rat MIRI model (in vivo) (Li C. Y.
et al., 2020)
2.5, 5, Rat MIRI model (in vivo) (Cui Regulating energy metabolism by
7.5 mg/kg, i.g. et al., 2017) RhoA signaling pathway
Ginsenoside Rb3 Panax ginseng C. A. Southwest China, East 2, 5 μM H9c2 cardiomyocytes HR model Inhibiting JNK-mediated NF-kB
Mey.; Panax notoginseng Asia and North America; (in vitro) (Ma et al., 2014) activation
(Burk.) F. H. Chen Southwest China 5, 10, 20 mg/kg, i.g. Rat MIRI model (in vivo) (Shi et al., Anti-oxidantive, anti-apoptotic and
2011; Liu et al., 2013) anti-inflammatory activity; improving
microcirculatory
Ginsenoside Rd Panax ginseng C. A. Southwest China, East 50 mg/kg, i.p. Rat MIRI model (in vivo) (Zeng et Activating Nrf2/HO-1 signaling
Mey.; Panax notoginseng Asia and North America; al., 2015) pathway
(Burk.) F. H. Chen Southwest China 50 mg/kg, Rat MIRI model (in vivo); neonatal Activating Akt/GSK-3β signaling
i.p.; 10 μM rat myocardial cells HR model pathway and inhibiting mitochondria-
(in vitro) (Wang et al., 2013) dependent apoptotic pathway
Ginsenoside Re Panax ginseng C. A. Southwest China, East 0.3, 1, 3, 10, 20 μM Guinea-pig cardiomyocyte NO-dependent modulation of the
Mey.; Panax notoginseng Asia and North America; electrophysiology (in vivo) (Bai et delayed rectifier K+ current and the
(Burk.) F. H. Chen Southwest China al., 2004) L-type Ca2+ current
30, 100 μM Rat MIRI model (in vivo) (Lim et Ameliorating the electrocardiographic
al., 2013) abnormality and inhibiting TNF-α level
Ginsenoside Rg1 Panax ginseng C. A. Southwest China, East 5 mg/kg/h, Rat MIRI model (in vivo) (Li et al., Inhibiting apoptosis and modulating
Mey.; Panax notoginseng Asia and North America; 30 min, i.v 2018, Yuan et al. 2019) energy metabolism through binding to
(Burk.) F. H. Chen Southwest China RhoA; activating HIF-1 α-ERK
signaling pathways
100 μM H9c2 cardiomyocytes HR model Inhibiting autophagosomal formation
(in vitro) (ZL et al., 2012; Qin et al, and apoptosis; activating the PI3K/
2018) AKT/mTOR pathways
Ginsenoside Rg3 Panax ginseng C. A. Southwest China, East 5, 20 mg/kg, i.g. Rat MIRI model (in vivo) (Zhang Anti-apoptosis and anti-inflammation
Mey.; Panax notoginseng Asia and North America; et al., 2016) properties
(Burk.) F. H. Chen Southwest China 60 mg/kg, i.p.; Rat MIRI model (in vivo); neonatal Regulating Akt/eNOS signaling
10 mM rat myocardial cells HR model pathway and Bcl-2/Bax signaling
(in vitro) (Wang Y. et al., 2015) pathway
Notoginsenoside Panax notoginseng Southwest China 5, 10, 20 μM Rat global MIRI injury model (ex Inhibiting oxidative stress and ERS
R1 (Burk.) F. H. Chen vivo); H9c2 cardiomyocytes HR
model (in vitro) (Yu et al., 2016c)
5 mg/kg, i.g.; 10, Rat MIRI model (in vivo); H9c2 Preventing energy metabolism
100 nM cardiomyocytes HR model disorder via inhibiting ROCK
(in vitro) (He et al., 2014)
20, 40, Rat MIRI model (in vivo) Regulating vitamin D3 upregulated
60 mg/kg, i.g. protein 1/NF-κB signaling pathway

FIGURE 2 | A schematic representation of mechanisms of saponins from Ginseng exerted cardioprotective effects in MIRI. Glc, glucose; Rha, rhamnose; Xyl,
xylopyranose. ↑means activate relevant pathways. ↓means suppress relevant pathways.
FIGURE 3 | A schematic representation of mechanisms of saponins from Aralia exerted cardioprotective effects in MIRI. Glc, glucose; Gal, galactose; Xyl,
xylopyranose. ↑means activate relevant pathways. ↓means suppress relevant pathways.
nourishing qi and is widely used in prescriptions and health HMGB1/TLR/NF-κB pathway (Liu K. et al., 2019). In addition,
products. Pharmacological studies have confirmed that Radix several studies on the anti-MIRI effect of astragaloside IV have
Astragali has a significant effect on the immune as well as identified it as the main component of Astragalus responsible for
cardiovascular systems (Tu et al., 2013). Huangqi Tongbi exerting cardiac protection. The mechanism of cardioprotection
decoction, an ancient prescription for treating coronary heart by astragaloside IV mainly focuses on the improvement of energy
disease that has Radix astragali as the main active ingredient, has metabolism disorders by recovering mitochondrial respiration,
been shown to significantly improve MIRI in rats; its cardiac preventing MPTP opening, and decreasing cytochrome C release
protection mechanism involves inflammation suppression via the (Xu et al., 2008; Han et al., 2011; Tu et al., 2013). The structure of

TABLE 2 | Anti-MIRI effects of saponins from Aralia.
Compound Major plant Geographical Dose/ Models Mechanism

source distribution Concentration
of plants
Total saponins of Aralia elata Northeast China, North 25, 50, Rat MIRI model (in vivo) (Wang R. et al.,
Alleviating calcium homeostasis
Aralia elata (Miq) (Miq) Seem Korea, Japan, Russia 100 mg/kg, i.g. 2018) imbalance and endoplasmic reticulum
Seem stress-related apoptosis
30, 60 mg/kg; 1.25, Dog hemodynamic indexes (in vivo), Ca2+ Positive inotropic effect by maintenance
2.5 and 5 mg/ml transients and sarcomere shortening of calcium homeostasis and increase of
detection (in vitro) (Wang et al., 2014) PKCε-dependent signaling pathway
Total saponins of Aralia Midwest China 60, 120, 240 mg/kg, Rat MIRI model (in vivo); H9c2 Suppressing apoptosis via the AMPK
Aralia taibaiensis taibaiensis i.g.; 25, 50 μg/ml cardiomyocytes HR model (in vitro) (Yan pathway
et al., 2015)
Elatoside C Aralia elata Northeast China, North 2, 10, 50 nM Rat global MIRI injury model (ex vivo) Attenuating oxidative stress and calcium
(Miq) Seem Korea, Japan, Russia (Wang M. et al., 2015) overload through the activation PI3K/Akt
and ERK1/2 and JAK2/STAT3 signaling
pathway and inhibiting the opening of
mPTPs
12.5, 25, 50 μM H9c2 cardiomyocytes HR model (in vitro) Activating STAT3 signaling pathway and
(Wang et al., 2014) reducing ER stress-associated
apoptosis
Araloside C Aralia elata Northeast China, North 0.5, 1, 2.5 μM; 3.125, Rat global MIRI injury model (ex vivo); Reducing oxidative stress, ER stress
(Miq) Seem Korea, Japan, Russia 6.25, 12.5, 25 μM H9c2 cardiomyocytes HR model (in vitro) and calcium overload by regulating
(Wang et al., 2017; Du et al., 2018) Hsp90
6.25, 12.5, 25 μM H2O2-induced H9c2 cardiomyocyte injury Reducing oxidative stress by regulating
(in vitro) (Wang et al., 2019) mitochondrial function and AMPK
activation
Calenduloside E Aralia elata Northeast China, North 0.02, 0.1, 0.5 μg/ml H2O2-induced H9c2 cardiomyocyte injury Inhibiting oxidative stress, apoptosis
(Miq) Seem Korea, Japan, Russia (in vitro) (Tian et al., 2017) and calcium overload
FIGURE 4 | Mechanism of anti-MIRI of saponins in Chinese Herbal Medicine. The saponins in Panax ginseng, Panax notoginseng, Aralia, Astragalus and other
Chinese herbal medicine can significantly alleviate MIRI. These saponins inhibit oxidative stress, energy metabolism disorder, calcium overload, inflammation and
apoptosis, and thus exert the cardioprotective effect.
astragaloside IV is similar to that of dammarane-type inflammation and oxidative stress by activating mitochondrial
ginsenosides, and both possess the same cardiac protection KATP channels and regulating p38-MAPK/JNK pathways
mechanism, which supports the idea of structure determines (Badalzadeh et al., 2014; Badalzadeh et al., 2015; Wang H. W.
function. et al., 2018). Estrogen and its receptors are both critical targets in
Dioscin is a phytoestrogen that exhibits anti-MIRI activity. the MIRI mechanism; therefore, dioscin can also be used as a drug
Diosgenin exerts cardioprotective effects by inhibiting candidate for the treatment of MIRI, and its cardioprotective

TABLE 3 | Anti-MIRI effects of other saponins.
Compound Major plant Geographical Dose/concentration Models Mechanism

source distribution
of plants
Astragaloside IV Astragalus Northern China 1, 10 mg/kg, i.g. Rat MIRI model (in vivo) (Tu et al., Regulating energy metabolism
membranaceus 2013)
(Fisch.) Bge. 3, 10, 30 μM Neonatal rat myocardial cells HR Improving intracellular calcium
model (in vitro) (Xu et al., 2008) handling via regulating SERCA
5 mg/kg, i.g.; 10, 20, Rat global MIRI injury model (ex Recovering mitochondrial
40, or 80 μM vivo); H9c2 cardiomyocytes HR respiration, preventing mPTP
model (in vitro) (Luo et al., 2019) opening, decreasing cytochrome
C release and preventing
apoptosis; regulating KATP
channel
0.1, 1, 10, 100 μM H9c2 cardiomyocytes HR model Regulating PI3K/Akt/HO-1
(in vitro) (Yang et al., 2018) signaling pathway
80 mg/kg, i.g.; 60 μM Rat MIRI model (in vivo); H9c2 Inhibiting CaSR/ERK1/2 and the
cardiomyocytes HR model (in vitro) related apoptotic signaling
(Yin et al., 2019) pathways; regulating energy
metabolism
Betulinic acid Syzygium jambos (L.) China, Indochina, 50, 100, 200 mg/kg, i.g. Rat MIRI model (in vivo) (Xia et al., Preventing cardiomyocyte
Alston; Betula Malaysia, Indonesia; 2011) apoptosis by reducing the release
platyphylla Suk. China, Russia, Mongolia of LDH and CK
5, 10, 20 μM H9c2 cardiomyocytes HR model Inhibiting oxidative stress and
(in vitro) (Wang D. et al., 2018) apoptosis by Nrf2/HO-1, p38 and
JNK pathways
Celastrol Tripterygium wilfordii East Asia 50 nM H9c2 cardiomyocytes HR model Inhibiting the activation of NF-κb
Hook.F. (in vitro) (Li et al., 2017)
0.01, 0.1, 1 μM H9c2 cardiomyocytes HR model (in Modulating HSP90 activity
vivo); rat global MIRI injury model (ex
vivo) (Aceros et al., 2019)
2, 4, 6 mg/kg, i.g. Rat MIRI model (in vivo) (Tong et al., Suppressing apoptosis,
2018) inflammatory and oxidative stress
via PI3K/Akt pathway activation
and HMGB1 inhibition
Clematichinenoside Clematis chinensis China, Vietnam 1, 10, 100 μM H9c2 cardiomyocytes HR (in vitro) Inhibiting apoptosis through
Osbeck (Ding et al., 2016) mitochondrial mediated apoptotic
signaling pathway
0.001, 0.01, 0.1 mg/ml; Rat global rat MIRI injury model (ex Restoring an antioxidant effect by
8, 16, 32 mg/kg, i.g.; 1, vivo); rat MIRI model (in vivo); restoring the balance between
10, 100 μM neonatal rat myocardial cells HR inducible NO synthase and
(in vitro) (Zhang et al., 2013) endothelial NO synthase
Dioscin Dioscorea China, Japan, South 0.1, 1 nM Rat global MIRI injury model (ex vivo) Activating mitochondrial KATP
oppositifolia L Korea (Badalzadeh et al., 2014; channels and NO system,
Badalzadeh et al., 2015) attenuating oxidative stress
50, 100 mg/kg, i.g. Rat MIRI model (in vivo) (Wang H. Inhibiting inflammation by
W. et al., 2018) regulating p38-MAPK/JNK
pathways and NF-κb pathways
Glycyrrhizin Glycyrrhiza uralensis China, Russia 2, 4, 10 mg/kg, i.g. Rat MIRI model (in vivo) (Han et al, Inhibiting oxidative stress, iNOS
Fisch. 2011; Zhai et al., 2012) and inflammatory, via HMGB1 and
MAPK expression
5, 10, 20 mg/kg, i.g. Rat MIRI model (in vivo) (Wu et al., Prolonging APD, inhibiting Ica-L and
2015) Ito; blocking phospho-JNK/Bax
pathway
Ilexsaponin A Ilex pubescens Hook. China 10, 40 mg/kg, i.g.; 10, Rat MIRI model (in vivo); neonatal rat Inhibiting apoptotic pathway
et Arn. 50, 250 μM myocardial cells HR model (in vitro)
(Zhang et al., 2017)
Ophiopogonin D Ophiopogon japonicus China, Japan, Vietnam, 20 mg/kg, i.p. Rat MIRI model (in vivo) (Huang Antioxidant and anti-apoptotic
(Linn. f.) Ker-Gawl. India et al., 2018) effects
Sasanquasaponin Camellia oleifera Abel Southern China 0.1, 1, 10 μM Neonatal rat myocardial cells HR Inhibiting oxidative stress via
model (in vitro) (Chen et al., 2007) attenuating ROS generation and
increasing antioxidant activities
0.1, 0.2, 0.4 mg/kg, Mouse MIRI model (in vivo); adult Modulating intracellular Cl-
i.g.; 0.1 μM mouse myocardial cell HR model homeostasis and anti-arrhythmia
(in vitro) (Lai et al., 2004) effects
(Continued on following page)

TABLE 3 | (Continued) Anti-MIRI effects of other saponins.
Compound Major plant Geographical Dose/concentration Models Mechanism

source distribution
of plants
Withaferin A Withania Somnifera India 1, 5 mg/kg, i.g. Rat MIRI model (in vivo) (R. et al., Upregulating AMP-activated
2019) protein kinase-dependent B-cell
lymphoma2 signaling
0.1, 1 μM Neonatal rat myocardial cells HR Inhibiting apoptosis via activated
model (in vitro) (Yan et al., 2018) Akt-mediated oxidative stress
suppression
mechanism needs further research. Celastrol, another anti-MIRI important roles of pyroptosis and ferroptosis in the
saponin, can interact with HSP90, which is similar to Aralia pathogenesis of MIRI (Wang Z. et al., 2018; Li W. et al.,
saponins. The structure of celastrol has more unsaturated bonds 2020). However, there is no relevant research on the effects of
than oleanolic acid, which indicates its superior antioxidant saponins on pyroptosis and ferroptosis. Therefore, the regulatory
activity (Aceros et al., 2019). Previous studies have also role of saponins on these new MIRI mechanisms needs to be
confirmed that cardiac heart protection mechanism of celastrol further studied to completely elucidate the protective mechanism
involves suppression of oxidative stress, inflammation, and of saponins against MIRI.
apoptosis via the PI3K/Akt and HMGB1 pathways (Li et al., Structurally, saponins with vigorous biological activity are
2017; Tong et al., 2018). Some studies have suggested that high- mainly oleanolic acid saponins and dammarane-type saponins.
mobility group box 1 (HMGB1) plays a role in early MIRI, Studies have shown that oleanolic acid saponins have a significant
activates the inflammatory response, and promotes regulatory effect on calcium homeostasis (Wang M. et al., 2015),
cardiomyocyte apoptosis (Tong et al., 2018). Glycyrrhizin, the whereas dammarane-type saponins have a more substantial
main active compound in licorice, is a natural HMGB1 inhibitor. regulatory effect on energy metabolism (Cui et al., 2017). In
Studies have also shown that glycyrrhizin reduces rat MIRI by addition, ginsenosides are more active in dammarane-type
inhibiting oxidative stress and inflammation (Zhai et al., 2012; saponins, while Aralia saponins are more active in oleanolic
Wu et al., 2015). acid saponins, which further proves that the unique
Furthermore, anti-MIRI saponins also include betulinic acid, characteristics of TCM are determined by the structure of its
clematichinenoside, ilexsaponin A, ophiopogonin D, key active components. The occurrence of MIRI is a multi-factor
sasanquasaponin, and withaferin A. Their cardiac protection interaction and an extremely complicated process; therefore,
mechanisms are different, and mainly involve suppression of multi-target therapy will be the future direction for drug
oxidative stress, inflammation, and apoptosis (Huang et al., 2018; development. Saponins in TCM can act on multiple pathways
Yan et al., 2018). Based on the current research progress, it can be simultaneously and effectively reduce MIRI (Figure 4). Thus,
concluded that the signaling pathways involved in the regulatory saponins provide a broad application prospect for the
mechanism of each saponin are different and that one saponin development of highly effective and low-toxicity anti-MIRI drugs.
may affect one or more signaling pathways, indicating the At present, the study of saponins is still in its initial stage of
diversity of their therapeutic targets. Saponins with different new structural saponin discovery and data accumulation.
structures regulate various signaling pathways to achieve Research on the structure–activity relationship of saponins
cardioprotection. However, the current research on the anti- against MIRI, at home and abroad, is still in its infancy.
MIRI effect of saponins is not comprehensive, requiring Although the different biological activities and mechanisms
researchers to continue their exploration so as to provide a of saponins have been gradually elucidated at the molecular
more theoretical basis and reliable drug candidates for MIRI level, their clinical applications and saponin-treatment studies
treatment. for MIRI are limited. Therefore, the systematic summary of the
anti-MIRI mechanism of saponins can potentially lay a
foundation for detailed study of the anti-MIRI effect and
CONCLUSIONS AND PERSPECTIVES structure–activity relationship of saponins, and thereby aid
the development of new anti-MIRI drugs with new
The targets and anti-MIRI mechanisms of saponins are diverse mechanisms or targets. A detailed study of the
and mainly include inhibition of oxidative stress, calcium structure–activity relationship of saponins against MIRI
overload, inflammation, and mitochondrial dysfunction. In would enable the identification of active components or
brief, saponins have a strong antioxidant effect, which in turn monomers of TCM saponins. This would finally aid the
helps restore mitochondrial function and intracellular calcium development of drugs with more active and less adverse
homeostasis, reduces the production of inflammatory factors, and reactions through chemical modification and artificial
inhibits cardiomyocyte apoptosis, thereby exerting a synthesis. Thus, the study of saponins will become an
cardioprotective function (Zhang et al., 2016; Zhang et al., important research direction in the development of anti-
2017; Yin et al., 2019). Recent studies have revealed the MIRI drugs.

AUTHOR CONTRIBUTIONS FUNDING

Conceptualization, RW, JZ, and MW; writing—original draft This research was funded by Central Public-Interest Scientific Institution
preparation, RW; writing—review and editing, MW, GS, and Basal Research Fund (No. 2018PT35030 by GS), the National Natural
XS; visualization, DW, JY, and JZ; funding acquisition, GS and Science Foundation of China (No. 81973514 by GS), the Drug
XS. All authors have read and agreed to the published version of Innovation Major Project (No. 2018ZX09711001-009 by XS) and
the manuscript. National Natural Science Foundation of China (No. 81891012 by XS).
reoxygenation injury. Eur. J. Pharmacol. 575, 21–27. doi:10.1016/j.ejphar.

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Clematichinenoside attenuates myocardial infarction in ischemia/reperfusion these terms.

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published: 14 January 2021

Saponins in Chinese Herbal Medicine

Frontiers in Pharmacology | www.frontiersin.org 1 January 2021 | Volume 11 | Article 570867

INTRODUCTION MECHANISMS OF MYOCARDIAL

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FIGURE 1 | Graphical summary of MIRI mechanism.

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TABLE 1 | Anti-MIRI effects of saponins from ginseng.

Compound Major plant Geographical Dose/ Models Mechanism

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TABLE 2 | Anti-MIRI effects of saponins from Aralia.

Compound Major plant Geographical Dose/ Models Mechanism

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TABLE 3 | Anti-MIRI effects of other saponins.

Compound Major plant Geographical Dose/concentration Models Mechanism

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TABLE 3 | (Continued) Anti-MIRI effects of other saponins.

Compound Major plant Geographical Dose/concentration Models Mechanism

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AUTHOR CONTRIBUTIONS FUNDING

reoxygenation injury. Eur. J. Pharmacol. 575, 21–27. doi:10.1016/j.ejphar.

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