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Danshen (Salvia miltiorrhiza Bunge): A Prospective Healing Sage for Cardiovascular Diseases

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Danshen (Salvia miltiorrhiza Bunge) is a valued herbal plant in the Traditional Chinese Medicine. The dried root of this plant (Radix Salvia miltiorrhiza), either alone or in combination with other herbal ingredients, has been used for hundreds of years to treat numerous ailments, especially cardiovascular diseases. For the past several decades, many studies have tried to delineate the putative cardioprotective effects of this folk medicine through the lens of modern scientific research. In this review, we have summarized the current knowledge about the pharmacological potentials of danshen. The main focus is laid on the predominant bioactive compounds in danshen, which include phenolic acids and tanshinones. We discussed the absorption and metabolism of these compounds, and examine in detail the cardioprotective mechanisms during atherosclerosis, thrombosis, and myocardial infarction reperfusion.
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Danshen (Salvia miltiorrhiza Bunge): A Prospective Healing Sage for Cardiovascular
Diseases
Wei Chen*,1 and Guoxun Chen2
1Yunnan Agricultural University - Key Laboratory of Pu-erh Tea Science, Ministry of Education Kunming, Yunnan, China:
2The University of Tennessee at Knoxville - Nutrition Knoxville, TN, United States
A R T I C L E H I S T O R Y
Received: January 11, 2017
Accepted: July 24, 2017
DOI:
10.2174/1381612823666170822101112!
Abstract: Danshen (Salvia miltiorrh iza Bunge) is a valued herbal plant in the Traditional Chinese Medicine. The
dried root of this plant (Radix Salvia miltiorrhiza), either alone or in combination with other herbal ingredients,
has been used for hundreds of years to treat numerous ailments, especially cardiovascular diseases. For the past
several decades, many studies have tried to delineate the putative cardioprotective effects of this folk medicine
through the lens of modern scientific research. In this review, we have summarized the current knowledge about
the pharmacological potentials of dansh en. The main focus is laid on the predominant bioactive compounds in
danshen, which include phenolic acids and tanshinones. We discussed the absorption and metabolism of these
compounds, and examine in detail the cardioprotective mechanisms during atherosclerosis, thrombosis, and myo-
cardial infarction reperfusion.
Keywords: Danshen, Salvia miltiorrhiza Bunge, cardiovascular diseases, atherosclerosis, thrombosis, myocardial reperfusion injury.
1. INTRODUCTION
Over the past several decades, countries around the world have
witnessed a rapid increase in the incidence and prevalence of obe-
sity [1], type 2 diabetes mellitus [2], and cardiovascular diseases
(CVDs) [3]. This alarming trend is accompanied by an unprece-
dented rise in the mortality and morbidity rates in the affected
populations. In 2008, an estimated 17.3 million people worldwide
expired from CVDs, accounting for almost one-third of the total
deaths [4,5]. In the same year, the number of deaths from diabetes
and its complications amounted to about 1.26 million globally [5].
A recent pooled analysis of the body mass index (BMI) from 19.2
million participants in 200 countries estimated that 641 million
people worldwide were clinically categorized as obese (BMI > 30
kg/m2) or severely obese (BMI > 35 kg/m2) in 2014 [6]. Should this
trend be allowed to continue without constraint, the total deaths due
to various metabolic disorders would reach 55 million in the world
by 2030 [5]. The resultant medical, social, and economic burdens
would not only weigh down the developed countries but also con-
siderably undermine the development of low-income and middle-
income countries [3,5].
The preferred strategies to combat the rise in CVDs and other
metabolic disorders involve prophylactic interventions that promote
healthy lifestyle choices in the high-risk populations [5]. For exam-
ple, decreased tobacco use and exposure, healthier choices in diet,
and ameliorated risk factors for CVDs in th e populations of a few
high-income European countries were found to reduce the cardio-
vascular death rate in the past decades [4]. Unfortunately, popula-
tion growth and aging during the same period continued to drive up
the overall number of cardiovascular deaths, counteracting the
beneficial effects of positive epidemiological changes [4]. For this
reason, it is equally crucial to use effective pharmaceutical treat-
ments to reduce the current high mortality and morbidity rates asso-
ciated with CVDs.
As an indispensable component of the complementary and al-
ternative medicine, traditional herbal medicine has been gainin g
*Address correspondence to this author at the Yunnan Agricultural Univer-
sity - Key Laboratory of Pu-erh Tea Science, Ministry of Education Kun-
ming, Yunnan, China; E-mail: wchenntr@gmail.com
customers from all cultural backgrounds [7]. It is especially popular
among people with CVDs and/or other metabolic disorders [8,9]. It
is estimated that the out-of-pocket purchase of natural products
totaled 14.8 billion dollars in the United States in 2008 [10]. In
countries where traditional herbal medicine has historical cultural
influences (e.g. China and Korea), the annual double-digit increase
in the sales market w as prominent in the past years [7]. Despite the
huge demand, insufficient knowledge about the quality, efficacy,
and safety of traditional herbal medicine hinders its application in
the practice of modern medicine [9]. In many countries around the
world, natural products from herbal plants can be obtained as food
supplem ents without a formal prescription from medical practitio-
ners [7]. This loose regulation may lead to irrational uses of the
herbal plants in the general public, and subsequently, complicate
the diagnosis, treatm ent and prognosis of the metabolic disorders
[8,9]. In view of these opportunities and challenges, World Health
Organization has called for a comprehensive investigation into the
medicinal values of traditional herbal plants and their evidence-
based applications in the modern medicine [7].
This review aims to summarize recent research progress on
danshen (Salvia miltiorrhiza Bunge), a popular herbal plant widely
used in China for the treatment of numerous ailments including
CVDs [11,12]. The content of this review will mainly focus on the
predominant bioactive compounds in danshen for the treatm ent of
CVDs. We will discuss the proposed cardioprotective mechanisms
of these compounds during atherosclerosis, thrombosis, and myo-
cardial infarction reperfusion. We will also presen t the results of
relevant clinical trials, and provide prospective areas of investiga-
tion regarding this herbal plant.
2. OVERVIEW OF THE GENUS SALVIA AND THE PLANT
DANSHEN
The plants in the genus Salvia of the Lamiaceae family (previ-
ously known as the Labiatae family) are commonly known as sages.
This genus contains about 1,000 recognized species, which spread
across the continents of Eurasia and Americas [13]. The name of
the genus, Salvia, origin ates from Latin and denotes the healing and
curativ e properties of the plants [14]. Indeed, members of the Salvia
were highly valued as wonder drugs among the early civilizations
worldwide to ward off plague, palsy, and other debilitating diseases
2 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Chen and Chen
[14]. Regardless of the scientific soundness of these proclaimed
remedial properties in the past, Salvia plants continue to be recog-
nized as healing agents after the emergence of modern medicine,
partly due to their deep cultural imprint in the course of human
history.
Salvia miltiorrhiza Bunge is a perennial sage plant native to
China, which grows to 40 to 80 cm with violet flowers (Fig. 1A)
[15]. Its characteristic scarlet root color gives the plant its common
Chinese name: danshen, dan- means scarlet, and shen means gin-
seng (also known as tanshen in Japanese). The dried root of this
plant (Radix Salvia miltiorrhiza) is a popular herbal drug in the
Traditional Chinese Medicine (TCM), and it shares the name dan-
shen with the plant. According to ancient Chinese medical docu-
ments, danshen was believed to be highly potent in disp ersing stasis
and activating circulation [11]. It was widely used in the treatment
of CVDs, amenorrhea, menorrhagia, abdominal pain and insomnia,
either alone or in combination with other herb al medicines [11].
Since TCM was consolidated with empirical evidence over time,
the identities of active ingredients in danshen could not be deter-
mined from the ancient texts. With the help of modern chemical
profiling, whole-genome sequencing, and transcriptome analyses of
danshen, it is clear that the underground part of the plant produces a
myriad of unique chemical compounds [16-19].
One caveat in the study of danshen is the quality control of the
herbal source. A survey of the Chinese herbal medicine production
regions and markets revealed that the danshen medicine may be
harvested from other members of the Salvia plants, or in some
cases, plants of other genera (Table 1) [20]. Moreover, the chemical
constituents and compositions in the roots of these plants were dif-
ferent from those of danshen [20]. On the downsid e, the compli-
cated herbal source for the dansh en medicine poses a major chal-
lenge for the experimental design from the standpoint of reproduci-
bility and cross-validation. It is worth noting that many functional
studies utilize self-prepared decoctions or extracts from commercial
dried roots of unknown sources. This has greatly hindered the sci-
entific evalu ation and interpretation of danshen’s physiological
efficacy [11,20]. On the upsid e, a d iverse herbal source opens up
the opportunities of finding additional bioactive compounds for
potential use as drugs and making better danshen breeding culti-
vars. In order to avoid confusion in this review, the word danshen
solely refers to (1 ) Salvia miltiorrhiza Bunge as the plant, and (2)
the dried root of Salvia miltiorrhiza Bunge as the medicine.
3. MAJOR BIOACTIVE COMPOUNDS IN DANSHEN AND
COMMERCIAL DRUGS
In view of the pharmaceutical potential of danshen, researchers
have isolated, purified and identified more than thirty phenolic
acids and fifty diterpenoid compounds over the past eighty years
[21,22]. Despite the known stru ctures and chemical properties, only
a handful of these compounds have been investigated for their
physiological and pharmaceutical activities.
The water-soluble phenolic acids in the danshen medicine
mainly comprise of the derivatives of caffeic acid, which is an im-
portant intermediate for the lignin biosynthesis in all plants [22,23].
The simple compound danshensu (DSS, also known as salvianic
acid or tanshinate, structure 1) is structurally very similar to caffeic
acid (structure 2, Fig. 1B). DSS and caffeic acid contain a charac-
teristic 3,4-dihydroxyphenyl moiety and a hydrophilic end group.
The presence of 3,4-dihydroxyphenyl moiety makes the compound
labile to oxygen, light and heat [11]. As a result, the phenolic acids
will readily deteriorate in the neutral or alkaline solutions due to
oxidization or polymerization [11]. More complex phenolic acid
compounds are the monomers or oligomers of caffeic acid and DSS
(Fig. 1B). These include rosmarinic acid (RMA, structure 3), salvi-
Fig. (1). Danshen and its major bioactive compounds. (A) Schematic graph of the danshen plant (courtesy o f People’s Medical Publishing House). (B) Major
water-soluble phenolic acids in danshen. (C) Major lipophilic tanshinones in danshen.
Danshen (Salvia miltiorrhiza Bunge): A Prospective Healing Sage Current Pharmaceutical Design, 2017, Vol. 23, No. 00 3
anolic acid A and B (SAA, SAB, stru ctures 5 and 6), and
lithospermic acid (LSA, structure 4) [22]. A compound with the
name of lithospermic acid B, which was investigated in a few early
publications, was later proven to be the same chemical as SAB [24].
The diterpenoid compounds were isolated from the lipophilic
extracts of the danshen medicine [25]. They exist in high quantities
in the periderm (outer layer of root) and contribute to the vivid
scarlet color of the root [26]. The major constituents include tanshi-
none I (structure 7), tanshinone IIA (structure 8), tanshinone IIB
(structure 9), and cryptotanshinone (structure 10, Fig. 1C). The
tanshinones share a distinctive ortho- or para-naphthoquinone
chromophore structure [22]. It is proposed that the two oxygen
atoms in the naphthoquinone chromophore are excellent electron
receivers, thereby, making this type of compounds excellent scav-
engers for free radicals [22].
In both mainland China and Taiwan, danshen products are the
most prescribed herbal pharmaceuticals in the treatment of various
CVDs [27,28]. This is partly due to the observ ation that danshen
causes no obvious adverse effect and toxicity in patients [11,14].
Besides the crude dried root, the danshen medicine has been made
into numerous modern pharmaceutical forms, including tablets,
capsules, granules, dripping pills, and injectables, particularly in the
Chinese market [21]. Depending on the chosen ingredients and
preparation methods, the composition of bioactive compounds var-
ies among different brands. In general, DSS and SAB account for
more than 50% of the total bioactive compounds [29-31]. No tan-
shinones are present in the dripping pills and injectables, and the
content of tan shinones is fairly low in the oth er drug forms [29-31].
4. THE ABSORPTION AND METABOLISM OF MAJOR
DANSHEN BIOACTIVE COMPOUNDS
4.1. The Oral Bioavailability, Absorption, and Metabolism of
Phenolic Acids
Extensive research work has been done to investigate the phar-
macokinetic properties of phenolic acids in danshen over the past
years [21,32]. One important pharmacokinetic benchmark is the
oral bioavailability of the phenolic drugs deduced from the experi-
Table 1. Possible plant source for the herbal danshen medicine (dried root) on the Ch inese market1.
Plant
Latin Name
Medicine (drie d root)
Market Name
Tanshinone IIA
Content (mg/g)
Salviano lic acid B
Content (mg/g)
Genus Salvia
S. miltiorrhiza Bunge (3 varieties)
Danshen
1.39-2.82
45.38-55.77
S. aerea
Danshen
-2
-
S. bowleyana
Danshen
trace
76.45-82.52
S. castanea
Danshen
0.36
trace
S. dabieshanensis
Danshen
0.62
55.36
S. digitaloides
Danshen
0.40-0.66
<5.23
S. evansiana
Danshen
trace
15.15
S. flava
Danshen
trace
1.37-9.77
S. kiaometiensis (2 varieties)
Danshen
-
-
S. plectranthoides
Danshen
0.14
18.80
S. paramiltiorrhiza
Danshen
0.80-1.65
36.70-52.39
S. przewalskii (3 varieties)
Danshen
1.78-6.67
1.44-4.22
S. sinica
Danshen
trace
55.94
S. trijuga
Danshen
2.99-4.03
7.79-12.08
S. yunnanensis
Danshen
1.34
58.00
Other Plant Genera
Agastache (several species)
Danshen
-
-
Ardisia crenata
White danshen
-
-
Incarvillea lutea
Red danshen
-
-
Rubia co rdifolia
Tu danshen
-
-
Phlomis betonicoides
White danshen
-
-
Prunella vulgaris L.
Self-heal danshen
-
-
1 This table was compiled according to the pla nt resource information in references [11, 20].
2 The symb ol “-” represents unknown amount.
4 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Chen and Chen
mental animal models. Oral bioavailability is defined as the portion
of a drug per os that enters the circulation. It is closely associated
with the efficacy, toxicity, and potential side effects of the drugs,
and is a crucial determinant of the optimal oral dosage [33].
As a phenolic acid with simple chemical structure, DSS exhib-
ited low oral bioavailability at the dosage of 20 mg/kg in the adult
male Sprague-Dawley rats [34]. It was estimated that about 11% of
the total DSS oral dose reached th e systemic circulation [34]. This
percentage is almost only half of the oral bioavailability of caffeic
acid, despite the high structural similarity between the two drugs
[35]. The oral administration of salvianolic acid ex tract containing
RMA (3.9% w/w), SAA (5.7% w/w) and SAB (50.6% w/w) in the
adult male Sprague-Dawley rats at the dosage of 800 mg/kg re-
vealed that the oral bioavailability of these polyphenolic acids
dropped into an even lower range of 2 - 5% [36]. The insufficient
absorption of these polyphenolic acids was further confirmed in a
few different studies using the purified compounds [37-40]. In or-
der to increase the gastrointestinal absorption of phenolic acids, an
assortment of absorption enhancers were designed and subsequently
tested both in vivo and in vitro [36,41-44]. It seems that these novel
methods of drug delivery could improve the oral bioavailability of
phenolic acids by several folds [36,41-44].
The absorption of phenolic acids in the gut predominantly relies
on two mechanisms of passive diffusions: (1) transcellular diffusion
across the epithelial membrane; or (2) paracellular d iffusio n
through the tight junctions in-between cells [45,46]. The efficiency
of transferring different phenolic acids across the gastrointestinal
epithelial cells depends on the innate physicochemical properties of
the compounds (e.g. solubility, polarity, hydrophobicity et. al) and
the resp ective concentrations on either side of the membrane
[45,46].
Despite these well-established theories, very few studies have
examined the absorption mechanisms for the danshen phenolic
acids in vivo (Fig. 2A). In th e pylorus-ligated rats, more than half of
the simple phenolic acids (e.g. caffeic acid, ferulic acid, and p-
coumaric acid) via intragastric gavage would appear in the portal
vein five minutes after the administration [47]. This suggests that
phenolic acids with simple chemical structures could be readily
absorbed in the stomach [47]. A hypothetic explanation for this
finding proposed the involvement of monocarboxylic acid trans-
porters (MCTs) in the gastric mucosa cells during the absorption of
simple phenolic acids [47]. But direct evidence from future studies
is needed to confirm this unique absorption mechanism. Given the
structural similarity between DSS and caffeic acid, it is possible
that DSS can also be absorbed in the stomach via an MCT-mediated
manner. In a separate study using pylorus-ligated rats, the gastric
absorption of SAB was estimated to be about 5% of the total
amount via intragastric gavage [41]. This low absorption rate sug-
gests that polyphenolic acids are less likely to pass the gastric mu-
cosa vi a paracellular diffusion.
The major passive diffusion location for various danshen phe-
nolic acids is believed to be the small intestine (Fig. 2A) [33]. Even
though phenolic acids are susceptible to oxidation in a neutral or
alkalin e environment, two independent in vitro gastrointestinal
models showed that polyphenolic acid such as RMA was not labile
to the hydrolysis by temperature, pH, bile salts, and digestive en-
zymes [48,49]. RMA was also resistant to the hydrolysis by mucosa
esterase in the Caco-2 cell line [50]. These data suggest that the
intrinsic intestinal constitu ents do not affect the absorption of dan-
shen phenolic acids. In contrary, a clinical trial with eleven health y
individuals showed that a standard diet 30 min prior to the drug
intake could delay the absorption of RMA and prolong the exposure
of RMA to the intestinal tract [51]. This finding is in line with the
fact that other bioactive compounds and inactive excipients could
modify the absorption of phenolic acids in the intestine [45,46].
Due to the low absorbability and degradation in the small intes-
tine, the majority of d anshen phenolic acids from the oral admini-
stration would eventually reach the colon in their intact forms (Fig.
2A). It is possible that colon plays an important role in the absorp-
tion of these compounds. Indeed, a single-pass intestinal perfusion
study on SAB revealed its preferred absorption sites at the distal
ileum and colon sections of the cannulated rat intestines [41]. Even
though no evidence from human studies is available to support this
observation, it is known that individuals after total colectomy have
impaired absorption of phenolic acids from black tea [52]. These
data imply the involvement of colonic microbiota in the absorption
of phenolic acids in vivo. An in vitro gastrointestinal model showed
that up to 99% of input RMA could be broken down into smaller
phenolic acid such as DSS and caffeic acid by the probiotic bacte-
rium Lactobacillus johnsonii [48]. Another in vitro model sug-
gested that these simple phenolic acids could be further metabolized
into various smaller phenolic compounds (e.g. phenylpropionic
acid, benzoic acid, et al.) [49] and eventually absorbed by the colon
cells [50,53].
Even though all major phenolic acids in danshen have low oral
bioavailability, the peak circulating concentrations of these com-
pounds are reached rather rapidly after oral administration
[34,38,39,54]. The absorbed phenolic acids are initially distributed
in the liver, kidneys, lungs and heart [55]. Profiling of the phenolic
metabolites in the plasma and urine samples from rodent and hu-
man showed extensive methylation, dehydrogenation, glucuronida-
tion, and sulfation modifications of the absorbed phenolic acids in
vivo [54-57]. These observations collectively demonstrate the rapid
metabolism, degradation, and excretion of danshen phenolic acids
in the body.
4.2. The Oral Bioavailability, Absorption, and Metabolism of
Tanshinones
Tanshinones are poorly absorbed in the gastrointestinal tract
(Fig. 2B). According to a few rodent studies, oral bioavailability of
a single tanshinone in surfactant dispersion was estimated in the
range of 2.9 - 3.5% [58-60]. Interestingly, co-administration of
tanshinone with other diterpenoid compounds could significantly
increase its oral bioavailability up to three-fold [61,62]. This im-
plies the presence of regulatory mechanisms on the intestinal ab-
sorption of tan shinones. Indeed, several in vitro studies with Caco-2
cells showed that the efflux transporters (e.g . P-glycoprotein, multi-
drug resistance associated protein) in the intestinal apical mem-
brane could shuttle the absorbed tanshinones back into the intestinal
lumen (Fig. 2B) [59,60]. Moreover, some coexisting diterpenoid
compounds in the crude tanshinone mix/extract could inhibit the
activities of the efflux transporters, thereby increasing the amount
of tanshinones in the epithelial cells [62]. Even though this mecha-
nism has not been confirmed in vivo, the in vitro findings will cer-
tainly assist the design of novel oral delivery strategies for tanshi-
nones.
Because tanshinones are highly hydrophobic chemicals, th e
general opinion believes that their mechanisms of intestinal absorp-
tion are very similar to that of other lipid-soluble nutrients and
compounds (Fig. 2B) [63]. In other words, the formation of tanshi-
none-containing bile salt m icelles in the intestinal lumen would b e
the first step for their absorption. However, there is no direct evi-
dence that bile salt is involved in the absorption of tanshinones.
Only one study showed that oral administration of purified danshen
water extract was able to induce the hepatic expression of two bile
acid pump genes in mice [64]. Upon crossing the unstirred water
layer overlying the intestinal epithelial cells, lipid molecules in
micelles could cross the brush-border membrane via the general
mechanisms of passive diffusion or facilitated transport [63]. It is
assumed that tanshinones enter th e intestinal epithelial cells via
passive diffusion. However, the intestinal absorption of tanshinone
Danshen (Salvia miltiorrhiza Bunge): A Prospective Healing Sage Current Pharmaceutical Design, 2017, Vol. 23, No. 00 5
IIA in rat would reach a plateau as the drug concentration increases
to a certain point [59,60]. This saturable absorption behavior sug-
gests the involvement of brush-border membrane transporters. The
absorbed tanshinones are then incorporated into chylomicrons for
the entry to the lymphatic circulation and subsequently transported
to the liver and other peripheral tissues. This is confirmed by the
fact th at more than 75% of tanshinones in the circulation are bound
to various lipoproteins [58].
The majority of absorbed tanshinones were distributed in the
liver and the lung 10 hours after an oral dose in rats, which sug-
gested fairly slow metabolism in vivo [65]. The main metabolite of
cryptotanshinone in the body is tanshinone IIA [66]. The latter can
be further metabolized into tanshinone IIB by CYP2A6 in hepato-
cyte microsomes [67]. It is proposed that tanshinone IIA is the key
compound in conferring potential h ealth benefits in the body.
5. ANTI-ATHEROSCLEROTIC PROPERTIES OF THE MA-
JOR BIOACTIVE COMPOUNDS IN DANSHEN
5.1. Overview of the Pathophysiology of Atherosclerosis
As the ultimate culprit of heart attack, atherosclerosis is charac-
terized by the deposition of fatty plaques in the inner walls of
stress-prone arteries (Fig. 3) [68]. The development of atherosclero-
sis is a chronic process. It can be expedited by a variety of risk fac-
tors, including cigarette smoking, hypertension, dyslipidemia, dia-
betes mellitus, and genetic predisposition [69]. The pathogenesis of
atherosclerosis starts with the injury to th e arterial endothelial cells.
It is proposed that mechanical shear, disturbed blood flow, hyper-
glycemia, and oxidative stress may over time compromise the endo-
thelial linings at certain arterial curves and branches [68,70]. The
dysfunctional endothelial lining ultimately allows the apolipopro-
tein B (apoB)-containing lipoproteins, such as low-density lipopro-
teins (LDLs) and chylomicron remnants, to accumulate in the
subendothelial space of the arterial intima [68]. The elevation of
reactive oxygen species (ROS) in the local environment leads to the
oxidation of these apoB lipoproteins (mainly oxLDL) [68]. At the
same time, the stress-affected endothelial cells will express adhe-
sion molecules and proinflammatory receptors on the cell mem-
brane, which promote the recruitment and transmembrane migra-
tion of monocytes [68]. The monocytes in the arterial intima subse-
quently turn into macrophages and scavengers of oxLDLs [68]. As
the lipid content increases, the monocyte-derived macrophages
become foam cells, marking the formation of fatty streaks [68]. The
foam cells can produce inflammatory molecules to recruit more
immune cells to the affected area, and secret chemoattractants to
promote the migration and infiltration of smooth muscle cells [68].
This leads to the formation of atherosclerotic plaques within the
arterial intima [68].
5.2. Effects of Danshen Bioactive Compounds on Lipid Metabo-
lism
High levels of circulating apoB-containing lipoproteins (mainly
LDL) and low levels of circulating high-density lipoproteins (HDL)
are the biggest risk factors for the development of atherosclerosis
[69]. For this reason, the first lin e treatment for atherosclero sis
includes the prescription of statins or proprotein convertase subtil-
Fig. (2). Proposed mechanisms of absorption, distribution and metabolism for the major danshen bioactive compounds. (A) Orally-administered polyphenolic
acids (double circle) could be absorbed in the stomach and the small intestine via paracellular diffusion. Simple phenolic acid (single circle) could be absorbed
in the stomach via monocarboxylic acid transporter (MCT)-mediated transport, or in small intestine via paracellular diffusion. The majority of the phenolic
acids reach the large intestine, where they are biotransformed into smaller metabolites by the local microbiota. The absorbed phenolic acids are transported to
different organs in the body in the blood circulation. (B) In the intestinal lumen, tanshinones need to form micelles with bile salts or other surfactants before
entering the intestinal epithelium via passive diffusion. In the intestinal epithelium, tanshinones will be incorporated into the chylomicron for subsequent
transportation to different organs. The absorbed compounds can also be shuttled back into the intestinal lumen by the efflux transporters in the apical mem-
brane.
6 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Chen and Chen
isin/kexin type 9 (PCSK9) inhibitors [71,72]. Both drugs can effec-
tively lower the plasma LDL levels in human [71,72]. Moreover,
the intensive lowering of apoB-containing lipoproteins in the circu-
lation can lead to plaque regression in both experimental animals
and humans [71,72], which shows that atherosclerosis could be a
reversible medical condition [71,72].
The possible lipid-lowering effect of bioactive compounds in
danshen was tested in several cell culture and rodent models. In a
diet-induced obesity mouse model, oral gavage of 35 mg tanshi-
none IIA every other day for two months could reduce the fat mass,
decrease the circulating LDL levels, and improve the LDL/HDL
ratio [73]. S imilarly, oral administration of purified danshen water
extract was shown to reduced the total serum cholesterol, LDL, and
triglyceride levels in diet-induced obese mice [64]. Additional ex-
periments with 3T3-L1 cells revealed tanshinone IIA as a natural
peroxisome proliferator-activated receptor γ (PPARγ) antagonist
that could inhibit preadipocyte differentiation in vitro [73]. These
findings suggest that both phenolic acids and tanshinones can ame-
liorate dyslipid emia in obese animals. In contrast, several studies
using hyperlipidemic non-obese rodents could only find marginal
lipid-lowering effects of tanshinone IIA in vivo [74-76]. Despite the
less pronounced hypolipidemic phenotype, it is worth noting that
SAB [77,78], tan shinone IIA [75,79,80], and cryptotanshinone
[81,82] can effectively prevent lipid peroxidation and oxLDL for-
mation in the experimental animals. Moreover, treatment of human
HepG2 cells with tanshinone IIA could inhibit the expression of
microsomal triglyceride transfer protein gene, causing reduced
apoB100 and TG secretion [83]. These observations imply that the
bioactive compounds in danshen exert their lipid-lowering effects
via distinct mechanisms, probably depending on the target cells or
tissues.
The effects of danshen on the serum lipid panel from a few
small-scale clinical trials were largely negative. In a randomized
controlled trial involving 20 participants with hyperlipidemia and
hypertension, oral intake of 3 grams/day danshen water extract for
four weeks in the treatment group surprising led to a minor but
significant increase in the serum total cholesterol and LDL-
cholesterol levels [84]. This study also recorded no significant dif-
ferences in the rest of the post-intervention clinical parameters ver-
sus baseline valu es [84]. In a different randomized controlled study
of 62 patients with chronic heart disease and diabetes (unspecified
type), oral intake of 5 grams of danshen extract (unspecified type)
twice a day for 60 days also failed to produce a significant decrease
in the serum total cholesterol and LDL-cholesterol levels [85]. In
contrast to these findings, a randomized controlled trial of 143
postmenopausal women with early hypercholesterolemia symptoms
showed that water extract from danshen and gegen (Pueraria miri-
fica) (unspecified formula and dosage) could significantly lower th e
serum total cholesterol and LDL-cholesterol levels in the treatment
group at the end of the 52-week intervention [86]. Despite the dis-
crepancy, it is hard to interpret these clinical studies for th e reasons
of small sample size and non-standardized drug formula.
5.3. Bioactive Compounds in Danshen Prevent Endothelial Dys-
function
Healthy endothelial functions are maintained by the steady
blood flow pattern (high shear stress), normal blood pressure (low
cyclic strain), low oxidative stress, and regular physical activity
[70]. The signals of mech anical forces in the blood vessel are
sensed and transduced in the endothelial cells via a group of special
membrane receptors [87]. Activation of these receptors leads to
increased production and release of vasorelaxants such as nitric
oxide (NO), endothelin-1, and prostacyclin [87]. It also enhances
the expression of superoxide dismutase (SOD) and heme oxy-
genase-1 (HO-1) in the endothelial cells through the activation of
nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2) and
Krüppel-like factor 2 (KLF2) [70]. These factors help create a vas-
cular environment low in ROS and high in vasorelaxants [70]. On
the contrary, the presence of pathophysiological stimuli w ill elevate
the expression of adhesion molecules and proinflammatory recep-
tors in the endothelial membrane via the activation of activator
protein 1 (AP-1) and nuclear factor kappa-light-chain-enhancer of
activated B cells (NF-κB) [70], thereby promoting atherosclerosis
progression.
In the experimental models of human umbilical vein endothelial
cells (HUVEC) and animals, the bioactiv e compounds in danshen
Fig. (3). Schematic graph of the cardioprotective effect of danshen during atherosclerosis. The phenolic acids and tanshinones are proposed to inhibit the pro-
duction of adhesion molecules and reactive oxygen species from the endothelial lining. These bioactive compounds could also inhibit the production of oxi-
dized low-density lipoprotein (oxLDL), thereby reducing the number of foam cells. Besides, danshen is able to inhibit the proliferation and migration of
smooth muscle cells into the fatty plaque.
Danshen (Salvia miltiorrhiza Bunge): A Prospective Healing Sage Current Pharmaceutical Design, 2017, Vol. 23, No. 00 7
were able to prevent or ameliorate endothelial dysfunction. For
instance, cryptotanshinone is a potent drug in reducing the
oxLDL/tumor necrosis factor α-induced expression of intracellular
adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1
(VCAM-1), and monocyte chemotactic protein 1 (MCP-1) both in
vivo and in vitro [81,82,88]. This positiv e effect is possibly
achieved via the inhibition of the NF-κB signaling pathway [82,89].
Treatment of tanshinone IIA, cryptotanshinone, or SAB has been
shown to reduce the activities of SOD and glutathion e peroxidase
[79], relieve oxidative stress [90], and ultimately decrease the pro-
duction of ROS [82,89,91]. Furthermore, SAA and SAB protect
endothelial cells from stress-induced apoptosis by the inhibition of
the c-Jun N-term inal kinase (JNK) signaling pathway and the acti-
vation of AKT signaling pathway [90,92,93]. Activation of Nrf2
and the subsequent expression of HO-1 are also found in the HU-
VECs treated with SAB. These data collectively demonstrate the
distinct roles of the danshen bioactive compounds in the prevention
of endothelial dysfunction.
5.4. Bioactive Compounds in Danshen Prevent Foam Cell For-
mation
Foam cell formation relies on the phagocytosis of oxLDL into
monocyte-derived macrophages in the arterial intima [68]. The
modification on the lipoproteins assists the uptake p rocess through
a few receptors, which include cluster of differentiation 36 (CD36),
scavenger receptor A (SRA), lectin-like receptors, and toll-like
receptors [68,94]. In the hypercholesterolemic ApoE knockout
mice, treatment of tanshinone IIA significantly inhibited the accu-
mulation of cholesterol in the macrophages, resulting in decreased
plaque formation [75,95]. The in vivo studies also showed that tan-
shinone IIA reduced the transcription of CD36 mRNA in the aorta
[75]. Subsequent investigations confirmed the downregulation of
CD36 at the gene expression and protein levels by tanshinone IIA
in the human macrophages [75], and by SAB in the RAW264.7
murine cells [77]. Despite these consisten t observations, the pro-
posed underlying mechanisms were different. It was argued that
tanshinone IIA acted as a PPARγ antagonist to reduce CD36 ex-
pressions, whereas SAB physically interacts with the receptor
CD36 and antagonizes it [75,77]. In a different study using human
macrophages, tanshinone IIA was found to suppress the mRNA
expression of SRA, but not CD36 [95]. At the same time, tanshi-
none IIA induced the gene expression of ATP-binding cassette
protein A1 (ABCA1) and ABCG1, which are two mediators of
cholesterol efflux [95]. It was proposed that the elevated gene ex-
pressions depended on the activation of extracellular signal-
regulated kinase (ERK)/Nrf2/HO-1 signaling pathway [95]. Fur-
thermore, sporadic studies suggested that various bioactive com-
pounds in danshen could decrease the production of ROS and pro-
inflammatory cytokines in the macrophage. [91,96]. These results
imply that the bioactive compounds in danshen may act on a variety
of signaling pathways to prevent foam cell formation.
5.5. Bioactive Compounds in Danshen and Smooth Muscle Infil-
tration
The migration and infiltration of vascular smooth muscle cells
(SMCs) into the fatty plaque lesions mark the advanced stage of
atherosclerosis [68]. In response to the macrophage-derived
chemoattractants and growth factors, the SMCs move in to secure
the foam cell-laden necrotic core by forming a fibrous cap on top
with secreted collagen, proteoglycans and elastin [68]. A small
group of SMCs also take up and accumulate cholesteryl esters in
the necrotic core, where dead foam cells abound [68]. Due to the
lasting inflammation in the area, it is shown that atherosclerosis at
this stag e is more difficult to regress [68,71,72].
Several studies investigated the antiproliferative effect of tan-
shinones and SAB in cultured SMCs, and found that these com-
pounds could block the cell cycle progression at the G0/G1 phase in
a dose-dependent manner [97-100]. This inhibitory effect was asso-
ciated with decreased phosphorylation of AKT and ERK1/2, re-
duced protein levels of cyclin D and S-phase kinase-associated
protein 2, and increased phosphorylation of AMP-activated protein
kinase [97-100]. These results suggest that tanshinones and SAB
target multiple signaling pathways to achieve the inhibito ry regula-
tions of SMC proliferation. The anti-migration effects of tanshi-
nones and SAB were also investigated in cultured SMCs. It was
proposed that the compounds inhibited the mRNA expressions and
enzyme activ ities of matrix-metalloproteinase-9, which mediates
the migration of SMCs in vivo [100,101].
6. ANTITHROMBOTIC PROPERTIES OF THE MAJOR
BIOACTIVE COMPOUNDS IN DANSHEN
The advanced atherosclerotic lesion is susceptible to plaque
rupture due to the thinning of the fibrou s cap over time [68]. The
burst of the plaque exposes a plethora of pro coagulant and
prothrombotic factors to the blood stream and subsequently acti-
vates platelets in the area [68]. Even though it is a natural response
to vascular injury, the activation of platelets triggers thrombus for-
mation that leads to myocardial infarction (MI), unstable angina,
and cardiac death [68,102]. In this regard, antiplatelet therapy is an
integral part of the treatment for CVDs.
The indirect clinical evidence for the antithrombotic properties
of danshen comes from the CVD patients receiving commercial
danshen injections (SAB as the main component) [103]. This treat-
ment was found to potentiate the antiplatelet effect of clopidogrel
and aspirin, but the ex act compound responsible fo r this phenome-
non was hard to determine [103]. In an arterio-venous shunt rat
model, intravenous administration of SAA dose-dependently re-
duced the weight of thrombus that formed around the silk threads in
the shunt [104]. Moreover, tanshinone IIA was capable of prolong-
ing the bleeding time in a dose-dependent manner in mice [105].
These data suggest that both phenolic acids and tanshinones possess
some antiplatelet properties.
Thrombus formation is a complex physiological event that de-
pends on platelet activation, adhesion, and aggregation [102]. The
function s of the platelet are mediated through a variety of mem-
brane receptors [106]. Preliminary in vitro studies using isolated
rodent and human platelets implied that the antiplatelet properties
of phenolic acids and tanshinones were attributed to multiple
mechanisms. For phenolic acids, SAB could inhibit the adhesion of
platelets to the collagen-coated surface by interfering the membrane
receptor glycoprotein Ia-IIa (GP Ia-IIa) [107]. Interestingly, the
primary platelet membrane receptor GP IIb-IIIa was not affected
[107]. Comparative proteomic analysis of rat platelets treated with
or without SAB not only confirmed these results but also identified
intracellular calcium level and cytoskeleton-related proteins as the
candidate regulatory targets in the signaling cascade [108]. In addi-
tion to this mechanism, SAB was shown to significantly suppress
the binding of ADP to its platelet membrane Gi-coupled P2Y12
receptor [103]. This particular receptor, when bound to ADP, act as
a signal amplifier for other thrombotic stimuli, thereby enhancing
the formation of thrombus [102]. Moreover, the investigation of
SAA suggested the involvement of platelet AKT signaling pathway
in its inhibitory effects on platelet aggregation [109]. For tanshi-
nones, tanshinone IIA-inhibited platelet aggregation was associated
with the tubulin acetylation and decreased phosphorylation of
ERK2, suggesting the participation of ERK signaling pathway
[105]. Computer-aided predictions showed that cryptotanshinone
and tanshinone IIA were also potential antagonists for the Gi-
coupled P2Y12 receptor on the platelet membrane [110].
7. PROTECTIVE PROPERTIES OF DANSHEN BIOACTIVE
COMPOUNDS IN MYOCARDIAL REPERFUSION INJURY.
Acute myocardial ischemia following a thrombotic event cre-
ates a local hypoxic area in th e heart, which eventually l eads to the
8 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Chen and Chen
death of the affected cardiomyocytes [111]. In order to reduce the
infarct size and prevent cardiac arrest, surgical interventions like
coronary angioplasty need to be performed promptly to open the
blocked arteries [111]. Even though these coronary procedures
rescue thousands of lives each year, accumulating clinical evidence
shows that acute restoration of the blood flow to the hypoxic area
can also induce cardiomyocyte death [111,112]. It is estimated that
up to 50% of the final myocardial infarct size results from the myo-
cardial reperfu sion injury [111,112]. The detailed molecular
mechanisms underlying this injury have not been fully explained. It
is proposed that the onset of myocardial reperfusion triggers the
opening of the mitochondrial permeability transition pores (MPTPs)
in the inner mitochondrial membrane of the cardiomyocytes
[111,112]. Then, MPTP opening causes uncoupled oxidative phos-
phorylation and mitochondrial swelling, which mediate cardiomyo-
cyte death [111,112]. Inhibition of the MPTP opening via either
pharmaceuticals (e.g. cyclosporine A, exenatide) or ischemic condi-
tioning can effectively reduce myocardial in farct size [111,112].
The protective effects seem to involve the activation of phosphati-
dylinositol-3-kinase (PI3K)/AKT, mitogen-activated protein kinase
kinase (MEK)/ERK, Janus kinase (JAK)/signal transducer and acti-
vator of transcription (STAT), and protein kinase G (PKG) signal-
ing pathw ays (Fig. 4) [111,112].
Fig. (4). Schematic graph of the cardioprotective effect of danshen during
myocardial reperfusion injury. The myocardial reperfusion injury is medi-
ated by the opening of mitochondrial permeability transition pores (MPTPs)
in the inner mitocho ndrial membrane. So far, the activation of four signaling
pathways is proposed to inhibit the opening of MPTPs. They are
JAK/STAT, Raf/MEK/ERK, PI3K/AKT, and PKG signaling pathways. It
has been shown that danshen is able to activate ERK1/2, AKT, and eNOS in
the cardiomyocytes after myocardial reperfusion. JAK, Janus kinase; STAT,
signal transducer and activator of transcription; MEK, mi togen-activated
protein kinase kinase; ERK, extracellular signal-regulated kinase; PI3K,
phosphatidylinositol-3-kinase; GSK3, glycogen synthase kina se 3; HKII,
hexokinase II; eNOS, endothelial nitric oxide synthase; NO, nitric oxide;
PKG, protein kina se G.
A meta-analysis of 13 randomized controlled trials involving
979 acute MI patients suggested that danshen injections could de-
crease the risks of various secondary cardiac events and increase
the odds of benefiting from reperfusion [113]. Rodent MI models
showed that phenolic acids and tanshinones both manifested protec-
tive properties against myocardial reperfu sion injury in vivo. DSS,
SAB, and tanshinone IIA could significantly reduce infarct size and
enhance cardiac function [114,115]. In line with this finding, these
danshen bioactive compounds also inhibited cardiac hypertrophy
and reduced the circulating levels of cardiac injury indicators such
as creatine kinase-MB and cardiac troponin [114,115]. Interestingly
in one study, microarray analysis was performed to compare the
differentially expressed genes in the hearts of MI rats treated with
or without danshen bioactive compounds [116]. The result sug-
gested that tanshinones acted upon cardiomyocytes in the earlier
period after MI to decrease intracellular calcium level, cell adhe-
sion, and alternative complement pathway, whereas salvianolic
acids exerted the function in the later period after MI to reduce
oxidative stress and apoptosis [116]. Accordingly, salvianolic acids
could affect the abundance of certain proteins in the cardiac infarct
tissue, which were associated with heat shock stress, cell survival
and proliferation, and lipid metabolism [117].
So far, it is not clear how danshen bioactive compounds protect
cardiomyocytes from myocardial reperfusion injury in vivo. Many
studies using cultured hypoxic rat myoblasts showed that phenolic
acid and tanshinone treatments were associated with the activation
of PI3K/AKT and ERK1/2 [114,118,119]. In addition, tanshinone
IIA could prevent th e increased expression of miR-133, a mi-
croRNA regulator of the cardiac hypertrophy [118]. DSS and cryp-
totanshinone were found to reduce the oxidative stress, possibly
through the activation of Nrf2/HO-1 signaling pathway [119,120].
Despite these hypotheses, it is not known if they directly or indi-
rectly influence the opening of MPTPs and mitochondrial function
during myocardial reperfusion. At last, two studies in the hypoxic
H9c2 rat myoblast showed that tanshinone IIA and cryptotanshi-
none inhibited the mitochondrial ROS production, decreased mito-
chondrial hyperpolarization, and reduced the activation of pro-
apoptotic proteins [121,122].
8. CONCLUDING REMARKS
In the past decade, accumulating exp erimental evidence has
shown the potential pharm aceutical valu es of danshen in the treat-
ment of CVDs. It appears that the phenolic acids and tanshinones
target multiple signaling pathways in a variety of cells and tissues
to ameliorate atherosclerosis, thrombosis, and myocardial reperfu-
sion injury. However, the clinical research of danshen remains a big
challenge in the field due to poor study design [123,124]. This
situation is further exacerbated by the non-standardized drug source
and complicated compositions of the commercially available drugs.
For these reasons, large-scale high-quality randomized control trials
are extremely important in the near future to advance this field. At
the same time, it is desirable to deepen our understanding on the
cardioprotective effects of every single danshen bioactive com-
pound. This entails the discovery of novel drug candidates, the
delineation of relevant biosynthetic pathways, the improvement of
oral bioavailability, and the identification of the exact drug targets
and detailed working mechanisms. S ince not many herbal medi-
cines are used alone in the practice of TCM, designing effectiv e
composite drug formulae will be easier if more solid information on
the single compound is available.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or other-
wise.
Danshen (Salvia miltiorrhiza Bunge): A Prospective Healing Sage Current Pharmaceutical Design, 2017, Vol. 23, No. 00 9
ACKNOWLEDGEMENTS
Declared none.
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... Salvia miltiorrhiza Bunge, also called Danshen, is a common TCM herb used for the treatment of joint diseases and cardiovascular diseases [132,133]. Salvianolic acid B is one of the most abundant and bioactive ingredients in Salvia miltiorrhiza Bunge, it can protect and reverse LPS-induced MH7A cell injury via anti-apoptotic and anti-inflammatory capacities [134]. Further studies revealed that salvianolic acid B alleviates the inflammatory condition of RA via up-regulation of miR-142-3p expression, thereby suppressing the NF-κB and JNK signaling pathways [134]. ...
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Background Cardiovascular diseases (CVDs) are among the primary and predominant threats to human health with increasing incidence. Danshen Decoction (DSD) as an adjuvant therapy can benefit CVDs patients by improving clinical efficacy. Purpose The purpose of this study was to identify the active components and potential pharmacological mechanisms of DSD by combining mass spectrometry with a network pharmacology strategy and to review the use of DSD in the treatment of CVDs. Method First, the composition of DSD was analyzed by ultrahigh-performance liquid chromatography/tandem mass spectrometry (UHPLC–MS/MS). Second, the network pharmacology method was used to elucidate the underlying material basis and possible pharmacological mechanism of DSD for the treatment of CVDs. Finally, clinical and experimental studies on DSD in the past ten years were retrieved from the PubMed and CNKI database, and the content of these studies was used to summarize the latest progress in DSD treatment of CVDs. Outcome A total of 35 compounds were found in DSD by manual identification from the analysis of MS, which may be the material basis for the therapeutic effect of DSD. After taking the intersection of 2086 targets related to CVDs, these 35 compounds are considered to play a role in the treatment of CVDs through 210 targets including signal transducer and activator of transcription 3 (STAT3), sarcoma (SRC) and phosphoinositide-3-kinase regulatory subunit (PIK3R), and a total of 168 signaling pathways were involved in the regulation of CVDs by DSD, including PI3K-AKT signaling pathway, Alzheimer disease, and Rap1 signaling pathway. A total of 29 clinical studies using DSD in the treatment of CVDs were included in the literature review, and these studies showed the positive significance of DSD as adjuvant therapy, while 14 experimental studies included in the literature review also demonstrated the effectiveness of DSD in the treatment of CVDs. Conclusion DSD plays a role in the treatment of CVDs through a variety of active ingredients. Large-scale clinical research and more in-depth experimental research will help to further reveal the mechanism of DSD in the treatment of CVDs.
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Objectives: This study aims to compare the fingerprint and the content of the three components of sweated and non-sweated Salvia miltiorrhiza alcoholic extracts (SSAE and NSAE). It also aims to investigate the difference in protective effects of SSAE and NSAE on myocardial ischaemia-reperfusion injury (MIRI). Methods: The fingerprints of SSAE and NSAE were established by HPLC with a UV detector to identify the common peaks and detect the content of the three major components (cryptotanshinone, tanshinone I and tanshinone IIA). The protective effects of SSAE and NSAE were compared with MIRI rat model after orally administered SSAE and NSAE (2 g/kg of raw drug) for 7 days. The ST segment, PR and QT interval changes and the infarct size were assessed in the rat hearts. Moreover, the activity of aspartate transaminase (AST), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and the level of cardiac troponin I (cTn I) in serum as well as the cardiac H&E staining were evaluated. Key findings: The results showed that the fingerprints of SSAE and NSAE were similar, and cluster analysis showed that the sweating methods had effects on the alcoholic extracts. The content determination showed that sweating could increase the total content of cryptotanshinone, tanshinone I and tanshinone IIA of S. miltiorrhiza. The results of electrocardiograms (ECG) showed that SSAE could make the ST segment drop more obviously, PR and QT intervals become shorter, and the size of the infarct much smaller. Compared with NSAE, SSAE had more significant effects on the enzymatic activity of AST, LDH and the level of cTn I in serum. The H&E staining showed that both SSAE and NSAE could reduce the degree of heart damage. Conclusions: The present investigation results demonstrated that sweating increased the content of tanshinone components in S. miltiorrhiza alcoholic extracts, and SSAE had a better protective effect on MIRI.
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Salvianolate lyophilized injection (SLI), a freeze-dried powder injection derived from aqueous extract of S. miltiorrhiza, is therapeutically used to treat the syndrome of blood stasis and collateral blockage during the recovery period after stroke. To date, it has remained a significant challenge to comprehensively characterize the compounds of SLI, particularly the minor components with potential bioactivities, in one sample injection analysis. Using an integrative four scan modes approach coupled with ultra-high performance liquid chromatography-triple quadrupole-linear ion trap mass spectrometry (UHPLC-QTRAP-MS/MS), we propose a novel, sensitive, and simple strategy for systematic and rapid profiling of the chemical components of SLI. First, an in-house database of constituents from the water-soluble extract of Danshen was created. Second, the fragmentation behaviors of the representative components in SLI were obtained using the untargeted scan mode enhanced MS (EMS)-information dependent acquisition (IDA)-enhanced product ion (EPI). The specific fragments acquired were then utilized to conduct precursor ion (Prec) and neutral loss (NL)-IDA-EPI scans. Following that, a sensitive predictive multiple reaction monitoring (pMRM)-IDA-EPI scan method with 454 transitions was developed based on the prominent fragment ions and plausible predictions. A total of 171 compounds were tentatively identified from SLI. Among them, 27 minor components have not been previously reported. This strategy allows most isomeric compounds at trace levels to be readily distinguished and annotated. Finally, 15 batches of 13 representative components in SLI selected by the qualitative results were accurately quantified. Salvianolic acid A (Sal A), Sal B, Sal D, lithospermic acid (LA), and rosmarinic acid (RA) were proved to be the predominant constituents. Sal B had the highest amount (195.08-350.46 μg·mg⁻¹), followed by LA, Sal A, Sal D, and RA. Moreover, these 15 batches of samples showed good uniformity, and no abnormal batches existed. These results suggest that this novel strategy can accelerate the identification of undiscovered chemical components and serve as an alternative method for in-depth profiling of compounds in other traditional Chinese medicines (TCMs).
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Background Cervical cancer is the most common malignancy of the female lower genital tract. Tanshinone I (Tan I) is one of the crucial lipid-soluble components of red sage (Salvia miltiorrhiza). While its mode of action against cervical cancer is unclear. Purpose Our study aimed to explore the role of Tan I on cervical cancer in vitro. Study design and methods Effects of Tan I on cervical cancer cells viability, migration and mitochondrial function were investigated by Cell Counting Kit-8, Transwell and Fluorescence laser confocal microscope assays respectively. The potential mechanism of Tan I was uncovered by an integrative approach combining RNA profiling and hydrogen nuclear magnetic resonance-based metabolic analysis, molecular docking and Western blot. Results Tan I significantly inhibited the growth and colony formation of HeLa and SiHa cells. It induced apoptosis and cell cycle S phase arrest at low (12.5-25μM) but not high (50μM) concentrations. It also altered the HeLa cell ultrastructure, decreased the membrane potential and increased the total mitochondrial content. Further, Tan I induced autophagic flux and the colocalization of mitochondria with lysosomes, led to decreased adhesion, invasion, and migration of cervical cancer cells. Transcriptomic analysis revealed that Tan I altered the RNA profile and signal processing in HeLa cells. Tan I significantly impacted “central carbon metabolism in cancer” and “mitophagy–animal” processes. A global metabolic analysis identified 25 metabolites affected by Tan I treatment in HeLa cells. Changes in the metabolic profile indicated that Tan I affected such processes as protein digestion and absorption, central carbon metabolism in cancer, and aminoacyl-tRNA biosynthesis in cervical cancer cells. Furthermore, Tan I significantly induced the expression of mitophagy-related proteins BNIP3, NIX and Optineurin and the conversion from LC3-I to LC3-II, inhibited the NDP52 and P62 level in a concentration-dependent manner. While CQ further increased the conversion of LC3-I to LC3-II and the expression of P62. Moreover, Tan I interacted with BNIP3 and NIX through hydrogen bond. Tan I induce mitophagy could be prevented by BNIP3 and NIX siRNA transfection. Conclusion Tan I induced the BNIP3/NIX-mediated mitophagy, and reprogrammed the mitochondrial metabolism in cervical cancer cells, thus inhibiting metastasis.
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Tanshinone IIA is the active compound isolated from Salvia miltiorrhiza bunge, which is a traditional Chinese medicine known as Danshen. The aim of the present study was to assess the effect of Tanshinone IIA on the regulation of lipid metabolism in the livers of hyperlipidemic rats and the underlying molecular events. An in vivo model of hyperlipidemia was established in rats, with the animals receiving a daily dose of Tanshinone IIA. The serum lipid profiles were analyzed using an automatic biochemical analyzer, and the histopathological alterations and lipid deposition in liver tissue were assessed using hematoxylin and eosin staining, and oil red O staining, respectively. The mRNA expression levels of microRNA (miR)‑33a, ATP‑binding cassette transporter (ABC)A1, ABCG1, sterol regulatory element‑binding protein 2 (SREBP‑2), proprotein convertase subtilisin/kexin type 9 (Pcsk9) and low‑density lipoprotein receptor (LDL‑R) in liver tissues were measured using reverse transcription‑quantitative polymerase chain reaction, and the protein expression levels of ABCA1, ABCG1, SREBP‑2, Pcsk9, and LDL‑R were analyzed using western blotting. Tanshinone IIA reduced lipid deposition and improved histopathology in the rat liver tissue, however, did not alter the lipid profile in rat serum. In addition, Tanshinone IIA treatment suppressed the expression of miR‑33a, whereas the protein expression levels of ABCA1, SREBP‑2, Pcsk9 in addition to LDL‑R mRNA and protein were upregulated. In conclusion, the present study indicated that Tanshinone IIA attenuated lipid deposition in the livers of hyperlipidemic rats and modulated the expression of miR‑33a and SREBP‑2/Pcsk9 signaling pathway proteins.
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The active ingredients of salvia (dried root of Salvia miltiorrhiza) include both lipophilic (e.g., tanshinone IIA, tanshinone I, cryptotanshinone and dihydrotanshinone I) and hydrophilic (e.g., danshensu and salvianolic acid B) constituents. The low oral bioavailability of these constituents may limit their efficacy. A solid self-microemulsifying drug delivery system (S-SMEDDS) was developed to load the various active constituents of salvia into a single drug delivery system and improve their oral bioavailability. A prototype SMEDDS was designed using solubility studies and phase diagram construction, and characterized by self-emulsification performance, stability, morphology, droplet size, polydispersity index and zeta potential. Furthermore, the S-SMEDDS was prepared by dispersing liquid SMEDDS containing liposoluble extract into a solution containing aqueous extract and hydrophilic polymer, and then freeze-drying. In vitro release of tanshinone IIA, salvianolic acid B, cryptotanshinone and danshensu from the S-SMEDDS was examined, showing approximately 60%-80% of each active component was released from the S-SMEDDS in vitro within 20 min. In vivo bioavailability of these four constituents indicated that the S-SMEDDS showed superior in vivo oral absorption to a drug suspension after oral administration in rats. It can be concluded that the novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of both lipophilic and hydrophilic constituents of salvia. Thus, the S-SMEDDS can be regarded as a promising new method by which to deliver salvia extract, and potentially other multicomponent drugs, by the oral route.
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Paeonol and danshensu is the representative active ingredient of traditional Chinese medicinal herbs Cortex Moutan and Radix Salviae Milthiorrhizae, respectively. Paeonol and danshensu combination (PDSS) has putative cardioprotective effects in treating ischemic heart disease (IHD). However, the evidence for the protective effect is scarce and the pharmacological mechanisms of the combination remain unclear. The present study was designed to investigate the protective effect of PDSS on isoproterenol (ISO)-induced myocardial infarction in rats and to elucidate the potential mechanism. Assays of creatine kinase-MB, cardiac troponin I and T and histopathological analysis revealed PDSS significantly prevented myocardial injury induced by ISO. The ISO-induced profound elevation of oxidative stress was also suppressed by PDSS. TUNEL and caspase-3 activity assay showed that PDSS significantly inhibited apoptosis in myocardia. In exploring the underlying mechanisms of PDSS, we found PDSS enhanced the nuclear translocation of Nrf2 in myocardial injured rats. Furthermore, PDSS increased phosphorylated PI3K and Akt, which may in turn activate antioxidative and antiapoptotic signaling events in rat. These present findings demonstrated that PDSS exerts significant cardioprotective effects against ISO-induced myocardial infarction in rats. The protective effect is, at least partly, via activation of Nrf2/HO-1 signaling and involvement of the PI3K/Akt cell survival signaling pathway.
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Endothelial dysfunction has been implicated in the pathogenesis of atherosclerosis. Salvia miltiorrhiza (danshen) is a traditional Chinese medicine that has been effectively used to treat cardiovascular disease. Cryptotanshinone (CTS), a major lipophilic compound isolated from S. miltiorrhiza, has been reported to possess cardioprotective effects. However, the anti-atherogenic effects of CTS, particularly on tumor necrosis factor-α (TNF-α)-induced endothelial cell activation, are still unclear. This study aimed to determine the effect of CTS on TNF-α-induced increased endothelial permeability, monocyte adhesion, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), monocyte chemoattractant protein 1 (MCP-1) and impaired nitric oxide production in human umbilical vein endothelial cells (HUVECs), all of which are early events occurring in atherogenesis. We showed that CTS significantly suppressed TNF-α-induced increased endothelial permeability, monocyte adhesion, sICAM-1, sVCAM-1 and MCP-1, and restored nitric oxide production. These observations suggest that CTS possesses anti-inflammatory properties and could be a promising treatment for the prevention of cytokine-induced early atherogenesis.
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Despite prompt reperfusion by primary percutaneous coronary intervention (PPCI), the mortality and morbidity of patients presenting with an acute ST-segment elevation myocardial infarction (STEMI) remain significant with 9% death and 10% heart failure at 1 year. In these patients, one important neglected therapeutic target is 'myocardial reperfusion injury', a term given to the cardiomyocyte death and microvascular dysfunction which occurs on reperfusing ischaemic myocardium. A number of cardioprotective therapies (both mechanical and pharmacological), which are known to target myocardial reperfusion injury, have been shown to reduce myocardial infarct (MI) size in small proof-of-concept clinical studies-however, being able to demonstrate improved clinical outcomes has been elusive. In this article, we review the challenges facing clinical cardioprotection research, and highlight future therapies for reducing MI size and preventing heart failure in patients presenting with STEMI at risk of myocardial reperfusion injury.
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Background: Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. Methods: We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. Findings: We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m2 (95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m2 (24·0–24·4) in 2014 in men, and from 22·1 kg/m2 (21·7–22·5) in 1975 to 24·4 kg/m2 (24·2–24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m2 in central Africa and south Asia to 29·2 kg/m2 (28·6–29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m2 (21·4–22·3) in south Asia to 32·2 kg/m2 (31·5–32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5–17·4) to 8·8% (7·4–10·3) in men and from 14·6% (11·6–17·9) to 9·7% (8·3–11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8–29·2) in men and 24·0% (18·9–29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4–4·1) in 1975 to 10·8% (9·7–12·0) in 2014 in men, and from 6·4% (5·1–7·8) to 14·9% (13·6–16·1) in women. 2·3% (2·0–2·7) of the world's men and 5·0% (4·4–5·6) of women were severely obese (ie, have BMI ≥35 kg/m2). Globally, prevalence of morbid obesity was 0·64% (0·46–0·86) in men and 1·6% (1·3–1·9) in women. Interpretation: If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia.
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The vascular endothelium is an interface between the blood stream and the vessel wall. Changes in this single cell layer of the artery wall are believed of primary importance in the pathogenesis of vascular disease/atherosclerosis. The endothelium responds to humoral, neural and especially hemodynamic stimuli and regulates platelet function, inflammatory responses, vascular smooth muscle cell growth and migration, in addition to modulating vascular tone by synthesizing and releasing vasoactive substances. Compromised endothelial function contributes to the pathogenesis of cardiovascular disease; endothelial ‘dysfunction’ is associated with risk factors, correlates with disease progression, and predicts cardiovascular events. Therapies for atherosclerosis have been developed, therefore, that are directed towards improving endothelial function.
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A multi-reactor gastrointestinal model was used to digest a mixture of pure polyphenol compounds, including non-flavonoid phenolic acids (chlorogenic acid, caffeic acid, ferulic acid) and a flavonoid (rutin) to identify phenolic metabolites and short chain fatty acids (SCFAs) and compare relative antioxidant capacities following a 24 h digestion. Biotransformation of these polyphenols occurred in the colonic compartments generating phenylpropionic, benzoic, phenylacetic and cinnamic acids. Total SCFAs increased in all colonic vessels with a rise in the proportion of propionic to acetic acid. Antioxidant capacity increased significantly in all compartments, but first in the stomach, small intestine and ascending colon. After 24 h, the colonic vessels without parent polyphenols, but containing new metabolites, had antioxidant capacities similar to the stomach and small intestine, containing parent compounds. Biotransformation of pure polyphenols resulted in different phenolic metabolite and SCFAs profiles in each colonic segment, with important health implications for these colonic compartments.
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Background: Salvianolic acid B (SalB) represents the most abundant and bio-active phenolic constituent among the water-soluble compounds of Salvia miltiorrhiza. But the therapeutic potential of SalB has been significantly restricted by its poor absorption. Methods: In this study, chitosans (CS) and CS nanoparticles (NPs) with different molecular weights (MWs), which have influence on the absorption of SalB, was also investigated. Results: As a preliminary study, water-soluble CS with various MWs (3, 30, 50, and 100 kDa) was chosen. We investigated the MW-dependent Caco-2 cell layer transport phenomena in vitro of CS and NPs at concentrations (4 μg/ml, w/v). SalB, in presence CS or NPs has no significant toxic effect on Caco-2 cell. As the MW increases, the absorption enhancing effect of CS increases. However, as the MW decreases, the absorption enhancing effect of NPs increases. The AUC0-∞ of the SalB-100 kDa CS was 4.25 times greater than that of free SalB. And the AUC0-∞ of the SalB-3 kDa NPs was 16.03 times greater than that of free SalB. Conclusion: CS and NPs with different MWs as the absorption enhancers can promote the absorption of SalB. And the effect on NPs is better than CS. Summary: Formation mechanism for NPs.
Article
Background: The World Health Organization (WHO) for some years has been focusing on what is now commonly referred to as an "epidemic of obesity and diabetes" ("diabesity"): behind this outbreak, there are several risk factors grouped in what is called "metabolic syndrome" (MetS). The basis of this "epidemic" is either a diet too often characterized by excessive consumption of saturated and trans-esterified fatty acids, simple sugars and salt, either a sedentary lifestyle. Purpose: The aim of this review is to focus on the phytochemicals that have a more positive effect on the treatment and/or prevention of MetS. Chapters: Treatment strategies for MetS include pharmacologic and non-pharmacologic options, with varying degrees of success rate. The first is indicated for patients with high cardiovascular risk, while the second one is the most cost-effective preventive approach for subjects with borderline parameters and for patients intolerant to pharmacological therapy. MetS non-pharmacological treatments could involve the use of nutraceuticals, most of which has plant origins (phytochemicals), associated with lifestyle improvement. The chapter will discuss the available evidence on soluble fibres from psyllium and other sources, cinnamaldehyde, cinnamic acid and other cinnamon phytochemicals, berberine, corosolic acid from banaba, charantin from bitter gourd, catechins and flavonols from green tea and cocoa. Vegetable omega-3 polyunsaturated fatty acids, alliin from garlic, soy peptides, and curcumin from curcuma longa. Conclusion: Some nutraceuticals, when adequately dosed, should improve a number of the MetS components.