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Citation: Song, X.; Wang, L.; Fan, D.
Insights into Recent Studies on
Biotransformation and
Pharmacological Activities of
Ginsenoside Rd. Biomolecules 2022,12,
512. https://doi.org/10.3390/
biom12040512
Academic Editor: Georgi Momekov
Received: 20 February 2022
Accepted: 24 March 2022
Published: 28 March 2022
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biomolecules
Review
Insights into Recent Studies on Biotransformation and
Pharmacological Activities of Ginsenoside Rd
Xiaoping Song 1,2,3,* , Lina Wang 3and Daidi Fan 1,2,3,*
1Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering,
Northwest University, 229 Taibai North Road, Xi’an 710069, China
2Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering,
Northwest University, 229 Taibai North Road, Xi’an 710069, China
3Biotechnology & Biomedicine Research Institute, Northwest University, 229 Taibai North Road,
Xi’an 710069, China; wanglina1@stumail.nwu.edu.cn
*Correspondence: 20185322@nwu.edu.cn (X.S.); fandaidi@nwu.edu.cn (D.F.)
Abstract:
It is well known that ginsenosides—major bioactive constituents of Panax ginseng—are
attracting more attention due to their beneficial pharmacological activities. Ginsenoside Rd, belonging
to protopanaxadiol (PPD)-type ginsenosides, exhibits diverse and powerful pharmacological activities.
In recent decades, nearly 300 studies on the pharmacological activities of Rd—as a potential treatment
for a variety of diseases—have been published. However, no specific, comprehensive reviews have
been documented to date. The present review not only summarizes the
in vitro
and
in vivo
studies
on the health benefits of Rd, including anti-cancer, anti-diabetic, anti-inflammatory, neuroprotective,
cardioprotective, ischemic stroke, immunoregulation, and other pharmacological effects, it also delves
into the inclusion of potential molecular mechanisms, providing an overview of future prospects
for the use of Rd in the treatment of chronic metabolic diseases and neurodegenerative disorders.
Although biotransformation, pharmacokinetics, and clinical studies of Rd have also been reviewed,
clinical trial data of Rd are limited; the only data available are for its treatment of acute ischemic
stroke. Therefore, clinical evidence of Rd should be considered in future studies.
Keywords: ginsenoside Rd; biotransformation; pharmacological activities
1. Introduction
Ginseng (Panax ginseng C.A. Mey, a perennial herb of the Araliaceae family) is con-
ventionally used as a tonic herbal medicine and a functional food, it is receiving more
attention due to its remarkable beneficial pharmacological activities. Ginsenosides are ma-
jor bioactive constituents of ginseng, of which, nearly 150 have been isolated and identified
from roots, fruits, leaves, and flower buds of ginseng [
1
]. Ginsenosides directly extracted
from Araliaceae plants (Panax ginseng, Panax quinquefolium, Panax notoginseng, etc.)
are called naturally prototype ginsenosides, also known as main ginsenosides due to their
relatively high contents, mainly including Ra, Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, Rg1, etc.
Rare ginsenosides or minor ginsenosides are the metabolites of prototype ginsenosides
catalyzed by enzymes, including Rh2, Rg3, Rk2, Rh3, Rk1, Rg5, Rk3, Rh1, Rh3, Rh4, CK,
etc., which have much higher anti-cancer activities and are more easily absorbed by the
human body [2].
Ginsenoside Rd, belonging to protopanaxadiol (PPD)-type ginsenosides, exhibits
diverse and powerful pharmacological activities, including anti-inflammatory, anti-tumor,
neuroprotective effects, cardiovascular protection, immunoregulation, and other beneficial
health effects. However, the content of ginsenoside Rd in wild ginseng is very low, and
traditional chemical conversion production methods, such as heating, mild acid hydrolysis,
and alkali treatment, display some unavoidable disadvantages, such as a lower yield and
more side reactions due to non-specific reactions. Therefore, studies have been conducted
Biomolecules 2022,12, 512. https://doi.org/10.3390/biom12040512 https://www.mdpi.com/journal/biomolecules
Biomolecules 2022,12, 512 2 of 34
on the biotransformation of ginsenosides Rb1, Rb2, and Rc, due to the advantages of
biotransformation (e.g., high selectivity, environmentally-friendly, etc.). Ginsenoside Rd,
in view of its high levels of safety and diverse biological functions, may be a potential
therapeutic agent for many diseases, in particular, neurological diseases, cardiovascular
diseases, and metabolic diseases.
Researchers, in previous studies, have delved into the promising role of ginsenoside
Rd on ischemic stroke and its neuroprotective effects [
3
,
4
]. The present paper, however,
differs significantly from previous works, not only by including detailed information on the
biotransformation of Rd, but also by including clinical pharmacokinetic studies, exploring
the anti-cancer, anti-inflammatory, antioxidative, neuroprotective, cardiovascular protec-
tion, and immunoregulation effects, as well as other
in vitro
and
in vivo
pharmacological
activities.
2. Biotransformation
The content of ginsenoside Rd differs from different wild ginseng and parts of ginseng,
and ranges from 0.02% to 1.66% [
4
]. Moreover, it is difficult and costly to isolate Rd from
natural products; thus, a microbial enzymatic transformation has become the predomi-
nant conversion modality of ginsenoside Rd due to its distinct selectivity, mild reactive
conditions, and environmental compatibility (Figure 1).
Biomolecules2022,12,xFORPEERREVIEW2of47
yieldandmoresidereactionsduetonon‐specificreactions.Therefore,studieshavebeen
conductedonthebiotransformationofginsenosidesRb1,Rb2,andRc,duetothead‐
vantagesofbiotransformation(e.g.,highselectivity,environmentally‐friendly,etc.).Gin‐
senosideRd,inviewofitshighlevelsofsafetyanddiversebiologicalfunctions,maybea
potentialtherapeuticagentformanydiseases,inparticular,neurologicaldiseases,cardi‐
ovasculardiseases,andmetabolicdiseases.
Researchers,inpreviousstudies,havedelvedintothepromisingroleofginsenoside
Rdonischemicstrokeanditsneuroprotectiveeffects[3,4].Thepresentpaper,however,
differssignificantlyfrompreviousworks,notonlybyincludingdetailedinformationon
thebiotransformationofRd,butalsobyincludingclinicalpharmacokineticstudies,ex‐
ploringtheanti‐cancer,anti‐inflammatory,antioxidative,neuroprotective,cardiovascular
protection,andimmunoregulationeffects,aswellasotherinvitroandinvivopharmaco‐
logicalactivities.
2.Biotransformation
ThecontentofginsenosideRddiffersfromdifferentwildginsengandpartsofgin‐
seng,andrangesfrom0.02%to1.66%[4].Moreover,itisdifficultandcostlytoisolateRd
fromnaturalproducts;thus,amicrobialenzymatictransformationhasbecomethepre‐
dominantconversionmodalityofginsenosideRdduetoitsdistinctselectivity,mildreac‐
tiveconditions,andenvironmentalcompatibility(Figure1).
Figure1.SchematicillustrationofbiotransformationofmajorginsenosidesRb1,Rb2,andRctoRd
(⟶majorpathway;⤏minorpathway).
Figure 1.
Schematic illustration of biotransformation of major ginsenosides Rb1, Rb2, and Rc to Rd
(→major pathway; 99K minor pathway).
2.1. Enzymatic Transformation
Ginsenoside Rd—characterized by tetracyclic, dammarane-type triterpenes with three
sugar moieties—is structurally similar to Rb1, Rb2, and Rc, but lacks one outer glycoside
moiety at the C-20 position. The preparation of ginsenosides via hydrolysis of glycosidic
Biomolecules 2022,12, 512 3 of 34
bonds using enzymatic transformation methods has exceptional advantages, e.g., high selec-
tivity, mild reactive conditions, and being environmentally-friendly. Therefore, it is viable to
obtain ginsenoside Rd from Rb1, Rb2, and Rc by hydrolyzing the monosaccharide residue
using a specific glycosidase, such as
α
-L-arabinofuranosidase,
α
-L-arabinopyranosidase,
β-glucosidase, or pectinase (Table 1).
Table 1. Bioconversion of major ginsenosides into Rd.
Enzymes Transformation Pathways Optimum
Conditions Yield and Reaction Scale Ref. Year
Enzymatic Transformation
Arabinofuranosidase
α-L-arabinofuranosidase AbfA from Rhodanobacter
ginsenosidimutans strain Gsoil 3054T Rc 99K Rd pH 7.5, 37 ◦C / [5] 2012
α-L-arabinofuranosidase, Abf22-3 from
Leuconostoc sp. 22-3 Rc 99K Rd pH 6.0, 30 ◦C 99.50% [6] 2013
α-L-arabinofuranosidase from Caldicellulosiruptor
saccharolyticus Rc 99K Rd pH 5.5, 80 ◦C, 227 U
enzyme/mL a molar yield of 100% [7] 2013
α-L-arabinofuranosidase (Tt-Afs) from Thermotoga
thermarum DSM5069 Rc 99K Rd pH 5.0, 85 ◦C 99.40% [8] 2016
α-L-arabinofuranosidase from Bacillus subtilis
Str. 168 Rc 99K Rd pH 5.0, 40 ◦C 90% [9] 2021
Arabinopyranosidase
α-L-Arabinopyranosidase from Blastococcus
saxobsidens (AbpBs) Rb2 99K Rd pH 7.0, 40 ◦C / [10] 2020
β-glucosidase
β-glucosidase Tt-BGL from Thermotoga thermarum
DSM 5069T Rb1 99K Rd pH 4.8, 90 ◦C 95% [11] 2013
β-glucosidase Bgp3 from Microbacterium
esteraromaticum Rb1 99K Rd 99K CK pH 7.0, 40 ◦C 77% [12] 2012
glycosidase Bgp2 from Microbacterium
esteraromaticum Rb2 99K Rd 99K 20(S)-Rg3 pH 7.0, 40 ◦C 65% [13] 2013
β-Glucosidase Bgy2 from Lactobacillus brevis Rb1 99K Rd99KF2 99K CK pH 7.0, 30 ◦C 69%91% [14] 2016
β-glucosidase from Aspergillus niger KCCM 11239 Rb1 99K Rd 99K Rg3
Rb1 99K Rd 99K F2 pH 4.0, 70 ◦C / [15] 2012
Pectinase
Pectinase coupled with one-pot process Rb1 99K Rd pH 6.0, 52.5 ◦C 83.14% [16] 2020
Microbial Transformation
Fungal System
Paecilomyces bainier 229-7 Rb1 99K Rd / 94.9% in shake flasks, 89% in
10 L fermenter [17] 2010
Paecilomyces bainier 229-7 Rb1 99K Rd / 92.44% [18] 2012
Aspergillus versicolor strain LFJ1403 Rb1 99K Rd pH 5.0, 37 ◦C94.9% in shake flasks85% in
2 L fermenter [19] 2015
Aspergillus niger strain TH-10a Rb1 99K Rd pH 5.0, 32 ◦C 86% [20] 2016
Bacteria system /
M. trichothecenolyticum Rb1 99K Rd99K Rh2 / / [21] 2013
Bacterial strain MAH-16T Rb1 99K Rd pH 5.0–7.0, 20–40 ◦C / [22] 2018
Bacterial strain MAHUQ-46T Rb1 99K Rd pH 7.5, 30 ◦C / [23] 2021
Bacterial strain FW-6T Rb1 99K Rd / / [24] 2013
Bacterium G9y Rc 99K Rd pH 7.0, 45 ◦C / [25] 2021
Gut microbiota
Gut bacteria
Rb1 99KRd 99K F2 99K CK
Rb1 99K G-XVII 99K G-LXXV
99K CK
/ / [26] 2013
Leuconostoc mesenteroides DC102 Rb1 99K G-XVII and Rd 99K
F299K CK pH 6.0–8.0, 30 ◦C 99% [27] 2011
Lactobacillus paralimentarius LH4 Rb1 99K G-XVII and Rd 99K
F2 99K CK pH 6.0, 30 ◦C 88% [28] 2013
Probiotics Rb1 99K Rd 99K F299K CK / / [29] 2021
Lactobacillus rhamnosus GG Rb1 99K Rd pH 6.0, 40 ◦C / [30] 2016
Food microorganisms
Dekkera anomala YAE-1 Rb1 99K Rd pH 5.0, 40 ◦C / [31] 2020
“99K” means convert to, “/” means not mentioned.
2.1.1. Arabinofuranosidase
Ginsenoside Rc, one of the major components of ginseng, comprising 7–22% of total
ginsenoside, has an arabinofuranosyl moiety and three glucopyranosyl moieties; thus, ara-
binofuranosidase and glucosidase could convert Rc to a deglycosylated ginsenoside [
5
]. In
order to improve the biotransformation rate of ginsenoside Rd and optimize the enzymatic
properties, studies about arabinofuranosidase have emerged in recent years. An et al. [
5
]
Biomolecules 2022,12, 512 4 of 34
identified a recombinant
α
-L-arabinofuranosidase AbfA, which was cloned from a soil bac-
terium; Rhodanobacter ginsenosidimutans Gsoil 3054T could biotransform ginsenoside Rc to
ginsenoside Rd. Recombinant AbfA demonstrated substrate-specific activity for the biocon-
version of ginsenosides, as it only hydrolyzed arabinofuranoside moieties from ginsenoside
Rc and derivatives, not other sugar groups from ginsenosides Rb1 or Rb2. The follow-
ing year, the same research team reported a novel recombinant
α
-L-arabinofuranosidase
(Abf22-3) from the ginsenoside converting Leuconostoc sp. 22-3 isolated from the Korean
fermented food kimchi, which could biotransform ginsenoside Rc into Rd [
6
]. Results
showed that over 99.5% of Rc was converted to Rd after 24 h under optimal conditions of
pH 6.0 and 30
◦
C. In another study, a molar yield of ginsenoside Rd was nearly 100% using
a thermostable recombinant α-L-arabinofuranosidase from Caldicellulosiruptor saccharolyti-
cus at a pH 5.5 and at 80
◦
C [
7
]. Later, Xie et al. [
8
] cloned and overexpressed the novel
thermostable
α
-L-arabinofuranosidase (Tt-Afs) from T. thermarum DSM5069, which showed
a high conversion and productivity of Rd. In addition, the ginsenoside Rc-hydrolyzing
α
-L-arabinofuranosidase gene, BsAbfA, was cloned from Bacillus subtilis and optimized.
The results of molecular docking and site-directed mutagenesis suggested that the E173
and E292 variants for BsAbfA were important in effectively recognizing ginsenoside Rc,
providing an effective biotransformation pathway of ginsenoside Rc into Rd [9].
Among the major ginsenosides, ginsenoside Rb2 accounts for 1–22% of the total
ginsenosides in ginseng root [
32
] and could also be used for converting into Rd. Kim
et al. [
10
] reported a recombinant enzyme
α
-L-arabinopyranosidase (AbpBs), which could
efficiently catalyze the conversion of ginsenoside Rb2 to Rd by selectively hydrolyzing the
outer arabinopyranoside moiety at the C-20 position.
2.1.2. β-glucosidase
β
-glucosidases, a heterogeneous group of enzymes, are capable of cleaving the
β
-
glycosidic linkages of aryl and alkyl
β
-glucosides,
β
-linked oligoglucosides, and several
other oligosaccharides. Some recombinant enzymes, especially
β
-glucosidases with dif-
ferent substrate specificities, have been widely applied to produce the rare ginsenosides.
To date, considerable attention has been placed on the transformation of ginsenoside Rb1
into Rd with the use of
β
-glucosidases. The thermostable
β
-glucosidase Tt-BGL from
extremophile Thermotoga thermarum DSM5069 selectively converts ginsenoside Rb1 into
ginsenoside Rd, with high productivity [
11
]. Additionally, ginsenoside Rd has been used as
an intermediate for the transformation of other rare ginsenosides. Quan et al. [
12
] reported
that the recombinant
β
-glucosidase Bgp3 from Microbacterium esteraromaticum isolated from
the ginseng field could catalyze the conversion of ginsenoside Rb1 to the more pharmaco-
logically active major ginsenoside Rd and ginsenoside CK. Subsequently, they isolated a
novel recombinant glycosidase Bgp2 from Microbacterium esteraromaticum, which belonged
to the glycosyl hydrolase family 2 protein and could hydrolyze the ginsenoside Rb2 along
the following pathway: Rb2
99K
Rd
99K
20(S)-Rg3 through the selective hydrolysis of the
arabinopyranose and glucose moieties [
13
]. The ginsenoside-hydrolyzing
β
-glucosidase
gene Bgy2, a member of the glycosyl hydrolase family 3 protein, was cloned and identified
from Lactobacillus brevis [
14
]. Under the optimal conditions (pH 7.0, 30
◦
C), 1.0 mg/mL
ginsenoside Rb1 was converted into 0.59 mg/mL ginsenoside Rd, with molar conversion
productivities of 69%. Moreover, Rb1-hydrolyzing
β
-glucosidase from Aspergillus niger
KCCM 11,239 was studied (and optimized) by Chang et al. [
15
]. The enzyme hydrolyzed
β
-(1
99K
6)-glucoside at the C-20 position of ginsenoside Rb1 to generate Rd and Rg3, and
hydrolyzed β-(199K2)-glucoside at the C-3 position to generate F2.
2.1.3. Pectinase
Pectinase specifically hydrolyzes protopanaxadiol (PPD)-type ginsenosides and is a
selective enzyme that converts ginsenoside Rb1 to Rd. Fang et al. [
16
] explored one-pot
production process of ginsenoside Rd by coupling enzyme-assisted extraction with selective
Biomolecules 2022,12, 512 5 of 34
enzymolysis, and provided a higher yield at 52.5
◦
C and pH 6.0, suggesting that pectinase
could be used as an efficient enzyme for producing ginsenoside Rd.
2.2. Microbial Transformation
Microbial transformation is also a major production method of Rd. The mechanism of
enzymatic transformation involves hydrolyzing ginsenosides using the catalytic activity of
the enzyme, which has the advantages of a short reaction cycle, low pollution, and high
product purity; however, the reaction conditions are difficult to control, the enzyme is easy
to inactivate, and the separation and purification processes of the enzymes are complicated.
In contrast, microbial transformation is characterized by low costs, few byproducts, and
wide applications, but the drawbacks of a long conversion time and a low biotransformation
rate are inevitable. Therefore, the enzymatic–microbial transformation of ginsenosides
have their own characteristics and complement each other in the actual production process.
The production of Rd could be achieved through microbial methods, including fungus,
bacteria, gut microbiota, and food microorganisms (Table 1).
2.2.1. Fungal System
A mutant filamentous fungus Paecilomyces bainier 229-7 that transformed ginsenoside
Rb1 to Rd with high selectivity and substrate tolerance was obtained (and identified) by
Feng et al. [
17
]. The highly substrate-tolerant mutant produced ginsenoside Rd from Rb1
with a bioconversion rate as high as 94.9% under optimized culture conditions in shake
flasks, along with an 89% bioconversion rate in 10 L fermenter, with a chromatographic
purity of 92.6% purified by macroporous resin, which rendered it a promising strain for
the preparation of Rd in the pharmaceutical industry. Later, the same team reported
on the effects of external calcium treatments on the biotransformation of ginsenoside
Rb1 to ginsenoside Rd by Paecilomyces bainier 229-7. Results suggested that both Ca
2+
channels and calmodulin (CaM) were involved in ginsenoside Rd biotransformation via
regulation of
β
-glucosidase activity [
18
]. Additionally, ginsenoside Rb1-converting fungus
Aspergillus versicolor LFJ1403 was isolated and identified from the ginseng field soil and
the biotransformation of ginsenoside Rb1 to Rd using an extracellular enzyme directly
from the fungus spore production phase was investigated. The results of HPLC showed
that Rd was the only product in this process, and the conversion rate was increased to
96% in shake flasks, indicating that the spore suspension biotransformation system had
potential in the industrial production of Rd [
19
]. A novel ginsenoside Rd transformation
fungus, Aspergillus niger TH-10a obtained from screening the survival library of LiCl and
UV irradiation, could efficiently convert ginsenoside Rd from Rb1, and achieve the highest
transformation rate of about 86% at 32 ◦C and pH 5.0 [20].
2.2.2. Bacteria System
Some studies have focused on the discovery and identification of ginsenoside-transforming
bacteria. To identify a microorganism that was capable of converting Rb1 into other ginsenosides,
12 Microbacterium spp. were screened by Hansoo et al. [
21
], and M. trichothecenolyticum was
identified to convert Rb1 into Rd and then into Rh2 based on TLC and HPLC analyses ofreaction
products. Then, Akter et al. [
22
] isolated a gram-positive, aerobic, motile, rod-shaped bacterial
strain (MAH-16T) from a soil sample of a vegetable garden and identified it as a member
of the genus Paenibacillus barengoltzii SAFN-016T according to the 16S rRNA gene sequence
comparisons, which might be responsible for the biosynthesis of ginsenoside Rd from major
ginsenoside Rb1. Later, they also isolated a novel, gram-positive, and ginsenoside-converting
bacterium (MAHUQ-46T) from forest soil, which was closely related to Paenibacillus pinihumi
S23T (97.3% similarity) [
23
]. Furthermore, a Gram-negative, strictly aerobic, non-spore-forming,
and rod-shaped bacterial strain (FW-6T) was isolated from a freshwater sample and displayed
β-glucosidase activity that could transform ginsenoside Rb1 to Rd [24].
There are various microorganisms in the ecological environment of plants; some are
attached to the surfaces of plants, while others live in the plants. Endophytes are fungi or
Biomolecules 2022,12, 512 6 of 34
bacteria commonly found in higher plants that live in the tissues and organs of healthy
plants for some (or all) of their stages. Previous research focused on microorganisms that
attached to plant surfaces and the rhizosphere, but the study of endophytes in plants was
fledgling. An endophytic bacterium, G9y, with the ability to specifically convert ginsenoside
Rc to Rd, was isolated from Panax quinquefolius; the transformation mechanism might be
related to the production of
α
-L-arabinofuranosidase, which specifically hydrolyzes the
terminal arabinofuranosyl moieties at the C-20 position of ginsenoside Rc [
25
]. Ginsenoside
Rc was completely converted to Rd by bacterium G9y within 25 h after inoculation under
the optimized conditions of pH 7.0 and 45 ◦C.
2.2.3. Gut Microbiota and Food Microorganisms
Gut microbiota mainly function in the biotransformation of prototype ginsenosides
into rare bioactive metabolites. When incubated anaerobically with pooled gut bacteria,
including human gut bacteria [
26
], Leuconostoc mesenteroides DC102 [
27
], Lactobacillus par-
alimentarius [
28
], and probiotics [
29
], Rb1 generated five metabolites, namely Rd, F2, CK,
and the rare gypenosides XVII (G-XVII) and LXXV (G-LXXV). Biocatalytic methods using
probiotic enzymes for producing deglycosylated ginsenosides, such as Rd, have a (growing)
role in the functional food industry. Lactobacillus rhamnosus GG, one of the most well-known
probiotic bacteria, could be successfully used to convert ginsenoside Rb1 into Rd at the
pH 6.0 and 40
◦
C [
30
]. Dekkera anomala YAE-1 strain separated from “airag” (Mongolian
fermented mare’s milk) could produce
β
-glucosidase and has shown great capacity in
converting ginsenoside Rb1 to Rd at 40 ◦C, pH 5.0 [31].
3. Pharmacological Activity
Ginsenoside Rd is known for its beneficial pharmacological activities. To date, ex-
tensive studies of
in vitro
cell biology and
in vivo
animal models have demonstrated that
ginsenoside Rd offers potential anti-cancer, anti-diabetic, anti-inflammatory, neuroprotec-
tive, cardioprotective, ischemic stroke, immunological, and other pharmacological activities.
In this section, we summarize recent studies on various health-promoting activities of gin-
senoside Rd to provide a systematic summary and analysis of the pharmacological effects
and the potential molecular mechanisms.
3.1. Anti-Cancer
The promising anti-cancer activity of ginsenoside Rd has been identified in various
types of cell lines and animal models, including gastric cancer, colorectal cancer, lung cancer,
breast cancer, glioblastoma, etc. (Table 2). The underlying anti-cancer mechanisms of gin-
senoside Rd are shown in Figure 2. Ginsenoside Rd significantly inhibits cell proliferation
and induces cell cycle arrest and cell apoptosis by increasing the expression of caspase-3,
caspase-9, and the ratio of Bax/Bcl-2 in human gastric cancer [
33
], cervical cancer Hela
cells [
34
], and human glioma U251 cells [
35
]. The possible mechanisms of Rd inhibiting
glioma cells might be related to inhibition of telomerase activity by downregulating human
telomerase catalytic subunit (hTERT) expressions at both mRNA and protein levels [
35
].
Moreover, it was reported that Rd reduced the proliferation and migration of glioblastoma
cells by upregulating the tumor suppressor miR-144-5p and downregulating its target
toll-like receptor 2 [
36
]. Lee et al. [
37
] identified fourteen proteins contributing to cell
growth inhibition after ginsenoside Rd treatment in HT29 through two-dimensional gel
electrophoreses, MALDI-TOF and TOF-MS, including proteins associated with mitosis
(such as stathmin 1, microtubule-associated protein RP/EB family, stratifin) and associated
with apoptosis (Rho GDP dissociation inhibitor, tropomyosin 1, annexin 5). The combi-
nation of combretastatin A4 phosphate (CA4P), a vascular disrupting agent, and Rd, had
synergistic anti-tumor effects in hepatocellular carcinoma, which the mechanism might
be related to the inhibition of HIF-1
α
via PI3K/AKT/mTOR signaling pathway [
38
]. The
divalent cation–selective channel transient receptor potential melastatin 7 (TRPM7) channel
was shown to affect the proliferation of some types of cancer cells. Several studies reported
Biomolecules 2022,12, 512 7 of 34
that ginsenoside Rd inhibited the proliferation and survival of gastric and breast cancer
cells by inhibiting TRPM7 channel activity [
39
,
40
]. Moreover, ginsenoside Rd significantly
inhibited metastasis in the human hepatocellular carcinoma, colorectal cancer, and breast
cancer [
41
–
43
]. Research by Wang et al. [
43
] showed that Rd treatment attenuated breast
cancer metastasis in part through derepressing miR-18a-mediated Smad2 expression regu-
lation. A blockade of angiogenesis was an important approach for cancer treatment and
prevention; thus, some studies investigated the effects of ginsenoside Rd on angiogenesis,
in vitro
and
in vivo
. Results demonstrated that Rd inhibited VEGF-induced migration, tube
formation, and proliferation of primary cultured human umbilical vascular endothelial
cells (HUVECs) dose-dependently [
44
]. Furthermore, Rd normalized the structure of tumor
vessels, and improved the anti-tumor effect of 5- FU in xenograft mice [
45
]. Clinical drug
resistance to chemotherapy is always considered a major obstacle in the successful treat-
ment of cancer. Notably, ginsenoside Rd was reported to reverse doxorubicin resistance in
MCF-7/ADR cells through downregulating the multidrug resistance 1 (MDR1) protein [
46
].
In addition, Rd could overcome cisplatin resistance in NSCLC by downregulating the
nuclear factor erythroid 2-related factor 2 (NRF2) pathway [47].
Manipulation of gut microbiota composition through the treatment of prebiotics could
be a novel preventive measure against cancer development. Interestingly, Rd exerted
anti-cancer effects by holistically reinstating mucosal architecture, improving mucosal
immunity, promoting beneficial bacteria, and downregulating cancer–cachexia associated
bacteria [48].
Biomolecules2022,12,xFORPEERREVIEW8of47
amajorobstacleinthesuccessfultreatmentofcancer.Notably,ginsenosideRdwasre‐
portedtoreversedoxorubicinresistanceinMCF‐7/ADRcellsthroughdownregulatingthe
multidrugresistance1(MDR1)protein[46].Inaddition,Rdcouldovercomecisplatinre‐
sistanceinNSCLCbydownregulatingthenuclearfactorerythroid2‐relatedfactor2
(NRF2)pathway[47].
Figure2.Anti‐cancermechanismofginsenosideRd.“↓”meansdownregulation,“↑”means
upregulation.
Manipulationofgutmicrobiotacompositionthroughthetreatmentofprebiotics
couldbeanovelpreventivemeasureagainstcancerdevelopment.Interestingly,Rdex‐
ertedanti‐cancereffectsbyholisticallyreinstatingmucosalarchitecture,improvingmu‐
cosalimmunity,promotingbeneficialbacteria,anddownregulatingcancer–cachexiaas‐
sociatedbacteria[48].
Figure 2.
Anti-cancer mechanism of ginsenoside Rd. “
↓
” means downregulation, “
↑
” means upregu-
lation.
Biomolecules 2022,12, 512 8 of 34
Table 2. Anti-cancer and anti-diabetic effects and the molecular mechanisms of Rb.
Anti-Cancer
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Cervical cancer Cell lines: HeLa In vitro: IC50 = 150.5 ±0.8 µg/mL (48 h) Inhibited proliferation and induced cell
apoptosis
Bcl-2↓, Bax↑, mitochondrial transmembrane potential↓,
caspase-3↑[34] 2006
Glioblastoma
Cell lines: U251 In vitro: IC50 = 88.89 µM (24 h); IC50 = 13.20
µM (28 h); IC50 = 9.55 µM (72 h)
Inhibited proliferation, promoted cell
apoptosis, enhanced the expression of
telomerase
caspase-3↑, Bcl-2↓, hTERT↓[35] 2019
Cell lines: U251, H4 (HTB148), U87 MG
(HTB-14) cells, NHA In vitro: Rd (100, 200 µM) Reduced proliferation and migration miR-144-5p↑[36] 2020
Gastric cancer
Cell lines: SGC-7901Cell lines: MKN-45
In vitro: IC50 = 86.96 ±0.23 µg/mL
(SGC-7901, 48 h) and 71.70 ±2.16 µg/mL
(MKN-45, 48 h)
Inhibited proliferation, induced apoptosis
and cell cycle arrest at G0/G1 phase Cyclin D1↓, caspase-3↑, caspase-9↑, Bax/Bcl-2↑[33] 2020
Cell lines: AGS, MCF-7 In vitro: IC50 =131.2 µM (AGS)
IC50 = 154.3 µM (MCF-7) Inhibited proliferation TRPM7 channel activity↓[40] 2013
Liver cancer
Cell lines: HepG2 In vitro: EC50 = 18.26 µMCombination of CA4P and Rd inhibited
proliferation and induced apoptosis HIF-1α↓, PI3K/AKT/mTOR↓[38] 2021
Cell lines: HepG2 In vitro: IC50 = 256.3 µM (24 h) and 172 µM
(48 h) Inhibited migration and invasion MMP↓, MAPK↓[41] 2012
Colorectal cancer
Cell lines: HT29 In vitro: IC50 = 277 µg/mL (48 h) Inhibited proliferation
caspase 3↑, stathmin 1c, PCNA↓, rho GDP dissociation
inhibitor (GDI) alpha↓, reticulocalbin 1 precursor↓,
nudix hydrolase NUDT5↓, microtubule-associated
protein RP/EB family↓, proteasome β6 subunit↓,
tyrosine 3/tryptophan 5-monooxygenase activation
protein, epsilon↓, tropomyosin 1 (α)↑, glutathione
S-transferase-P1↑, annexin 5↑, Nm23 protein↑,
tropomodulin 3↑, and stratifin ↑
[37] 2009
Cell lines: HT29 and SW620 In vitro: 0, 10, 50, 100 µM (72 h) Inhibited metastasis Bound to EGFR with a high binding affinity, stemness-
and EMT-related genes↓[42] 2019
Cell lines: HUVEC animals: LoVo
xenograft BALB/C mice
In vitro: Rd (2, 10, 50 µM
In vivo: SMI (10 mL/kg/day, 13 days)
Suppressed neovascularization in tumors,
normalized the structure of tumor vessels,
and improved the anti-tumor effect of 5-FU
/ [45] 2019
Animals: heterozygous
C57BL/6J-ApcMin/+ mice In vivo: Rd (20 mg/kg, 8 weeks)
suppressed cancer-promoting signaling
markers, reduced the size and the number
of the polyps, and improved intestinal
barrier
iNOS↓, STAT3/pSTAT3↓, Src/pSrc↓, reinstated
mucosal architecture, improved mucosal immunity,
promoted beneficial bacteria, cancer cachexia
associated bacteria↓
[48] 2017
Biomolecules 2022,12, 512 9 of 34
Table 2. Cont.
Anti-Cancer
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Breast cancer
Cell lines: HEK293, MDA-MB-231,
AU565, and T47D In vitro: Rd (100–400 µM) Suppressed the viability of
TRPM7-expressing breast cancer cells S phase↑, G0/G1 phase↓[39] 2020
Cell lines: AGS, MCF-7 In vitro: IC50 = 131.2 µM (AGS) and 154.3
µM (MCF-7)
Inhibited proliferation, induced cell
apoptosis TRPM7 channel activity↓[40] 2013
Cell lines: 4T1, MDA-MB-231 In vitro: Rd (50, 100, 150 µM, 72 h) Suppressed cell migration and invasion miR-18a-mediated Smad2↓[41] 2016
Cell lines: HUVECs, MDA-MB-231 In vitro: Rd (5, 10, 25, 50 µM)
Inhibited VEGF-induced migration, tube
formation and proliferation of HUVECs,
Inhibited proliferation and induced
apoptosis
AKT/mTOR/P70S6↓[42] 2017
Cell lines: MCF-7, MCF-7/ADR In vitro: Rd (10, 100 µg/mL, 24 h) Reversed doxorubicin resistance in
MCF-7/ADR cells MDR1 protein↓[44] 2010
Lung cancer Cell lines: A549 In vitro: IC50 = 246.4 µM (24 h)
IC50 = 149.0 µM (48 h) IC50 = 93.7 µM (72 h)
Inhibited proliferation, induced G0/G1
phase arrest, reversed cisplatin resistance NRF2 pathway↓[47] 2019
Anti-diabetic
Diabetes
Animals: postnatal day 1 SD rats In vivo: Rd (5, 10, 20, 50 µM) Ameliorated the cell viability of
MG-treated astrocytes Improved insulin signaling and inhibited apoptosis [49] 2014
Cell lines: human pancreatic islets In vitro: Rd (0.1,1,10 µM, 72 h)
Inhibited the progress of death of cultured
human pancreatic islets, no effects on
glucose-induced insulin and C-peptide
stimulation secretion
Apoptosis of the islet cells↓, Bax↓, Bcl2↑, and
caspase-3↓[50] 2019
Animals: type-2 diabetic db/db mice In vivo: GS-E3D (100 or 250 mg/kg/d, oral, 6
weeks) Renal protective roles ROS↓[51] 2021
Diabetic
retinopathy (DR)
Cell lines: HUVEC
Animals: STZ-induced diabetic mouse
model
In vitro: Rd (1, 3, 10, 30 µM, 24 h)
In vivo: Rd (100 mg/kg, 1 month)
Ameliorated diabetes-driven vascular
damage, modulated oxidative stress and
apoptosis
AMPK↑, SIRT1↑, AMPK/SIRT1 interaction↑[52] 2022
“/” means not mentioned, “↑” means upregulation, “↓” means downregulation.
Biomolecules 2022,12, 512 10 of 34
3.2. Anti-Diabetic
Diabetes mellitus is characterized by chronic hyperglycemia, which also results in
the abnormal accumulation of methylglyoxal (MG, one of the most reactive advanced
glycation end-product precursors) and induces neuronal cell death in the central nervous
system. Ginsenoside Rd and Rh2 were shown to ameliorate the cell viability of MG-treated
astrocytes and improve insulin signaling, indicating that Rd and Rh2 might have thera-
peutic potential in treating diabetes-induced neurodegeneration [
49
]. Kaviani et al. [
50
]
evaluated the effects of ginsenoside Rd on the apoptosis-associated cell death in human
pancreatic islets, and results showed that Rd inhibited the progress of death of cultured
human pancreatic islets by diminishing the apoptosis of the islet cells. Moreover, Jung
et al. [
51
] developed a new pectin lyase-modified ginseng (GS-E3D), with enhanced ginseno-
side Rd content, which had a potent protective role in diabetes-induced renal dysfunction
through antioxidative and antiapoptotic activities. Diabetic retinopathy (DR) is a complex
complication of diabetes that can lead to blindness. A recent report demonstrated that
ginsenoside Rd ameliorated diabetes-driven vascular damage through enhancement of
AMPK/SIRT1 interaction, which supported the potential vascular protective evidence of
Rd for early DR [52] (Table 2).
3.3. Anti-Inflammatory and Antioxidative
Inflammatory response is a complex network composed of multiple mediators, cells,
and pathways, which is involved in the occurrence and development of various diseases,
such as cancer, atherosclerosis, and neurodegenerative diseases. Ginsenoside Rd exhib-
ited significant anti-inflammatory activities against many inflammatory diseases, such as
chronic hepatitis [
53
], neuroinflammation [
54
], osteoarthritis [
55
], and gastritis [
56
], through
the downregulation of inducible nitric-oxide synthase (iNOS) and COX-2 by inhibiting
NF-
κ
B, furthering the inhibition of the production of NO and PGE2 [
57
,
58
] (Table 3). How-
ever, recent studies have strengthened the understanding of the mechanistic implications
at molecular and cellular levels. The anti-inflammatory mechanism of ginsenoside Rd is
shown in Figure 3.
Biomolecules2022,12,xFORPEERREVIEW17of47
Biomolecules2022,12,x.https://doi.org/10.3390/xxxxxwww.mdpi.com/journal/biomolecules
Figure3.Anti‐inflammatorymechanismofginsenosideRd.“↓”meansdownregulation.
GinsenosideRdamelioratedcolitisbyinducingp62‐drivenmitophagy‐mediated
NLRP3inflammasomeinactivationandupregulatingofAMPK/ULK1signalingpathway
inDSS‐inducedmurinecolitismodel[59].Moreover,ginsenosideRdattenuatedthein‐
flammatoryresponseinratswithTNBS‐inducedrelapsingcolitisandrecurrentulcerative
colitisviamodulatingp38andJNKsignalingpathways,inhibitingneutrophilinfiltration
andpromotingtheantioxidantcapacity[60,61].ArecentstudyevaluatedtheutilityofRd
ingastrointestinalmucosalregenerationandclarifiedthatRdcouldstimulatetheprolif‐
erationanddifferentiationofendogenousintestinalstemcellsandimproverecoveryof
intestinalfunctioninaratmodelofinflammatoryboweldisease(IBD)byincreasingthe
expressionlevelsofBmi,CDX‐2,andMsi‐1[62].Inaddition,ginsenosideRdand
bifidobacterial‐fermentedethanol‐extractedredginsengcouldalleviateallergicrhinitisby
suppressingIgE,IL‐4,IL‐5,andIL‐13expressionandrestoringthecompositionofgutmi‐
crobiota[63].Zhangetal.[64,65]reportedthatginsenosideRdsignificantlyinhibitedthe
productionofpro‐inflammatorycytokinesandmediatorsincarrageenan‐inducedratpaw
edema;thedetailedmechanismsmightberelatedtoreducingtheinflammatorycellinfil‐
trationintoinflammatorysites,inhibitingthetissuelipidperoxidationandincreasingthe
antioxidantenzymeactivitiesthroughdownregulationofNF‐κBactivation.
Additionally,oxidativestress‐inducedcelldamagehasbeenimplicatedinavariety
ofdisease,suchasaging,neurodegenerativedisordersandcertainchronicdiseases.Gin‐
senosideRdcouldbeconsideredapotentialantioxidantagentforprolongingthelifespan
insenescence‐acceleratedmiceandC.elegans[66,67].Moreover,ginsenosideRdwasre‐
portedtohaveananti‐oxidativeeffectbyenhancingglutathionelevelsinH4IIEcellsvia
NF‐κB‐dependentγ‐glutamylcysteineligaseinduction[69].Yeandco‐workersinvesti‐
Figure 3. Anti-inflammatory mechanism of ginsenoside Rd. “↓” means downregulation.
Biomolecules 2022,12, 512 11 of 34
Table 3. Anti-inflammatory and antioxidative effects and the molecular mechanisms of Rd.
Anti-Inflammatory
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Chronic hepatitis Cell lines: HepG2 In vitro: Rd (IC50 = 12.05 ±0.82 µM) Anti-inflammatory activity NF-KB↓, iNOS↓, COX-2↓[53] 2012
Neuroinflammation Cell lines: mouse primary neuron-glia
Animals: pregnant OF1/SPF mice In vivo: Rd (1, 10, 50 µM) Protected dopaminergic neurons against
LPS-neurotoxicity iNOS↓, COX-2↓, iNOS↓, PGE2↓[54] 2007
Osteoarthritis Cell lines: S12 In vitro: Rd (100 µg/mL) Exerted a protective effect against the
cartilage degradation of OA p-p38↓, MMP3↓[55] 2009
Gastritis
Animals: ethanol- or
indomethacin-induced gastric mucosal
lesions in rat model
In vivo: Rd (100 mg/kg)
Showed gastroprotective effects on ethanol-
and indomethacin-induced gastric mucosal
lesions
/ [56] 2007
Colitis
Animals: DSS-induced murine colitis
model In vivo: Rd (10, 20, 40 mg/kg)
Ameliorated DSS-induced colitis, inhibited
inflammatory cell recruitment into colonic
tissue
p62-driven mitophagy-mediated NLRP3
inflammasome↓,
AMPK/ULK1↑
[59] 2018
Animals: TNBS-induced ulcerative
colitis rat model In vivo: Rd (10, 20, 40 mg/kg/d, orally
Against TNBS-induced recurrent ulcerative
colitis and increased superoxide dismutase
and glutathione peroxidase activities
Inhibited neutrophil infiltration and promoted the
antioxidant capacity of the damaged colonic tissue [60] 2012
Animals: TNBS-induced ulcerative
colitis rat model In vivo: Rd (10, 20, 40 mg/kg/d, 7 days) Attenuated the inflammatory response to
TNBS-induced relapsing colitis
MPO↓, proinflammatory cytokine TNF-α, IL-1β, and
IL-6↓, p-p38↓, JNK↓[61] 2012
Inflammatory bowel
diseases(IBD)
Animals: indomethacin-induced IBD rat
model In vivo: Rd (10, 20, 40 mg/kg, 7 days)
Stimulated the proliferation and
differentiation of endogenous intestinal
stem cells in IBD model rats, improved
recovery of intestinal function
Bmi, CDX-2, and Msi-1↑[62] 2020
Allergic rhinitis Cell lines: RBL-2H3Animals:
ovalbumin-induced AR mice model In vivo: Rd (10 µM, 18 h) Alleviated ovalbumin-induced allergic
rhinitis in mice
IgE, IL-4, IL-5, and IL-13↓, restored the composition of
gut microbiota [63] 2019
Inflammatory
Cell lines: RAW264.7Animals: ICR
mouse
In vitro: LPS (5 mg/kg) + Rd (2, 10,
50 mg/kg) Anti-inflammatory effects NF-kB↓, iNOS↓, COX-2↓, NO↓, PGE2↓[57] 2013
Cell lines: HepG2 In vitro: Rd (IC50 = 3.47 µM) Suppressed inflammatory responses NF-κB↓, COX-2↓and iNOS↓[58] 2014
Animals: carrageenan-induced hind paw
edema rat model In vivo: Rd (12.5, 25, 50 mg/kg, i.m.) Anti-inflammatory effects against
carrageenan-induced edema NF-kB↓[64] 2012
Animals: carrageenan -induced rat paw
edema rat model In vivo: Rd (12.5, 25, 50 mg/kg)
Reduced the inflammatory cell infiltration
into inflammatory sites, inhibited the tissue
lipid peroxidation, increased the
antioxidant enzyme activities, and
suppressed the proinflammatory enzyme
expressions
NF-κB↓, p-ERK↓, p- JNK↓[65] 2013
Biomolecules 2022,12, 512 12 of 34
Table 3. Cont.
Anti-Inflammatory
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Antioxidative
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Antioxidative
Animals: senescence-accelerated mice
(SAM) of 10 months In vivo: Rd (1 or 5 mg/kg/d, 30 days) Attenuated the oxidative damage and
enhanced the antioxidative defense system Regulated the GSH/GSSG redox status [66] 2004
Animals: synchronized L4 larvae worms In vivo: TG (10 µg/mL)
Has antiaging effects and only Rd
prolonged the lifespan of C. elegans to
levels comparable to total ginsenoside (TG)
Via lipid metabolism and activating the stress response
signaling pathway [67] 2021
Cell lines: PC12 In vitro: Rd (1, 10 µM) Antioxidative properties ROS↓, MDA↓, SOD↑, GSH-Px↑, stabilized the
mitochondrial membrane potential [68] 2008
Cell lines: H4IIE In vitro: Rd (1–30 µg/mL)
Antioxidative effects; increased both
cellular glutathione (GSH) content and the
protein level of γ-glutamylcysteine ligase
heavy chain
p65↑via NF-κB-dependent γ-glutamylcysteine ligase
induction [69] 2007
“/” means not mentioned, “↑” means upregulation, “↓” means downregulation.
Biomolecules 2022,12, 512 13 of 34
Ginsenoside Rd ameliorated colitis by inducing p62-driven mitophagy-mediated
NLRP3 inflammasome inactivation and upregulating of AMPK/ULK1 signaling pathway
in DSS-induced murine colitis model [
59
]. Moreover, ginsenoside Rd attenuated the
inflammatory response in rats with TNBS-induced relapsing colitis and recurrent ulcerative
colitis via modulating p38 and JNK signaling pathways, inhibiting neutrophil infiltration
and promoting the antioxidant capacity [
60
,
61
]. A recent study evaluated the utility of Rd in
gastrointestinal mucosal regeneration and clarified that Rd could stimulate the proliferation
and differentiation of endogenous intestinal stem cells and improve recovery of intestinal
function in a rat model of inflammatory bowel disease (IBD) by increasing the expression
levels of Bmi, CDX-2, and Msi-1 [
62
]. In addition, ginsenoside Rd and bifidobacterial-
fermented ethanol-extracted red ginseng could alleviate allergic rhinitis by suppressing
IgE, IL-4, IL-5, and IL-13 expression and restoring the composition of gut microbiota [
63
].
Zhang et al. [
64
,
65
] reported that ginsenoside Rd significantly inhibited the production of
pro-inflammatory cytokines and mediators in carrageenan-induced rat paw edema; the
detailed mechanisms might be related to reducing the inflammatory cell infiltration into
inflammatory sites, inhibiting the tissue lipid peroxidation and increasing the antioxidant
enzyme activities through downregulation of NF-κB activation.
Additionally, oxidative stress-induced cell damage has been implicated in a variety of
disease, such as aging, neurodegenerative disorders and certain chronic diseases. Ginseno-
side Rd could be considered a potential antioxidant agent for prolonging the lifespan in
senescence-accelerated mice and C. elegans [
66
,
67
]. Moreover, ginsenoside Rd was reported
to have an anti-oxidative effect by enhancing glutathione levels in H4IIE cells via NF-
κ
B-
dependent
γ
-glutamylcysteine ligase induction [
69
]. Ye and co-workers investigated the
protective role of ginsenoside Rd against the cytotoxicity in PC12 cell lines induced by
exposure to hydrogen peroxide, indicating the potential neuroprotective effects [68].
3.4. Cognition and Neuroprotection
Various ginseng species and ginsenosides have been documented to possess therapeu-
tic effects in many central nervous system (CNS) ailments, for instance, Alzheimer’s disease,
Parkinson’s disease, spinal cord injury, depression, and other cognitive impairment. The
protective effects could be ascribed to reducing neuroinflammation, improving oxidative
stress, regulating neurotransmitter release, and promoting nerve regeneration. Recent
studies have shown that ginsenoside Rd could be a promising natural neuroprotective
agent [
4
]. The current review summarizes the recent progress in neuroprotective effects of
ginsenoside Rd in detail (Table 4, Figure 4).
Alzheimer’s disease (AD), is a neurodegenerative disease characterized by the so-
phisticated and unknown pathogenesis. Currently, the main popular hypotheses include
neuronal dysfunction triggered by deposition of amyloid
β
(A
β
) proteins, neurofibrillary
tangles triggered by hyperphosphorylation of tau protein, and cholinergic nerve degen-
eration [
70
]. Several studies examined the neuroprotective effects of Rd against neuronal
insults in A
β25–35
or A
β1–40
induced AD rat models by ameliorating oxidative stress, allevi-
ating the inflammation and reducing neuronal apoptosis [
71
,
72
]. Rd could also improve
learning and memory ability in A
β
-protein precursor (APP) transgenic mice through in-
hibiting the transcription activity of NF-
κ
B [
73
]. Furthermore, ginsenoside Rd attenuated
A
β
-induced pathological tau phosphorylation by altering the functional balance of GSK-
3
β
and PP-2A in A
β
-treated cortical neurons and in A
β1–40
induced rat model and APP
transgenic mice model [
74
]. A deficiency of the neurotransmitter acetylcholine (ACh) is
also the major characteristic of Alzheimer’s disease. Results by Kim revealed that Re and
Rd effectively induced the expression of cholinergic markers ChAT/VAChT genes and
elevated ACh in Neuro-2a cells, as well as played an important role in neuronal differ-
entiation and the nerve growth factor (NGF)-TrkA signaling pathway [
75
]. Ginsenoside
Rd reduced OA-induced neurotoxicity and tau hyperphosphorylation in OA induced rat
model (10 mg/kg) or in cultured cortical neurons (2.5 or 5
µ
M for 12 h) by enhancing
the activities of protein phosphatase 2A (PP-2A) indicating that Rd might be a potential
Biomolecules 2022,12, 512 14 of 34
preventive drug candidate for AD and other tau pathology-related neuronal degenerative
diseases [
76
]. Another recent research documented the protective effects of Rd against
ovariectomy rat model. Rd enhanced learning and memory function of ovariectomy rats
by increasing levels of sAPP
α
in the hippocampi, reducing extracellular A
β
and activating
estrogen-like activity [77].
Biomolecules2022,12,xFORPEERREVIEW20of47
Figure4.NeuroprotectivemechanismofginsenosideRd.“↓”meansdownregulation,“↑”means
upregulation.
Figure 4.
Neuroprotective mechanism of ginsenoside Rd. “
↓
” means downregulation, “
↑
” means
upregulation.
Recent findings highlighted the efficacy of ginsenoside Rd as neuroprotective com-
pounds for Parkinson’s disease (PD) prevention and treatment through reducing oxidative
stress, improving mitochondrial integrity and functions, and inhibiting apoptosis [
78
–
80
].
As a potential neuroprotective agent, ginsenoside Rd exhibited anti-neurotoxicity effect
on various neurotoxic injury responses induced by Pb, trimethyltin (TMT), or kainic acid
(KA) [
81
–
83
]. Cong et al. [
84
] evaluated the neuroprotective effects of ginsenoside Rd
in a rat model of spinal cord injury (SCI), and the results demonstrated that Rd (25 and
50 mg/kg) significantly improved the locomotor function of rats after SCI through re-
versing the redox-state imbalance, inhibiting the inflammatory response and apoptosis in
the spinal cord tissue. Another study investigated the protective effects of Rd on spinal
cord mitochondrial dysfunction by regulating mitochondrial permeability transition pore
formation and cytochrome c release [85].
Additionally, several recent studies focused on the effects of stress-related disorders of
Rd and other protopanaxatriol-type ginsenosides. Sustained stress has been considered
a risk factor for human ailments, including depression, anxiety, and cognitive dysfunc-
tion. Brain-derived neurotrophic factor (BDNF), a neurotrophin, is crucial to the survival,
Biomolecules 2022,12, 512 15 of 34
growth, and maintenance of neurons involved in emotional and cognitive function in brain.
Results of Han et al. [
86
] showed that Rd mitigated anxiety/depression, colitis and gut dys-
biosis by regulating NF-
κ
B-mediated BDNF expression. Moreover, Rd improved cognitive
impairment in chronic restraint stress mice by mitigating oxidative stress and inflam-
mation, while upregulating the hippocampal BDNF-mediated cAMP-reflecting element
binding (CREB) protein signaling pathway [
87
]. Moreover, Rd ameliorated impairment of
learning and memory behaviors in chronic cerebral hypoperfusion (CCH) mice through
regulation of BDNF by reestablishing the balance between Ac-H3 and HDAC2 [
88
]. The
occurrence of metabolic and psychiatric disorders may be caused by higher levels of gluco-
corticoids. Ginsenoside Rd could inhibit adrenocorticotrophic hormone (ACTH)-induced
corticosterone production through blockading the MC2R-cAMP/PKA/CREB pathway
in adrenocortical cells, which might represent an important therapeutic option for the
treatment of stress-related disorders [
89
]. Ginsenoside Rd also exerted neuroprotective
effects after noise-induced auditory system damage through a mechanism involving the
SIRT1/PGC-1
α
signaling pathway, which could be an attractive pharmacological target for
the development of novel drugs for noise-induced hearing loss treatment [90].
The effect of ginsenoside Rd on inducing neural stem cells differentiation remains to
be obscure. One study showed that ginsenoside Rd enhanced the proliferation but did not
affect the differentiation of neural stem cells in adult rats and cultured neural stem cells [
91
],
however, another study illustrated that Rd promoted the differentiation of neurospheres
into astrocytes in a dose-dependent manner [
92
]. PC12 cells respond to nerve growth
factor (NGF) and could be serve as a model for neuronal cells. Wu et al. [
93
] provided
the first evidence that Rd promoted the neurite outgrowth of PC12 cells by upregulating
GAP-43 expression via ERK- and ARK-dependent signaling pathways. Furthermore,
Rd inhibited glutamate-induced Ca
2+
entry in a concentration-dependent manner and
prevented glutamate-induced apoptosis in rat cortical neurons, which provided potential
evidence of Rd as a new neuroprotective drug for the prevention of neuronal apoptosis
and death induced by cerebral ischemia [94].
3.5. Ischemic Stroke
In previous articles, the promising role of ginsenoside Rd on ischemic stroke has been
described [
3
,
95
], the underlying mechanisms include the suppression of oxidative stress
and inflammation, activation of PI3K/AKT pathway, suppression of the NF-
κ
B as well as
reduction of cytochrome c-releasing and apoptosis-inducing factor and so on. Thus, current
review summarized the recent progress of Rd on ischemic stroke from 2015 to 2020 and
focused on the molecular mechanisms underlying the beneficial role of ginsenoside Rd on
ischemic stroke (Table 5).
There are multiple molecular mechanisms of ischemic stroke, of which oxidative DNA
damage can trigger dysfunction and death of brain neurons and eventually lead to poor
outcomes. The endonuclease VIII-like (NEIL) proteins NEIL1, NEIL2, and NEIL3, are major
DNA glycosylases that remove oxidative base lesions. Yang et al. [
96
] investigated the effect
of Rd on the expression of NEILs in the MCAO rat model and found that Rd significantly
upregulated NEIL1 and NEIL3 expressions in both mRNA and protein levels.
Biomolecules 2022,12, 512 16 of 34
Table 4. Neuroprotective effects and the molecular mechanisms of Rd.
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Alzheimer’s disease (AD)
Animals: Aβ1–40 induced AD rat model In vivo: Rd (10, 30 mg/kg/d, 30 days)
Protected cognitive impairment, improved
memory function, alleviated Aβ1–40
induced inflammation
caspase-3↓, apoptosis↓[71] 2012
Cell lines: Aβ25–35 induced primary
hippocampal neurons In vitro: Rd (0.1, 1, 10 µM)
Ameliorated Aβ25–35 induced damage in
primary cultured hippocampal neurons,
inhibited Aβ25–35 induced apoptosis and
oxidative stress, reversed Aβ25–35 induced
alterations
ROS↓, MDA↓, GSH-Px↑,
SOD↑, Bcl-2↑, Bax↓, Cyt c↓, c-caspase-3↓[72] 2015
Animals: APP transgenic mice In vivo: Rd (10 mg/kg) Improved learning and memory ability in
APP transgenic mice NF-KB↓[73] 2015
Cell lines: cortical neurons from mice
E17–18 embryosAnimals: Aβ1–40
induced AD rat model and APP
transgenic mice
In vitro: Rd (2.5, 5 µM, 12 h)
In vivo: Rd (5 mg/kg)
Inhibited OA-induced tau phosphorylation
in vivo and in vitro Altered the functional balance of GSK-3βand PP-2A [74] 2013
Cell lines: Neuro-2a In vitro: Rd (2.5 to 5 µg/mL) Enhanced the expression of cholinergic
markers and neuronal differentiation
ChAT/VAChT↑, ERK and AKT↓; MAP-2↑, p75↑, p21↑,
NGF-induced TrkA↑[75] 2014
Animals: OA induced AD rat model In vivo: Rd (2.5, 5 µM) Protected SD rats and cultured cortical
neurons against OA-induced toxicity
Decreased OA-induced the hyperphosphorylation of
tau by the increase in activities of PP-2A [76] 2011
Animals: ovariectomy (OVX) rat model In vivo: Rd (10 mg/kg, 2 months)
Enhanced learning and memory function
of OVX rats and attenuated cognitive and
memory impairment
α-Secretase and sAPPα↑,β-secretase and Aβ↓,
p-ER-αat Ser118 residue↑[77] 2017
Parkinson’s disease (PD)
Cell lines: SH-SY5Y In vitro: Rd (0.5, 1 µM, 24 h)
Reduced oxidative stress, improved
mitochondrial integrity and functions, and
inhibited apoptosis
Bax/Bcl-2↓, Cyt c↓, caspase-3↓[78] 2017
Cell lines: SH-SY5Y In vitro: Rd (1, 10 µM)
Exerted protective effect on
neurodegenerative diseases, attenuated
MPP+-induced cell death
Oxidative stress↓, mitochondrial function↑and
inhibited MPP+induced ATP depletion, Bax/Bcl-2↓,
Prevented p-AKT downregulation induced by MPP+
treatment
[79] 2015
Cells: CCL4-treated primary
dopaminergic cell cultures In vitro: Rd (1, 5, 10 µM)
Protected dopaminergic neurons against
CCl4-induced neurotoxicity; inhibited both
oxidative stress and inflammation
LDH↓, NO↓, superoxide formation↓[80] 2016
Neurotoxicity
Animals: lead (Pb)-treated old rat model In vivo: Rd (50 mg/kg/d, 7 days) Neuroprotective effects in old rats
following acute Pb exposure IL-1β↓, IL-6↓, TNF-α↓[81] 2013
Cells: TMT-treated hippocampal neurons In vitro: Rd (1–40 µg/mL, 24 h)
Prevented TMT-induced cell apoptosis;
attenuated the tremor seizures and
cognitive decline; reduced neuronal loss
Bcl-2↑, Bcl-2↓, caspase-3↓[82] 2017
Animals: KA-induced ICR mice In vivo: Rd (50 mg/kg) Attenuated the KA-induced lethal toxicity p-ERK↑and p-CREB↓[83] 2003
Biomolecules 2022,12, 512 17 of 34
Table 4. Cont.
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Spinal cord injury (SCI)
Animals: spinal cord injury (SCI) rat
model In vivo: Rd (12.5, 25, 50 mg/kg)
Attenuated SCI-induced secondary injury
through reversing the redox-state
imbalance, inhibiting the inflammatory
response and apoptosis
MAPK↓, MDA↓, GSH and SOD↑, TNF-α, IL-1β↓[84] 2016
Mitochondria isolated from mouse
spinal cord tissues
Animals: male C57BL/6J mice
In vitro: Rd (0.1, 1, 10 µM, 60 s)
In vivo: Rd(10, 50 mg/kg, 7 days)
Protected isolated spinal cord
mitochondria against Ca2+ induced MPT
and cytochrome c release in a
mitochondrial protein kinases-dependent
manner
Ca2+ induced Cyt c↓, intramitochondrial AKT and
ERK↑[85] 2014
Stress-related disorders
Animals: immobilization stress (IS) or
Escherichia coli (E. coli)-treated
anxiety/depression mice model
In vivo: Rd (5 mg/kg/d, oral, 5 days)
Alleviated the IS-induced
anxiety/depression and E. coli-induced
anxiety/depression, colitis, and gut
dysbiosis in mice
Myeloperoxidase activity↓, NF-κB↓, NF-κB+/CD11c+
cell population↓[86] 2020
Animals: CRS induced cognitive
impairment mice model In vivo: Rd (20, 40 mg/kg/d, 28 days) Improved cognitive impairment subjected
to chronic stress
Oxidative stress↓, inflammation↓, hippocampal
BDNF-mediated CREB signaling pathway↑[87] 2020
Animals: chronic cerebral hypoperfusion
(CCH) mice model In vivo: Rd (10, 30 mg/kg/d, 21 days) Ameliorated CCH-induced impairment of
learning and memory behaviors Neuron survival↑, BDNF expression↑[88] 2016
Cell lines: mouse adrenocortical tumor
cell line Y1 In vitro: Rd (2 µM)
Inhibited corticosterone secretion in the
cells and impeded ACTH-induced
corticosterone biosynthesis
cAMP/PKA/CREB signaling pathway↓; attenuated
the induction of MC2R and MRAP by ACTH [89] 2020
Noise-induced hearing loss
(NIHL) Animals: noise-induced guinea pigs In vivo: Rd (30 mg/kg, i.p.)
Exerted neuroprotective effects after
noise-induced auditory system damage;
ameliorated auditory cortex injury
associated with military aviation NIHL
SIRT1/PGC-1αsignaling pathway↑[90] 2020
Neural cells
Cells: neural stem cells
Animals: male SD rats (180–220 g)
In vitro: Rd (0.1, 1, 10, 50 µM)
In vivo: Rd (10, 30 mg/kg)
Had beneficial effects on learning and
memory, promoted the size and number of
neurospheres; but did not affect the
differentiation of neural stem cells into
neurons, astrocytes and oligodendrocytes
/ [91] 2012
Cells: neural stem cells In vitro: Rd (0.1, 1 µM)
Promoted the differentiation of
neurospheres into astrocytes and increased
the production of astrocytes
Number of neurons↓, astrocytes↑[92] 2005
Cell lines: PC12 In vitro: Rd (10 µM) Promoted the neurite outgrowth of PC12
cells GAP-43↑via ERK and ARK signaling pathways [93] 2016
Cells: rat cortical neurons In vitro: Rd (1, 3, 10, 30 µM) Prevented glutamate-induced apoptosis in
rat cortical neurons Inhibited voltage-independent Ca2+ entry [94] 2010
“/” means not mentioned, “↑”means upregulation, “↓”means downregulation.
Biomolecules 2022,12, 512 18 of 34
Table 5. Ischemic stroke, cardiovascular protection, and immunological activities and the molecular mechanisms of Rd.
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Ischemic stroke
Animals: MCAO rat models In vivo: Rd (30 mg/kg) Reduced mtDNA and nDNA damages and
had the neuroprotective function
Survival rate and neurological function↑, cell
apoptosis↓, cleaved caspase-3↓, NEIL1 and NEIL3↑[96] 2016
Cell lines: cortical neurons cells from
embryonic day 18 SD ratsAnimals:
MCAO rat models
In vitro: Rd (1, 3, 10, 30, 100 µM)
In vivo: 10 mg/kg
Neuroprotectant for the treatment of
ischemic stroke; exerted an inhibitive effect
on NMDAR-triggered currents and
sequential excitotoxicity
DAPK1-mediated NR2B phosphorylation↓, calcineurin
activity↓[97] 2020
Cell lines: cortical neuronsAnimals:
MCAO rat models
In vitro: Rd (10 µM)
In vivo: Rd (50 mg/kg)
Improved the behavior score, infarct
volume, and viability of the cultured
neurons after ischemia
Hyperphosphorylation of NR2B subunit↓and
expression levels of NR2B subunit in cell membrane↓[98] 2016
Cells: microglia from P1 newborn SD
rats, BV2, MC3T3-E1
Animals: MCAO rat models
In vitro: Rd (1, 10, 50, 100 µM)
In vivo: 10 mg/kg, i.p.
Improved the outcome of patients with
ischemic stroke
Microglial proteasome activity and sequential
inflammation↓[99] 2016
Animals: MCAO rat models In vivo: Rd (1, 10, 100 µM)
In vivo: 30 mg/kg, i.p.
Attenuated the pathogenesis of cerebral
ischemia-induced BBB damage, suppressed
proteasome-mediated inflammation
Proteasome activity and NF-κB/MMP-9 pathway↓[100] 2020
Cell lines: BV-2
Animals: MCAO rat models
In vitro: Rd (0.1, 1, 10 µM)
In vivo: CPA (4.5, 9 g/kg) Attenuated cerebral injury after stroke NLRP3↓, OGD/R-induced BV-2 cell injury↓,
Drp1-mediated mitochondrial fission↓, Drp1↓[101] 2020
Cardiovascular diseases
Cell lines: A10 embryonic rat thoracic
aortic, rat aorta smooth muscle cells
prepared from rat thoracic aorta
In vitro: Rd (100 µM) Had an effect on cardiovascular diseases
and inhibited Ca2+ entry
Through ROCC and SOCC without effects on VDCC
and Ca2+ release [102] 2006
Cerebrovascular
remodeling
Cell lines: BAVSMCs from rat basilar
arteries
Animals: two-kidney, two-clip (2k2c)
stroke-prone hypertensive rat model
In vitro: Rd(2.5, 5, 10, 20, 40 µM, 48 h)
In vivo: Rd (20 mg in 2 mL saline solution
containing 20% propylene glycol/kg/d)
Attenuated basilar hypertrophic inward
remodeling in 2k2c hypertensive rats
without affecting systemic blood pressure;
attenuated hypertensive cerebrovascular
remodeling
Inhibited voltage-independent Ca2+ entry and
BAVSMC proliferation, but not with VDCC-mediated
Ca2+ entry
[103] 2009
Cell lines: BASMCs from rat basilar
arteries In vivo: Rd (10 µM) Potentiated H2O2-induced cell death and
cell apoptosis Cyt c release↑, caspase-9/caspase-3↑, Bcl-2/Bax↓[104] 2011
Cell lines: RAW264.7
Animals: apolipoprotein E deficient
(ApoE−/−) mice
In vitro, Rd (20 µM)
In vivo: Rd (20 mg/kg/d)
Prevented the development of
atherosclerosis
Through voltage-independent Ca2+ channels, SR-A↓,
ox-LDL↓, cholesterol ↓[105] 2011
Cell lines: ventricular myocytes from the
hearts of male SD rats In vitro: Rd (IC50 = 32.4 ±7.1 µM) Protected the heart and inhibited ICa,L
ICa,L peak amplitude↓, the current-voltage (I-V)
curve↑, changed the steady-state activation curve of
ICa,L and slowed down the recovery of ICa,L from
inactivation
[106] 2015
Cardiac hypertrophy
Cells: rat neonatal cardiac myocytes
(NRCMs) from 24 h old SD ratsAnimal:
C57BL/6 mice
In vitro: Rd (150 µg/mL)
In vivo: Rd (50 µg/kg/d, i.v., 14 days)
Improved cardiac dysfunction and
remodeling induced by pressure overload AKT↓, calcineurin A↓, ERK1/2 and TGF-β1↓[107] 2019
Biomolecules 2022,12, 512 19 of 34
Table 5. Cont.
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Myocardial I/R injury
Cells: neonatal rat cardiomyocytes
(NRCs)
Animals: MI/R injury rat model
In vitro: Rd (10 µM)
In vivo: Rd (50 mg/kg)
Augmented rat cardiac function, reduced
myocardial infarct size, apoptotic cell death
Left ventricular ejection fraction (LVEF)↑,
±dP/dt↑;inhibited caspase-9 and caspase-3, p-AKT
and GSK-3β↑, and Bcl-2/Bax ratio↑
[108] 2013
Cells: neonatal rat cardiomyocyte
(NRCs)
Animals: MI/R injury rat model
In vivo: Rd (50 mg/kg) Improved cardiac function and attenuated
myocardial infarction
Serum creatine kinase, LDH and cTnI↓, Nrf2, HO-1
and NQO1↑[109] 2015
Vascular endothelial
injury
Cell lines: HUVECs, THP-1Animal:
nicotine-administered SD rat model
In vitro: Rd (30 µM, 24 h)
In vivo: Rd (25, 50 mg/kg/d, 4 weeks)
Prevented nicotine-induced cardiovascular
diseases
Vascular endothelial NO signaling↑, platelet
aggregation and vasoconstriction↓, endothelial cell
adhesion↓
[110] 2020
Multiple sclerosis (MS)
Animals: MOG35–55 induced EAE mouse
model In vivo: Rd (40 mg/kg/d, 35 days) Ameliorated clinical severity and improved
histopathology, reduced BBB dysfunction IFN-γ↓, IL-4↑; BDNF and NGF↑[111] 2014
Cells: Mouse bone marrow stem
cellsAnimals: EAE C57BL/6 mice In vivo: 50 µM
Ameliorated the severity of EAE and
attenuated the characteristic signs of
disease; had modulation potential on gut
microbiota in EAE mice
IL-6 and IL-17↓, TGF-βand IL-10↑, modulated
Treg/Th17 imbalance [112] 2020
Guillain–Barré
syndrome (GBS)
Cells: mouse bone marrow stem cells
Animals: P0180–199 induced EAN
mouse model
In vitro: Rd(10, 30, 50 µM)
In vivo: Rd (20, 50, 100 mg/kg, 30 days)
Preventive function on GBS, attenuated
experimental autoimmune neuritis in mice
Modulated monocytes infiltration and macrophage
polarization, regulated monocyte phenotype [113] 2021
Immunosuppressive
Cells: mouse spleen T
lymphocytesAnimals: allo-skin
transplantation rat model
In vivo: Rd (25 mg/kg) Antagonized transplant rejection Th1 cytokines IL-2↓, IFN-γ↓, TNF-α↓, IL-12↓, Th2
cytokine IL-10↑[114] 2012
Immunoadjuvant
Animals: OVA-immunized mouse model In vivo: Rd (25 µg, 2 weeks)
Had immunological adjuvant activity, and
elicited a Th1 and Th2 immune response,
enhanced the Con A-, LPS-, and
OVA-induced splenocyte proliferation
Regulated production and gene expression of Th1
cytokines and Th2 cytokines [115] 2007
Strains: C. albicans strains
Animals: vaccinated BALB/c mice
In vitro: Rd (1 mg/mL)
In vivo: Rd (1 mg/mL, i.p., 10 days)
Protected mice against disseminated
candidiasis and enhanced Th1 immunity
Elicited higher titers of Th1 type antibody and a
Th1-dominant immune response [116] 2013
Anaphylactoid reactions
Cells: RBL-2H3 MCs, mouse peritoneal
mast cells (MPMC) isolated from mouse,
LAD2 cells Animals: ICR male mice
(18–22 g)
In vitro: Rd (0.11, 0.21, 0.42 mM)
In vivo: Rd (10, 20, 40 mg/kg)
Potential allergens, induced the release of
mediators associated with anaphylactoid
reactions
β-hexosaminidase↑, histamine↑, translocation of
phosphatidylserine↑, Ca2+↑[117] 2017
“↑”means upregulation, “↓”means downregulation.
Biomolecules 2022,12, 512 20 of 34
The NMDA receptor (NMDAR) is a major excitatory neurotransmitter in central ner-
vous system, which is involved in the pathological process of central nervous system
diseases such as cerebral infarction, cerebral hemorrhage, ischemic stroke, brain trauma, etc.
A recent study found that Rd could exert an inhibitory effect on NMDAR-triggered currents
and sequential excitotoxicity through mitigation of DAPK1-mediated NR2B phosphoryla-
tion by attenuating calcineurin activity [
97
]. Rd protected ischemia–reperfusion injury (IRI)
models rats and cultured neurons via inhibiting the hyperphosphorylation of NMDAR 2B
subunit (NR2B subunit) and decreasing its expression levels in cell membrane [98].
It was well known that inflammation played an important role in the pathogenesis
of ischemic stroke; however, the detailed mechanism of inflammatory modulation after
ischemic stroke remained elusive. Microglia, the main immune cells in brain, are activated
and subsequently release proinflammatory cytokines and other inflammatory mediators,
worsening the neurologic outcome for stroke patients. Zhang et al. [
99
] demonstrated that
Rd could safely improve the outcome of patients with ischemic stroke and revealed that
administration of Rd in middle cerebral artery occlusion rat models could significantly
inhibit ischemia-induced microglial activation and proteasome activity in microglia. Then,
in 2020, the same research team further illuminated the downstream mechanisms that
Rd was efficient for attenuating the pathogenesis of cerebral ischemia-induced blood–
brain barrier damage by suppressing proteasome-mediated inflammation and sequentially
suppressing NF-
κ
B/MMP-9 pathway [
100
]. Moreover, nod-like receptor protein 3 (NLRP3)
inflammasome plays a key role in mediating inflammatory response in the process of
cardiovascular disorder, diabetes and ischemic stroke. It was reported that the combination
of Panax ginseng and Angelica sinensis treatment attenuated cerebral injury via inhibition
of NLRP3 inflammasomes activation and microglial pyroptosis after stroke, along with
Drp1-mediated mitochondrial fission [101].
3.6. Cardiovascular Protection
A previous study has shown that ginsenoside Rd blocked Ca
2+
influx through receptor-
and store-operated Ca
2+
channels in vascular smooth muscle cells, which might contribute
to the cerebrovascular benefits [
102
] (Table 5). Nowadays, there is growing evidence that
cerebrovascular remodeling is the common pathological basis of hypertension target organ
damage, and circulatory dysfunction. Thus, effective cerebrovascular remodeling reversal
therapy is an important measure to improve the prognosis of patients with hypertension,
atherosclerosis, etc. Guan et al. [
103
] examined the effects of ginsenoside Rd on blood
pressure, cerebrovascular remodeling and Ca
2+
entry in freshly isolated basilar arterial
vascular smooth muscle cells (BAVSMCs). Results showed that the attenuation of hyper-
tensive cerebrovascular remodeling after Rd treatment, which the underlying mechanism
might be associated with inhibition of voltage-independent Ca
2+
entry and basilar artery
smooth muscle cells (BASMCs) proliferation. Later, they investigated whether Rd influ-
enced H
2
O
2
-induced apoptosis in BAVSMC [
104
]. The data strongly provided evidence that
Rd potentiated H
2
O
2
-induced apoptosis of BASMCs through the mitochondria-dependent
pathway. Then, ginsenoside Rd, as a voltage-independent Ca
2+
channels blocker, reduced
ox-LDL uptake and cholesterol accumulation in macrophages via inhibition of scavenger
receptor A activity and expression, suggesting that Rd prevented the development of
atherosclerosis [
105
]. Additionally, Lu et al. [
106
] focused on the effects of Rd on L-type
calcium channel current in isolated rat ventricular myocytes and its potential mechanism
and drew a conclusion that Rd might exert its protective effects via blocking of Ca
2+
channel
in cardiomyocytes.
Cardiac hypertrophy, the gradual compensatory function of chronic stress load, eventu-
ally leads to myocardial ischemia and chronic heart failure. Results from Zhang et al. [
107
]
revealed that ginsenoside Rd improved cardiac dysfunction and remodeling induced by
pressure overload, which was related to the inhibition of protein levels of AKT, calcineurin
A, ERK1/2 and TGF-
β
1. Myocardial ischemia–reperfusion (MI/R) injury refers to the
structural and functional damage of myocardial cells caused by ischemic myocardium after
Biomolecules 2022,12, 512 21 of 34
resuming blood reperfusion; the mechanisms are still diverse and unknown. Rd-mediated
cardioprotective effects against myocardial ischemia/reperfusion were found by both re-
ducing intracellular reactive oxygen species, inhibiting mitochondria-mediated apoptosis
and Ca
2+
influx. Evidence suggested that Rd attenuated myocardial ischemia/reperfusion
injury via inhibition of AKT/GSK-3
β
signaling and mitochondria-dependent apoptotic
pathway in MI/R injury rat model and an
in vitro
neonatal rat cardiomyocyte (NRC)
model [
108
]. Another report showed that Rd protected against MI/R injury as evidenced
by improving cardiac function, decreasing infarct size and levels of serum creatine kinase,
LDH and cTnI via Nrf2/HO-1 signaling, which played a key role in attenuating oxidative
stress [
109
]. A recent study investigated the potential protective efficacy of Rd against
nicotine-induced vascular endothelial cell injury by preserving normal vascular endothelial
NO signaling, suppressing platelet aggregation and vasoconstriction, and by preventing
endothelial cell-monocyte adhesion [110].
3.7. Immunological Activities
Recently, more attention has been paid to the effect of ginsenoside Rd on immune
regulation in many immune-mediated diseases (Table 5). Multiple sclerosis (MS), one
of the most common central nerve demyelinating diseases, is an autoimmune inflamma-
tory disease affecting the central nervous system of the body. Ginsenoside Rd effectively
ameliorated the clinical severity in EAE mice, providing a potential for amelioration of
neuroimmune dysfunction diseases [
111
]. While the underlying mechanism of Rd in in-
hibiting the clinical course of EAE remains unclear. Furthermore, recent study investigated
the potential mechanisms underlying the efficacy of Rd in alleviating the injury of EAE
by modulating inflammation and autoimmunity via the downregulation of related proin-
flammatory cytokines IL-6 and IL-17, upregulation of inhibitory cytokines TGF-
β
and
IL-10, and modulation of Treg/Th17 imbalance [
112
]. Similarly, Guillain–Barrésyndrome
(GBS) is also one of the most common immune-mediated neuropathies, characterized by
demyelination and axonal damage, mainly peripheral nerve demyelination. A recent study
by Ren et al. [
113
] provided the evidence of preventive effect of Rd on GBS by modulat-
ing monocyte subsets conversion and elevating the transcription factors, such as Nr4a1,
through the
in vivo
experimental autoimmune neuritis mice model and
in vitro
mouse
bone marrow stem cells.
Organ transplant rejection, a manifestation of the body’s immune response, seriously
affects the prognosis of patients. It was reported that ginsenoside Rd could effectively
antagonize transplant rejection via regulating the balance of Th1/Th2 type cytokines
secretion, as well as reducing the percentages of CD4+ T cells and CD8+ T cells in the
peripheral blood of rat recipients [
114
]. In parallel, ginsenoside Rd from Panax ginseng
could enhance Th1 immunity, which might qualify Rd as an immunoadjuvant to induce
surface mannan extract to produce a protective antibody [
115
,
116
]. However, it was
noted that ginsenoside Rd and 20(S)-Rg3 isolated from red ginseng were identified as
potential allergens that induced the release of mediators associated with anaphylactoid
reactions [117].
3.8. Others
In addition, ginsenoside Rd was reported to have renal protection, lung protection,
promotion of wound healing and bone differentiation, weight loss and other pharmacologi-
cal activities (Table 6). Yokozawa and coworkers [
118
,
119
] evaluated the protecting effects
of Rd against cisplatin-induced renal injury, a process in which apoptosis played a central
role. Another study demonstrated that Rd possessed a protective function against renal
ischemia/reperfusion injury (IRI) via downregulating M1 macrophage polarization [
120
].
Likewise, the protective effect of Rd on lipopolysaccharide (LPS)-induced acute lung injury
(ALI) was recently investigated to explore the improvement of survival in endotoxemic
mice by inhibiting the PI3K-AKT signaling pathway [121].
Biomolecules 2022,12, 512 22 of 34
Table 6. Other health-beneficial activities and the molecular mechanisms of Rd.
Disease Type Cell Lines/Animal Effective Concentration/Dose Effects Mechanisms of Action Refs. Year
Renal injury
Animals: cisplatin-induced acute renal
failure rat model In vivo: Rd (1, 5 mg/kg/d, 30 days) Decreased the severity of renal injury
induced by cisplatin
MDA↓, blood urea nitrogen↓, Cr↓, urinary excretion of
glucose↓[118] 2000
Cell lines: LLC-PK1 cells cultured with
cisplatin
Animals: cisplatin-induced acute renal
failure rat model
In vitro: Rd (125 µM)
In vivo: Rd (1, 5 mg/kg/d, 30 days)
Ameliorated cisplatin-induced renal injury,
caused restoration of the renal function
DNA fragmentation↓, apoptosis↓, urea nitrogen and
creatinine↓[119] 2001
Cell lines: mouse polarized
macrophagesAnimals: renal IRI mouse
model
In vitro: Rd (10, 20, 50, 100 µg/mL)
In vivo: Rd (10, 20, 50, 100 mg/kg)
Alleviated mouse acute renal
ischemia/reperfusion injury M1 macrophage polarization↓[120] 2016
Acute lung injury (ALI) Animals: LPS-induced ALI mouse model In vivo: Rd (25, 50 mg/kg) Protected mice against LPS-induced ALI;
improved survival in endotoxemic mice PI3K/AKT↓[121] 2021
Small intestinal
transport
Animals: carbachol/BaCl2-induced
accelerated small intestinal transit mouse
model
In vivo: Rd (0.4, 1.0, 2.0 mg/kg)
Ameliorative effects on the
carbachol-induced accelerated small
intestinal transport
Intestinal motility↓, cholinergic nervous system↓[122] 2003
Anti-obesity Animal: high-fat diet-induced obese
mouse model In vivo: Rd (15 mg/kg/d, 23 days) Ameliorated obesity and insulin resistance Cyclic adenosine monophosphate (cAMP)↑[123] 2020
Whitening activity Cell lines: Melan-a cellsAnimal:
zebrafish
In vitro: Rd (10, 20 µM)
Re (20, 40, 80 µM)
FGA (20, 40, 80, 160 µM)
In vivo: FGA (80, 160 µM)
Inhibited melanin biosynthesis AKT↑, ERK↑[124] 2017
Anti-alopecia Cells: HFsAnimals: shaved skin
B57CL/6 mouse model In vivo: Rd and Rb1 (300 mg/kg/d, 35 days) Promoted hair growth p63 expression↑in hair follicles [125] 2012
Anti-osteoporotic Cell lines: MC3T3-E1 In vitro: Rd (10, 20, 40 µM) Stimulated osteoblastic differentiation and
mineralization AMPK/BMP-2/Smad signaling pathways↑[126] 2012
Duchenne muscular
dystrophy (DMD)
Cells: D2325 fibroblasts from a DMD
patient
Animals: mdx5cv mice
In vitro: Rd (5 µM)
In vivo: Rd (10 mg/kg)
Ameliorated some of the skeletal muscle
phenotypes caused by dystrophin
deficiency
FLT3 signaling↑[127] 2020
Wound healing effects Cell lines: KPCs, HDFsAnimal: hairless
wound mice model
In vitro: Rd (0.1, 1, 10 µM)
In vivo: Rd (10 µM, every 2 days, 10 days) Promoted skin regeneration Collagen type 1↑, matrix metalloproteinase-1 (MMP-1)
↓, cAMP-dependent protein kinase pathway↑[128] 2013
Irradiation-induced
damage
Cell lines: rat intestinal epithelial IEC-6
cells In vitro: Rd (2.5, 5, 10, 20, 40 µM, 24 h)
Protected and rescued rat intestinal
epithelial cells from irradiation-induced
apoptosis
Bax/Bcl-xL↓, Cyt c↓, cleaved-caspase-3↓, PI3K/AKT↑,
MEK↓, mitochondria/caspase pathway↓[129] 2008
“↑”means upregulation, “↓”means downregulation.
Biomolecules 2022,12, 512 23 of 34
Ginsenoside Rd also had beneficial effects on weight loss, skin whitening and hair
growth. Ginsenoside Rb1 and Rd were reported as representative compounds for im-
proving the accelerated movement of the small intestine [
122
]. The beneficial effects of
ginsenoside Rd on obesity and insulin resistance were found by Yao and co-workers in 2020,
and its mechanisms were related to upregulation of thermogenesis in a cAMP-dependent
manner [
123
]. Moderate melanogenesis inhibition activity of Rd at 20
µ
M purified from
Panax ginseng berry in in melan-a cells, while floralginsenoside A (FGA) was observed to
display the most potent inhibitory effect, which the potential whitening mechanism might
be related to inhibition of melanin content and tyrosinase activity [
124
]. Moreover, ginseno-
side Rb and Rd were reported to promote cell proliferation in HFs through p63 induction
in follicular keratinocytes, which might be the therapeutic agent for the prevention of hair
loss [
125
]. Kim et al. [
126
] identified ginsenoside Rd as the most active anti-osteoporotic
agents via inducing the differentiation and mineralization of MC3T3-E1 cells through the
activation of the AMPK/BMP-2/Smad signaling pathways. Moreover, ginsenoside Rd
was screened through a Duchenne muscular dystrophy (DMD) hiPSC-derived myoblast
screening platform and identified to significantly ameliorate some of the skeletal muscle
phenotypes caused by dystrophin deficiency [
127
]. Later, the wound-healing effect of the
ginsenoside Rd isolated from ginseng leaves was tested through
in vitro
the keratinocyte
progenitor cells (KPCs), human dermal fibroblasts (HDFs) and animal wound models [
128
].
Ginsenoside Rd was also reported to prevent and rescue rat intestinal epithelial cells from
irradiation-induced apoptosis [129].
4. Pharmacokinetics and Clinical Studies
Researchers have focused on ginsenoside Rd for its bioactivities; however, little is
known about its pharmacokinetic behavior, solubility, bioavailability, safety, and clinical
efficacies. A systematic and comprehensive understanding of Rd is not only necessary to
further study its pharmacological actions and protective mechanisms, but to also provide a
scientific basis for the clinical application of Rd and the development of new dosage forms.
This review provides a profile of the pharmacokinetics, metabolism, safety, tolerance, and
clinical efficacy of Rd (Table 7).
4.1. Preclinical Studies
Previous literature reviewed the validity of Rd as a neuroprotective agent for acute
ischemic stroke, including the pharmacokinetics, pharmacodynamics, clinical efficacy,
safety, and putative therapeutic mechanisms of Rd [
95
]. In fact, in 2007, Wang et al. [
130
]
first reported on the pharmacokinetic studies of ginsenoside Rd in dog plasma by liquid
chromatography–mass spectrometry after solid-phase extraction. Sun et al. [
131
] ana-
lyzed the pharmacokinetic, tissue distribution, and excretion of ginsenoside Rd in rodents
performed by HPLC and radioactive tracer assays. Results showed that intravascular
administration with 20, 50, or 150 mg/kg Rd was rapidly distributed to various tissues; the
dynamic changes were consistent with a two-compartment mode. Then, pharmacokinetic
characteristics of eight ginsenosides, including Rd, Rh1, Rh2, Rg1, Rg2, Rg3, and so on, were
investigated after an oral administration of GTSSL at a single dose of 400 mg/kg to rats
based on the LC–ESI–MS/MS method [
132
]. Jeon et al. [
133
] investigated and compared
ginsenoside pharmacokinetics in mice and rats following the repeated oral administration
of red ginseng extract (RGE); results showed the pharmacokinetics and metabolic path-
ways of ginsenosides exhibited species differences. In mouse plasma, seven PPD-type
ginsenosides (20(S)-Rb1, Rb2, Rc, Rd, Rg3, CK, and 20(S)-PPD) and one protopanaxa-
triol (PPT)-type 20(S)-Re were detected, whereas 20(S)-Rb1, Rb2, Rc, Rd, 20(S)-PPD, and
20(S)-PPT were detected in SD rat plasma. In addition, the T
max
and T
1/2
of 20(S)-PPD
and 20(S)-PPT in rats were greater than those in mice, suggesting the species-dependent
difference in the gut metabolism and absorption of ginsenosides. Recent study examined
the pharmacokinetic profiles of ginsenosides Rd and Rg3 in mice orally gavaged with
red ginseng (RG). Results showed that Rd absorbed was substantially high in fermented
Biomolecules 2022,12, 512 24 of 34
RG extract (fRGe)-treated mice, which suggested that oral administration of RG extracts
could modify gut microbiome and consequently affect the bioavailability of RG ginseno-
sides [
134
]. Shenqi Jiangtang granule (SJG) is a traditional Chinese medicine prescription;
Zhang et al. investigated the plasma pharmacokinetics during absorption of SJG after oral
administration in rats [
135
]. The results showed that
in vivo
absorption and exposure of
gomisin D and ginsenoside Rd were better than other analytes. It has been proven that
some PPD-type ginsenosides, including G-Rb1, G-Rd, and partial PPT-type ginsenosides,
have antidepressant and neuroregulatory effects. Recent literature reviewed the absorption
and metabolism of Rd between normal and depressed rats [
136
]. As shown in Table 7,
AUC values and Cmax values of Rd in the depression model group were increased and
CL/F was decreased as compared with the normal group, suggesting the bioavailability of
ginsenosides in the depression model could be improved.
4.2. Clinical Studies
In vivo
pharmacokinetics and metabolism data of ginsenoside Rd may also be valuable
for better understanding its pharmacologic activities and clinical application. In early 2007,
Liu et al. Identified the metabolites of Rd in a rat and pharmacokinetic study in healthy
volunteers [
137
]. Seven metabolites of Rd, mainly including oxygenation, glycosylation
deglycosylation, were detected from rat urine collected from 0 to 24 h after oral and
intravenous administration. The average half-life time of Rd in human plasma was detected
as 19.29 h, indicating that the ginsenoside Rd may be metabolized slowly after intravenous
administration. Later, the pharmacokinetics and safety of Rd were assessed in healthy
Chinese participants through a phase I, randomized, open-label, single, and multiple-dose
study [
138
]. Data showed that Rd was well tolerated with no dose-related adverse events,
and had a good pharmacokinetics and safety profile, allowing it to be explored in future
clinical studies in patients with acute ischemic stroke. Liu et al. [
139
,
140
] documented the
improvement effects of Rd against acute ischemic stroke through a phase
Π
randomized,
double-blind, placebo-controlled trial. In patients with acute ischemic stroke, Rd had
favorable safety and tolerability, and improved the clinical symptoms of acute ischemic
stroke. Two recent clinical trials showed that Rd had fewer side effects than glucocorticoid
and could improve the outcome of patients with ischemic stroke by suppressing microglial
proteasome activity and sequential inflammation [99].
Moreover, gut microbiota is not only involved in the biotransformation of ginsenosides,
but also in the pharmacokinetics of ginsenosides in humans. However, few studies focused
on the roles of the gut microbiota on the pharmacokinetics of ginsenosides in humans,
and the effects had not yet been fully elucidated. A recent study determined the serum
concentrations of the ginsenosides in humans after the administration of RG extracts
(RG and fRG) and researchers analyzed their correlations with the fecal ginsenoside-
metabolizing activities [
141
]. The gut bacteria seemed to exert their metabolic activity
mainly on the biotransformation into ginsenoside CK via Rd rather than Rg3, suggesting
that the profile and composition of the gut microbiota might affect the bioavailability
and the pharmacological effects of ginsenosides. Overall, clinical studies on ginsenoside
Rd are still limited, and mainly focused on phase 1 and phase 2 clinical studies of acute
ischemic stroke, indicating that further studies on the potential efficacy of natural products
in experimental animal models and randomized clinical trials are essential.
Biomolecules 2022,12, 512 25 of 34
Table 7. Pharmacokinetics and clinical studies of Rd.
Compound Subject Dose
Pharmacokinetics Parameters
Ref. Year
Cmax (ng/mL) Tmax (h) AUC (ng h/L) MRT (h) CL/F (L·h−1) T1/2 (h)
Preclinical Studies
Rd Dogs 2 mg/kg, i.g. 81.0 ±24.6 2.67 ±1.17 1890.2 ±668.6 25.5 ±3.84 1.14 ±0.40 24.2 ±2.85 [130]2007
0.2 mg/kg, i.v. / / 76,403.4 ±15,880.6 26.7 ±1.63 0.0020 ±0.0005 39.4 ±12.0
Rd Kunming mice
Wistar rats
20 mg/kg,
50 mg/kg,
150 mg/kg,
i.v.
/ / 305.0 ±22.3 / 0.066 ±0.005 14.19 ±2.37
[131]2012
/ / 293.2 ±279.4 / 0.280 ±0.172 12.83 ±2.92
/ / 312.6 ±139.5 / 0.569 ±0.306 14.02 ±10.57
GTSSL SD rats 400 mg/kg, i.g. 22.05 ±2.21 2 2180.10 ±18.69 12.43 ±1.46 / 7.30 ±3.32 [132] 2015
RG ICR mice 2 g/kg/day, 7 days 51.7 ±24.7 2.8 ±3.3 1145 ±555.6 / / 40.1 ±6.1 [133]2020
SD rats 6.5 ±1.5 7.0 ±2.0 257.8 ±49.6 / / 94.0 ±23.7
Rd Wistar rats—normal 80 mg/kg, i.g. 97.458 ±1.80 1.00 ±0.01 2061.658 ±1011.618 13.997 ±0.390 64.895 ±2.255 9.631 ±0.206 [136]2021
Wistar rats—depression model 104.959 ±5.0 1.00 ±0.03 2583.439 ±1254.680 15.126 ±0.671 55.744 ±2.366 10.198 ±0.511
Clinical studies
Rd 199 + 390 patients 10, 20 mg, i.v. / / / / / / [99] 2016
Rd SD rats 60 mg/mL, i.v.
150 mg/kg, i.g. / / / / / / [137]2007
10 healthy Chinese volunteers 10 mg, i.v. 2841.18 ±473.03 0.50 ±0.00 27261.63 ±8116.88 17.52 ±3.73 0.39 ±0.12 19.29 ±3.44
Rd 24 healthy Chinese volunteers
10 mg 2.8 ±0.5 0.5 ±0.0 27.3 ±8.1(mg·h/L) 17.5 ±3.7 0.39 ±0.12 19.3 ±3.4
[138]2010
45 mg 10.5 ±1.7 0.5 ±0.0 112.6 ±24.1 (mg·h/L) 18.3 ±2.7 0.36 ±0.08 18.4 ±2.9
75 mg, i.v. 19.3 ±2.6 0.5 ±0.0 208.4 ±51.4 (mg·h/L) 18.6 ±2.7 0.37 ±0.09 17.7 ±2.0
Rd 199 patients 10, 20 mg, i.v. / / / / / / [139] 2009
Rd 390 patients 10 mg, i.v. / / / / / / [140] 2012
RG 34 healthy Korean volunteers 3 g, i.g. 1.77 ±2.09 15.12 ±9.35 7.85 ±11.24 / / / [141] 2020
“/” means not mentioned.
Biomolecules 2022,12, 512 26 of 34
5. Concluding Remarks
Collectively, this review systematically summarized recent advances on the biotrans-
formation, pharmacological, pharmacokinetic, and clinical studies of ginsenoside Rd. Most
pharmacological activities of Rd, including anti-cancer, anti-inflammatory, antioxidative,
cardiovascular protection, and immunoregulation effects were exhibited and summarized.
Other health-beneficial activities that have previously received less attention, such as kid-
ney protection, lung protection, promotion of wound healing and bone differentiation, and
anti-obesity, were also included. Moreover, the limited number of pharmacokinetic and
clinical studies on ginsenoside Rd have also been documented.
Overall, Rd is a very promising candidate agent for the treatment of diverse diseases,
while the following issues require greater attention in the future: (i) the exact mechanisms
and targets that contribute toward the pharmacological activity of ginsenoside Rd require
further detailed investigation; (ii) experimental animal model studies and randomized
clinical trials should be performed to evaluate the therapeutic efficacy of ginsenoside
Rd; (iii) the effects of ginsenoside Rd combined with chemotherapy, target therapy, or
immunotherapy need to be determined.
Author Contributions:
X.S., L.W. and D.F. contributed to the study conception and design. Con-
ceptualization, X.S.; validation, D.F.; investigation, L.W.; writing—original draft preparation, X.S.;
writing—review and editing, X.S.; visualization, X.S.; supervision, D.F.; funding acquisition, X.S. and
D.F. All authors have read and agreed to the published version of the manuscript.
Funding:
This work was supported by the National Natural Science Foundation of China (no.
22078264), Natural Science Foundation of Shaanxi Province (no. 2022JQ-112), Scientific Research Plan
of Shaanxi Education Department (no. 19JK0850).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
2k2c two-kidney, two-clip;
5-FU 5-fluorouracil;
ACh acetylcholine;
Ac-H3 acetylated histone H3;
ACTH adrenocorticotrophic hormone;
AD Alzheimer’s disease;
ADR Adriamycin;
ALI acute lung injury;
AMP adenosine monophosphate;
AMPK adenosine 5‘-monophosphate (AMP)-activated protein kinase;
APP Aβ-protein precursor;
Aβamyloid β;
BASMCs basilar artery smooth muscle cells;
BAVSMCs basilar arterial vascular smooth muscle cells;
BBB blood–brain barrier;
Bax Bcl2-Associated X;
Bcl-2 B-cell lymphoma-2;
BDNF brain-derived neurotrophic factor;
Bmi-1 B cell-specific MLV insertion site-1;
C/EBP CCAAT/enhancer binding protein;
CA4P combretastatin A4 phosphate;
CaM calmodulin;
CCH chronic cerebral hypoperfusion;
Biomolecules 2022,12, 512 27 of 34
CDX-2 caudal type homeobox 2;
ChAT choline O-Acetyltransferase;
COX cyclooxygenase;
CREB cAMP-response element binding protein;
CRS chronic restraint stress;
CPA combination of Panax ginseng and Angelica sinensis;
cTnI cardiac troponin I;
DAPK1 death associated protein kinase 1;
Drp1 dynamin-related protein 1;
DSS dextran sulfate sodium;
EAE experimental autoimmune encephalomyelitis;
EAN experimental autoimmune neuritis;
ERK extracellular regulated protein kinases;
EGFR epidermal growth factor receptor;
EMT epithelial–mesenchymal transition;
E. coli Escherichia coli;
FGA floralginsenoside A;
fRG fermented red ginseng;
GAP-43 growth associated protein-43;
GBS Guillain–Barrésyndrome;
GS-E3D pectin-lyase-modified ginseng;
GSH glutathione;
GSSG oxidized glutathione;
GSH-Px glutathione peroxidase;
HDAC2 histone deacetylase 2;
HO-1 heme oxygenase-1;
HPLC high performance liquid chromatography;
hiPSCs human induced pluripotent stem cells;
hTERT human telomerase reverse transcriptase;
HUVECs human umbilical vascular endothelial cells;
HFs hair follicles;
IBD inflammatory bowel disease;
iNOS inducible nitric-oxide synthase;
IRI ischemia-reperfusion injury;
i.p. intraperitoneal;
i.v. intravenous;
i.g. intragastrically;
IS immobilization stress;
JNK c-Jun N-terminal kinase;
KPCs keratinocyte progenitor cells;
KA kainic acid;
Cyt c cytochrome c;
DMD Duchenne muscular dystrophy;
LPS lipopolysaccharide;
LVEF left ventricular ejection fraction;
MDR1 multidrug resistance protein 1;
MI/R myocardial ischemia- reperfusion;
MMP mitochondrial membrane potential;
MEK methyl ethyl ketone;
MS multiple sclerosis;
Msi-1 Musashi-1;
MPO myeloperoxidase;
MPP+ 1-methyl-4-phenylpyridinium;
MPMC mouse peritoneal mast cells;
MC2R melanocortin 2 receptor;
MCAO middle cerebral artery occlusion;
MDA malondialdehyde;
mTOR mammalian target of rapamycin;
NHA normal human astrocytes;
NEIL Nei-like DNA glycosylase;
Biomolecules 2022,12, 512 28 of 34
NF-κB nuclear factor kappa-B;
NGF nerve growth factor;
NLRP3 nod-like receptor protein 3;
NMDA N-methyl-D-aspartic acid;
TMT trimethyltin;
Tt-Afs thermostable α-L-arabinofuranosidase;
TRPM7 transient receptor potential melastatin 7;
NMDAR N-methyl-D-aspartic acid receptor;
Nr4a1 nuclear receptor subfamily 4 group A member 1;
NRCMs neonatal rat cardiac myocytes;
NRF2 nuclear factor erythroid 2-related factor 2;
NIHL noise-induced hearing loss;
NSC neural stem cell;
NSCLC non-small-cell lung cancer;
OA okadaic acid;
ox-LDL oxidized low density lipoprotein;
PD Parkinson’s disease;
LDH lactate dehydrogenase;
LDL low-density lipoprotein;
PGE2 prostaglandin E2;
LC-ESI-MS/MS liquid chromatography–electrospray ionization tandem mass spectrometry
PPD protopanaxadiol;
Rd ginsenoside Rd;
ROS reactive oxygen species;
ROCC receptor-operated Ca2+ channels;
sAPPαsoluble amyloid precursor protein alpha;
SCI spinal cord injury;
SD rats Sprague–Dawley rats;
SIRT1 sirtuin 1 SAM, senescence-accelerated mice;
SR-A scavenger receptor A;
STAT3 signal transducer and activator of transcription 3;
SMI Shenmai injection;
PKA protein kinase A;
SFI Shenfu injection;
SOCC store-operated Ca2+ channels;
TUNEL TdT-mediated dUTP nick-end labeling;
TG total ginsenoside;
TNBS 2,4,6-trinitrobenzenesulfonic acid;
TLC thin-layer chromatography;
TNBS 2,4,6-trinitrobenzenesulfonic acid;
Treg regulatory T cells;
TRPM7 transient receptor potential melastatin 7;
PP-2A protein phosphatase 2A;
SOD superoxide dismutase;
OVX mice, ovariectomy mice;
PGC-1αperoxisome proliferator-activated receptor-γcoactivator-1α;
TGF-βtransforming growth factor-β;
Th17 T helper cell 17;
Tt-Afs thermostable α-L-arabinofuranosidase;
TNF-αtumor necrosis factor-α;
ULK1 unc-51-like autophagy activating kinase 1;
VAChT vesicular acetylcholine transporter;
VDCC voltage dependent Ca2+ channel;
GTSSL total saponins in the stems-leaves of Panax ginseng C. A. Meyer.
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