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Biological Activities of 2,3,5,4'-Tetrahydroxystilbene-2-O-[beta]-D-Glucoside in Antiaging and Antiaging-Related Disease Treatments.

1. Introduction

Aging is inevitable; it is a progressive, irreversible process that every human will experience in his life. The aging population of the international community brings increasing medical expenses and health care costs. Therefore, prevention and early treatment of aging-related diseases can be effective means of relieving society's burden and living a better life for individuals. There are many theory researches of aging mechanisms. The most famous one is the oxidative stress theory. Free radicals and peroxides attack all components of cells, including proteins, lipids, RNA, and DNA. Oxidative damage occurs in various aging-associated disease pathologies, especially the cardiovascular diseases and neurological diseases. Theoretically, antioxidant supplementation should be able to reduce the risk of aging-related diseases. The Mediterranean diet with red wine, fruits, vegetables, and other plant foods has been shown to have cardiovascular protection against oxidative damage. At present, the extraction of biological antioxidants from plants is becoming one of the hot topics in the field of medical chemistry.

Polygonum multiflorum Thunb. ([text not reproducible], he-shou-wu) (Figures 1(a) and 1(b)) is a traditional Chinese medicinal plant. As early as 973 A.D., it was incorporated into Kaibao Bencao, an encyclopedia of medical plants edited under an imperial edict of Song Taizu, the first emperor of the Song Dynasty. The plant is processed to product radixPolygoni Multiflori preparata (Figure 1(c)), traditionally taken to increase vitality, improve the health of blood and blood vessels, blacken hair, strengthen bones, nourish the liver and kidney, and prolong life. Currently, Polygonum multiflorum Thunb. is listed in the Chinese Pharmacopoeia, and radix Polygoni Multiflori preparata is widely used for clinically treating of arteriosclerosis, hyperlipidemia, hypercholesterolemia, and diabetes. It is also used in many Chinese medicinal supplements to improve general health.

2,3,5,4'-Tetrahydroxystilbene-2-O-[beta]-D-glucoside (THSG) (Figure 1(d)) is the main component of Polygonum multi-florum Thunb., which is used as a standard compound for appraising Polygonum multiflorum Thunb. in the Chinese Pharmacopoeia [1]. THSG belongs to polyhydroxystilbene group. The structure of THSG is similar to that of resveratrol (3,4',5-Trihydroxy-trans-stilbene), which is quite well known for its numerous biological activities especially

in cardiovascular protection. As a resveratrol analog with glucoside, THSG has been proved to possess strong antioxidant and free radical scavenging activities even much stronger than resveratrol in superoxide anion radical scavenging, hydroxyl radical scavenging, and DPPH radical scavenging [2]. It is because THSG has a 2-O-Glu group in chemical structure, in which [C.sub.5]-OH and [C'.sub.4]-OH are more active to H-abstraction [3]. Furthermore, 2-O-Glu group can stabilize the phenoxyl free radicals and they are easy to be hydrolyzed in extreme pH environments (in the gastrointestinal environment).

Contemporary pharmacological studies have demonstrated that THSG exhibits numerous biological functions in antiaging and antiaging-related disease treatments. In this review, we focus on THSG, discussing its biological effects and molecular mechanisms.

2. Delaying the Senescence Effect

A few years ago, we found that THSG can delay vascular senescence and markedly enhance blood flow in spontaneously hypertensive rats (SHRs), but it does not affect blood pressure or body weight [4]. The data revealed that senescence-associated [beta]-galactosidase (SA-[beta]-gal) staining, [gamma]H2AX phosphorylation, and p53 acetylation are suppressed by THSG in the aortic arches of SHRs. THSG promotes deacetylation of p53, a transcription factor associated with aging. THSG also induces endothelial nitric oxide synthase (eNOS) expression in the aortas and urinary mononitrogen oxide (N[O.sub.X]) production. In vitro, THSG activates SIRT1 activity, stimulates eNOS promoter reporter gene activity, and ameliorates [H.sub.2][O.sub.2]-induced human umbilical vein endothelial cell (HUVEC) senescence [4]. Our unpublished data show that in vivo THSG is more effective in delaying vascular senescence than resveratrol.

A recent study revealed that THSG prolongs the lifespan of senescence-accelerated prone mouse (SAMP8) by 17% and notably improves their memory. THSG also increase neural klotho protein level and reduce levels of the neural insulin, the insulin receptors, insulin-like growth factor-1 (IGF-1), and IGF-1 receptor in the brain of SAMP8 [5]. In a subsequent report, this research group again demonstrated that THSG improves memory, reduces levels of reactive oxygen species (ROS), nitric oxide (NO), and IGF-1, and increases protein levels of superoxide dismutase (SOD) and klotho in serum. Furthermore, THSG upregulates klotho protein expression in cerebrum, heart, kidney, testis, and epididymis tissues of D-galactose induced aging mice [6].

A German study reported that THSG exerted a DAF-16-independent antiaging effect in a Caenorhabditis elegans model [7]. THSG prolongs the mean, median, and maximum adult lifespans of C. elegans by 23.5%, 29.4%, and 7.2%, respectively, and increases the resistance of C. elegans to lethal thermal stress, comparable to the effects of resveratrol. THSG also exerts a higher antioxidative capacity in nematode compared with resveratrol and reduces the levels of the aging pigment lipofuscin.

3. Cardiovascular Protection

3.1. Atherosclerosis and Lipid Metabolism. An experimental investigation using New Zealand rabbits demonstrated that THSG reduces atherosclerotic plaque accumulation caused by a high cholesterol diet, and lower plasma cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, and triglyceride levels [8]. Moreover, THSG decreases secretion protein levels of the intercellular adhesion molecule- (ICAM-) 1 and the vascular endothelial growth factor (VEGF) in the U937 foam cell cultured medium [8]. Subsequent studies have reported that in rat aortic walls in high-cholesterol-fed rats THSG improves the serum lipid profile and suppresses serum C-reactive protein (CRP), IL-6 and TNF-[alpha] levels, and matrix metalloproteinase-(MMP-) 2, MMP-9 mRNA, and protein expressions [9]. THSG also restores the mRNA and protein expression of eNOS in the rat aorta and improves acetylcholine-induced endothelium-dependent relaxation [10]. THSG exhibited antioxidant properties and protected against apoptosis in a lysophosphatidylcholine- (LPC-) induced endothelial cell injury model [11]. THSG suppresses intracellular ROS and malondialdehyde (MDA) and restores SOD and glutathione peroxidase (GSH-Px) levels. THSG apparently reversed the loss of mitochondrial membrane potential, the activation of caspase-3 and poly(ADP-ribose) polymerase 1 (PARP-1), the decrease of Bcl-2, the upregulation of Bax, and the release of cytochrome C in LPC-stimulated HUVECs [11].

Ten years ago, a Japanese group found that THSG does not affect the food intake, growth, or blood pressure of SHRs, consistent with our data [4, 12], but significantly reduces free fatty acid content in serum. THSG significantly reduces cholesterol and neutral lipid content in the VLDL fraction and neutral lipid content in the high-density lipoprotein (HDL) fraction in the blood, as well as neutral lipid content in the liver [12]. Another study reported that THSG administration to rats for 1 week can effectively control serum levels of total cholesterol and LDL cholesterol. The expression of LDL receptors in the liver was significantly upregulated in a high-fat-fed rat model [13]. Furthermore, in vitro experiments revealed a downregulation effect of THSG on 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and an upregulation effect on cholesterol 7 alpha-hydroxylase (CYP7A) in human steatosis L02 cells. THSG enhanced downregulation activities in TC, LDL cholesterol, and VLDL contents and increased activity in HDL cholesterol [14].

3.2. Vascular Remodeling and Fibrosis. In vitro, THSG prevents the proliferation of vascular smooth muscle cells (VSMCs) and blocks the G1/S phase progression of the cell cycle in platelet-derived growth factor-BB- (PDGF-BB-) or angiotensin II-induced VSMCs [15, 16]. THSG inhibits the phosphorylation of Rb and extracellular signal-regulated kinase 1/2 (ERK1/2); it also inhibits the expressions of cyclin D1, cyclin-dependent kinase-4 (CDK4), CDK2, cyclin E, the proliferating cell nuclear antigen (PCNA) in PDGF-BB-induced VSMCs [15], phosphorylated ERK1/2, MEK1/2, Src, c-fos, c-jun, and c-myc mRNA in angiotensin II-induced VSMCs [16]. In vivo, THSG inhibits neointimal hyperplasia in a rat carotid arterial balloon injury model [17], and the ratio of intima-to-media was significantly reduced, and the expressions of PCNA, [alpha]-smooth muscle actin ([alpha]-SMA), and PDGF-BB were suppressed. Moreover, signaling pathways associated with smooth muscle cell proliferation, migration, and inflammation were inhibited, in addition to the activation of AKT, ERK1/2, and nuclear factor [kappa]B (NF-[kappa]B) and the expressions of c-myc, c-fos, c-jun, MMP-2, MMP-9, and collagens I and III [17]. Our recent study reported that orally administering THSG for 14 weeks significantly inhibited vascular remodeling and fibrosis in SHRs with increasing blood flow and with constant blood pressure [18]. THSG reduces intima-media thickness in the aortic arch of SHRs, increases the vascular diastolic rate in response to acetylcholine, and reduces remodeling and fibrosis-related mRNA expression, such as that of genes ACTA2, CCL3, COL1A2, COL3A1, TIMP1 WISP2, IGFBP1, ECE1, KLF5, MYL1 BMP4, FN1, and the plasminogen activator inhibitor-1 (PAI-1). THSG inhibits the acetylation of Smad3 and prevents Smad3 binding to the PAI-1 proximal promoter in SHR aortas [18].

3.3. Heart. THSG improves cardiac ischemia-reperfusion, cardiac remodeling, and cardiac stem cells. The infarct size, ST segment recovery, and incidence of arrhythmia in the THSG postconditioning group are all significantly improved compared with the control group [19]. THSG has also been shown to promote mitochondrial biogenesis and induce the expression of erythropoietin (EPO) in nonhematopoietic cells, including primary cardiomyocytes, and enhance EPO-EPO receptor autocrine activity. THSG robustly increases the endurance performance activity of healthy and doxorubicin-induced cardiomyopathic mice in ischemic disorders, stimulates myocardial mitochondrial biogenesis, and improves cardiac function [20].

In cardiac remodeling, THSG can attenuate pressure overload-induced cardiac pathological changes. Such pathological changes include increases in heart weight/body weight and left ventricular weight/body weight ratios, increased myocyte cross-sectional areas and left ventricular posterior wall, hypertrophic ventricular septum, and accumulation of myocardial interstitial perivascular collagen, as well as elevated cardiac hydroxyproline content [21]. Furthermore, THSG significantly reduces myocardium angiotensin II, enhances the activities of SOD and GSH-Px in serum and myocardial tissue, and inhibits the protein expression of transforming growth factor beta 1 (TGF-[beta]1) and the phosphorylation of ERK1/2 and p38 MAP kinase in myocardial tissue [22]. However, THSG treatment increases the percentage of the S-phase in sorted c-kit(+) rat cardiac stem cells and promotes expressions of PCNA, VEGF, the T-box transcription factor, hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2), HCN4, the a myosin heavy chain, [beta] myosin heavy chain mRNA, stem cell antigen 1, cardiac troponin-I, GATA-4, Nkx2.5, and connexin 43 protein [22].

3.4. Platelets. In vitro, THSG treatment inhibits adenosine diphosphate- (ADP-) or thrombin-induced platelet aggregation dose-dependently. THSG does not affect intracellular calcium ion dynamics at rest; however, in the ADP or thrombin stimulation, THSG reduces dose-dependently the rise in intracellular calcium flow [23]. Another study demonstrated that THSG prevents dose-dependently collagen-induced platelet aggregation and ATP secretion [24]. THSG also inhibits platelet P-selectin expression, glycoprotein IIb-IIIa binding, and platelet spreading on immobilized fibrinogen, as well as Fc receptor Fc[gamma]RIIa, Akt (Ser473), and GSK3[beta] (Ser9) phosphorylations [24].

4. Neuroprotective Effects

4.1. Learning and Memory. In [beta]-amyloid peptide-induced dementia mice, ischemia-reperfusion gerbils, and D-galactose induced dementia mouse models, oral administration of THSG for dementia prevention or treatment improves learning and memory function in Morris water maze tests. THSG significantly decreases MDA level and monoamine oxidase B activity in the cerebral cortex, reduces the affinity of NMDA receptors with [sup.3.H]-MK801, and increases expression of nerve growth factor (NGF) and neurotrophic factor-3 in the hippocampal CA1 region [25-27]. Moreover, THSG promotes the differentiation of PC12 cells, increases the intracellular calcium level in hippocampal neurons, and facilitates high-frequency stimulation-induced hippocampal long-term potentiation (LTP) in a bell-shaped manner. The facilitation of LTP induction by THSG required calcium/calmodulin-dependent protein kinase II and ERK activation [28]. In vivo, THSG treatment also restores memory impairment, as assessed using the passive avoidance test, in models for sleep-deprived mice, amyloid-[beta]-injected aging mice, and kainic acid-injected brain-damage mice. Concurrently, THSG induces expressions of erythropoietin, PPAR-[gamma] coactivator 1[alpha] (PGC-1[alpha]), and hemoglobin in astrocytes and PC12 neuronal-like cells and in the hippocampus of mice [29].

4.2. Neuroinflammation. Neuroinflammation is closely implicated in the pathogenesis of neurological diseases. Thus, the inhibition of microglial inflammation may have potential therapeutic significance for neurological diseases. Researchers have used a microglia BV2 cell line as a model to investigate the antineuroinflammatory effects of THSG, finding that THSG reduced the LPS-induced microglia-derived release of proinflammatory factors such as TNF-[alpha], IL-1[beta], IL-6, and NO and attenuated LPS-induced nicotinamide adenine dinucleotide phosphate oxidase activation and subsequent ROS production [30, 31]. THSG failed to suppress I[kappa]B-[alpha] degradation, NF-[kappa]B phosphorylation and nuclear translocation, and ERK1/2, JNK, and p38 phosphorylation. However, THSG markedly reduced the binding of NF-[kappa]B to its DNA element in the iNOS promoter [31]. Moreover, THSG stimulates the secretion of the glial cell-line derived neurotrophic factor and the secretion of brain-derived neurotrophic factor and NGF in cultured rat primary astroglial cells, by activating the ERK1/2 pathway [32].

4.3. Alzheimer and Parkinson Diseases. In chronic aluminum exposure or amyloid-[[beta].sub.(1-42)]-injected rat models, THSG improves cognitive impairment evaluated using passive avoidance task or Morris water maze tests. THSG reverses the rise in amyloid precursor protein (APP) expression and the downregulation in Src and NR2B mRNA and protein levels in the rat hippocampus [33, 34]. In APP transgenic mouse models, THSG also reverses the increase in [alpha]-synuclein expression and aggregation in the hippocampus at the late stage of transgenic mice [35].

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57BL/6 mouse models of Parkinson disease, THSG protects dopaminergic neurons from degradation in substantia nigra tyrosine hydroxylase-positive cells, enhances striatal dopaminergic transporter protein levels, and increases striatal Akt and GSK3[beta] phosphorylation and the upregulation of the Bcl-2/BAD ratio. Furthermore, in the pole test, THSG reduces the times required to turn the body and climbing down to the floor [36]. In vitro, THSG protects PC12 cells and SH-SY5Y cells against MPP+-induced neurotoxicity. The antiapoptotic effects of THSG were probably mediated through the inhibition of ROS generation and modulation of JNK activation [37, 38], involving activation of PI3K-Akt pathway [39].

4.4. Cerebral Ischemia. Previous studies have shown that THSG significantly decreases the percentage of apoptotic cells in injured rat brain tissue induced by ischemia reperfusion, promotes Bcl-2, and inhibits Bax protein expression in brain tissue [40]. THSG also promotes changes in animal nerve behavior; improves neurological function scores; increases the expression of NGF, growth-associated protein 43, and PKA catalytic subunit proteins; and presents a positive correlation between neurological function scores and determined protein expression [41]. In the middle cerebral artery occlusion (MCAO) models, THSG significantly reduces the brain infarct volume and the number of apoptosis cells in the cerebral cortex according to a TUNEL assay [42]. Furthermore, the authors used an in vitro ischemic model of oxygen-glucose deprivation followed by reperfusion (OGD-R), revealing that THSG reverses intracellular ROS generation and mitochondrial membrane potential dissipation and inhibits c-Jun N-terminal kinase (JNK) and Bcl-2 family-related apoptotic signaling pathway. Concurrently, THSG prevents the expression of iNOS induced by OGDR through the activation of SIRT1 and inhibition of NF-[kappa]B [42].

5. Diabetes and Other Diseases

5.1. Diabetes. The beneficial effects of THSG in alleviating diabetic complications are reflected in diabetic nephropathy and gastrointestinal disorders. Treatment with THSG reduces the increase in total cholesterol and triglyceride levels of diabetic rats [43]. Treatment with THSG also significantly reduces blood urea nitrogen, creatinine, 24 hours urinary protein levels, the ratio of kidney weight/body weight, and MDA and markedly increases the activities of SOD and GSH-Px in diabetic rats. Furthermore, THSG inhibits diabetes-induced expression of TGF-[beta]1 and cyclooxygenase-2 and restores the reduction of SIRT1 expression in diabetic nephropathy [43]. For disorders of gastrointestinal function in diabetes, long-term preventive treatment with THSG relieves delayed gastric emptying and increases intestinal transit, impaired nonadrenergic-noncholinergic relaxations, and deficiency of neuronal NO synthase expression in streptozotocin-induced diabetic mice. Moreover, THSG prevented significant decreases in PPAR-[gamma] and SIRT1 expression in diabetic ileum [44].

5.2. Bone Mineral Density. Recently, a study reported that THSG promotes bone mineral density and bone strength in the femoral bones of rats and enhances the bone mineral weight and bone mineral size in the iliac and humeral section after 90 days of administration [45]. Another report described in greater detail how in vitro THSG significantly enhances the cell survival, alkaline phosphatase (ALP) activity, and calcium deposition in [H.sub.2][O.sub.2]-injured osteoblastic MC3T3-E1 cells. THSG enhances mRNA expressions of ALP, collagen I, and osteocalcin but weakens the receptor activator of nuclear factor-[kappa]B ligand and IL-6, as well as intracellular ROS and MDA production [46].

5.3. Hair Growth. A report indicated that a THSG fed group had significantly more hair growth compared with the control group, and that THSG accelerated the growth rate of early hair in C57BL/6J mice. In vitro, THSG also promoted hair growth in the cultured tentacles follicles of mice, with longer hair than that in the control group after 8 days [47]. Another report indicated that in vitro THSG increased the proliferation of dermal papilla cells of mice compared with the control group [48]. In addition, THSG promoted tyrosinase activity and melanin biosynthesis dose-dependently [49, 50].

6. Summary

Although THSG has been found to exhibit many medicinal properties, because no systematic study has investigated its regulatory mechanisms and proteomics or genomics data, its functional targets remain unclear. Nevertheless, we summed up the signal transduction pathways that are regulated by THSG, shown in Figure 2, which presents multipathway multitarget characteristics that block and activate different signaling and gene expression. In all the animal experiments in this study, the rats and mice were the main models (Table 1). However, the experiments involving the genetic model and the specific gene knockout model were used less. Most experimental drug dosages of THSG are between 20 and 120 mg/kg, with some individual extreme doses of 300 mg/kg or more. In most studies, THSG has been administered daily by oral gavage, but in some cases it has been delivered by intraperitoneal injection. The pharmacologic activity of THSH in low concentration in cellular studies is summarized in this review (Table 2). Dosages of THSG in vitro are normally between 0.1 and 100 [micro]mol/L, whilst in some dosages the concentration will reach a maximum of 300 [micro]mol/L. Then the high concentration of THSG may play a role in toxicological effects instead of activation effects. Because of this, clinical value may be restricted.

From the perspective of drug effects, THSG achieves favorable results in delaying senescence and in treating aging-related diseases, especially in the cardiovascular and nervous system. Some studies have shown that THSG may be more effective than resveratrol in delaying senescence. Nevertheless, more research is necessary to explain the mechanism of THSG.

ADP:                 Adenosine diphosphate
ALP:                 Alkaline phosphatase
Ang II:              Angiotensin II
APP:                 Amyloid precursor protein
BDNF:                Brain-derived neurotrophic factor
CaMKII:              Calcium/calmodulin-dependent
                     protein kinase II
CASMC:               Coronary arterial smooth cell
CDK:                 Cyclin-dependent kinases
COX-2:               Cyclooxygenase-2
CRP:                 C-reactive protein
CYP7A:               Cholesterol 7 alpha-hydroxylase
CSC:                 Cardiac stem cells
DAF-16:              A homologous protein of Forkhead box
                     protein O in C. elegans
DAT:                 Dopaminergic transporter
eNOS:                Endothelial NO synthase
EPO:                 Erythropoietin
ERK1/2:              Extracellular signal-regulated kinase 1/2
GAP-43:              Growth associated protein 43
GDNF:                Glial cell-line derived neurotrophic
GPIIb-IIIa/PAC-1:    Glycoprotein IIb/IIIa
GSH-Px:              Glutathione peroxidase
HCN2:                Hyperpolarization-activated cyclic
                     nucleotide-gated 2
HDL:                 High-density lipoprotein
yH2AX:               Histone H2AX phosphorylated on
                     serine 139
HMG-CoA:             3-Hydroxy-3-methylglutaryl-coenzyme A
HUVECs:              Human umbilical vein endothelial cells
ICAM-1:              Intercellular adhesion molecule-1
IGF-1:               Insulin-like growth factor-1
iNOS:                Inducible NO synthase
JNK:                 c-Jun N-terminal kinase
LDL:                 Low-density lipoprotein
LTP:                 Long-term potentiation
LPC:                 Lysophosphatidylcholine
LPS:                 Lipopolysaccharide
MAO-B:               Monoamine oxidase B
MCAO:                Cerebral artery occlusion
MDA:                 Malondialdehyde
MMP:                 Matrix metalloproteinase
MPO:                 Myeloperoxidase
MPP+:                1-Methyl-4-phenylpyridinium ion
MPTP:                Ethyl-4-phenyl-1,2,3,6-
NADPH:               Nicotinamide adenine dinucleotide
NANC relaxation:     Nonadrenergic-noncholinergic
NF-kappaB:           Nuclear factor [kappa]B
NGF:                 Nerve growth factor
nNOS:                Neuronal NO synthase
NO:                  Nitric oxide
N[O.sub.x]:          Nitric oxide and nitrogen dioxide (NO
                     and N[O.sub.2])
NT-3:                Neurotrophic factor-3
OGD-R:               Oxygen-glucose deprivation followed
                     by reperfusion
PAI-1:               Plasminogen activator inhibitor-1
PARP-1:              Poly(ADP-ribose) polymerase 1
PCNA:                Proliferating cell nuclear antigen
PDGF-BB:             Platelet-derived growth factor-BB
PGC-1[alpha]:        PPAR-[gamma] coactivator 1[alpha]
PLC:                 Lysophosphatidylcholine
PPAR-[gamma]:        Peroxisome proliferator activated
                     receptor gamma
RANKL:               Receptor activator of nuclear factor-[kappa]B
ROS:                 Reactive oxygen species
SA-[beta]-gal:       Senescence-associated [beta]-galactosidase
SAMP8:               Senescence-accelerated prone mouse
[alpha]-SMA:         [alpha]-smooth muscle actin
SOD:                 Superoxide dismutase
Tbx5:                T-box transcription factor
THSG:                2,3,5,4 -Tetrahydroxystilbene-2-O-[beta]-D-
TGF-[beta]1:         Transforming growth factor beta 1
TNF-[alpha]:         Tumor necrosis factor [alpha]
TUNEL assay:         Terminal deoxynucleotidyl transferase
                     mediated dUTP nick end labeling assay
VCAM-1:              Vascular cell adhesion molecule 1
VEGF:                Vascular endothelial growth factor
VLDL:                Very-low-density lipoprotein
VSMCs:               Vascular smooth muscle cells.

Competing Interests

The authors declare that they have no competing interests.


This work was supported by grants from the Specialized Research Fund for the National Natural Science Foundation of China (81274130), the National Natural Science Foundation of China Youth Fund (81102532), the Doctoral Program of Higher Education of China (20113107110006), and the Shanghai 085 Project of Higher Education Connotation Construction (085ZY1202).


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Shuang Ling and Jin-Wen Xu

Murad Research Institute for Modernized Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

Correspondence should be addressed to Jin-Wen Xu;

Received 17 April 2016; Accepted 29 May 2016

Academic Editor: Ryuichi Morishita

Caption: Figure 1: The images of medicinal material Polygonum multiflorum and molecular structure of THSG. (a) Seedling herbs, (b) harvested herbs, (c) processed herbs, radix Polygoni Multiflori preparata, and (d) chemical structure of THSG.

Caption: Figure 2: The signal transduction pathways regulated by THSG in the antiaging and aging-related diseases. THSG displays different activities in blocking and activating signaling and gene expression in vitro and in vivo.
Table 1: Summary of animal experiments of THSG.

Classification        Diseases         Animals          Sex

Antiaging             Vascular        SHRs rats        Male

                     Senescence       SAMP8 mice       Male

                     Senescence      Kunming mice      Male

                     Longevity        C. elegans    Male/female

                       Dermal        Kunming mice      Male

Atherosclerosis   Atherosclerosis    NZW rabbits       Male

                      Vascular         SD rats         Male

Myocardial            Cardiac        Wistar rats       Male
ischaemia            ischemia-

                      Cardiac          C57BL/6J        Male
                     ischemia-           mice

Cardiovascular        Vascular         SD rats         Male
organ                  injury

                      Vascular         SHR rats        Male
                    and fibrosis

                      Cardiac          SD rats         Male

Lipid                  Serum           SHR rats        Male
metabolism          cholesterol

                       Serum           SD rats         Male

Learning and          [beta]-        BALb/c mice      Female
memory                amyloid

                     Ischemia-         Gerbils         Male

                      Stress;          C57BL/6J        Male
                    aging; brain     mice SD rats

Alzheimer's         Alzheimer's
and                   disease

                    Alzheimer's        SD rats         Male

                    Alzheimer's      APP Tg mice       Male

                    Parkinson's      C57BL/6 mice      Male

Cerebral              Cerebral         SD rats         Male
ischemia              ischemia

                      Cerebral         SD rats         Male

                      Cerebral           Mice          Male

Diabetes              Diabetic         SD rats         Male

                      Diabetic       Kunming mice      Male

Bone                Bone mineral       SD rats       Male and
                    density and                       female

Hair                Hair growth        C57BL/6J       Female

Classification        Diseases          Induction         Treatment

Antiaging             Vascular           Genotype       Posttreatment

                     Senescence          Genotype       Posttreatment

                     Senescence        D-galactose      Posttreatment

                     Longevity           Genotype       Posttreatment

                       Dermal            Natural        Posttreatment
                      thinning            aging

Atherosclerosis   Atherosclerosis          High         Posttreatment

                      Vascular         Atherogenic-     Posttreatment
                    dysfunction            Diet

Myocardial            Cardiac           Occluding       Pretreatment
ischaemia            ischemia-             left
                    reperfusion          anterior

                      Cardiac          Doxorubicin-     Posttreatment
                     ischemia-           induced
                    reperfusion       cardiomyopathy

Cardiovascular        Vascular           Carotid        Posttreatment
organ                  injury            arterial
remodeling                               balloon

                      Vascular           Genotype       Posttreatment
                    and fibrosis

                      Cardiac           Pressure-       Posttreatment
                     remodeling         overloaded
                                       rats induced
                                       by abdominal

Lipid                  Serum             Genotype       Posttreatment
metabolism          cholesterol

                       Serum            20% lard,       Posttreatment
                    cholesterol            10%
                                         and 0.2%

Learning and          [beta]-          Intracranial     Posttreatment
memory                amyloid          injection of
                     peptide-or         3 [micro]L
                         D-              [beta]-
                     galactose-        [amyloid.sub
                      induced           .1-40] or
                      dementia         subcutaneous
                                       injection of
                                       50 mg/kg D-
                                       for 60 days

                     Ischemia-          Ischemia-       Posttreatment
                    reperfusion        reperfusion

                      Stress;             Sleep-        Posttreatment
                    aging; brain        deprived;       Posttreatment
                       damage            amyloid-
                                       kainic acid-
                                       brain damage

Alzheimer's         Alzheimer's          Chronic
and                   disease            aluminum
Parkinson's                              exposure

                    Alzheimer's          Amyloid-       Posttreatment
                      disease          [[beta].sub.

                    Alzheimer's        APPV717I Tg      Posttreatment
                      disease              mice

                    Parkinson's        [MPP.sup.+]-     Posttreatment
                      disease            induced

Cerebral              Cerebral            Middle        Posttreatment
ischemia              ischemia           cerebral

                      Cerebral            Middle        Posttreatment
                      ischemia           cerebral

                      Cerebral            Middle        Posttreatment
                      ischemia           cerebral

Diabetes              Diabetic           60 mg/kg       Posttreatment
                    nephropathy       streptozotocin

                      Diabetic          150 mg/kg       Posttreatment
                  gastrointestinal    streptozotocin
                    dysmotility      intraperitoneal

Bone                Bone mineral         Natural        Posttreatment
                    density and        development
                        bone               (110
                      strength           [+ or -]

Hair                Hair growth          Natural        Posttreatment
                                        (20-26 g)

Classification        Diseases         Duration        Dosage

Antiaging             Vascular         14 weeks       50 mg/kg

                     Senescence        30 days      2, 20, or 50
                                       70 days        [micro]M

                     Senescence        4 weeks       42, 84, or
                                       8 weeks        168 mg/kg

                     Longevity         10 hours       50 or 100

                       Dermal          8 weeks        18 mg/kg

Atherosclerosis   Atherosclerosis      12 weeks      25, 50, or
                                                      100 mg/kg

                      Vascular         12 weeks      30, 60, or
                    dysfunction                       120 mg/kg

Myocardial            Cardiac           10 min        7.5 mg/kg
ischaemia            ischemia-          before
                    reperfusion      reperfusion

                      Cardiac           1 week       10, 30, or
                     ischemia-                        90 mg/kg

Cardiovascular        Vascular         2 weeks       30, 60, or
organ                  injury                         120 mg/kg

                      Vascular         14 weeks       50 mg/kg
                    and fibrosis

                      Cardiac          30 days       30, 60, or
                     remodeling                       120 mg/kg

Lipid                  Serum           4 weeks       0.15% THSG
metabolism          cholesterol                       in rodent

                       Serum            1 week      90, 180 mg/kg

Learning and          [beta]-          60 days       33, 100, or
memory                amyloid                         300 mg/kg

                     Ischemia-          7 days      1.5, 3, or 6
                    reperfusion                         mg/kg

                      Stress;         3 days; 17     50, 100, or
                    aging; brain     days and 24      200 mg/kg
                       damage          days; 2

Alzheimer's         Alzheimer's       1, 3, or 5        4g/kg
and                   disease           months

                    Alzheimer's        4 weeks        25 mg/kg

                    Alzheimer's        6 months      120 or 240
                      disease                        [micro]mol/

                    Parkinson's        14 days      20 or 40 mg/
                      disease                            kg

Cerebral              Cerebral       7 days prior    30, 60, or
ischemia              ischemia        to surgery      120 mg/kg

                      Cerebral       7 days prior     60 or 120
                      ischemia        to surgery        mg/kg

                      Cerebral       At the onset     15 or 40
                      ischemia            of            mg/kg

Diabetes              Diabetic         8 weeks        10 or 20
                    nephropathy                         mg/kg

                      Diabetic         8 weeks       10, 30, or
                  gastrointestinal                    60 mg/kg

Bone                Bone mineral       90 days      150, 300, or
                    density and                       600 mg/kg

Hair                Hair growth       9,18 days      50, 100, or
                                                      150 mg/kg

Classification        Diseases       Administration

Antiaging             Vascular         Oral gavage
                     senescence           daily

                     Senescence         Water ad

                     Senescence        Oral gavage

                     Longevity           Culture

                       Dermal          Oral gavage
                      thinning            daily

Atherosclerosis   Atherosclerosis      Oral gavage

                      Vascular         Oral gavage
                    dysfunction           daily

Myocardial            Cardiac          Intravenous
ischaemia            ischemia-          injection

                      Cardiac          Ad libitum

Cardiovascular        Vascular         Oral gavage
organ                  injury             daily

                      Vascular         Oral gavage
                     remodeling           daily
                    and fibrosis

                      Cardiac          Oral gavage
                     remodeling           daily

Lipid                  Serum           Ad libitum
metabolism          cholesterol

                       Serum           Oral gavage
                    cholesterol           daily

Learning and          [beta]-          Oral gavage
memory                amyloid             daily

                     Ischemia-       Intraperitoneal
                    reperfusion         injection

                      Stress;          Ad libitum
                    aging; brain       Oral gavage
                       damage             daily

Alzheimer's         Alzheimer's
and                   disease

                    Alzheimer's        Oral gavage
                      disease             daily

                    Alzheimer's        Oral gavage
                      disease             daily

                    Parkinson's        Oral gavage
                      disease             daily

Cerebral              Cerebral         Oral gavage
ischemia              ischemia            daily

                      Cerebral         Oral gavage
                      ischemia            daily

                      Cerebral       Intraperitoneal
                      ischemia       administration

Diabetes              Diabetic          Treatment
                    nephropathy         with TSG

                      Diabetic         Oral gavage
                  gastrointestinal        daily

Bone                Bone mineral       Oral gavage
                    density and           daily

Hair                Hair growth        Oral gavage

Classification        Diseases       Evaluation          Reference

Antiaging             Vascular       SA-[beta]-             [4]
                     senescence      gal stain;
                                     blood flow
                                     assay; p53
                                     and phospho-

                     Senescence      SA-[beta]-             [5]
                                     gal stain;
                                     Morris water
                                     maze assay;
                                     Morris water
                                     maze assay;

                     Senescence      Klotho                 [6]
                                     in cerebrum,
                                     testis, and

                     Longevity       Lifespan               [7]

                       Dermal        Dermal layer          [51]
                      thinning       thickness

Atherosclerosis   Atherosclerosis    Atherosclerotic        [8]
                                     plaque area;

                      Vascular       Vascular             [9, 10]
                    dysfunction      reactivity
                                     study; eNOS,
                                     CRP, IL-6,
                                     and TNF-[alpha]

Myocardial            Cardiac        ST segment            [16]
ischaemia            ischemia-       recovery;
                    reperfusion      myocardial
                                     infarct size

                      Cardiac        Myocardial            [17]
                     ischemia-       mitochondrial
                    reperfusion      biogenesis,

Cardiovascular        Vascular       Carotid               [14]
organ                  injury        neointimal
remodeling                           formation;
                                     PCNA, a-
                                     SMA, PDGF-
                                     BB gene

                      Vascular       Intima-               [15]
                     remodeling      media
                    and fibrosis     thickness in
                                     the aortas,
                                     related mRNA
                                     and effect
                                     on Smad3

                      Cardiac        Heart weight          [18]
                     remodeling      and left
                                     MMPs, TIMPs,
                                     ERK1/2, JNK,
                                     and p38

Lipid                  Serum         Cholesterol           [20]
metabolism          cholesterol      and neutral
                                     content VLDL
                                     and HDL
                                     Serum TC,
                                     TG, LDL-and

                       Serum         HDL-                  [21]
                    cholesterol      cholesterol
                                     levels, and
                                     LDL receptor

Learning and          [beta]-        Morris water        [25, 26]
memory                amyloid        maze assay;
                     peptide-or      passive
                         D-          avoidance
                     galactose-      test; MAO-B
                      induced        activity in
                      dementia       the cerebral
                                     cortex; NGF
                                     and NT-3
                                     CA1 region

                     Ischemia-       Morris water          [27]
                    reperfusion      maze test

                      Stress;        Passive               [29]
                    aging; brain     avoidance
                       damage        task;
                                     PGC-1[alpha], and

Alzheimer's         Alzheimer's      Passive               [33]
and                   disease        avoidance
Parkinson's                          task or
diseases                             Morris water
                                     maze tests;

                    Alzheimer's      Passive               [34]
                      disease        avoidance
                                     task or
                                     Morris water
                                     maze tests;
                                     Src and

                    Alzheimer's      [alpha]-              [35]
                      disease        synuclein
                                     in the

                    Parkinson's      Pole test;            [36]
                      disease        tyrosine
                                     neurons in

Cerebral              Cerebral       Percentage            [40]
ischemia              ischemia       of apoptotic
                                     cells in
                                     injured rat
                                     tissue; Bcl-
                                     2 and Bax
                                     in brain

                      Cerebral       Animal's              [41]
                      ischemia       nerve
                                     behavior and
                                     of NGF, GAP-
                                     43, and PKA

                      Cerebral       The brain             [42]
                      ischemia       infarct
                                     volume and
                                     the number
                                     of positive

Diabetes              Diabetic       Blood urea            [43]
                    nephropathy      nitrogen,
                                     24 h urinary
                                     ratio of
                                     weight, SOD
                                     and GSH-Px
                                     and TGF-
                                     [beta]1 and

                      Diabetic       Gastric               [44]
                  gastrointestinal   emptying,
                    dysmotility      intestinal
                                     transit, and

Bone                Bone mineral     Bone mineral          [45]
                    density and      density and
                        bone         bone
                      strength       strength;
                                     bone mineral
                                     weight and
                                     bone mineral

Hair                Hair growth      Hair                  [47]

Table 2: Summary of experiments of THSG in vitro.

Classification           Model                Cell types

Antioxidation             ROS              3T3 cells; MCF-7

                     Apoptosis; ROS        Human umbilical
                      accumulation               vein
                                            cells (HUVECs)

Cardiovascular      VSMCs migration        Vascular smooth
protection                               muscle cells (VSMCs)

                      Endothelial               HUVECs

                    Cardioprotection         Primary rat

                      Endothelial               HUVECs

                  VSMCs proliferation           VSMCs

                   Cardiac fibroblast    Primary rat cardiac
                     proliferation            fibroblast

                      Endothelial             937 cells

                  VSMCs proliferation           VSMCs

                  VSMCs proliferation           VSMCs

                  VSMCs proliferation;     Porcine coronary
                      oxidation of         arterial smooth
                      lipoprotein           cells (CASMCs)

                      Inflammation       RAW 264.7 macrophage

                      Endothelial               ECV304

                   Cardiac stem cells          Rat CSCs
                  (CSCs) proliferation

                      Normal cells       Primary hepatocytes;
                                           C2C12 myoblasts

Lipid              Steatosis hepatic      Steatosis hepatic
metabolism                cell                 L02 cell

Learning                   --              Astrocytes; PC12
and memory                                      cells

                     Neurotoxicity         Rat hippocampal

                   Neuroinflammation     Mouse microglial BV2
                                              cell lines

                   Neuroinflammation     Mouse microglial BV2
                                              cell lines

                     Cell model of        Human dopaminergic
                  Parkinson's disease     neuroblastoma SH-
                                             SY5Y cells.

                   Differentiation of         PC12 cells
                       PC12 cells

                           --                 PC12 cells

                           --                 PC12 cells

Bone                Oxidative stress     Osteoblastic MC3T3-
                                               E1 cells

Platelet                Platelet              Platelets

Pigmentation          Induction of       B16F1 melanoma cells

                      Induction of        B16 melanoma cells

Classification           Model                  Induction

Antioxidation             ROS                Doxorubicin on
                      accumulation                MCF-7

                     Apoptosis; ROS      Lysophosphatidylcholine
                      accumulation                (LPC)

Cardiovascular      VSMCs migration          Tumor necrosis
protection                                   factor [alpha]

                      Endothelial              TNF-[alpha]

                    Cardioprotection           Doxorubicin

                      Endothelial             Oxidized low-
                      dysfunction          density lipoprotein

                  VSMCs proliferation      Angiotensin II (Ang

                   Cardiac fibroblast       Ang II; hydrogen
                     proliferation              peroxide

                      Endothelial                Ox-LDL

                  VSMCs proliferation       Platelet-derived
                                             growth factor-
                                               (PDGF-) BB

                  VSMCs proliferation            PDGF-BB

                  VSMCs proliferation;     LDL, VLDL, ox-LDL,
                      oxidation of             and ox-VLDL

                      Inflammation         Lipopolysaccharide

                      Endothelial                  LPC

                   Cardiac stem cells              --
                  (CSCs) proliferation

                      Normal cells                 --

Lipid              Steatosis hepatic               --
metabolism                cell

Learning                   --                      --
and memory

                     Neurotoxicity            Staurosporine

                   Neuroinflammation               LPS

                   Neuroinflammation               LPS

                     Cell model of             1-Methyl-4-
                  Parkinson's disease       phenylpyridinium

                   Differentiation of              --
                       PC12 cells

                           --                     MPP+

                           --                     MPP+

Bone                Oxidative stress        Hydrogen peroxide

Platelet                Platelet           Collagen; thrombin;
                      aggregation,             U46619; ADP

Pigmentation          Induction of                 --

                      Induction of                 --

Classification           Model            THSG concentration

Antioxidation             ROS             60, 120, 180, and
                      accumulation         240 [micro]mol/L

                     Apoptosis; ROS         0.1, 1, and 10
                      accumulation           [micro]mol/L

Cardiovascular      VSMCs migration      0.1-100 [micro]mol/L

                      Endothelial         1, 10, 25, 50, and
                      dysfunction          100 [micro]mol/L

                    Cardioprotection     10-300 [micro]mol/L

                      Endothelial         1, 10, 25, 50, and
                      dysfunction          100 [micro]mol/L

                  VSMCs proliferation     1, 10, 25, 50, and
                                           100 [micro]mol/L

                   Cardiac fibroblast    3/100 [micro]mol/L;
                     proliferation         30 [micro]mol/L

                      Endothelial          30, 60, and 120
                      dysfunction             [micro]g/L

                  VSMCs proliferation    0.1, 1, 10, and 100

                  VSMCs proliferation     1-50 [micro]mol/L

                  VSMCs proliferation;   0.1-100 [micro]mol/L
                      oxidation of

                      Inflammation          1, 10, and 100

                      Endothelial          10 [micro]mol/L

                   Cardiac stem cells       1, 10, and 100
                  (CSCs) proliferation       [micro]mol/L

                      Normal cells       1.5, 6, 25, and 100

Lipid              Steatosis hepatic       50, 100, and 300
metabolism                cell               [micro]mol/L

Learning                   --               0.4, 2, and 10
and memory                                   [micro]g/mL

                     Neurotoxicity         200 [micro]mol/L

                   Neuroinflammation      20-80 [micro]mol/L

                   Neuroinflammation      1, 10, 30, 50, and
                                           100 [micro]mol/L

                     Cell model of        3.125, 6.25, 12.5,
                  Parkinson's disease         25, and 50

                   Differentiation of     1, 5 [micro]mol/L
                       PC12 cells

                           --               0.1, 1, and 10

                           --                1, 5, and 10

Bone                Oxidative stress        0.1, 1, and 10

Platelet                Platelet              10, and 50
                      aggregation,           [micro]mol/L

Pigmentation          Induction of          10 [micro]g/L

                      Induction of       0.1-12.5 [micro]g/mL

Classification           Model             Potential targets
                                            or/and pathway

Antioxidation             ROS              SOD; ROS; MitoSOX

                     Apoptosis; ROS        Caspase-3, Bcl-2,
                      accumulation           PARP-1, Bax,
                                          cytochrome C, SOD,
                                          peroxidase, and MDA

Cardiovascular      VSMCs migration      Vimentin, TGF[beta]1,
protection                                 TGF[beta]R1, and

                      Endothelial        Vimentin, TGF[beta]/
                      dysfunction           Smad signaling,
                                          phosphorylation of
                                         Smad2 and Smad3, and
                                           translocation of

                    Cardioprotection      Apoptosis pathway;
                                            ROS generation;
                                          membrane potential
                                          loss; intracellular

                      Endothelial          Vimentin, ICAM-1,
                      dysfunction         VCAM-1, TGF[beta]1,
                                          phosphorylation of
                                         Smad2 and Smad3, and
                                           translocation of
                                           Smad4, TGF[beta]/
                                             Smad pathway;
                                         caspase-3 activation

                  VSMCs proliferation    Phosphorylated ERK1/
                                          2, MEK1/2, and Src;
                                         c-fos, c-jun, and c-
                                          myc; intracellular
                                            ROS; Src-MEK1/
                                            2-ERK1/2 signal

                   Cardiac fibroblast      ROS-extracellular
                     proliferation         signal-regulated
                                          kinase 1/2 pathway;
                                          ERK1/2 activation;
                                           MMP-2; MMP-9; MEK

                      Endothelial           ICAM-1; VCAM-1

                  VSMCs proliferation     NO-cGMP/PKG pathway

                  VSMCs proliferation           ERK1/2

                  VSMCs proliferation;       Oxidation of
                      oxidation of           lipoprotein,
                      lipoprotein         proliferation, and
                                            decrease of NO

                      Inflammation               COX-2

                      Endothelial        Vascular endothelial
                      dysfunction        growth factor (VEGF)

                   Cardiac stem cells         VEGF; T-box
                  (CSCs) proliferation   transcription factor
                                           activated cyclic
                                          nucleotide-gated 2
                                           activated cyclic
                                          nucleotide gated 4
                                         (HCN4), alpha myosin
                                              heavy chain
                                          ([alpha]MHC), beta
                                          myosin heavy chain
                                           ([beta]MHC), stem
                                         cell antigen 1 (Sca-
                                              1), cardiac
                                          troponin-I, GATA-4,
                                         Nkx2.5, and connexin
                                              43 protein

                      Normal cells             EPO-EPOR;
                                            activity and Hb

Lipid              Steatosis hepatic      HMG-CoA reductase;
metabolism                cell               DGAT1; CYP7A;

Learning                   --               Erythropoietin;
and memory                                   PPAR-[gamma]
                                         coactivator 1[alpha]

                     Neurotoxicity        PI3K/Akt signaling;
                                          apoptotic pathways

                   Neuroinflammation          NF-[kappa]B
                                          signaling pathway;
                                          ROS production and
                                             NADPH oxidase

                   Neuroinflammation      iNOS; reducing the
                                          binding activity of

                     Cell model of        ROS; mitochondrial
                  Parkinson's disease     membrane potential;
                                          the ratio of Bax to
                                           Bcl-2; caspase-3;

                   Differentiation of         MEK and ERK
                       PC12 cells         signaling pathways;
                                            calcium, CaMKII

                           --             PI3K/Akt signaling
                                          pathway; apoptotic

                           --             ROS generation; JNK

Bone                Oxidative stress       ALP; OCN; COL-I;
                                           RNAKL; IL-6; MDA;

Platelet                Platelet          Platelet Fc [gamma]
                      aggregation,        RIIa, Akt (Ser473),
                       secretion         and GSK3[beta](Ser9)

Pigmentation          Induction of          Microphthalmia-
                      pigmentation            associated
                                         transcription factor
                                             (MITF); cAMP
                                           response element
                                             (CRE) binding
                                            protein (CREB)
                                         activation; p38 MAPK

                      Induction of         Murine tyrosinase

Classification           Model           Reference

Antioxidation             ROS              [52]

                     Apoptosis; ROS        [14]

Cardiovascular      VSMCs migration        [53]

                      Endothelial          [54]

                    Cardioprotection       [55]

                      Endothelial          [56]

                  VSMCs proliferation      [16]

                   Cardiac fibroblast      [57]

                      Endothelial          [58]

                  VSMCs proliferation      [59]

                  VSMCs proliferation      [15]

                  VSMCs proliferation;     [60]
                      oxidation of

                      Inflammation         [61]

                      Endothelial          [62]

                   Cardiac stem cells      [22]
                  (CSCs) proliferation

                      Normal cells         [20]

Lipid              Steatosis hepatic       [12]
metabolism                cell

Learning                   --              [29]
and memory

                     Neurotoxicity         [63]

                   Neuroinflammation       [30]

                   Neuroinflammation       [31]

                     Cell model of         [38]
                  Parkinson's disease

                   Differentiation of      [28]
                       PC12 cells

                           --              [39]

                           --              [37]

Bone                Oxidative stress       [46]

Platelet                Platelet           [24]

Pigmentation          Induction of         [50]

                      Induction of         [49]
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Author:Ling, Shuang; Xu, Jin-Wen
Publication:Oxidative Medicine and Cellular Longevity
Date:Jan 1, 2016
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