Biological Activities of 2,3,5,4'-Tetrahydroxystilbene-2-O-[beta]-D-Glucoside in Antiaging and Antiaging-Related Disease Treatments.
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 . 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 . 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 . 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 . 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 . 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 . 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 .
A German study reported that THSG exerted a DAF-16-independent antiaging effect in a Caenorhabditis elegans model . 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 . 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 . 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 . THSG also restores the mRNA and protein expression of eNOS in the rat aorta and improves acetylcholine-induced endothelium-dependent relaxation . THSG exhibited antioxidant properties and protected against apoptosis in a lysophosphatidylcholine- (LPC-) induced endothelial cell injury model . 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 .
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 . 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 . 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 .
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 , phosphorylated ERK1/2, MEK1/2, Src, c-fos, c-jun, and c-myc mRNA in angiotensin II-induced VSMCs . In vivo, THSG inhibits neointimal hyperplasia in a rat carotid arterial balloon injury model , 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 . 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 . 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 .
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 . 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 .
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 . 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 . 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 .
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 . Another study demonstrated that THSG prevents dose-dependently collagen-induced platelet aggregation and ATP secretion . 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 .
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 . 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 .
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 . 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 .
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 .
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 . 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 .
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 . 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 . 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 . 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 .
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 . 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 . 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 .
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 . 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 .
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 . Another report indicated that in vitro THSG increased the proliferation of dermal papilla cells of mice compared with the control group . In addition, THSG promoted tyrosinase activity and melanin biosynthesis dose-dependently [49, 50].
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.
Abbreviations 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 factor 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- tetrahydropyridine NADPH: Nicotinamide adenine dinucleotide phosphate NANC relaxation: Nonadrenergic-noncholinergic relaxation 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 ligand 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- glucoside 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.
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; email@example.com
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 Senescence SAMP8 mice Male Senescence Kunming mice Male Longevity C. elegans Male/female Dermal Kunming mice Male thinning Atherosclerosis Atherosclerosis NZW rabbits Male Vascular SD rats Male dysfunction Myocardial Cardiac Wistar rats Male ischaemia ischemia- reperfusion Cardiac C57BL/6J Male ischemia- mice reperfusion Cardiovascular Vascular SD rats Male organ injury remodeling Vascular SHR rats Male remodeling and fibrosis Cardiac SD rats Male remodeling Lipid Serum SHR rats Male metabolism cholesterol Serum SD rats Male cholesterol Learning and [beta]- BALb/c mice Female memory amyloid peptide-or D- galactose- induced dementia Ischemia- Gerbils Male reperfusion Stress; C57BL/6J Male aging; brain mice SD rats damage Alzheimer's Alzheimer's and disease Parkinson's diseases Alzheimer's SD rats Male disease Alzheimer's APP Tg mice Male disease Parkinson's C57BL/6 mice Male disease Cerebral Cerebral SD rats Male ischemia ischemia Cerebral SD rats Male ischemia Cerebral Mice Male ischemia Diabetes Diabetic SD rats Male nephropathy Diabetic Kunming mice Male gastrointestinal dysmotility Bone Bone mineral SD rats Male and density and female bone strength Hair Hair growth C57BL/6J Female mice Classification Diseases Induction Treatment Antiaging Vascular Genotype Posttreatment senescence Senescence Genotype Posttreatment Senescence D-galactose Posttreatment Longevity Genotype Posttreatment Dermal Natural Posttreatment thinning aging Atherosclerosis Atherosclerosis High Posttreatment cholesterol diet Vascular Atherogenic- Posttreatment dysfunction Diet Myocardial Cardiac Occluding Pretreatment ischaemia ischemia- left reperfusion anterior descending coronary artery Cardiac Doxorubicin- Posttreatment ischemia- induced reperfusion cardiomyopathy Cardiovascular Vascular Carotid Posttreatment organ injury arterial remodeling balloon injury Vascular Genotype Posttreatment remodeling and fibrosis Cardiac Pressure- Posttreatment remodeling overloaded rats induced by abdominal aortic banding Lipid Serum Genotype Posttreatment metabolism cholesterol Serum 20% lard, Posttreatment cholesterol 10% cholesterol, and 0.2% propylthiouracil 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- galactose for 60 days Ischemia- Ischemia- Posttreatment reperfusion reperfusion Stress; Sleep- Posttreatment aging; brain deprived; Posttreatment damage amyloid- [beta]- injected; kainic acid- injected brain damage Alzheimer's Alzheimer's Chronic and disease aluminum Parkinson's exposure diseases Alzheimer's Amyloid- Posttreatment disease [[beta].sub. (1-42)]- injected Alzheimer's APPV717I Tg Posttreatment disease mice Parkinson's [MPP.sup.+]- Posttreatment disease induced damage Cerebral Cerebral Middle Posttreatment ischemia ischemia cerebral artery occlusion Cerebral Middle Posttreatment ischemia cerebral artery occlusion Cerebral Middle Posttreatment ischemia cerebral artery occlusion Diabetes Diabetic 60 mg/kg Posttreatment nephropathy streptozotocin intraperitoneal injection Diabetic 150 mg/kg Posttreatment gastrointestinal streptozotocin dysmotility intraperitoneal injection Bone Bone mineral Natural Posttreatment density and development bone (110 strength [+ or -] 10g) Hair Hair growth Natural Posttreatment development (20-26 g) Classification Diseases Duration Dosage Antiaging Vascular 14 weeks 50 mg/kg senescence 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 [micro]M Dermal 8 weeks 18 mg/kg thinning 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 reperfusion Cardiovascular Vascular 2 weeks 30, 60, or organ injury 120 mg/kg remodeling Vascular 14 weeks 50 mg/kg remodeling and fibrosis Cardiac 30 days 30, 60, or remodeling 120 mg/kg Lipid Serum 4 weeks 0.15% THSG metabolism cholesterol in rodent chow Serum 1 week 90, 180 mg/kg cholesterol Learning and [beta]- 60 days 33, 100, or memory amyloid 300 mg/kg peptide-or D- galactose- induced dementia 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 weeks Alzheimer's Alzheimer's 1, 3, or 5 4g/kg and disease months Parkinson's diseases Alzheimer's 4 weeks 25 mg/kg disease Alzheimer's 6 months 120 or 240 disease [micro]mol/ kg/d 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 reperfusion Diabetes Diabetic 8 weeks 10 or 20 nephropathy mg/kg Diabetic 8 weeks 10, 30, or gastrointestinal 60 mg/kg dysmotility Bone Bone mineral 90 days 150, 300, or density and 600 mg/kg bone strength Hair Hair growth 9,18 days 50, 100, or 150 mg/kg Classification Diseases Administration Antiaging Vascular Oral gavage senescence daily Senescence Water ad libitum Senescence Oral gavage daily Longevity Culture liquid Dermal Oral gavage thinning daily Atherosclerosis Atherosclerosis Oral gavage daily Vascular Oral gavage dysfunction daily Myocardial Cardiac Intravenous ischaemia ischemia- injection reperfusion Cardiac Ad libitum ischemia- reperfusion Cardiovascular Vascular Oral gavage organ injury daily remodeling 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 peptide-or D- galactose- induced dementia Ischemia- Intraperitoneal reperfusion injection Stress; Ad libitum aging; brain Oral gavage damage daily Alzheimer's Alzheimer's and disease Parkinson's diseases 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 dysmotility Bone Bone mineral Oral gavage density and daily bone strength Hair Hair growth Oral gavage daily Classification Diseases Evaluation Reference number Antiaging Vascular SA-[beta]-  senescence gal stain; blood flow assay; p53 and phospho- [gamma]H2AX determination Senescence SA-[beta]-  gal stain; Morris water maze assay; lifespan assays Morris water maze assay; Senescence Klotho  expression in cerebrum, heart, kidney, testis, and epididymis tissues Longevity Lifespan  assays Dermal Dermal layer  thinning thickness determination Atherosclerosis Atherosclerosis Atherosclerotic  plaque area; plasma cholesterol; LDL cholesterol; VLDL cholesterol; plasma triglyceride. Vascular Vascular [9, 10] dysfunction reactivity study; eNOS, CRP, IL-6, and TNF-[alpha] expression Myocardial Cardiac ST segment  ischaemia ischemia- recovery; reperfusion myocardial infarct size Cardiac Myocardial  ischemia- mitochondrial reperfusion biogenesis, improving cardiac function; EPO expression Cardiovascular Vascular Carotid  organ injury neointimal remodeling formation; PCNA, a- SMA, PDGF- BB gene expression; VSMCs proliferation and migration. Vascular Intima-  remodeling media and fibrosis thickness in the aortas, remodeling- related mRNA expressions, and effect on Smad3 deacetylating Cardiac Heart weight  remodeling and left ventricular weight indexes, MMPs, TIMPs, collagens, TGF-[beta]1 protein, ERK1/2, JNK, and p38 activation Lipid Serum Cholesterol  metabolism cholesterol and neutral lipid content VLDL and HDL fraction Serum TC, TG, LDL-and Serum HDL-  cholesterol cholesterol levels, and LDL receptor mRNA expression 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 expression in hippocampal CA1 region Ischemia- Morris water  reperfusion maze test Stress; Passive  aging; brain avoidance damage task; erythropoietin, PGC-1[alpha], and haemoglobin expression Alzheimer's Alzheimer's Passive  and disease avoidance Parkinson's task or diseases Morris water maze tests; APP Alzheimer's Passive  disease avoidance task or Morris water maze tests; synaptic structures; Src and NR2B expression Alzheimer's [alpha]-  disease synuclein expression and aggregation in the hippocampus Parkinson's Pole test;  disease tyrosine hydroxylase- positive neurons in the substantia nigral compacts Cerebral Cerebral Percentage  ischemia ischemia of apoptotic cells in injured rat brain tissue; Bcl- 2 and Bax protein expression in brain tissue Cerebral Animal's  ischemia nerve behavior and neurological function score; expression of NGF, GAP- 43, and PKA catalytic subunit proteins. Cerebral The brain  ischemia infarct volume and the number of positive cells Diabetes Diabetic Blood urea  nephropathy nitrogen, creatinine, 24 h urinary protein, ratio of kidney weight/body weight, SOD and GSH-Px activities, and TGF- [beta]1 and COX-2 expression. Diabetic Gastric  gastrointestinal emptying, dysmotility intestinal transit, and NANC relaxations Bone Bone mineral Bone mineral  density and density and bone bone strength strength; bone mineral weight and bone mineral size Hair Hair growth Hair  follicles and capillary growth Table 2: Summary of experiments of THSG in vitro. Classification Model Cell types Antioxidation ROS 3T3 cells; MCF-7 accumulation Apoptosis; ROS Human umbilical accumulation vein endothelial cells (HUVECs) Cardiovascular VSMCs migration Vascular smooth protection muscle cells (VSMCs) Endothelial HUVECs dysfunction Cardioprotection Primary rat cardiomyocytes Endothelial HUVECs dysfunction VSMCs proliferation VSMCs Cardiac fibroblast Primary rat cardiac proliferation fibroblast Endothelial 937 cells dysfunction VSMCs proliferation VSMCs VSMCs proliferation VSMCs VSMCs proliferation; Porcine coronary oxidation of arterial smooth lipoprotein cells (CASMCs) Inflammation RAW 264.7 macrophage cells Endothelial ECV304 dysfunction Cardiac stem cells Rat CSCs (CSCs) proliferation Normal cells Primary hepatocytes; primary cardiomyocytes; C2C12 myoblasts Lipid Steatosis hepatic Steatosis hepatic metabolism cell L02 cell Learning -- Astrocytes; PC12 and memory cells Neurotoxicity Rat hippocampal neurons 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 aggregation, secretion Pigmentation Induction of B16F1 melanoma cells pigmentation Induction of B16 melanoma cells pigmentation Classification Model Induction Antioxidation ROS Doxorubicin on accumulation MCF-7 Apoptosis; ROS Lysophosphatidylcholine accumulation (LPC) Cardiovascular VSMCs migration Tumor necrosis protection factor [alpha] (TNF-[alpha]) Endothelial TNF-[alpha] dysfunction Cardioprotection Doxorubicin Endothelial Oxidized low- dysfunction density lipoprotein (oxLDL) VSMCs proliferation Angiotensin II (Ang II) Cardiac fibroblast Ang II; hydrogen proliferation peroxide Endothelial Ox-LDL dysfunction VSMCs proliferation Platelet-derived growth factor- (PDGF-) BB VSMCs proliferation PDGF-BB VSMCs proliferation; LDL, VLDL, ox-LDL, oxidation of and ox-VLDL lipoprotein Inflammation Lipopolysaccharide (LPS) Endothelial LPC dysfunction 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 (MPP+) Differentiation of -- PC12 cells -- MPP+ -- MPP+ Bone Oxidative stress Hydrogen peroxide Platelet Platelet Collagen; thrombin; aggregation, U46619; ADP secretion Pigmentation Induction of -- pigmentation Induction of -- pigmentation 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 protection 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 [micro]mol/L VSMCs proliferation 1-50 [micro]mol/L VSMCs proliferation; 0.1-100 [micro]mol/L oxidation of lipoprotein Inflammation 1, 10, and 100 [micro]mol/L Endothelial 10 [micro]mol/L dysfunction Cardiac stem cells 1, 10, and 100 (CSCs) proliferation [micro]mol/L Normal cells 1.5, 6, 25, and 100 [micro]mol/L 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 [micro]mol/L Differentiation of 1, 5 [micro]mol/L PC12 cells -- 0.1, 1, and 10 [micro]mol/L -- 1, 5, and 10 [micro]mol/L Bone Oxidative stress 0.1, 1, and 10 [micro]mol/L Platelet Platelet 10, and 50 aggregation, [micro]mol/L secretion Pigmentation Induction of 10 [micro]g/L pigmentation Induction of 0.1-12.5 [micro]g/mL pigmentation Classification Model Potential targets or/and pathway Antioxidation ROS SOD; ROS; MitoSOX accumulation Apoptosis; ROS Caspase-3, Bcl-2, accumulation PARP-1, Bax, cytochrome C, SOD, glutathione peroxidase, and MDA Cardiovascular VSMCs migration Vimentin, TGF[beta]1, protection TGF[beta]R1, and Smad2/3 Endothelial Vimentin, TGF[beta]/ dysfunction Smad signaling, TGF[beta]1, phosphorylation of Smad2 and Smad3, and nuclear translocation of Smad4 Cardioprotection Apoptosis pathway; ROS generation; mitochondrial membrane potential loss; intracellular [[Ca.sup.2+]] Endothelial Vimentin, ICAM-1, dysfunction VCAM-1, TGF[beta]1, phosphorylation of Smad2 and Smad3, and nuclear 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 pathway Cardiac fibroblast ROS-extracellular proliferation signal-regulated kinase 1/2 pathway; ERK1/2 activation; MMP-2; MMP-9; MEK Endothelial ICAM-1; VCAM-1 dysfunction VSMCs proliferation NO-cGMP/PKG pathway VSMCs proliferation ERK1/2 VSMCs proliferation; Oxidation of oxidation of lipoprotein, lipoprotein proliferation, and decrease of NO content Inflammation COX-2 Endothelial Vascular endothelial dysfunction growth factor (VEGF) Cardiac stem cells VEGF; T-box (CSCs) proliferation transcription factor (Tbx5), hyperpolarization- activated cyclic nucleotide-gated 2 (HCN2), hyperpolarization- 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; mitochondrial activity and Hb production Lipid Steatosis hepatic HMG-CoA reductase; metabolism cell DGAT1; CYP7A; lipolysis Learning -- Erythropoietin; and memory PPAR-[gamma] coactivator 1[alpha] (PGC-1[alpha]); haemoglobin-[beta] Neurotoxicity PI3K/Akt signaling; mitochondrial apoptotic pathways Neuroinflammation NF-[kappa]B signaling pathway; ROS production and NADPH oxidase activation Neuroinflammation iNOS; reducing the binding activity of NF-[kappa]B Cell model of ROS; mitochondrial Parkinson's disease membrane potential; the ratio of Bax to Bcl-2; caspase-3; apoptosis 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; calcium Platelet Platelet Platelet Fc [gamma] aggregation, RIIa, Akt (Ser473), secretion and GSK3[beta](Ser9) phosphorylation. Pigmentation Induction of Microphthalmia- pigmentation associated transcription factor (MITF); cAMP response element (CRE) binding protein (CREB) activation; p38 MAPK pathway Induction of Murine tyrosinase pigmentation Classification Model Reference number Antioxidation ROS  accumulation Apoptosis; ROS  accumulation Cardiovascular VSMCs migration  protection Endothelial  dysfunction Cardioprotection  Endothelial  dysfunction VSMCs proliferation  Cardiac fibroblast  proliferation Endothelial  dysfunction VSMCs proliferation  VSMCs proliferation  VSMCs proliferation;  oxidation of lipoprotein Inflammation  Endothelial  dysfunction Cardiac stem cells  (CSCs) proliferation Normal cells  Lipid Steatosis hepatic  metabolism cell Learning --  and memory Neurotoxicity  Neuroinflammation  Neuroinflammation  Cell model of  Parkinson's disease Differentiation of  PC12 cells --  --  Bone Oxidative stress  Platelet Platelet  aggregation, secretion Pigmentation Induction of  pigmentation Induction of  pigmentation
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|Author:||Ling, Shuang; Xu, Jin-Wen|
|Publication:||Oxidative Medicine and Cellular Longevity|
|Date:||Jan 1, 2016|
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