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2,3,5,4'‐Tetrahydrostilbene‐2‐o‐β‐d‐glucoside (TSG) is the main active component of Polygonum multiflorum Thunb. It has effects on hypertension. However, the mechanism is unclear. Current research is devoted to exploring the mechanism of TSG improving HHcy‐induced hypertension. The mice received a subcutaneous injection of Hcy in the presence or absence of TSG for 4 weeks. Blood pressure (BP) was measured using a noninvasive tail‐cuff plethysmography method. Levels of plasma Hcy and endothelin‐1 were measured using ELISA. Rat SMA without endothelium was cultured in a serum‐free medium in the presence or absence of TSG with or without Hcy. The contractile response to sarafotoxin 6c or endothein‐1 was studied using a sensitive myography. The levels of protein were detected using Western blotting. The results showed that TSG lowered HHcy‐elevated BP and decreased levels of plasma Hcy and endothelin‐1 in mice. Furthermore, the results showed that TSG inhibited Hcy‐upregulated ET receptor expression and ET receptor‐mediated contractile responses as well as the levels of p‐ERK1/2 and p‐p65 in SMA. In vivo results further validate the in vitro results. In conclusion, TSG can decrease the levels of plasma Hcy and ET‐1 and downregulate Hcy‐upregulated ET receptors in VSMCs by inhibiting the ERK1/2/NF‐κB/ETB2 pathway to lower the BP. [ABSTRACT FROM AUTHOR]

Abstract Background The idiosyncratic hepatotoxicity of Polygonum multiflorum (PM) has attracted considerable interest, but the idiosyncratically hepatotoxic components and endogenous metabolite changes resulting from idiosyncratic hepatotoxicity of PM are not well understood. The aim of this study was to identify the idiosyncratically hepatotoxic components and potential endogenous metabolic biomarkers for PM-induced liver injury. Methods Serum biochemical indicators and hematoxylin and eosin (H&E) staining were evaluated to identify pathological changes. Gas chromatography/mass spectrometry (GC-MS) was performed to identify changes in metabolic biomarkers. Orthogonal projection to latent structures discriminant analysis (OPLS-DA) was applied to determine group clustering trends and differential metabolites. Results The results for the liver index, the liver function index and liver pathology showed that Polygonum multiflorum ethanol extract (PME), 50% ethanol elution fractions and tetrahydroxystilbene glucoside (TSG) from PME can induce idiosyncratic hepatotoxicity. TSG was the main idiosyncratically hepatotoxic component. Forty endogenous metabolites were identified in the rat liver. Six biomarkers, including lower levels of L-valine and higher levels of 3-hydroxybutyric acid, hexadecanoic acid, ribose, phosphoric acid and oxalic acid, were related to PM-induced liver injury. These differential biomarkers led to disruptions in amino acid, fatty acid, oxalate, energy and glucose metabolism. A total of 32 types of endogenous metabolites were identified in rat serum. Ten biomarkers were related to the liver injury induced by TSG, including lower levels of L-valine and L-proline and higher levels of urea, caproic acid, DL-malic acid, D-mannose, 3-hydroxybutyric acid, D-galactose, octadecane and hexadecanoic acid. These differential biomarkers led to disruptions in amino acid, glucose and fat metabolism. The mechanism of idiosyncratic hepatotoxicity in PM involves TSG-induced disruptions in amino acid metabolism, lipid metabolism, energy metabolism and glucose metabolism. Conclusions These findings reflect the material basis and metabolic mechanism of idiosyncratic PM hepatotoxicity.

Trauma is the main cause of death for people aged 1-45, and among them, traumatic brain injury (TBI) is the major condition, which causes over 50,000 deaths each year and costs over 80 billion per year. Tetrahydroxystilbene glucoside (TSG) is the active ingredient of polygonum multiflorum, a traditional Chinese herbal medicine, which presented multiple pharmacological effects, including antioxidative, anti-inflammatory, reducing blood fat and neuroprotection effects. However, the effect of TSG in promoting the recovery of the nerve system after TBI is not fully understood. PARP1 is a key enzyme in repair of the damage in DNA, which is activated by binding to DNA breaks, initiating both single-strand and double-strand DNA break repair. And we thought that overexpression of TSG might enhance the effect of TSG in TBI treatment. In this study, we firstly detected the oxidative stress response related molecules in serum samples of TBI patients and a TBI mice model, and found that oxidative stress response was activated after TBI, and TSG would reduce this effect. We further noticed that inflammation related molecules presented a similar trend with oxidative stress response related molecules. These results indicated that inflammatory response and oxidative stress processes were both activated after TBI, and reduced after TSG treatment. We further detected that the apoptosis related proteins and anti-oxidative proteins were increased after TSG treatment, and these effects were enlarged after overexpression of PARP1. We further noticed that these effects might be mediated by inhibition of the Ras/JNK signalling pathway. Thus, we thought overexpression of PARP1 might enhance the therapeutic effect of TSG in TBI treatment.

Endothelial dysfunction plays a central role in the patho-genesis of diabetic vascular complications. 2,3,5,4′-tetra-hydroxystilbene-2-O-β-D-glucoside (TSG), an active component extracted from the roots of Polygonum multiflorum Thunb, has been shown to have strong antioxidant and antiapoptotic activities. In the present study, we investigated the protective effect of TSG on apoptosis induced by high glucose in human umbilical vein endothelial cells (HUVECs) and the possible mechanisms. Our data demonstrated that TSG significantly reversed the high glucose-induced decrease in cell viability, suppressed high glucose-induced generation of intracellular reactive oxygen species (ROS), the activity of caspase-3, and decreased the percentage of apoptotic cells in a dose-dependent manner. In addition, we found that TSG not only increased the expression of Bcl-2, while decreasing Bax expression, but also activated phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) with subsequent nitric oxide production and ultimately reduced high glucose-induced apoptosis. However, the antiapoptotic effects of TSG were abrogated by pretreatment of the cells with PI3K inhibitor (LY294002) or eNOS inhibitor NG-L-nitro-arginine methyl ester, respectively. These results suggest that TSG inhibits high glucose-induced apoptosis in HUVECs through inhibition of ROS production, activation of the PI3K/Akt/eNOS pathway, and upregulation of the Bcl-2/Bax ratio, and thus may demonstrate significant potential for preventing diabetic cardiovascular complications. [ABSTRACT FROM AUTHOR]

Background: The idiosyncratic hepatotoxicity of Polygonum multiflorum (PM) has attracted considerable interest, but the idiosyncratically hepatotoxic components and endogenous metabolite changes resulting from idiosyncratic hepatotoxicity of PM are not well understood. The aim of this study was to identify the idiosyncratically hepatotoxic components and potential endogenous metabolic biomarkers for PM-induced liver injury. Methods: Serum biochemical indicators and hematoxylin and eosin (H&E) staining were evaluated to identify pathological changes. Gas chromatography/mass spectrometry (GC-MS) was performed to identify changes in metabolic biomarkers. Orthogonal projection to latent structures discriminant analysis (OPLS-DA) was applied to determine group clustering trends and differential metabolites. Results: The results for the liver index, the liver function index and liver pathology showed that Polygonum multiflorum ethanol extract (PME), 50% ethanol elution fractions and tetrahydroxystilbene glucoside (TSG) from PME can induce idiosyncratic hepatotoxicity. TSG was the main idiosyncratically hepatotoxic component. Forty endogenous metabolites were identified in the rat liver. Six biomarkers, including lower levels of L-valine and higher levels of 3-hydroxybutyric acid, hexadecanoic acid, ribose, phosphoric acid and oxalic acid, were related to PM-induced liver injury. These differential biomarkers led to disruptions in amino acid, fatty acid, oxalate, energy and glucose metabolism. A total of 32 types of endogenous metabolites were identified in rat serum. Ten biomarkers were related to the liver injury induced by TSG, including lower levels of L-valine and L-proline and higher levels of urea, caproic acid, DL-malic acid, D-mannose, 3-hydroxybutyric acid, D-galactose, octadecane and hexadecanoic acid. These differential biomarkers led to disruptions in amino acid, glucose and fat metabolism. The mechanism of idiosyncratic hepatotoxicity in PM involves TSG-induced disruptions in amino acid metabolism, lipid metabolism, energy metabolism and glucose metabolism. Conclusions: These findings reflect the material basis and metabolic mechanism of idiosyncratic PM hepatotoxicity. [ABSTRACT FROM AUTHOR]

Polyhydroxy stilbenes have been reported to possess various biological activities and have potential for treatment of Alzheimer's disease. Tetrahydroxystilbene glucoside is one of the major polyhydroxy stilbenes, which provides the underlying therapeutic activities for neuroprotective actions in various experimental conditions. This study investigates the impact of a tetrahydroxystilbene glucoside remedy for cognitive disorder and oxidative stress in Aβ1-42-induced Alzheimer's disease mice and clarifies the mechanisms of action through the Kelch-like erythroid cell-derived protein with conserved non-coding homology-associated protein 1/nuclear factor erythroid 2-related factor pathway. It was found that the swimming time of Aβ1-42-induced mice treated with tetrahydroxystilbene glucoside (30, 60, and 120 mg/kg) was significantly increased in the target quadrant of a Morris water maze experiment and the number of avoidances was increased during a passive avoidance experiment, Moreover, tetrahydroxystilbene glucoside attenuated Aβ1-42-induced memory impairment. However, the locomotor and exploratory activity of mice were not affected. Tetrahydroxystilbene glucoside clearly decreased the levels of malondialdehyde and oxidized glutathione in both hippocampus and cortex compared with the Aβ1-42-treated group, and also clearly increased the level of glutathione and activities of catalase and superoxide dismutase in those tissues. The results of this study demonstrated that tetrahydroxystilbene glucoside increased nuclear factor erythroid 2-related factor and heme oxygenase-1 protein expression and decreased Kelch-like erythroid cell-derived protein with conserved non-coding homology-associated protein 1 protein expression in a concentration-dependent manner in Aβ1-42-treated mice, which involved the Kelch-like erythroid cell-derived protein with conserved non-coding homology-associated protein 1/nuclear factor erythroid 2-related factor antioxidant pathway in hippocampus and cerebral cortex tissue. These results demonstrate that tetrahydroxystilbene glucoside as a natural drug that may provide a potential treatment for Alzheimer's disease.

Abstract Background Microglia-mediated neuroinflammation is recognized to mainly contribute to the pathogenesis of Parkinson’s disease (PD). Tetrahydroxystilbene glucoside (TSG) has been proved to be beneficial for health with a great number of pharmacological properties. We examined the effects of TSG against dopamine (DA) neuronal loss towards development of a PD treatment strategy. Methods Substantia nigral stereotaxic single injection of lipopolysaccharide (LPS)-induced rat DA neuronal damage was employed to investigate TSG-produced neuroprotection. In addition, primary rat midbrain neuron-glia co-cultures were performed to explore the underlying mechanisms. Results Daily intraperitoneal injection of TSG for seven consecutive days significantly attenuated LPS-induced loss of DA neurons in the substantia nigra. In addition, glia-dependent mechanisms were responsible for TSG-mediated neuroprotection. First, TSG ameliorated microglia-mediated neuroinflammation and the subsequent production of various pro-inflammatory and neurotoxic factors. Second, astroglial neurotrophic factor neutralization weakened TSG-mediated neuroprotection, showing that TSG was protective in part via increasing astroglia-derived neurotrophic factor secretion. Conclusions TSG protects DA neurons against LPS-induced neurotoxicity through dual modulation on glial cells by attenuating microglia-mediated neuroinflammation and enhancing astroglia-derived neurotrophic effects. These findings might open new alternative avenues for PD treatment.

Abstract Tetrahydroxystilbene glucoside (TSG) is the main water-soluble component in Polygonum multiflorum Thunb, and it has many cardioprotective effects. Although TSG is able to relax blood vessels, its relaxation of rat superior mesenteric arteries and the underlying mechanism of this process are not clearly understood. The aim of the present study was to use in vivo and in vitro models to investigate the arterial relaxation effect of TSG on rat superior mesenteric arteries and the mechanisms involved. We found that TSG concentration-dependently relaxed the superior mesenteric artery with or without endothelium. The vasorelaxation induced by TSG is not related to the vasodilator derived factor NO but is rather by the inhibition of COX-2 activity and decreased TXA 2. We also found that the vasorelaxation induced by TSG was attenuated by 4‑AP. Moreover, TSG also inhibited the contraction induced by an increase in external calcium concentration in Ca2+-free medium plus KCl (60 mM). These results suggest that TSG induces relaxation in mesenteric arterial rings through an endothelium-dependent pathway that involves the inhibition of COX-2 activity and decreased in TXA 2 and through an endothelium-independent pathway via opening of a voltage-dependent K+ channel, blockade of Ca2+ influx and release of intracellular Ca2+. Highlights • TSG induces relaxation through the inhibition of COX-2 and decreased in TXA 2. • TSG induces relaxation through opening of a voltage-dependent K+ channel. • TSG induces relaxation through blockade of Ca2+ influx and release of intracellular Ca2+. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to explore the protective effect and related mechanism of tetrahydroxystilbene glucoside (TSG) on apoptosis of osteoblast precursor cells (MC3 T3-E1) induced by H2O2. Methods MC3 T3-E1 cells pretreated with different concentrations of TSG were treated with 300 μmol/L H2O2 for 24 h. The experiment consisted of 6 groups, including the control group, H2O2, H2O2+TSG (0.1 μmol/L), H2O2+TSG (1 μmol/L), H2O2+TSG (10 μmol/L) and H2O2+NAC (1 mmol/L)(anti-oxidant positive control group). We evaluated the protective effect of TSG on the apoptosis of MC3 T3-E1 cells by MTT assay and Hoechst33258 staining. We tested the production of ROS and MDA by fluorescence microplate reader and MDA assay kit to investigate the oxidative stress status. We tested the production of Bcl-2 and Bax by Western-blotting and the gene expression of Bcl-2 and Bax by RT-PCR. Results Cell death induced by H2O2 alone was observed under microscope, and Hoechst33258 staining showed more cells with nuclear pyknosis and nuclear enrichment, which was improved after being pretreated with different concentrations of TSG. H2O2 alone could lead to a large degree of apoptosis in MC3 T3-E1 cells, and the apoptosis rate decreased after pretreatment with different concentrations of TSG. At the same time, TSG(1-10 μmol/L) could significantly reduce the level of ROS and MDA (P<0.05) and improve the oxidative stress status in MC3 T3-E1 cells. The result of Western-blotting and real-time quantitative RT-PCR demonstrated that pretreatment with TSG could decrease the expression of pro-apoptosis protein Bax and increase the expression of anti-apoptosis protein Bcl-2. Conclusion The apoptosis of MC3 T3-E1 cells increased after induced by H2O2 and decreased by pretreatment with TSG. The mechanism of the protective effect could be through decreasing the expression of pro-apoptosis protein Bax and increasing the expression of anti-apoptosis protein Bcl-2. [ABSTRACT FROM AUTHOR]

Tetrahydroxystilbene glucoside (TSG) is a unique component of the bone-reinforcing herb Radix Polygoni Multiflori Preparata (RPMP). It has the ability to promote bone formation and protect osteoblasts. However, the underlying mechanism remains unclear. To better understand its biological function, we determined TSG's effect on murine pre-osteoblastic MC3T3-E1 cells by the MTT assay, flow cytometry, FQ-PCR, Western blot, and ELISA. The results showed that TSG caused an elevation of the MC3T3-E1 cell number, the number of cells in the S phase, and the mRNA levels of the runt-related transcription factor-2 (Runx2), osterix (Osx), and collagen type I α1 (Col1a1). In addition, the osteoprotegerin (OPG) mRNA level was up-regulated, while the nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) mRNA levels were down-regulated by TSG. Furthermore, TSG activated the phosphoinosmde-3-kinase/protein kinase B (also known as PI3K/Akt) pathway, and blocking this pathway by the inhibitor LY-294002 could impair TSG's functions in relation to the MC3T3-E1 cells. In conclusion, TSG could activate the PI3K/Akt pathway and thus promote MC3T3-E1 cell proliferation and differentiation, and influence OPG/RANKL/M-CSF expression. TSG merits further investigation as a potential therapeutic agent for osteoporosis treatment. [ABSTRACT FROM AUTHOR]

Polyhydroxy stilbenes have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease (AD). Tetrahydroxystilbene glucoside is one of the major polyhydroxy stilbenes, which provides underlying therapeutic activities for neuroprotective actions in various experimental conditions. This study intends to investigate the impact of tetrahydroxystilbene glucoside remedy for cognitive disorder and oxidative stress in Aβ1-42-induced AD mice and to clarify the mechanisms of action through Keap1/Nrf2 pathway. It was found that The swimming time of Aβ1-42-induced mice which were treated by tetrahydroxystilbene glucoside (30, 60 and 120 mg/kg) was significantly increased in the target quadrant through the Morris water maze experiment and the number of avoidances was increased through the passive avoidance experiment. Moreover, tetrahydroxystilbene glucoside attenuated Aβ1-42-induced memory impairment, however, the locomotor and exploratory activity of the mice were not affected. Tetrahydroxystilbene glucoside obviously decreased the levels of MDA and GSSG in both hippocampus and cortex compared with the Aβ1-42-treated group, and obviously increased the level of GSH and activities of CAT and SOD in above tissues. The results of this study also demonstrated that tetrahydroxystilbene glucoside increased Nrf2 and HO-1 protein expression and decreased Keap1 protein expression in a concentration-dependent manner in Aβ1-42-treated mice, which involved in the Keap1/Nrf2 antioxidant pathway in hippocampus and cerebral cortex tissue. These results demonstrated that tetrahydroxystilbene glucoside as a natural drug might provide potential treatment for AD. [ABSTRACT FROM AUTHOR]

Background: Tetrahydroxystilbene glucoside (TSG) is a main bioactive component of Polygonum multiflorum, a traditional Chinese medicine known for certain anti-aging effects. Since TSG has been found to extend lifespan in the nematode Caenorhabditis elegans, we hypothesized that TSG might produce anti-aging benefits in mammals.Objective: The aim was to evaluate the anti-aging potential of TSG and to explore its relative molecular mechanism.Methods: Mice were maintained on standard diet, high-calorie diet (HC), or high-calorie plus TSG diet. Survival rates and body weight changes were recorded weekly. Rotarod analysis was performed to assess the physical fitness of mice. Bone mineral density was assessed using micro-computed tomography. Hematoxylin and eosin staining was used for the histological examination of heart, liver, and kidney pathology. The mRNA and protein expression of target genes were analyzed by quantitative real-time polymerase chain reaction and western blotting, respectively. Mitotracker deep red staining and high-content analysis were used to quantify cellular mitochondrial mass and function.Results: In this study, we found that TSG improved the physiology of aged mice consuming excess calories and delayed senile symptoms. The anti-aging benefits of TSG were mediated at least in part by the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) signaling cascade, leading to significant improvement in motor function, bone mineral density, HC-induced organ pathology, and mitochondrial function.Conclusion: Our findings show that TSG could be a potential drug candidate for the treatment of aging- and high-calorie intake-associated disorders. [ABSTRACT FROM AUTHOR]

Background: Endothelial cell dysfunction triggered by oxidized low-density lipoprotein (oxLDL) is the main event occurring during the development of atherosclerosis. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum, exhibits significant anti-atherosclerotic activity. However, the protective effects of TSG against oxLDL-induced endothelial dysfunction have not been clarified. We investigated the cytoprotective effects of TSG in human umbilical vein endothelial cells (HUVECs) and explored underlying mechanisms. Methods and Results: TSG pretreatment markedly attenuated oxLDL-mediated loss of cell viability, release of lactate dehydrogenase (LDH), cell apoptosis, and monocyte adhesion. OxLDL increased vimentin mRNA and protein levels, vimentin cleavage, caspase-3 activation, adhesion molecules levels and their colocalization with vimentin in HUVECs. These alterations were attenuated by pretreatment with TSG. Meanwhile, TSG inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by oxLDL. Using shRNA, oxLDL-induced cell apoptosis and monocyte adhesion were significantly inhibited by vimentin suppression in HUVECs. Conclusions: These results suggest that TSG protects HUVECs against oxLDL-induced endothelial dysfunction through inhibiting vimentin expression and cleavage, and the expression of adhesion molecules and their colocalization with vimentin. The interruption of TGFβ/Smad pathway and caspase-3 activation appears to be responsible for the downregulation of TSG on vimentin expression and fragmentation, respectively.

Alternative splicing of amyloid precursor protein ( APP ) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Aβ) production. Here, we determined the effect of Tetrahydroxystilbene glucoside (TSG) on the AKT-GSK3β pathway. We found GSK3β increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT-GSK3β signaling pathway suppressed APP-KPI inclusion. Moreover, TSG treatment attenuated amyloid deposition in APP/PS1 mice. This study demonstrates the neuroprotective effect of TSG on APP expression, suggesting that TSG may be beneficial for AD prevention and treatment. [ABSTRACT FROM AUTHOR]

Our previous work demonstrated that tetrahydroxystilbene glucoside (TSG) was able to effectively attenuate 1-methyl-4-phenylpyridinium (MPP)-induced apoptosis in PC12 cells partially via inhibiting reactive oxygen species (ROS) generation. However, the precise molecular mechanisms of TSG responsible for suppressing neuronal apoptosis have not been fully elucidated. To investigate the possible mechanism, we studied the neuroprotective effects of TSG on MPP-induced PC12 cells apoptosis and explored the molecular mechanisms that mediated the effects of TSG. Our results showed that treatment with TSG prior to MPP exposure effectively attenuated the cell viability decrease in PC12 cells, reversed the cell apoptosis, and further restored the mitochondria membrane potential (MMP). In addition, TSG remarkably enhanced the anti-oxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and efficiently reduced the malondialdehyde (MDA) content in the PC12 cells. Meanwhile, TSG markedly upregulated the Bcl-2/Bax ratio, reversed release of Cytochrome c, and inhibited the activation of caspase-3 induced by MPP. Furthermore, TSG significantly inhibited the activation of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway, while extracellular signal-regulated protein kinases (ERK) phosphorylation was not affected. Together, these findings provide the basis for TSG clinical application as a new therapeutic strategy in the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Polygonum multiflorum Thunb. is a traditional Chinese medicinal herb that has been widely used to treat age-associated diseases. Tetrahydroxystilbene glucoside (TSG), also known as 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-gluco side, is a major component of this herb. The present study was designed to investigate the osteogenic differentiation promoting activity of TSG in rat mesenchymal stem cells (MSCs) and in zebrafish. Preliminary experiments using MTT assay and ALP methods indicate that the high potential activity for promoting osteogenic differentiation was observed when 50% ethanol eluate was used. Further isolation and purification of TSG from the 50% ethanol eluate was performed by bioassay-guided fractionation, and its structure was confirmed using nuclear magnetic resonance and mass spectrometry analyses. In addition, the relative content of TSG with the highest potential activity in the promotion of osteogenic differentiation was identified as 14.34% by reversed-phase high performance liquid chromatography. Subsequently, the osteogenic differentiation promoting abilities of TSG in MSCs were examined. The results demonstrated that TSG promoted the alkaline phosphatase activity at concentrations of 1.56-25 μg/ml, while it increased the content of osteocalcin 7 days after treatment with 6.25-25 μg/ml in MSCs. Furthermore, experiments in zebrafish indicated that different concentrations of TSG (3.12-12.5 μg/ml) protected against further bone loss induced by 10 μmol/l dexamethasone (Dex), simulating an osteoporosis (OP) model. TSG treatment (12.5 μg/ml) in Dex-induced zebrafish significantly increased the area of nodules by 50.14% compared with the untreated model group. In conclusion, TSG, as a major component of P. multiflorum Thunb. exhibited an osteogenic promoting activity in MSCs and in zebrafish. The results provided scientific evidence to support the potential use of TSG for protecting the bone in degenerative diseases, such as OP. [ABSTRACT FROM AUTHOR]

Background and Aims Current antidepressants in clinic need weeks of administration and always have significant limitations. Tetrahydroxystilbene glucoside (TSG) is one of the major bioactive ingredients of Polygonum multiflorum with neuroprotective effects. This study aimed to evaluate the antidepressant effects of TSG in mice. Methods The antidepressant-like effects of TSG in mice were examined in the forced swim test (FST), tail suspension test (TST), and chronic social defeat stress (CSDS) model of depression. The effects of CSDS and TSG on the hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway and neurogenesis were further investigated. Moreover, the pharmacological inhibitors and lentiviral-shRNA were used to explore the antidepressant mechanisms of TSG. Results TSG produced antidepressant-like effects in the FST and TST and also reversed the CSDS-induced depressive-like symptoms. Moreover, TSG treatment significantly restored the decreased hippocampal BDNF signaling pathway and neurogenesis in CSDS mice. Importantly, blockade of the hippocampal BDNF system fully abolished the antidepressant-like effects of TSG in mice. Conclusion In conclusion, TSG produces antidepressant-like effects in mice via enhancement of the hippocampal BDNF system. [ABSTRACT FROM AUTHOR]

Increasing evidence has solidified the involvement of α-synuclein (α-Syn) and neurotoxins in the pathogenesis of Parkinson's disease (PD), suggesting a combination of genetic and environmental influences. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on α-Syn aggregation, mitochondrial dysfunction, oxidative stress, and apoptosis in vitro. A53T mutant α-synuclein-transfected cells (A53T AS cells) plus MPP+ exposure were used as a complex cell model of PD. The expression of proteins was determined by Western blot assay. Flow cytometry was utilized to measure mitochondrial membrane potential and apoptosis. The results showed that MPP+ exposure for 24 h induced more severe damage in A53T AS cells than in vector control cells. Pretreatment of TSG for 24 h significantly increased the cell viability; decreased lactate dehydrogenase leakage; inhibited α-Syn over-expression and aggregation; elevated mitochondrial membrane potential; decreased reactive oxygen species, Bax/Bcl-2 ratio, and caspase-3 activity; and inhibited apoptosis in A53T AS cells exposed to MPP+. These results suggest that TSG may be an attractive candidate for PD therapy. [ABSTRACT FROM AUTHOR]

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Macrophage foam cell formation triggered by oxLDL is an important event that occurs during the development of atherosclerosis. 2,3,5,4′-Tetrahydroxystilbene-2- O -β- d -glucoside (TSG) exhibits significant anti-atherosclerotic activity. Herein we used U937 cells induced by PMA and oxLDL in vitro to investigate the inhibitory effects of TSG on U937 differentiation and macrophage foam cell formation. TSG pretreatment markedly inhibited cell differentiation induced by PMA, macrophage apoptosis and foam cell formation induced by oxLDL. The inhibition of vimentin expression and cleavage was involved in these inhibitory effects of TSG. The suppression of vimentin by siRNA in U937 significantly inhibited cell differentiation, apoptosis and foam cell formation. Using inhibitors for TGFβR1 and PI3K, we found that vimentin production in U937 cells is regulated by TGFβ/Smad signaling, but not by PI3K-Akt-mTOR signaling. Meanwhile, TSG pretreatment inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by PMA and oxLDL. Furthermore, TSG attenuated the induced caspase-3 activation and adhesion molecules levels by PMA and oxLDL. PMA and oxLDL increased the co-localization of vimentin with ICAM-1, which was attenuated by pretreatment with TSG. These results suggest that TSG inhibits macrophage foam cell formation through suppressing vimentin expression and cleavage, adhesion molecules expression and vimentin-ICAM-1 co-localization. The interruption of TGFβ/Smad pathway and caspase-3 activation is responsible for the downregulation of TSG on vimentin expression and degradation, respectively. [ABSTRACT FROM AUTHOR]

Vascular smooth muscle cell (VSMC) migration triggered by TNF-α is an important event that occurs during the development of atherosclerosis. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) has been proven to exhibit significant anti-atherosclerotic activity. Herein we investigate the inhibitory effect of TSG on TNF-α-induced VSMC migration and explore the underlying mechanisms. TSG pretreatment markedly inhibited TNF-α-induced cell migration. The inhibition of vimentin redistribution and expression was involved in the inhibitory effect of TSG on VSMC migration. The suppression of vimentin expression by shRNA in VSMCs significantly inhibited TNF-α-induced cell migration. Furthermore, TSG inhibited the TNF-α- induced expression of TGFβ1 and TGFβR1, and phosphorylation of TGFβR1 and Smad2/3. TSG also suppressed the nuclear translocation of Smad4 induced by TNF-α. These results suggest that TSG inhibits VSMC migration induced by TNF-α through inhibiting vimentin rearrangement and expression. The interruption of TGFβ/Smad pathway appears to be responsible for the suppression of TSG on vimentin expression. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) on the memory and movement functions and its mechanisms related to synapses and α-synuclein in aged mice. Methods: The memory ability of mice was detected by step-through passive avoidance task. The movement function was measured by the pole test and rotarod test. Transmission electron microscopy was used to observe the synaptic ultrastructure. Western blotting was applied to measure the expression of synapse-related proteins and α-synuclein. Results: Intragastrical administration of TSG for 3 months significantly improved the memory and movement functions in aged mice. TSG treatment obviously protected the synaptic ultrastructure and increased the number of synaptic connections in the hippocampal CA1 region and striatum; enhanced the expression of synaptophysin, phosphorylated synapsin I and postsynaptic density protein 95 (PSD95), elevated phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) expression, and inhibited the overexpression and aggregation of -synuclein in the hippocampus, striatum and cerebral cortex of aged mice. Conclusion: TSG improved the memory and movement functions in aged mice through protecting synapses and inhibiting α-synuclein overexpression and aggregation in multiple brain regions. The results suggest that TSG may be beneficial to the treatment of ageing-related neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

1. To investigate the effects of tetrahydroxystilbene glucoside (TSG), the main active component of Polygonum multiflorum, on mouse liver cytochrome P450 (Cyp) enzyme protein expressions. Male mice were randomly divided into the control, TSG low (10 mg/kg) and high dose (40 mg/kg) groups. After TSG intragastrical administration for 3, 5 and 7 d, mice were sacrificed and the mouse body and liver weight were detected. The Cyp enzymes and various transcription factors such as AhR, PXR and PPARα protein expressions in mouse livers were measured by Western blotting assay. 2. No significant difference of mouse body and liver weight between the control and TSG treatment groups was detected. Additionally, TSG decreased Cyp1a2 and Cyp2e1 protein expressions after TSG treatment for 3, 5 and 7 d, respectively. Moreover, TSG suppressed Cyp3a11 protein expression after TSG treatment for 5 and 7 d. Furthermore, TSG high dose inhibited AhR and PXR protein expressions after TSG treatment for 5 and 7 d, while both TSG low dose and high dose obviously decreased PPARα protein level from TSG treatment for 3 d. 3. TSG has inhibitory effects on mouse liver Cyp1a2, Cyp2e1 and Cyp3a11 protein expressions through the suppression of AhR, PXR and PPARα activation. [ABSTRACT FROM AUTHOR]

A Chinese herb, Polygonatum multiflorum , has been reported to prolong animal life span, but the relevant molecular mechanism remains unclear. Tetrahydroxystilbene glucoside (TSG) is one main component of P. multiflorum and may contribute to extending life span of mammals. On the other hand, neuronal insulin signaling mediates the life span of mammals. Therefore, we investigated the effects of TSG on memory ability, life span, and the neural insulin signaling in the senescence-accelerated prone mouse (SAMP8). TSG improved the memory ability significantly ( p < 0.01, compared with a control group). TSG prolonged the life span of SAMP8 by 17% at the most ( p < 0.01, compared with a control group). TSG increased the protein level of neural klotho and reduced the levels of neural insulin, insulin-receptor, insulin-like growth factor-1, and insulin-like growth factor-1 receptor in the brain of SAMP8 ( p < 0.01, compared with a control group). All these proteins are key factors of the pathways related to neural insulin/IGF-1 signaling. These findings suggest that TSG has anti-aging effects on mammals. From these results, TSG from P. multiflorum should be developed as a potential anti-age drug. [ABSTRACT FROM AUTHOR]

Introduction. Although doxorubicin (Dox)-induced cardiac toxicity and pegylated liposomal doxorubicin (PLD)–induced hand-foot syndrome (HFS) were reported to be correlated with reactive oxygen species (ROS) generation, there is no effective preventive treatment at present. Therefore, the aim of this study was to investigate whether antioxidants—resveratrol (RSVL), tetrahydroxystilbene glucoside (THSG), curcumin, and the ethanolic extract of Antrodia cinnamomea (EEAC)—have the ability to reduce Dox-induced ROS and have a synergistic anticancer effect with Dox that could prevent those side effects and enhance the efficacy of cancer treatment. Methods. 3T3 normal cells were used as a model to evaluate the effects of these antioxidants in reducing ROS accumulation. Furthermore, the synergistic anticancer effect of antioxidants with Dox on the MCF-7 breast cancer model was also evaluated. Results. Pretreatment of cells with RSVL, curcumin, and EEAC increased the cell antioxidant ability by improving the activity of superoxide dismutase (SOD), prevented or limited intracellular damage, and ameliorated the harmful effects of ROS. Additionally, RSVL, curcumin, and EEAC had synergistic effects with Dox against MCF-7 breast cancer cells. Conclusion. RSVL, curcumin, and EEAC have the potential to be clinically applied to prevent cardiac toxicity and HFS and enhance the anticancer efficiency of Dox. [ABSTRACT FROM PUBLISHER]

Background: Endothelial cell dysfunction triggered by oxidized low-density lipoprotein (oxLDL) is the main event occurring during the development of atherosclerosis. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum, exhibits significant anti-atherosclerotic activity. However, the protective effects of TSG against oxLDL-induced endothelial dysfunction have not been clarified. We investigated the cytoprotective effects of TSG in human umbilical vein endothelial cells (HUVECs) and explored underlying mechanisms. Methods and Results: TSG pretreatment markedly attenuated oxLDL-mediated loss of cell viability, release of lactate dehydrogenase (LDH), cell apoptosis, and monocyte adhesion. OxLDL increased vimentin mRNA and protein levels, vimentin cleavage, caspase-3 activation, adhesion molecules levels and their colocalization with vimentin in HUVECs. These alterations were attenuated by pretreatment with TSG. Meanwhile, TSG inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by oxLDL. Using shRNA, oxLDL-induced cell apoptosis and monocyte adhesion were significantly inhibited by vimentin suppression in HUVECs. Conclusions: These results suggest that TSG protects HUVECs against oxLDL-induced endothelial dysfunction through inhibiting vimentin expression and cleavage, and the expression of adhesion molecules and their colocalization with vimentin. The interruption of TGFβ/Smad pathway and caspase-3 activation appears to be responsible for the downregulation of TSG on vimentin expression and fragmentation, respectively. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Highlights: [•] TSG promoted dopamine neuron survival in MPTP-treated mouse model of PD. [•] The PI3K/Akt signaling pathway may have mediated the protection of TSG against MPTP. [•] TSG has potential as a naturally derived treatment to halt the progression of PD. [ABSTRACT FROM AUTHOR]

Highlights: [•] Tetrahydroxystilbene glucoside (TSG) improved the memory ability of mice. [•] TSG reduced the serum levels of ROS, NO and IGF-1 and increased the levels of SOD, Ca2+ and Klotho protein. [•] TSG up-regulated the expression of Klotho protein in cerebrum, heart, kidney, testis and epididymis tissues. [Copyright &y& Elsevier]

2,3,5,4'-Tetrahydrostilbene-2-o-β-d-glucoside (TSG) is the main active component of Polygonum multiflorum Thunb. It has effects on hypertension. However, the mechanism is unclear. Current research is devoted to exploring the mechanism of TSG improving HHcy-induced hypertension. The mice received a subcutaneous injection of Hcy in the presence or absence of TSG for 4 weeks. Blood pressure (BP) was measured using a noninvasive tail-cuff plethysmography method. Levels of plasma Hcy and endothelin-1 were measured using ELISA. Rat SMA without endothelium was cultured in a serum-free medium in the presence or absence of TSG with or without Hcy. The contractile response to sarafotoxin 6c or endothein-1 was studied using a sensitive myography. The levels of protein were detected using Western blotting. The results showed that TSG lowered HHcy-elevated BP and decreased levels of plasma Hcy and endothelin-1 in mice. Furthermore, the results showed that TSG inhibited Hcy-upregulated ET receptor expression and ET receptor-mediated contractile responses as well as the levels of p-ERK 1/2 and p-p65 in SMA. In vivo results further validate the in vitro results. In conclusion, TSG can decrease the levels of plasma Hcy and ET-1 and downregulate Hcy-upregulated ET receptors in VSMCs by inhibiting the ERK 1/2 /NF-κB/ET B2 pathway to lower the BP., (© 2022 John Wiley & Sons Ltd.)

Abstract: Oxidative stress can induce apoptosis and decrease activities of osteoblasts. 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), is a potent antioxidant derived from a Chinese herb Polygonum multiflorum Thunb. To evaluate the protective effect provided by TSG to osteoblastic MC3T3-E1 cells, the cells were pretreated with TSG for 24h before being treated with 0.3mM hydrogen peroxide (H2O2) for 24h, then some markers of osteoblast function and oxidative damage of the cells were examined. Our data demonstrated that TSG significantly (P< 0.05) increased cell survival, alkaline phosphatase (ALP) activity, calcium deposition, and the mRNA expression of ALP, collagen I (COL-I) and osteocalcin (OCN) in the presence of H2O2. In addition, TSG decreased the production of receptor activator of nuclear factor-κB ligand (RANKL), interleukin-6 (IL-6), intracellular reactive oxygen species and malondialdehyde (MDA) of osteoblastic MC3T3-E1 cells induced by H2O2. Taken together, these results demonstrated that the protective effect provided by TSG to osteoblastic MC3T3-E1 cells was mediated, at least in part, via inhibition of the release of bone-resorbing mediators and oxidative damage of the cells. Our results indicated that TSG may be effective in providing protection against osteoporosis associated with oxidative stress. [Copyright &y& Elsevier]

Abstract: 1-Methyl-4-phenylpyridinium (MPP+), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin for inducing a cell model of Parkinson''s disease. This study aimed to evaluate the effects of 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), an active component extracted from Polygonum multiflorum, on MPP+-induced cytotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells. The results from the MTT and lactate dehydrogenase (LDH) assays showed that incubating cells with 500μM MPP+ for 24h decreased cell viability and increased LDH leakage, whereas preincubating cells with 3.125 to 50μM TSG for 24h protected the cells against MPP+-induced cell damage. Using 2′,7′-dichlorofluorescin diacetate (DCFH-DA) and rhodamine 123, respectively, we found that TSG inhibited both the elevation of intracellular reactive oxygen species and the disruption of mitochondrial membrane potential induced by MPP+. In addition, TSG suppressed both the upregulation of the ratio of Bax to Bcl-2 and the activation of caspase-3 induced by MPP+, and TSG inhibited apoptosis as detected by flow cytometric analysis using Annexin-V and propidium (PI) label. These results suggest that TSG may protect neurons against MPP+-induced cell death through improving mitochondrial function, decreasing oxidative stress and inhibiting apoptosis, and this may provide a potentially new strategy for preventing and treating neurodegenerative disorders such as Parkinson''s disease. [Copyright &y& Elsevier]

Abstract: Oxidative stress plays an important role in the pathogenesis of Parkinson''s disease (PD). 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), which is an active component of the rhizome extract from polygonum multiflorum, shows potent antioxidant properties. In this paper, the neuroprotective effects of TSG on 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis in PC12 cells were investigated. Pretreatment with TSG markedly attenuated MPP+-induced loss of cell viability and release of lactate dehydrogenase (LDH), and reduced MPP+-induced apoptotic cell death in a dose-dependent manner. The anti-apoptotic effects of TSG were probably mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway since TSG failed to rescue cells from MPP+ injury in the presence of the PI3K inhibitor, LY294002. These results indicate that TSG affords a significant neuroprotective effect against MPP+-induced damage and apoptosis in PC12 cells. The PI3K/Akt signaling pathway might be involved in the TSG-mediated anti-apoptotic effects. [Copyright &y& Elsevier]

Abstract: It is known that oxidative stress plays a major role in the progression of Parkinson''s disease (PD). Previous studies have suggested that 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), an active component extracted from a traditional Chinese herb Polygonum multiflorum Thunb., has significant antioxidant and free radical-scavenging activities. This is the first study that investigated the protective effects of TSG against MPP+-induced apoptosis in PC12 cells and determined the underlying mechanism. The results showed that incubation of PC12 cells with TSG before exposing them to MPP+ could significantly decrease cell viability loss and reverse cell apoptosis in a dose-dependent manner. The anti-apoptotic effects of TSG were probably mediated via the inhibition of ROS generation and modulation of JNK activation because TSG blocked ROS increase and JNK phosphorylation induced by MPP+. Taken together, these results indicated that TSG may provide a useful therapeutic strategy for the treatment of neurodegenerative diseases such as PD. [Copyright &y& Elsevier]

Abstract: Many natural polyphenolic compounds have been shown to attenuate reactive oxygen/nitrogen species (ROS/RNS) formation and protect against ischemia/reperfusion injury both in vitro and in vivo. 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum, exhibits antioxidative and anti-inflammatory effects. Here, we used an in vitro ischemic model of oxygen–glucose deprivation followed by reperfusion (OGD-R) and an in vivo ischemic model of middle cerebral artery occlusion (MCAO) to investigate the neuroprotective effects of TSG on ischemia/reperfusion brain injury and the related mechanisms. We demonstrated that OGD-R-induced neuronal injury, intracellular ROS generation, and mitochondrial membrane potential dissipation were reversed by TSG. The elevation of H2O2-induced [Ca2+]i was also attenuated by TSG. Inhibition of the c-Jun N-terminal kinase (JNK) and Bcl-2 family-related apoptotic signaling pathway was involved in the neuroprotection afforded by TSG. Meanwhile, TSG inhibited iNOS mRNA expression induced by OGD-R, which may be mediated by the activation of SIRT1 and inhibition of NF-κB activation. In vivo studies further demonstrated that TSG significantly reduced the brain infarct volume and the number of positive cells by TUNEL staining in the cerebral cortex compared to the MCAO group. Our study indicates that TSG protects against cerebral ischemia/reperfusion injury through multifunctional cytoprotective pathways. [Copyright &y& Elsevier]

Abstract: The aim of the present study is to investigate the changes in hippocampal synapses and their relation with learning-memory abilities at different ages, and evaluate the effects of 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), which is one of the major components of a traditional Chinese herb Polygonum multiflorum, on brain aging. Sprague–Dawley rats at the age of 1, 3, 6, 18 and 24 months were used. TSG at doses of 30 and 60 mg/kg/day was intragastrically administered to 21-month-old rats for 3 months, respectively. Learning-memory abilities were determined by Morris water maze and passageway water maze tests. The ultrastructure of synapses in the hippocampal CA1 region was observed by electronic microscopy. The expression of synaptophysin (SYP) in whole hippocampus was measured by using immunohistochemistry. Compared with rats at 6 months of age, both the 1-month-old rats and 24-month-old rats showed longer escape latency and swimming distance in the Morris water maze test, while more errors were detected in the passageway water maze test, with a smaller number of synapses and synaptic vesicles and less expression of SYP in the hippocampus. Treatment with high-dose TSG in rats at 24 months of age had significant improvement in the learning-memory abilities in the water maze tests associated with an increase in the number of synapses and synaptic vesicles, and an elevation of expression of SYP in the hippocampus. In conclusion, hippocampal synapses count and synaptophysin expression decreased in aged rats, which may be one of the mechanisms involved in learning-memory deficit. TSG reversed the above changes in aged rats, suggesting that TSG may be beneficial for the treatment of Alzheimer disease or cognitive impairment in old people. [Copyright &y& Elsevier]

Abstract: Objective: To investigate learning-memory deficit in different ages of AD-like APP transgenic mice and to observe the protective effects of 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), which is the main component of Polygonum multiflorum, on learning-memory abilities. Methods: PDAPPV717I transgenic (Tg) mice were randomly divided into 3 model groups (4, 10 and 16 months old mice) and TSG treated (at doses 120 and 240μmol/kg/d) groups. TSG was administered to some Tg mice with an age range 4–10 months. In untreated 10 months old Tg mice, the TSG was administrated to those falling in the age range 10–16 months. For the control group we adopted the same age and background C57BL/6J mice. The learning-memory ability was measured by applying Morris water maze (MWM) and object recognition test (ORT). Results: In the 4 months old PDAPPV717I Tg mice, the learning-memory deficit was detected. The escape latency in MWM was prolonged, and the discrimination index decreased in ORT. In the 10 months old Tg mice, the learning-memory deficit was aggravated. TSG improved all spatial learning-memory impairment in MWM as well as the object recognition impairment in ORT. In the 16 months old Tg mice, the learning-memory deficit remained to exist but abated a lot. TSG showed significant improvement in learning-memory ability in both MWM and ORT. Conclusion: PDAPPV717I transgenic mice with an age range 4–16 months revealed the existence of learning-memory deficit compared with the control group. Tetrahydroxystilbene glucoside not only prevents, i.e. at an early stage, the learning-memory deficit in AD-like model, but also can reverse the learning-memory deficit in the late stage of AD-like model. Thus, TSG could be considered among the future therapeutic drugs indicated for the treatment of AD. [Copyright &y& Elsevier]

The idiosyncratic hepatotoxicity of Polygonum multiflorum Thunb. (PM) has attracted great interest, and tetrahydroxy stilbene glucoside (TSG) was the main idiosyncratic hepatotoxicity constituent, but biological detoxification on idiosyncratic hepatotoxicity of PM was not well investigated. This study aimed to illustrate biological detoxification mechanism on PM-induced idiosyncratic hepatotoxicity by Ganoderma lucidum (G. lucidum). G. lucidum was used for biological detoxification of tetrahydroxy stilbene glucoside (TSG)-induced idiosyncratic hepatotoxicity of PM. The TSG consumption and products formation were dynamically determined during transformation using high-performance liquid chromatography coupled with diode-array detection and electrospray ionization tandem mass spectrometry (HPLC-DAD-MSn). The transformation invertases (β -D-glucosidase and lignin peroxidase) were evaluated by using intracellular and extracellular distribution and activity assay. The key functions of lignin peroxidase (LiP) were studied by experiments of adding inhibitors and agonists. The entire TSG transformation process was confirmed in vitro simulated test. The cellular toxicity of TSG and the transformation products was detected by MTT. A suitable biotransformation system of TSG was established with G. lucidum , then p -hydroxybenzaldehyde and 2,3,5-trihydroxybenzaldehyde can be found as transformation products of TSG. The transformation mechanism involves two extracellular enzymes, β -D-glucosidase and LiP. β -D-glucosidase can remove glycosylation of TSG firstly and then LiP can break the double bond of remaining glycosides. The toxicity of TSG after biotransformation by G. lucidum was attenuated. This study would reveal a novel biological detoxification method for PM and explain degradation processes of TSG by enzymic methods. [Display omitted] • The idiosyncratic hepatotoxicity of Polygonum multiflorum Thunb. has attracted great interest. • Ganoderma lucidum can used for biological detoxification of tetrahydroxy stilbene glucoside (TSG) of Polygonum multiflorum. • TSG first formed TSG aglycone, and then formed p -hydroxybenzaldehyde and 2,3,5-trihydroxybenzaldehyde. • β -D-glucosidase can remove glycosylation of TSG firstly and then LiP can break the double bond of remaining glycosides. • The cellular toxicity of TSG was attenuated after biotransformation in vitro. [ABSTRACT FROM AUTHOR]

To investigate the mechanism of the protective effect of tetrahydroxystilbene glucoside (TSG) on nerve cells, an injury model induced by rotenone in PC12 cells was constructed. Cell viability was detected by using cell counting kit-8 (CCK8) assay. Apoptosis was detected by using flow cytometry. The mitochondrial membrane potential (MMP) was detected by using the fluorescent probe JC-1. Generation of reactive oxygen species (ROS) in PC12 cells was determined using the 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester (CM-H 2 DCFDA) probe. Protein expression in PC12 cells was detected using Western blotting. The results showed that TSG (20-100 µM) attenuated the cytotoxic effects of rotenone on PC12 cells. TSG pretreatment attenuated the apoptosis rate, the degradation of poly(ADP-ribose)polymerase (PARP) and the activation of cleaved caspase 3, which was induced by rotenone. TSG can significantly reduce the effect of rotenone on the reduction of MMP and the expression of cytoC in the cytosolic fraction. TSG attenuated rotenone-induced de-phosphorylation and mitochondrial translocation of cofilin, as well as rotenone-induced accumulation of ROS. The Western blot results showed that ROT could decrease the expression level of phosphorylated (p)-Glycogen synthase kinase-3β (GSK)-3β and p-AKT, and TSG could weaken these effects of rotenone. In addition, TSG increased the expression level of nuclear factor-E2-related factor 2 (Nrf2) in the nuclear fraction. These results suggest that TSG could protect PC12 cells against rotenone through multiple pathways. Thus, TSG has the potential to become a novel neuroprotective agent.

• PD is a common neurodegenerative disorder. • NSCs are the most promising cells for cell-replacement therapy for PD. • TSG can induce NSCs differentiation into dopaminergic neurons. • TSG can promote the expression of Wnt/β-catenin signaling molecules. Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are the most promising cells for cell-replacement therapy for PD. However, the poor differentiation and maturation of DA neurons and decreased cell survival after transplantation are a challenge. Tetrahydroxystilbene glucoside (2,3,5,4′-tetrahydroxystilbene-2- O -glucoside; TSG), an active component of the popular traditional Chinese medicinal plant Polygonum multiflorum Thunb, possesses multiple pharmacological actions. In this study, we determined whether TSG can induce neural stem cell (NSCs) differentiation into neurons, especially DA neurons, and the possible involvement of Wnt/β-catenin signaling pathways. Results revealed that NSCs differentiated primarily into astrocytes when cultured in 2 % serum-containing medium. However, TSG treatment during NSC differentiation in vitro increased the number of Tuj-1-positive neurons, as well as the proportion of tyrosine hydroxylase(TH)-positive cells and dopamine- transporter- positive neurons, a late marker of mature DA neurons. We also found that TSG enhanced the expression of nuclear receptor related factor 1, a transcription factor specific for the development and maintenance of midbrain DA neurons in inducing NSC differentiation into TH -immunoreactive DA neurons. Moreover, TSG upregulated the expression of Wnt/β-catenin signaling molecules (Wnt1, Wnt3a, Wnt5a, and β-catenin). However, these promoting effects were significantly inhibited by the application of IWR1, a Wnt signaling-specific blocker in culture. Our findings suggested that TSG may have potential in inducing the DA neuronal differentiation of mouse NSCs mediated by triggering the Wnt/β-catenin signaling pathway. These results indicated the possible role for TSG in the transplantation of NSCs for PD. [ABSTRACT FROM AUTHOR]

Objective: Mitochondrial dysfunction is evident in the early stage of Alzheimer's disease (AD). Therefore development of drugs that protect mitochondrial function is a promising strategy for AD. The present work was to investigate the effects of 2, 3, 5, 4'-Tetrahydroxystilbene-2-O-β-d-glucosides (TSG) on a mitochondrial dysfunction cell model induced by sodium azide and elucidate the underlying mechanisms., Methods: Mitochondrial membrane potential (MMP) was detected by a fluorescence method. Cellular adenosine triphosphate (ATP) level was measured using a firefly luciferase-based kit. Reactive oxygen species (ROS) was detected using dichlorofluorescin diacetate (DCFH-DA). The expression levels of Bcl-2 and Bax were measured by Western blotting assay. Flow cytometry was utilized to measure apoptosis., Results: Pretreatment of TSG (25-200 μmol/L) for 24 h significantly elevated MMP and ATP content, reduced ROS level and Bax/Bcl-2 ratio, and inhibited apoptosis in SH-SY5Y cells exposed to sodium azide., Conclusion: These results suggest that TSG protects SH-SY5Y cells against sodium azide-induced mitochondrial dysfunction and apoptosis. These findings are helpful to understand the protective effect of TSG on mitochondria, which are involved in the early stage of AD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.)