Effects Of Tetrahydroxystilbene Glucoside Research Articles

Anti-atherosclerotic effect of tetrahydroxy stilbene glucoside via dual-targeting of hepatic lipid metabolisms and aortic M2 macrophage polarization in ApoE-/- mice

Tetrahydroxy stilbene glucoside (TSG) is a water-soluble natural product that has shown potential in treating atherosclerosis (AS). However, its underlying mechanisms remain unclear. Here, we demonstrate that an 8-week TSG treatment (100 mg/kg/d) significantly reduces atherosclerotic lesions and alleviates dyslipidemia symptoms in ApoE-/- mice. 1H nuclear magnetic resonance metabolomic analysis reveals differences in both lipid components and water-soluble metabolites in the livers of AS mice compared to control groups, and TSG treatment shifts the metabolic profiles of AS mice towards a normal state. At the transcriptional level, TSG significantly restores the expression of fatty acid metabolism-related genes (Srepb-1c, Fasn, Scd1, Gpat1, Dgat1, Pparα and Cpt1α), and regulates the expression levels of disturbed cholesterol metabolism-related genes (Srebp2, Hmgcr, Ldlr, Acat1, Acat2 and Cyp7a1) associated with lipid metabolism. Furthermore, at the cellular level, TSG remarkably polarizes aortic macrophages to their M2 phenotype. Our data demonstrate that TSG alleviates arthrosclerosis by dual-targeting to hepatic lipid metabolism and aortic M2 macrophage polarization in ApoE-/- mice, with significant implications for translational medicine and the treatment of AS using natural products.

Tetrahydroxystilbene Glucoside Attenuates Oxidative Stress-Induced Aging by Regulating Oxidation Resistance and Inflammation in Larval Zebrafish.

Population aging is a global problem worldwide, and the discovery of antiaging drugs and knowledge of their potential molecular mechanisms are research hotspots in biomedical field. Tetrahydroxystilbene glucoside (TSG) is a natural component isolated from Heshouwu (Polygonum multiflorum Thunb.). It has been widely used to treat various chronic diseases for its remarkable biological activities. In this study, we successfully established aging larval zebrafish by exposing larvae to 2 mM hydrogen peroxide (H2O2). Using this aging model, we assessed the antiaging effect of TSG with different concentrations (25-100 μg/mL). After being treated with H2O2, zebrafish showed the obvious aging-associated phenotypes characterized by higher senescence-associated β-galactosidase activity, significantly downregulated expression of sirtuin 1 (sirt1) and telomerase reverse transcriptase (tert), and upregulated serpine1 mRNA level compared to the control group. TSG pretreatment delayed the aging process of oxidative stress-induced zebrafish, indicative of the reduced positive rate of senescence-associated β-galactosidase, improved swimming velocity, and stimulus-response capacity. Further studies proved that TSG could suppress reactive oxygen species production and enhance the activity of antioxidant enzymes superoxide dismutase and catalase. TSG also inhibited the H2O2-induced expressions of inflammation-related genes il-1β, il-6, cxcl-c1c, and il-8 in aging zebrafish, but it did not affect apoptosis-related genes (bcl-2, bax, and caspase-3) of aging zebrafish. In conclusion, TSG can protect against aging by regulating the antioxidative genes and enzyme activity, as well as inflammation in larval zebrafish, providing insight into the application of TSG for clinical treatment of aging or aging-related diseases.

Tetrahydroxy Stilbene Glucoside Alleviates Ischemic Stroke by Regulating Conformation-Dependent Intracellular Distribution of PKM2 for M2 Macrophage Polarization.

Tetrahydroxy stilbene glucoside (TSG) is a bioactive ingredient with powerful anti-inflammatory and neuroprotective properties. However, the detailed mechanisms concerning the neuroprotective effect of TSG are not fully understood. This study aims to address the molecular mechanism involved in the protective effects of TSG on murine ischemic stroke. We found that TSG meliorated the phenotypes of ischemic stroke in vivo, which was correlated with the increased percentage of infiltrated M2 macrophages in brain after stroke. Mechanistically, TSG regulated macrophage polarization by significantly downregulating the transcriptional levels of M1 marker genes (iNOS and IL-1β) but upregulating that of the M2 marker genes (arg-1 and IL-4) following lipopolysaccharide/interferon-γ stimulation. Consistently, TSG reversed the metabolic profiling of M1 macrophage toward the M2 status at intracellular energy levels. Surprisingly, the knockdown of an established metabolic enzyme pyruvate kinase M2 (PKM2) that is important for M1 switch in macrophages abolished the promotive effect of TSG on the M2 polarization. Further investigation revealed that TSG markedly downregulated the intracellular ratio of dimer/monomer to the tetramer of PKM2 without affecting its total protein expression, leading to a suppressed nuclear translocation of functioning PKM2 in macrophages for M1 differentiation. Taken together, we identified a novel mechanism for macrophage M2 polarization regulation by a small-molecule chemical that controls the quality (conformation) rather than the quantity (expression) of an intracellular M1-promoting metabolic enzyme, which offers a better understanding of the mechanisms of macrophage plasticity and has serious implication in translational strategies for the treatment of macrophage-mediated neurological diseases with natural bioactive products.

Effects of Tetrahydroxystilbene Glucoside on VEGF and MMP-9 Protein Expression in Kidney Tissues of Rats with Diabetic Nephropathy

Effects of Tetrahydroxystilbene Glucoside on VEGF and MMP-9 Protein Expression in Kidney Tissues of Rats with Diabetic Nephropathy

Tetrahydroxy Stilbene Glucoside Ameliorates Cognitive Impairments and Pathology in APP/PS1 Transgenic Mice.

Cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD), and amyloid-β (Aβ) deposition and senile plaques are the characteristic neuropathological hallmarks in AD brains. This study aimed to explore the effect and mechanism of tetrahydroxy stilbene glucoside (TSG) on cognitive function in APP/PS1 mice during long-term administration. Here, we treated APP/PS1 model mice of AD with different doses of TSG (50 mg/kg and 100 mg/kg) for 5 to 17 months by gavage, and we further observed whether TSG could ameliorate the cognitive decline in APP/PS1 mice using behavioral tests, and investigated the possible mechanisms by immunohistochemistry and Western blotting. Our results showed that TSG treatment rescued the spatial and non-spatial learning and memory impairments of APP/PS1 mice at Morris water maze test and novel object recognition test. Furthermore, Aβ40/42 deposition in the cortex and hippocampus of APP/PS1 mice treated with TSG was significantly reduced compared to the wild type mice using the immunohistochemical technique. Finally, Western blotting showed that TSG primarily decreased the APP expression to avoid the Aβ plaque deposition in the cortex and hippocampus of mice. These results reveal the beneficial effects of TSG in APP/PS1-AD mice, which may be associated with the reduction of Aβ deposits in the brain.

PARP1 might enhance the therapeutic effect of tetrahydroxystilbene glucoside in traumatic brain injury via inhibition of Ras/JNK signalling pathway.

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.

Tetrahydroxy stilbene glucoside protected against diabetes‐induced osteoporosis in mice with streptozotocin‐induced hyperglycemia

Tetrahydroxy stilbene glucoside (TSG), an active component from medicinal herb Polygonum multiflorum Thunb, could block the activity of the tissue renin-angiotensin system (RAS), which plays a critical role in development of diabetic osteoporosis. This study aimed to determine if TSG therapy could alleviate bone deteriorations in diabetic mouse model induced by streptozotocin. The diabetic mice showed the loss of trabecular bone mass and the changes of trabecular bone microarchitectural parameters as well as the increase in amount of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts at the distal metaphysis of femur when compared with those of nondiabetic mice. Treatment with TSG significantly elevated calcium content in serum and bone and improved biological parameters of trabecular bone, accompanied by increasing messenger RNA (mRNA) expression of RUNX-2, COL-I, and OCN and protein expression of β-catenin as well as down-regulating protein expression of RAS components including renin and AT1R. In addition, TSG repressed diabetes-induced decrease in ratio of OPG/RANKL expression and increase in sclerostin expression in bone. The similar effects of TSG on osteoblasts-specific genes were found in MC3T3-E1 cells. Taken together, the present study demonstrated the osteopreserve effects of TSG in diabetic mice, and the underlying mechanism might be attributed to its regulation on osteogenesis and osteoclastogenesis.

Tetrahydroxystilbene glucoside-induced relaxation of the superior mesenteric artery via both endothelium-dependent and endothelium-independent mechanisms

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 TXA2. 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 TXA2 and through an endothelium-independent pathway via opening of a voltage-dependent K+ channel, blockade of Ca2+ influx and release of intracellular Ca2+.

Cognitive enhancing and antioxidant effects of tetrahydroxystilbene glucoside in Aβ1-42-induced neurodegeneration in mice

Cognitive enhancing and antioxidant effects of tetrahydroxystilbene glucoside in Aβ1-42-induced neurodegeneration in mice

Dual modulation on glial cells by tetrahydroxystilbene glucoside protects against dopamine neuronal loss

BackgroundMicroglia-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.MethodsSubstantia 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.ResultsDaily 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.ConclusionsTSG 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.

Effects of tetrahydroxy-stilbene glucoside on cognitive and motor functions, alpha-synuclein aggregation and synapse in transgenic mice and in aged mice

Effects of tetrahydroxy-stilbene glucoside on cognitive and motor functions, alpha-synuclein aggregation and synapse in transgenic mice and in aged mice

Tetrahydroxystilbene Glucoside (TSG) Restores the Effect of Transient Hypoxia on Reperfusion Injury in Senescent H9c2 Cells by Regulating Mitochondrial Energy Metabolism.

Tetrahydroxystilbene glucoside (TSG) is extracted from a famous Chinese herbal medicine which is widely used as an antiaging agent in history. Lots of studies gave evidence that TSG exhibited benefits to brain, like improvement of learning and memory and synaptic plasticity. Moreover, the polyphenolic structure of TSG enables its capability to prevent cerebral ischemia/reperfusion injury (IRI) by reducing apoptosis and ROS/RNS generation. Due to its antioxidant profile, TSG had been demonstrated to alleviate cardiac toxicity by regulating biochemical indexes and ROS. However, whether TSG exhibited cardioprotective effects via mitochondrial energy metabolic functions, which played crucial role in IRI, remained unclear. Here, we used an in vitro aging model of cardiomyocytes to evaluate the effects of TSG on transient hypoxia-pretreated hypoxia/reoxygenation (H/R) injury and mitochondrial energy metaolism. Our results showed that TSG enhanced cardioprotective effect of transient hypoxia on H/R by reducing excessive ROS production and calcium overloading. Significant improvements of mitochondrial respiratory functions and ketone body metabolism elucidated that TSG restored the effect of transient hypoxia on H/R injury in aging cardiomyocytes via upregulating mitochondrial energy metabolism.

Tetrahydroxystilbene glucoside modulates amyloid precursor protein processing via activation of AKT-GSK3β pathway in cells and in APP/PS1 transgenic mice

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.

Potential molecular mechanisms mediating the protective effects of tetrahydroxystilbene glucoside on MPP+-induced PC12 cell apoptosis.

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.

Tetrahydroxy stilbene glucoside ameliorates H2O2-induced human brain microvascular endothelial cell dysfunction invitro by inhibiting oxidative stress and inflammatory responses.

Tetrahydroxy stilbene glucoside (TSG) is one of the main active ingredients of Polygonum multiflorum and performs various types of biological activity, particularly anti-inflammatory and anti-oxidative activities. However, the beneficial effect of TSG in H2O2-induced human brain microvascular endothelial cell (HBMEC) dysfunction has not been fully elucidated. In the present study, H2O2-induced oxidative stress and inflammatory responses, and the pharmacological effect of TSG were investigated. The results demonstrated that H2O2 appeared to exert a cytotoxic effect on HBMECs, as the cell viability was significantly inhibited in H2O2-treated HBMECs. Conversely, TSG did not exert a toxic effect on HBMECs, and TSG inhibited H2O2-induced HBMEC cytotoxicity in a dose-dependent manner. Furthermore, the findings indicated that TSG restricted the oxidative stress caused by H2O2 via inhibition of malondialdehyde and reactive oxygen species, and upregulation of superoxide dismutase and glutathione. H2O2-induced injury was associated with enhancing the levels of inflammatory cytokines, tumor necrosis factor-α, interleukin (IL)-6 and IL-1β in the cultured HBMECs, which were attenuated by TSG treatment. Furthermore, the findings demonstrated that TSG inhibited necrosis factor-κB protein expression levels, which, as an upstream transcription factor, may regulate inflammatory responses. Thus, TSG protected HBMECs from H2O2-induced dysfunction by inhibiting oxidative stress and inflammatory responses.

Effects of Tetrahydroxystilbene Glucoside on Liver P450 Enzym e Expressions in Lipopolysaccharide-induced Dopamine Neuronal Dama ge Rats

Background: Tetrahydroxystilbene glucoside (TSG), the main active ingredient derived from the dried tubor root of Polygonum multiflorum, presents different pharmacological activities such as anti-oxidant and anti-inflammation. Recent studies indicated that TSG produced neuroprotection against Parkinson’s disease (PD). However, few researches focusing on the effects of TSG on the liver cytochrome P450 (Cyp) enzyme expressions in PD animal model were also shown. Keywords: Tetrahydroxystilbene glucoside, rat liver, dopaminergic neuronal damage, cytochrome P450, protein expression, rats.

Antidepressant-like effects of tetrahydroxystilbene glucoside in mice: Involvement of BDNF signaling cascade in the hippocampus.

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. 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. 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. In conclusion, TSG produces antidepressant-like effects in mice via enhancement of the hippocampal BDNF system.

Heavy metal recovery through nanoparticle synthesis

Amyloid-beta peptide (Aβ) ranks as a pivotal cause of Alzheimer’s disease (AD), a common devastating dementia form in elderly. Recent research corroborated the beneficial roles of tetrahydroxystilbene glucoside (TSG) in alleviating the learning and memory of AD model and aged mice. Unfortunately, the underlying mechanism remains poorly elucidated. Here, treatment with non-toxic TSG dose-dependently antagonized Aβ-induced cytotoxic death in hippocampal neuronal cells by increasing cell viability and decreasing cell apoptosis. Furthermore, TSG also alleviated cell oxidative stress injury in response to Aβ by attenuating lactate dehydrogenase (LDH) release, ROS levels and MDA leakage. Importantly, TSG administration abrogated Aβ-triggered loss of mitochondrial membrane potential (Δym), release of cytochrome c from mitochondrial to cytosol, increase in caspase-3 activity and pro-apoptotic protein Bax, and decrease in Bcl-2 protein, indicating that TSG could rescue mitochondrial dysfunctions of neuron cells under adverse Aβ condition. Subsequently, TSG induced the activation of Nrf2-HO-1 pathway. Importantly, blocking this pathway by si-Nrf2 transfection or HO-1 antagonist ZnPP notably muted the cytoprotective effects of TSG on neuronal cell cytotoxic injury upon Aβ stimulation. Together, this research substantiated a new mechanism that TSG protectively antagonized Aβ-induced hippocampal neuronal cell damage by restoring mitochondrial function via Nrf2-HO-1 pathway, implying a promising candidate against neurodegenerative diseases including AD.

Tetrahydroxystilbene Glucoside Improves Neurotrophic Factors Release in Cultured Astroglia.

Tetrahydroxystilbene glucoside (TSG), one of the main ingredients of Polygonum multiflorum, has a great number of beneficial effects for health including anti-oxidant, free radicalscavenging and anti-inflammatory properties. However, the potential effects of TSG on neurotrophic factors release remain unclear. In this study, rat primary astroglia cultures were applied to investigate TSG-mediated neurotrophic effects. The protein levels and production of glial cell-line derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in astroglia and the culture medium were determined by western blotting assay and ELISA, respectively. Results indicated that TSG increased the production of neurotrophic factors in a concentration-dependent manner. At different time points of TSG treatment, the BDNF and NGF production in the culture medium was increased 48 h after treatment, while GDNF secretion was initially induced 24 h after TSG treatment. Consistent with the neurotrophic factors release, TSG significantly increased the BDNF, GDNF and NGF protein expressions in astroglia. Furthermore, TSG significantly induced the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and a specific ERK inhibitor-U0126 inhibited TSG-mediated secretion of BDNF, GDNF and NGF. Overall, this study demonstrated that TSG induces astroglia-derived neurotrophic factors release, suggesting TSG might hold a therapeutic potential for neurological disorders.

Protective effect of tetrahydroxy stilbene glucoside on learning and memory by regulating synaptic plasticity.

Damage to synaptic plasticity induced by neurotoxicity of amyloid-beta is regarded to be one of the pathological mechanisms of learning and memory disabilities in Alzheimer's disease patients. This study assumed that the damage of amyloid-beta to learning and memory abilities was strongly associated with the changes in the Fyn/N-methyl-D-aspartate receptor 2B (NR2B) expression. An APP695V7171 transgenic mouse model of Alzheimer's disease was used and treatment with tetrahydroxy-stilbene glucoside was administered intragastrically. Results showed that intragastric administration of tetrahydroxy-stilbene glucoside improved the learning and memory abilities of the transgenic mice through increasing NR2B receptors and Fyn expression. It also reversed parameters for synaptic interface structure of gray type I. These findings indicate that tetrahydroxy stilbene glucoside has protective effects on the brain, and has prospects for its clinical application to improve the learning and memory abilities and treat Alzheimer's disease.