Tetrahydroxystilbene Glucoside Research Articles

Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2

IntroductionAging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now. ObjectivesWe aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms. MethodsWe screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging. ResultsTSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay. ConclusionTSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.

Therapeutic potential of stilbenes in neuropsychiatric and neurological disorders: A comprehensive review of preclinical and clinical evidence.

Neuropsychiatric disorders are anticipated to be a leading health concern in the near future, emphasizing an outstanding need for the development of new effective therapeutics to treat them. Stilbenes, with resveratrol attracting the most attention, are an example of multi-target compounds with promising therapeutic potential for a broad array of neuropsychiatric and neurological conditions. This review is a comprehensive summary of the current state of research on stilbenes in several neuropsychiatric and neurological disorders such as depression, anxiety, schizophrenia, autism spectrum disorders, epilepsy, traumatic brain injury, and neurodegenerative disorders. We describe and discuss the results of both in vitro and in vivo studies. The majority of studies concentrate on resveratrol, with limited findings exploring other stilbenes such as pterostilbene, piceatannol, polydatin, tetrahydroxystilbene glucoside, or synthetic resveratrol derivatives. Overall, although extensive preclinical studies show the potential benefits of stilbenes in various central nervous system disorders, clinical evidence on their therapeutic efficacy is largely missing.

Tetrahydroxy stilbene glycoside ameliorates neuroinflammation for Alzheimer's disease via cGAS-STING

Alzheimer's disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear. In this study, we demonstrated that AD transgenic mice exhibited cognitive deficits accompanied by the elevated serum and brain inflammation. Treating with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) from the Chinese herb Polygonum multiflorum that has been well known for its unique anti-aging effect, learning-memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN-γ induced microglia activation showed that TSG reversed the polarization status of M1-type microglia to restore the quiescence, and cGAS-STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL-1β, IL-6, TNF-α, IFN-α and IFN-β, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN-γ-stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS-STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS-STING inhibitors. Taken together, our findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS-STING signaling pathway in AD.

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.

Tetrahydroxy stilbene glucoside alters neurogenesis and neuroinflammation to ameliorate radiation-associated cognitive disability via AMPK/Tet2

Along with the extensive application of radiation in medical, military and other fields, human beings carry a greater risk of exposure to radiation environment that causes a range of physical injure, particularly to the brain in cognition. However, the radiation-associated cognitive disability is poorly understood and there is no effective prevention or long-term treatment. Here, we demonstrate that neurogenesis and neuroinflammation disorder are primarily involved in the pathophysiological basis of irradiation-induced cognitive decline. Furthermore, we discovered that tetrahydroxy stilbene glucoside (TSG), a natural active ingredient from Heshouwu that has been well known for its unique anti-aging effect as the Chinese herb, can be a promising mitigator to improve learning-memory ability by facilitating the neurogenesis in the proliferation and differentiation of the surviving neural progenitor cells via AMPK/Tet2, and attenuating the neuroinflammation in the microglial NLRP3 inflammasomes activation via AMPK in vivo. Additionally, TSG was also revealed to activate AMPK by molecular docking and kinase enzyme system assay in vitro. Taken together, our findings identify TSG, as the AMPK activator, prevents radiation-induced cognitive dysfunction by regulating neurogenesis and neuroinflammation via AMPK/Tet2 in rodents, and represents a very promising candidate for developing drugs that can be used for radiation-associated brain injury.

Neuroprotective Effects of Tetrahydroxystilbene Glucoside against Rotenone-Induced Toxicity in PC12 Cells.

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-H2DCFDA) 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.

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

Investigation of toxicity attenuation mechanism of tetrahydroxy stilbene glucoside in Polygonum multiflorum Thunb. by Ganoderma lucidum

Ethnopharmacological relevanceThe 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. Aim of the studyThis study aimed to illustrate biological detoxification mechanism on PM-induced idiosyncratic hepatotoxicity by Ganoderma lucidum (G. lucidum). Materials and methodsG. 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. ResultsA 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. ConclusionsThis study would reveal a novel biological detoxification method for PM and explain degradation processes of TSG by enzymic methods.

The Protective Effect of Tetrahydroxystilbene Glucoside on High Glucose-Induced Injury in Human Umbilical Vein Endothelial Cells through the PI3K/Akt/eNOS Pathway and Regulation of Bcl-2/Bax

Endothelial dysfunction plays a central role in the patho­genesis of diabetic vascular complications. 2,3,5,4′-tetra­hydroxystilbene-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.

Investigation of the idiosyncratic hepatotoxicity of Polygonum multiflorum Thunb. through metabolomics using GC-MS

BackgroundThe 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.MethodsSerum 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.ResultsThe 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.ConclusionsThese findings reflect the material basis and metabolic mechanism of idiosyncratic PM hepatotoxicity.

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.

Tetrahydroxystilbene glucoside protects against sodium azide-induced mitochondrial dysfunction in human neuroblastoma cells

ObjectiveMitochondrial 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. MethodsMitochondrial 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. ResultsPretreatment 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. ConclusionThese 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.

Effects of retinoic acid-induced osteoporosis on pharmacokinetics and tissue distribution of 2,3,5,4'-tetrahydroxy stilbene-2-Ο-β-D-glucoside and β-ecdysterone in rats

Background: The compatibility of Radix Polygoni multiflori-Achyranthes (RPMA) root is a Traditional Chinese medicine pair frequently used in the clinic and has good anti-osteoporosis (OP) effects. Materials and Methods: The extract of the compatibility of RPMA root was given orally in this study. The pharmacokinetics and the distribution in the tissues of tetrahydroxystilbene glucoside and β-ecdysterone were considered by high-performance liquid chromatography in OP rats induced by retinoic acid and healthy rats. Quercetin was employed as the internal standard. According to the above results, the effects of Osteoporosis on the process of β-ecdysterone and 2,3,5,4'-tetrahydroxy stilbene 2-Ο-β-D-glucoside in rats were analyzed. Results: The results displayed that the peak time of β-ecdysterone in plasma of OP model rats was earlier and the plasma concentration and pharmacokinetic parameters of tetrahydroxystilbene glucoside in the model group were suggestively different from those in the normal group. The concentration distribution of the two components in each tissue of the model group was significantly diverse from that of the normal group. In particular, the concentrations of the two components in kidney tissue of the model group were inferior than those of the normal group at most time points. Conclusion: It is ventured that the two components may be convoluted in the treatment of OP. This experiment can deliver the reference for the further pharmacodynamic study of the compatibility of RPMA root and the correlation analysis of pharmacodynamics and the content of active ingredients in vivo.

Promotive effects of tetrahydroxystilbene glucoside on the differentiation of neural stem cells from the mesencephalon into dopaminergic neurons

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.

Tetrahydroxystilbene glucoside alleviates angiotensin II induced HUVEC senescence via SIRT1.

Tetrahydroxystilbene glucoside (TSG), an active ingredient of Polygonum multiflorum, has been known for certain anti-aging effects. In this study, the possible protective mechanism of TSG on human umbilical vein endothelial cell (HUVEC) senescence induced by angiotensinII (AngII) was investigated. The results revealed that TSG pretreatment could reduce the percentage of senescence-associated β-galactosidase (SA-β-gal) positive cells and decrease the expression levels of the cellular senescence biomarker proteins p53 and PAI-1. At the same time, the expression of SIRT1 in senescent cells showed an upward trend due to TSG treatment. When inhibiting the expression of SIRT1 by EX527, our results showed that TSG reversed the effect of EX527 by promoting the expression level of SIRT1, reducing the expression of SA-β-gal positive cells and the expression level of p53 and PAI-1 proteins. The present study demonstrated that TSG could protect against HUVEC senescence induced by AngII, potentially through modulation of SIRT1 activity.

A Candidate Drug for Nonalcoholic Fatty Liver Disease: A Review of Pharmacological Activities of Polygoni Multiflori Radix.

Nonalcoholic fatty liver disease, a type of metabolic syndrome, continues to rise globally. Currently, there is no approved drug for its treatment. Improving lifestyle and exercise can alleviate symptoms, but patients' compliance is poor. More and more studies have shown the potential of Polygoni Multiflori Radix (PMR) in the treatment of NAFLD and metabolic syndrome. Therefore, this paper reviews the pharmacological effects of PMR and its main chemical components (tetrahydroxystilbene glucoside, emodin, and resveratrol) on NAFLD. PMR can inhibit the production of fatty acids and promote the decomposition of triglycerides, reduce inflammation, and inhibit the occurrence of liver fibrosis. At the same time, it maintains an oxidation equilibrium status in the body, to achieve the therapeutic purpose of NAFLD and metabolic syndrome. Although more standardized studies and clinical trials are needed to confirm its efficacy, PMR may be a potential drug for the treatment of NAFLD and its complications. However, the occurrence of adverse reactions of PMR has affected its extensive clinical application. Therefore, it is necessary to further study its toxicity mechanism, enhance efficacy and control toxicity, and even reduce toxicity, which will contribute to the safe clinical use of PMR.

P2X7 receptor-targeted regulation by tetrahydroxystilbene glucoside in alcoholic hepatosteatosis: A new strategy towards macrophage-hepatocyte crosstalk.

Regulating macrophage-hepatocyte crosstalk through P2X7 receptors has led to new pharmacological strategies to reverse alcoholic hepatosteatosis. We investigated how tetrahydroxystilbene glucoside (2354glu), isolated from Polygonum multiflorum, modulates macrophage-hepatocyte crosstalk during alcoholic hepatosteatosis. A model of alcoholic hepatosteatosis was established by giving ethanol intragastrically to C57BL/6 mice. HepG2 cells were incubated in conditioned medium from LPS+ATP-activated THP-1 human macrophages with silenced or overexpressed P2X7 receptors. THP-1 macrophages or mouse peritoneal macrophages were pretreated with 2354glu for 1 hr prior to LPS+ATP stimulation. Western blots, RT-PCR and immunohistochemical analysis were used, along with over-expression and silencing of P2X7 receptors. Knockdown or overexpression of P2X7 receptors in THP-1 macrophages affected release of mature IL-1β and, subsequently, modulated lipid metabolism in HepG2 cells via the LKB-AMPK pathway. 2354glu ameliorated alcoholic hepatosteatosis in mice by regulating LKB1-AMPK-SREBP1 pathway and its target genes. Suppression of P2X7 receptor activation by 2354glu inhibited IL-1β release and reduced macrophage and neutrophil infiltration. In macrophages stimulated with LPS+ATP, expression of P2X7 receptors, caspase-1 and NF-κB, release of IL-1β, calcium influx and PI uptake were reduced by 2354glu. SIRT1-LKB1-AMPK-SREBP1 axis-mediated lipid accumulation in HepG2 cells was reduced when they were cultured with conditioned media from LPS+ATP-activated THP-1 macrophages pretreated with 2354glu. Modulation of P2X7 receptors in macrophages regulated lipid accumulation in hepatocytes during alcoholic hepatosteatosis. 2354glu might be a promising candidate that targets P2X7 receptors in macrophages interacting with hepatocytes during alcoholic hepatosteatosis.

Tetrahydroxystilbene Glucoside Ameliorates Infrasound-Induced Central Nervous System (CNS) Injury by Improving Antioxidant and Anti-Inflammatory Capacity.

Background Infrasound is a major threat to global health by causing injuries of the central nervous system (CNS). However, there remains no effective therapeutic agent for preventing infrasound-caused CNS injury. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glycoside (THSG) exerts protective function against CNS injuries and may have beneficial effects on infrasound-induced CNS impairment. Methods A mouse model with CNS (oxidative stress-induced inflammation and neuronal apoptosis) injuries was established when the mouse was exposed to the infrasound of 16 Hz at 130 dB for 2 h each day and the duration of treatment was 8 d. The mice were divided into the control (CG, healthy mice), the model (MG, model mice), and the THSG (EG, experimental group, model mice treated with THSG) groups. The learning and memory impairments caused by infrasound were examined using a Morris water maze test. Lipid profiles, antioxidant biomarkers, and inflammatory cytokines in hippocampus tissue were measured by using corresponding ELISA kits. Meanwhile, BCL-2/BAX/caspase-3 signaling pathway was measured in the hippocampi and prefrontal cortex of the mouse brain using real-time qPCR and Western blot. Nissl's stain was used to measure neuronal necrosis in the hippocampi and prefrontal cortex of the mouse brain. Results THSG significantly ameliorated the learning and memory impairments caused by infrasound. On the other hand, THSG improved lipid profiles, increased antioxidant properties by affecting the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA), and displayed anti-inflammatory action via the downregulation of IL- (interleukin-) 6, IL-8, IL-10, TNF- (tumor necrosis factor-) α, and hs-CRP (high-sensitivity C-reactive protein) in the hippocampal tissues of the mouse model (P < 0.05). Additionally, Nissl's stain showed that THSG inhibited infrasound-induced neuronal necrosis in the hippocampi and prefrontal cortex. Besides, THSG exerted antiapoptosis function by upregulating the level of Bcl-2 and downregulating the levels of BAX and caspase-3 in the hippocampi. Conclusion THSG may be an effective anti-infrasound drug against CNS injury by improving antioxidant, anti-inflammatory, antiapoptosis, and antinecrosis capacities. Further research is still needed to confirm the exact molecular mechanism.

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.