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Background: Polygonum multiflorum (PM), a widely used traditional Chinese medicine herb, is divided into two forms, namely raw polygonum multiflorum (RPM) and polygonum multiflorum praeparata (PMP), according to the processing procedure. Emerging data has revealed the differential hepatotoxicity of RPM and PMP, however, its potential mechanism is still unclear., Methods: In our study, we investigated the differential hepatotoxicity of RPM and PMP exerted in C57BL/6 mice. First, sera were collected for biochemical analysis and HE staining was applied to examine the morphological alternation of the liver. Then we treated L02 cells with 5 mg / mL of RPM or PMP. The CCK8 and EdU assays were utilized to observe the viability and proliferation of L02 cells. RNA sequencing was performed to explore the expression profile of L02 cells. Western blotting was performed to detect the expression level of ferroptosis-related protein. Flow cytometry was used to evaluate ROS accumulation., Results: In our study, a significant elevation in serum ALT, AST and TBIL levels was investigated in the RMP group, while no significant differences were observed in the PMP group, compared to that of the CON group. HE staining showed punctate necrosis, inflammatory cell infiltration and structural destruction can be observed in the RPM group, which can be significantly attenuated after processing. In addition, we also found RPM could decrease the viability and proliferation capacity of L02 cells, which can be reversed by ferroptosis inhibitor. RNA sequencing data revealed the adverse effect of PM exerted on the liver is closely associated with ferroptosis. Western blotting assay uncovered the protein level of GPX4, HO-1 and FTL was sharply decreased, while the ROS content was dramatically elevated in L02 cells treated with RPM, which can be partially restored after processing., Conclusions: The hepatotoxicity induced by RPM was significantly lower than the PMP, and its potential mechanism is associated with ferroptosis., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Polygoni Multiflori Radix Praeparata (Zhiheshouwu) has been a Wudang Taoist medicine for tonifying the liver and kidney, resolving turbidity and reducing lipid. Emodin is one of the active anthraquinones in Zhiheshouwu. Our previous studies showed that emodin (EM) and the other anthraquinones in Zhiheshouwu extract (HSWE) exerted similar inhibitory effects on liver cancer cells in vitro. However, it is still unknown if the other anthraquinones enhance pharmacokinetics (PK) of EM in HSWE in vivo., Aim of the Study: In this study, we compared the PK characteristics of EM alone with that in Zhiheshouwu aiming to explore which anthraquinones in HSWE contribute to the changed PK of EM in rats., Materials and Methods: Quality control of HSWE was determined using high performance liquid chromatography (HPLC). The ratios of emodin to other anthraquinones, physcion (PH), chrysophanol (CH), rhein (RH), aloe-emodin (AE), emodin-8-O-β-D-glycoside (EMG), physcion-1-O-β-D-glycoside (PHG) and chrysophanol-8-O-β-D-glycoside (CHG) in HSWE were determined and analyzed using UPLC combined with tandem mass spectrometry (UPLC/MS). The PK parameters and intestinal tissue concentration of EM alone, EM in HSWE, or with other anthraquinones in SD rats were analyzed using UPLC/MS., Results: The quality of the Zhiheshouwu samples met the quality standard of the Chinese Pharmacopoeia (Version 2020). The PK results showed that compared with EM alone, C max (239.90 ± 146.71 vs. 898.46 ± 291.62, P < 0.001), T max (0.26 ± 0.15 vs. 12.55 ± 1.33, P < 0.001), AUC 0-t (1575.09 ± 570.46 vs. 12154.96 ± 5394.25, P < 0.001), and AUC 0-∞ (4742.51 ± 1837.62 vs. 37131.34 ± 21647.39, P < 0.001) of EM in HSWE were decreased due to PH and EMG, while the values of V d (380.75 ± 217.74 vs. 11.75 ± 7.35, P < 0.001), T 1/2 (10.81 ± 1.99 vs. 6.65 ± 2.76, P < 0.05) and CL (19.30 ± 7.82 vs. 2.78 ± 1.88, P < 0.001) of EM in HSWE were increased due to PH and AE. In addition, the intestinal tissue concentration of emodin in HSWE was decreased compared with that of EM alone in 20 and 780 min (25.37 ± 5.98 vs. 43.29 ± 4.16 and 26.72 ± 4.03 vs. 43.40 ± 14.19, respectively. P < 0.05) dominantly due to RH and PH., Conclusion: In conclusion, compared with treatment of EM alone, the AUC 0-t value of EM in HSWE was decreased with different ways in rats. PH shortened T max , and increased V d and CL. While AE prolonged T 1/2 of EM. This indicated that the other anthraquinones in HSWE changed the PK of EM in rats and participated in the complex effects of EM on liver cancer. Besides the other anthraquinones, other components (e.g., 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside) in Zhiheshouwu may contribute in the pharmacokinetic and pharmacodynamic interactions with EM for anti-liver cancer., Competing Interests: Declaration of competing interest 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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The roots of Polygonum multiflorum (PM) serve as a classical traditional Chinese medicine (TCM), which has multiple biological activities. However, many cases of hepatotoxicity in PM have been reported in recent years. Processing PM with black beans decoction is one of the typical processing methods to reduce the hepatotoxicity of PM since ancient times., Objectives: To find potential effective constituents, as well as the optimal variety and origin of black beans for the processing of PM., Methods: Based on ultrahigh-performance liquid chromatography Q-Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS) analysis, we measured the contents of the two potential toxic compounds (emodin-8-O-glucoside and torachrysone-O-hexose) in raw PM (R-PM), PM processed with big black beans (B-PM) and PM processed with small black beans (S-PM). The flow cytometry method analysed the effects of different processed products of PM on apoptosis of L02 cells in different drug concentration. Proton nuclear magnetic resonance ( 1 H-NMR) and UHPLC-Q-Orbitrap-MS together with multivariate statistical analysis were used to systematically analyse the different components between small black beans (Small-BB) and big black beans (Big-BB) from 30 different habitats., Results: The toxicity was ranked from small to large: S-PM < B-PM < R-PM. Processing PM with black beans could significantly decrease the apoptosis rate of L02 cells, especially when the drug concentration is 80 μg/mL. Besides, we find five differential compounds (α-arabinose, α-galactose, proline, isomer of daidzein and isomer of genistein) may be potential active ingredients. In terms of the black beans collected from 30 producing areas, we find that Small-BB from Weifang in Shandong province was optimum to processing PM, followed by Shangqiu in Henan province, Jilin and Liaoning province., Conclusion: The ingredients that affect the processing of PM may be attributed to α-arabinose, α-galactose, proline, isomer of daidzein and isomer of genistein in black beans. When the drug concentration is higher, the effect of reducing the hepatotoxicity of PM is better. Besides, Small-BB was more effective than Big-BB for reducing the toxicity of PM, especially Small-BB from Weifang in Shandong, Shangqiu in Henan province and northeast China., (© 2020 John Wiley & Sons, Ltd.)

In this study, we aimed to establish a rat liver micro-tissue evaluation system to evaluate the hepatotoxicity of the main monomers in Polygonum multiflorum. Rat primary hepatocytes were isolated and purified by two-step in situ perfusion method to prepare hepatic parenchymal cells. The ultra-low adsorption plate and the inverted model were used to establish an in vitro hepatotoxicity evaluation system. After the system was established, the main monomer components(monanthone with emodin type, rhein, emodin, emodin-8-O-β-D-glucopyranoside, physcion) of P. multiflorum were selected for in vitro hepatotoxicity evaluation. This study showed that the primary cells of the liver can form liver micro-tissues in the low adsorption plate method and the mold perfusion method, with good liver structure and function, which can be used to evaluate the hepatotoxicity of the drug to be tested after long-term administration. The five monomers to be tested in P. multiflorum can significantly affect the proliferation of primary liver micro-tissues in rats in a dose-and time-dependent manner. The hepatotoxic effects were as follows: monanthone with emodin type &gt; rhein &gt; emodin &gt; emodin-8-O-β-D-glucopyranoside &gt; physcion. The results suggested that the emodin-type monoterpene and rhein might be the potential hepatotoxic components, while the metabolites of emodin-8-O-β-D-glucoside and emodin methyl ether showed more toxic risks. The rat primary hepatocyte micro-tissue model system established in this experiment could be used to achieve long-term drug administration in vitro, which was consistent with the clinical features of liver injury caused by long-term use of P. multiflorum. The experimental results provided important information and reference on the clinical application and toxic component of P. multiflorum.

This study focused on the differential metabolomic effects between water extracts of Polygoni Multiflori Radix and Polygoni Multiflori Radix Preparata in rats. The extracts were subsequently administered for 28 d. Serum biochemical indicators were tested, hematoxylin-eosin staining and immunohistochemistry staining were used to detect histopathological changes in the livers. Ultra-performance LC/quadrupole time-of-flight mass spectrometry was used to detect the changes in endogenous metabolites. Finally, we performed detailed analysis of the changes in metabolic pathways. Hematoxylin-eosin staining and immunohistochemistry staining results indicated that the water extracts of Polygoni Multiflori Radix and Polygoni Multiflori Radix Preparata had mild liver injury effect. Fifty-two differential endogenous biomarkers were confirmed as potential biomarkers between Polygoni Multiflori Radix and Polygoni Multiflori Radix Preparata groups. In the positive ion mode, the biomarkers included 31 Phosphatidyl cholines (PCs), six lysoPCs, and ceramide. In the negative ion mode, 12 biomarkers were confirmed, including glycodeoxycholic acid, chenodeoxycholic acid, and deoxycholic acid, etc. In Hydrophilic Interaction Liquid Chromatography (HILIC) mode, nine biomarkers were confirmed, including niacinamide, L-palmitoylcarnitine, and butyrylcarnitine, etc. Using MetaboAnalyst 4.0, six related metabolic pathways, including taurine and hypotaurine metabolism, sphingolipid metabolism, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism, arginine and proline metabolism, and tryptophan metabolism and primary bile synthesis, were confirmed as the most differential pathways between the Polygoni Multiflori Radix and Polygoni Multiflori Radix Preparata groups.

To explore the immune status of patients with drug-induced liver injury caused by Polygonum multiflorum preparations,and analyze their immune characteristics. Case-control design was used to collect the cases of drug-induced liver injury caused by P. multiflorum preparations through key specialized surveillance. Five matching factors,namely type of P. multiflorum preparations,gender,age,basic diseases and concomitant medication were controlled. According to the ratio of 1 ∶ 1,cases of patients who took P. multiflorum preparations but with no liver injury were monitored at prospective hospitals. The demographic information,disease information,medication information and laboratory examination information of the two groups were recorded,and venous blood was collected. The gene sequence was detected by high-throughput sequencing technology,and the characteristics of TCR immune repertoire of the two groups were analyzed. A total of 46 pairs of patients were enrolled in the study. The results showed significant differences in the number of CDR3 and clone species,the length of amino acid sequence in CDR3 region,the abundance of V gene and J gene,the cross-linking of V-J gene and the diversity of immune repertoire between patients with drug-induced liver injury and patients without liver injury. The immunohistochemical diversity and high-frequency V-J cross-linking characteristics of patients with liver injury caused by P. multiflorum preparations were found,which provided a reference for screening out drug users to reduce the occurrence of liver injury caused by P. multiflorum preparations.

Currently, an increasing number of patients are seriously affected by acute thrombotic events. In China, Polygonum multiflorum (PM) is commonly used to treat diseases associated with thrombosis. Our previous work showed that PM could inhibit the platelet aggregation that plays a key role in the pathogenesis of thrombosis. However, the constituents of PM are complicated, and quality control methods cannot completely ensure the quality and clinical efficacy. In an attempts to explore this problem, we constructed a direct bioassay method to evaluate the antiplatelet aggregation effects of PM. To ensure the precision and reliability of this bioassay, we optimized and standardized the experimental conditions and then tested the standardized bioassay by analyzing 10 PM samples. Additionally, we combined chemical and biological evaluation methods to identify antiplatelet aggregation markers. The evaluation indicated that 10 samples of PM could inhibit platelet aggregation and there was a notable difference in biopotency between the different PM groups. Chemical fingerprints revealed variations in the contents of the 7 main peaks. Trans-2,3,5,4'-tetrahydroxy-stilbene-2-O-β-d-glucoside and catechin might be active constituents of antiplatelet aggregation as determined by spectrum-effect relationships. This work indicates that bioassay and spectrum-effect relationships are useful tools to associate sample quality with the potential chemical markers linked to the clinical effects of Traditional Chinese Medicines., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rapid, economic, and highly effective determination of multiple mycotoxins in complex matrices has given huge challenges for the analytical method. In this study, an economic analytical strategy based on sensitive and rapid ultrafast liquid chromatography coupled to hybrid triple quadrupole/linear ion trap mass spectrometry technique was developed for the determination of seven mycotoxins of different chemical classes (aflatoxin B 1 , B 2 , G 1 , and G 2 , ochratoxin A, T-2 toxin, and HT-2 toxin) in Polygonum multiflorum. Target mycotoxins were completely extracted using a modified quick, easy, cheap effective, rugged, and safe method without additional clean-up steps. The types of extraction solvents and adsorbents for the extraction procedure were optimized to achieve high recoveries and reduce coextractives in the final extracts. Due to significant matrix effects for all analytes (≤68.9% and ≥110.0%), matrix-matched calibration curves were introduced for reliable quantification, exploring excellent linearity for the seven mycotoxins with coefficients of determination >0.9992. The method allowed high sensitivity with limit of detection in the range of 0.031-2.5 μg/kg and limit of quantitation in the range of 0.078-6.25 μg/kg, as well as satisfactory precision with relative standard deviations lower than 8%. Recovery rates were between 74.3 and 119.8% with relative standard deviations below 7.43%. The proposed method was successfully applied for 24 batches of P. multiflorum samples, and six samples were found to be positive with aflatoxin B 1 , B 2 , G 1 , or ochratoxin A. The method with significant advantages, including minimum analytical time, low time and solvent consumption, and high sensitivity, would be a preferred candidate for economic analysis of multiclass mycotoxins in complex matrices., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Polygonum multiflorum Thunb. is a traditional herbal medicine that is rich in polyphenols. The major compound, 2,3,5,4'-tetrahydroxystilbene-2- O -β-d-glucoside (THSG) has many pharmacological activities, such as antioxidative and free radical-scavenging properties, and the abilities to reduce hyperlipidemia, prevent lipid peroxidation, and protect the cardiovascular system. In this study, the anti-osteoarthritis (OA) effects of THSG were explored using in vitro and in vivo models. THSG inhibited nitric oxide (NO) and prostaglandin E₂ (PGE₂) production and inducible NO synthase (iNOS) and cyclooxygenase-2 expressions by lipopolysaccharide-stimulated RAW 264.7 cells. On the other hand, THSG inhibited PGE₂ production and iNOS and matrix metalloproteinase-13 expressions by interleukin-1β-stimulated primary rat chondrocytes. Through a mono-iodoacetate-induced rat OA model assay, THSG reduced paw edema and improved the weight-bearing distribution. Therefore, THSG has anti-inflammatory activity and could be applied as a lead compound for the development as an OA drug., Competing Interests: The authors declare no conflict of interest.

The root of Polygonum multiflorum (PM) is an important Chinese herbal medicine for treatment of various diseases. Extensive pharmacological studies have been conducted and demonstrated that it shows a wide range of bioactivities. Meanwhile, a considerable number of hepatotoxicity cases owing to oral administration of PM have been reported and have attracted great attention. However, the limited knowledge regarding the metabolism of PM restricts the deeper studies on its pharmacological/toxicological mechanism and therapeutic material basis. The present study aimed to develop a high-performance liquid chromatography coupled with a linear ion trap-Orbitrap hybrid mass spectrometry method for separation and identification of metabolites in rat urine and plasma after oral administration of PM. Based on the proposed strategy, metabolism profiles of PM in rats were proposed for the first time and 43 metabolites were characterized or tentatively identified. Phase II metabolism, such as glucuronidation and sulfation, are the principal pathways of the main components. These findings will be beneficial to further understanding of the pharmacological mechanism and pharmacodynamic material basis of PM., (Copyright © 2017 John Wiley & Sons, Ltd.)

Polygoni Multiflori Radix is the dried root of Polygonum multiflorum Thunb officially recorded in the Chinese Pharmacopoeia as HeShouWu (HSW) in Chinese pinyin. The processed HSW are commonly used in TCM to treat liver disease and Chinese Pharmacopoeia has described the actions of it to tonify liver-kidney, replenish essence and blood, blacken beard and hair, strengthen sinew and bone, and resolve turbidity and lower lipid hence making it use not only as a herbal medicine in TCM but also as supplementary food in health care., Aim of the Study: Concerns about the hepatotoxicity in association with Polygoni Multiflori Radix and its processed products have been reported in some countries. In the present study, we aim to investigate the potential hepatotoxicity of HSW in rats with oral administration of 95% ethanol-extracts of Polygoni Multiflori Radix by using metabolomics method., Materials and Methods: Here, male rats with 150-180g body weight were received vehicle control or Polygoni Multiflori Radix extracts (HSW-Ex) orally at 19.2 (low dose), 192 (medium dose), or 1920mg/kg/day (high dose), respectively, for 28 consecutive days. Signs of HSW-induced toxicity were monitored by traditional toxicity assessments (e.g., clinical pathology and histopathology). Metabolomics investigation of serum was performed to identify potential endogenous metabolites which may be relevant to liver injury., Results: Rats received High and Medium dose of HSW-Ex showed greater sign of liver injury with increased levels of ASP, ALT, and AST, as well as reduced SOD activity when compared to vehicle control. In contrast, there are no significant changes relevant to liver injury observed in rats by receiving the low dose of HSW-Ex. Metabolomics analyses have identified ten potential endogenous metabolites varied significantly among the treatment groups with varying doses of HSW-Ex, of which might be related to liver injury., Conclusion: Our data has further suggested that liver damage resulting from HSW-Ex consumption is dosage dependent in rats. It is possible that disruption in amino acid and energy metabolism might lead to subsequent oxidative damage in the liver of rats. Because the clinic practice often use low dose in a short time, therefore HSW usage in TCM still keep safe currently, but we present a warning to the clinical doctors and make them has some concern about high dose of HSW usage in a long term that has potential danger to damage liver., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Chinese herbal medicine (CHM) has been used for treating insomnia for centuries. The most used CHM for insomnia was Polygonum multiflorum. However, the molecular mechanism for CHM preventing insomnia is unknown. Stilbene glucoside (THSG), an important active component of P. multiflorum, may play an important role for treating insomnia. To test the hypothesis, Kunming mice were treated with different dosages of THSG. To examine the sleep duration, a computer-controlled sleep-wake detection system was implemented. Electroencephalogram (EEG) and electromyogram (EMG) electrodes were implanted to determine sleep-wake state. RT-PCR and Western blot was used to measure the levels of lactate dehydrogenase (LDH) and saliva alpha amylase. Spearman's rank correlation coefficient was used to identify the strength of correlation between the variables. The results showed that THSG significantly prolonged the sleep time of the mice (p<0.01). THSG changed sleep profile by reducing wake and rapid eye movement (REM) period, and increasing non-REM period. RT-PCR and Western blot analysis showed that THSG could down-regulate the levels of LDH and saliva alpha amylase (p<0.05). The level of lactate and glucose was positively related with the activity of LDH and saliva alpha amylase (p<0.05), respectively. On the other hand, the activities of LDH and amylase were negatively associated with sleep duration (p<0.05). The levels of lactate and glucose affect sleep homeostasis. Thus, THSG may prevent insomnia by regulating sleep duration via LDH and salivary alpha amylase.

Four new dianthrone glycosides, named polygonumnolides C1-C4 (1-4), were isolated from the dried roots of Polygonum multiflorum Thunb, together with two known emodin dianthrones (5-6). Their hepatotoxicities were evaluated against L-02 cell lines. Compounds 1-4 showed weak hepatotoxicity against L-02 cell lines with IC50 values of 313.05, 205.20, 294.20, and 207.35 μM, respectively.

Aging is an inevitable process of life caused by a combination of organs and tissues events which manifests as loss of structure and function. It is accompanied with organ hypofunction, decline in defense against stress and energy metabolism, and lots of age-related diseases. Therefore, it is critical to understand the mechanism of aging, as well as to discover new drugs to slow aging. Polygonum multiflorum has long been recognized in traditional Chinese medicine as anti-aging medicine. Interestingly, its extract has been shown to prolong lifespan in drosophila and elegans. Tetrahydroxystilbene glucoside (TSG), the main ingredient of P. multiflorum, shares a strong structural similarity with resveratrol, a well-known anti-aging natural product. This review summarized up-to-date literature reports and our laboratory findings on the mechanism of TSG anti-aging efficiency and function against age-related disease. It could provide reference for searching for anti-aging tradition Chinese medicine., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Ethnopharmacology Relevance: Raw and processed Polygoni Multiflori Radix (PMR and PMRP) are used in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD), hyperlipidemia or related diseases. In our previous research, 2, 3, 5, 4'-tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) displayed the most important role in the total cholesterol (TC) lowering effect among all the chemical constituents of Polygonum multiflorum. Emodin and physcion displayed more favorable triglyceride (TG) reducing effects than TSG. However, there are few researches focus on the approach and mechanism of how do Polygonum multiflorum exhibit good lipid regulation activity. The targeted sites of active substances of Polygonum multiflorum are still not clearly elucidated. This research pays close attention to how major chemical components of Polygonum multiflorum affect the TC and TG contents in liver cells., Materials and Methods: In this research, a sensitive, accurate and rapid in vitro model, steatosis hepatic L02 cell, was used to explore target sites of active chemical substances of Polygonum multiflorum for 48h. Steatosis hepatic L02 cell was exposed to emodin, physcion and TSG, respectively. The contents of four key enzymes in the pathway of synthesis and decomposition of TC and TG were investigated after exposure. Meanwhile, the contents of lipid transfer protein were also tested. The diacylgycerol acyltransferase 1 (DGAT1) controlled the biosynthesis of TG from free fatty acids while 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) limited the biosynthesis of TC. Hepatic triglyceride lipase (HTGL) and cholesterol 7α-hydroxylase (CYP7A) played the key role in the lipolysis procedure of TG and TC., Results: The synthesis of TC and TG in steatosis L02 cells were apparently increased in the model group compared to the control group. Intracellular contents of HMG-CoA reductase and DGAT1 increased 32.33% and 56.52%, while contents of CYP7A and HTGL decreased 21.61% and 47.37%. Emodin, physcion and TSG all showed down-regulation effects on HMG-CoA reductase, while up-regulation effects on CYP7A. The most remarkable effect on HMG-CoA reductase was found on emodin. Emodin could reduce the DGAT1 content from 438.44 ± 4.51 pg/mL in model group to 192.55 ± 9.85 pg/mL (100 μm). The content of HTGL in 300 μm physcion group was 3.15 ± 0.15 U/mL, which was more significantly effective than the control, lovastatin and fenofibrate group., Conclusions: TSG could raise the content of CYP7A and then promote the lipolysis of cholesterol. Moreover, TSG also showed the best LDL-reducing effect. Emodin could inhibit HMG-CoA reductase and DGAT1, which were key enzymes in the synthesis of TC and TG. Physcion increased the content of HTGL, and then could boost the lipolysis of triglyceride. At the same time, physcion showed the best VLDL-reducing effect. In view of the above conclusions, we contributed the lipid regulation activity to an overall synergy of TSG, emodin and physcion., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Polygonum multiflorum is a popular Chinese herbal medication. In this case series, we report on 18 otherwise healthy non-viral hepatitis patients who developed liver dysfunction following consumption of P. multiflorum alone., Methods: Concurrent and retrospective analysis was used in this study. The causality of P. multiflorum in liver injury was graded by the Council for International Organizations of Medical Sciences (CIOMS) toxicity scale., Results: From 2005 to 2012, 18 cases of hepatotoxicity potentially involving P. multiflorum. The median age was 42 years old (range from 18 to 63). Median time of onset of symptoms was 27 days (1-120). Prevailing clinical symptoms were fatigue, loss of appetite and jaundice. Sixteen patients had elevated level of total bilirubin (>21 mol/L); liver enzymes elevated markedly in all patients (ALT>40 U/L, AST>40 U/L, GGT>50 U/L), except for alkaline phosphatase which elevated only in nine patients. Based on the liver enzyme pattern, the type of liver injuries were hepatocellular according to CIOMS. In terms of causality, 14 of 18 patients were evaluated as being highly probable. All patients were responding well to P. multiflorum stoppage, and liver protective-supportive care., Conclusions: P. multiflorum products can be associated with hepatotoxicity in otherwise healthy non-viral hepatitis infected patients, regardless of herbal processing., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Dried roots of Polygonum multiflorum have traditionally been used in the retarding of aging process in East Asian countries and its extracts exhibit anti-oxidative activities., Materials and Methods: Neuroprotective effects of ethyl acetate extract from Polygonum multiflorum (EEPM) were investigated against glutamate-induced oxidative cell death in HT22 hippocampal cells. Cell viability, cytotoxicity, morphological, flow cytometry, and Western blot assays were performed in order to observe alterations of neuronal cell survival or death related pathways., Results: Pretreatment with EEPM resulted in significantly decreased glutamate-induced neurotoxicity and also resulted in drastically inhibited glutamate-induced apoptotic and necrotic neuronal death. To elucidate possible pathways of neuroprotection by EEPM, we explored the activation of mitogen activated protein kinases (MAPKs), phosphatidylinositol-3-kinase, and cAMP responsive element binding protein (CREB). Treatment with glutamate alone led to activation of extracellular regulated kinase (ERK), Jun N-terminal kinase, and p38 during the late phase after glutamate exposure, but pretreatment with EEPM resulted in significantly attenuated activation of these proteins. Pretreatment with EEPM resulted in increased activation of CREB. The specific inhibitors of ERK and p38, PD98059 and SB203580, abrogated the neuroprotective effects of EEPM. When we evaluated calpain I and striatal-enriched protein tyrosine phosphatase (STEP), active form of calpain I was significantly increased after glutamate exposure, and, along with this, active form of STEP showed a decrease. Pretreatment with EEPM resulted in significant recovery of pro-calpain I and active form of STEP caused by glutamate. Co-treatment with calpain inhibitor ALLN and EEPM had a synergistic effect on neuronal death and contributed to blockade of activation of both ERK and p38 with increased activation of CREB., Conclusions: These results suggest that Polygonum multiflorum extract may have neuroprotective effects through both alleviation of ERK and p38 activation with increased activation of CREB under oxidative stress and has potential as a therapeutic intervention for treatment of oxidative neuronal death., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

Two new compounds, gallic acid ester of torachrysone-8-O-β-D-glucoside (1) and (E)-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-xyloside (4), along with eight known compounds (2, 3, 5-10) were isolated from a 70% ethanol extract of Polygonum multiflorum roots. The structures were determined by (1)H and (13)C NMR, HMQC, and HMBC spectrometry. Extracts of P. multiflorum have been reported to promote hair growth in vivo. This study was carried out to evaluate the effects of isolated compounds from P. multiflorum on promoting hair growth using dermal papilla cells (DPCs), which play an important role in hair growth. When DPCs were treated with compounds (1-10) from P. multiflorum, compounds 1, 2, 3, 6, and 10 increased the proliferation of DPCs compared with the control. Specifically, compound 2 (10 and 20 μM) induced a greater increase in the proliferation of DPCs than minoxidil (10 μM). Additionally, treatment of vibrissa follicles with compound 2 for 21 days increased hair-fiber length significantly. On the basis of this result, further investigation and optimization of these derivatives might help in the development of therapeutic agents for the treatment of alopecia., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A study on the phytochemical composition of the roots of Polygonum multiflorum collecting in Vietnam and an evaluation of its capacity to inhibit pancreatic lipase enzyme was conducted. In total, 12 metabolites (1 – 12) were isolated from anti-lipase activity-guided fractionation of P. multiflorum. The isolated compounds (1 – 12) were identified as trans -resveratrol (1), methyl protocatechuate (2), methyl gallate (3), catechin (4), epicatechin (5), myrciaphenone A (6), quercetin (7), kaempferol (8), apigenin (9), luteolin (10), tricin (11), and afzelin (12). This is the first time Compound 12 has been reported from P. multiflorum. However, 12 second metabolites (1 – 12) were tested in vitro to assess the anti-lipase potential. The results revealed Compound 7 exhibited the most significant lipase inhibition, with an IC50 value of 0.30 ± 0.04 μM. Following closely, Compounds 6, 8, 10, and 12 displayed IC50 values of 5.38 ± 0.65, 0.72 ± 0.10, 0.79 ± 0.19, and 1.22 ± 0.18 μM, respectively. For comparison, orlistat (positive control), the most common anti-obesity drug available on the market, has an IC50 value of 0.91 ± 0.10 μM. Molecular docking was applied to explore the affinity and interactions between active compounds 6 – 8, 10, and 12 and proteins associated with obesity, namely pancreatic lipase–colipase complex (PLCC) and pancreatic lipase-related protein 1 (PLRP1). In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) were used in predictions. The results indicate that the active compounds isolated from P. multiflorum could be further in-depth research on lipase inhibition. [ABSTRACT FROM AUTHOR]

The processing of traditional Chinese medicine (TCM) plays an important role in the clinical application, which usually has the function of "increasing efficiency and reducing toxicity". Polygonum multiflorum (PM) has been reported to induce hepatotoxicity, while it is believed that the toxicity is reduced after processing. Studies have shown that the hepatotoxicity of PM is closely related to the changes in chemical components before and after processing. However, there is no comprehensive investigation on the chemical changes of PM during the processing progress. In this research, we established a comprehensive method to profile both small molecule compounds and polysaccharides from raw and different processed PM samples. In detail, an online two-dimensional liquid chromatography coupled with quadrupole-orbitrap mass spectrometry (2D-LC/Q-Orbitrap MS) was utilized to investigate the small molecules, and a total of 150 compounds were characterized successfully. After multivariate statistical analysis, 49 differential compounds between raw and processed products were screened out. Furthermore, an accurate and comprehensive method for quantification of differential compounds in PM samples was established based on ultra-high performance liquid chromatography/Q-Orbitrap-MS (UHPLC/Q-Orbitrap-MS) within 16 min. In addition, the changes of polysaccharides in different PM samples were analyzed, and it was found that the addition of black beans and steaming times would affect the content and composition of polysaccharides in PM significantly. Our work provided a reference basis for revealing the scientific connotation of the processing technology and increasing the quality control and safety of PM. [ABSTRACT FROM AUTHOR]

Polygonum multiflorum (PM) Thunb., a typical Chinese herbal medicine with different therapeutic effect in raw and processed forms, has been used worldwide for thousands of years. However, hepatotoxicity caused by PM has raised considerable concern in recent decades. The exploration of toxic components in PM has been a great challenge for a long time. In this study, we developed a stepwise strategy integrating metabolomics and pseudotargeted spectrum-effect relationship to illuminate the potential hepatotoxic components in PM. First, 112 components were tentatively identified using ultraperformance liquid chromatography-quadrupole-time-of-flight-mass spectrometry (UPLC-Q-TOF-MS). Second, based on the theory of toxicity attenuation after processing, we combined the UPLC-Q-TOF-MS method and plant metabolomics to screen out the reduced differential components in PM between raw and processed PM. Third, the proposed pseudotargeted MS of 16 differential components was established and applied to 50 batches of PM for quantitative analysis. Fourth, the hepatocytotoxicity of 50 batches of PM was investigated on two hepatocytes, LO2 and HepG2. Last, three mathematical models, gray relational analysis, orthogonal partial least squares analysis, and back propagation artificial neural network, were established to further identify the key variables affecting hepatotoxicity in PM by combining quantitative spectral information with toxicity to hepatocytes of 50 batches of PM. The results suggested that 16 components may have different degrees of hepatotoxicity, which may lead to hepatotoxicity through synergistic effects. Three components (emodin dianthrones, emodin-8-O-ß-D-glucopyranoside, PM 14-17) were screened to have significant hepatotoxicity and could be used as toxicity markers in PM as well as for further studies on the mechanism of toxicity. Above all, the study established an effective strategy to explore the hepatotoxic material basis in PM but also provides reference information for indepth investigations on the hepatotoxicity of PM. [ABSTRACT FROM AUTHOR]

As a traditional tonic Chinese medicine, Polygonum multiflorum is widely used in clinical practice. However, with the deepening of modern pharmacological research, its drug toxicity, especially hepatotoxicity, has become increasingly prominent. Based on a large number of clinical and experimental evidence, it has been confirmed that Polygonum multiflorum and its main active ingredients such as anthraquinones and diphenylethylene glucoside can cause different degrees of hepatotoxicity. Further studies have shown that the toxicological mechanisms involved in the hepatotoxicity of different extracts and components of Polygonum multiflorum may include oxidative phosphorylation, bile acid excretion, different metabolic pathways, genetic and metabolic factors, immune homeostasis, etc. By sorting out and summarizing the literature related to hepatotoxicity of Polygonum multiflorum in recent years, this paper discussed the hepatotoxicity mechanism of Polygonum multiflorum and its main components and some contradictions in related reports. [Display omitted] • This study discussed the hepatotoxicity mechanism of Polygonum multiflorum and some contradictions in related reports. • The hepatotoxicity mechanism of main components of Polygonum multiflorum was discussed. • Network toxicological study of hepatotoxicity induced by Polygonum Multiflorum was performed. • The hepatotoxicity mechanism may include oxidative phosphorylation, bile acid excretion, different metabolic pathways, etc. [ABSTRACT FROM AUTHOR]

In the present study, we discussed the drug-induced liver injury caused by Chinese patent medicines containing Polygonum multiflorum to provide a reference for clinical rational drug use of Polygonum multiflorum and its preparations. One case of long-term taking Jingwu capsule and Huolisu oral liquid, which led to the drug-induced liver injury, was reported. The other case took Runzaozhiyang capsule for a long time, which also led to drug-induced liver injury. Jingwu capsule, Huolisu oral liquid, and Runzaozhiyang capsule all contained Polygonum multiflorum, which could result in liver injury when used long-term. Moreover, we explored the clinical features and toxicity of liver damage induced by Polygonum multiflorum. Liver damage in serum transaminase was significantly increased, and the increasing rate of ALT was more than that of AST. Jaundice appeared obviously. The liver damage mechanisms included drug metabolism, immune response, physical fitness, and many other reasons. Corresponding suggestions on rational use of Polygonum multiflorum and its preparations were presented. The dosage and period should be regulated. The index of liver function should be monitored during the medication periods. Collectively, patients with a history of liver disease or a history of allergies should pay more attention when using the above-mentioned drugs. [ABSTRACT FROM AUTHOR]

Polygonum multiflorum Thunb. is a traditional herb which was widely distributed in China. The leaves of P. multiflorum (PML), which contains lots of antioxidant constituents, are often used for tea. In this study, three flavonoid glycosides were successfully separated and characterized from the ethyl acetate fraction of 80% ethanol extracts of PML by high-speed counter-current chromatography (HSCCC). The biphasic solvent system which can isolate purified myricitrin (44.5 mg), quercitrin (23.86 mg) and afzelin (14.39 mg) from 110 mg of the ethyl acetate fraction of PML was composed of n-hexane–ethyl acetate–methanol–water (0.5:3:1:2, v/v/v/v). Moreover, the purities of each compound were 94.9, 97.0, and 95.7% as determined by high-performance liquid chromatography (HPLC), respectively. Three flavonoid glycosides were obtained using only one-step HSCCC separation for the first time and the chemical structures of these three compounds were identified using the techniques of NMR and ESI–MS. The antioxidant activities of these three compounds, ethyl acetate fraction, and crude extract were evaluated by three antioxidant assays. The results of antioxidation assays showed that myricitrin and quercitrin have strong antioxidant activity and the two components may be the material basis of the antioxidant potential of PML. This work confirmed the feasibility of HSCCC to separate compounds from complex samples and it suggests that PML have pharmaceutical potential as natural antioxidant agents. [ABSTRACT FROM AUTHOR]

Background: Drug-induced liver injury is a common adverse effect in clinical practice, with severe cases resulting in liver failure and even death. Identification and prediction of individuals susceptible to idiosyncratic DILI continues to remain a challenge. Methods: In this study, we report that cytokines in human serum can be used to identify and predict individuals susceptible to Polygonum multiflorum-induced DILI (PM-DILI) in retrospective and prospective cohort studies. Findings: In the retrospective pilot study, we compared serum cytokine expression profiles of the PM-DILI group (n=10) and the PM-Tolerant group (n=12) and found 10 cytokines with significant differences. In the replication cohort study, differences in the 10 cytokines between PM-DILI (n =11) and PM-Tolerant (n=13) groups were verified. Among them, 6 cytokines showed no significant differences at two time points, including liver injury and recovery stage of PM-DILI, suggesting that these 6 cytokines have no correlation with PM-DILI, however, they may be related to susceptibility. Furthermore, all the retrospective cohorts were combined, and a PM-DILI susceptibility prediction model was built by screening the 6 cytokines. The combination of (TNF-α and CCL-2) or VEGF showed the highest sensitivity and specificity. Finally, the efficacy of the above 3 cytokine combination models in predicting PM-DILI-susceptible individuals was verified before PM exposure in another independent prospective cohort (n=24), with sensitivity and specificity of 66.7% and 83.3%, respectively. Conclusion: This proof-of-concept study demonstrates that the serum cytokine combination reflecting dysimmunity could be used as a new method to predict PM-DILI, thus providing a new perspective for improving the clinical management of IDILI. [ABSTRACT FROM AUTHOR]

[Display omitted] • Elasticnet NIRS quantitative model of the herb Polygonum multiflorum was constructed. • The absorbance coefficient weights for each wave number were determined by the Elasticnet NIRS model. • The final coefficients may reflect the compounds of spectral feature indirectly. • The Elasticnet NIRS model showed better performance than the other four NIRS models. This study constructed a near-infrared spectroscopy (NIRS) quantitative analysis model of 2,3,5,4′-tetrahydroxy stilbene-2-O-β-D-glucoside (TSG) and Polygonum multiflorum 's water content based on Elasticnet regression (ER). NIRS data, TSG and the moisture content data sets of 117 samples of P. multiflorum were obtained by using NIR scanning and high-performance liquid chromatography analysis (HPLC) methods. MSE was used to determine the hyperparameters α and λ of Elasticnet. The optimal α values of TSG and water content were 0.83 and 0.01, and the optimal λ values were 0.03 and 1.13, respectively. By preprocessing the original spectral data, the NIRS model was established based on the source data set using ER, compared with the model established by PLS and its optimization algorithm. The results show that the ER model has good performance compared with other methods, with R2 c value was 0.9879, RMSEC value was 0.09, R2 p value was 0.9784, RMSEP value was 0.13 and RPD value was 6.8. In addition, according to the properties of Elasticnet's variable selection, we speculate that the final coefficients of spectral features may indirectly reflect the spectral features of different components. The results showed better prediction accuracy and superior performance. This is a much more reliable method used to forecast the content of effective components in plants. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction. To date, identifying individuals at risk for IDILI remains challenging. This is a prospective study, where a nested case–control (1:5) design was adopted. For six patients who had abnormalities in liver function test after Polygonum multiflorum Thunb. (PM) ingestion (susceptible group), 30 patients with normal liver function were matched (tolerant group). Based on liquid chromatography–mass spectrometry, metabolomics analysis was done on serum samples prior to PM ingestion, to screen the differential metabolites and characterize metabolomic profiles of patient serum in the two groups. Multivariate analysis showed that there were remarkable separations between susceptible and tolerant groups. A total of 25 major differential metabolites were screened out, involving glycerophospholipid metabolism, sphingolipid metabolism, fatty acid metabolism, histidine metabolism and aromatic amino acid metabolism. Wherein, the area under the curve of the receiver operating characteristic curves of metabolites PE 22:6, crotonoyl-CoA, 2E-tetradecenoyl-CoA, phenyllactic acid, indole-5,6-quinone, phosphoribosyl-ATP were all greater than 0.9. The overall serum metabolic profile comprising of 25 metabolites could clearly distinguish susceptible and tolerant groups. This proof-of-concept study used metabolomics to characterize the metabolic profile of IDILI risk individuals before drug ingestion for the first time. The metabolome characteristics in patient serum before PM ingestion may predict the risk of liver injury after PM ingestion. [ABSTRACT FROM AUTHOR]

The dry roots of Polygonum multiflorum (PM), involving both the raw and processed materials, are widely used as the traditional Chinese medicine for treating various diseases in China. Hepatotoxicity has been occasionally reported in patients who consume PM. Unfortunately, no definite criteria are currently available regarding the processing technology of PM for reduction the toxicity. In this work, we aimed to investigate the variations of PM metabolite profiles induced by different processing technologies by UHPLC/Q-Orbitrap-MS and multivariate statistical analysis, and to discover the potential toxic compounds by correlating the cytotoxicity of L02 cell with the contents of metabolites in raw and processed PM samples. We could identify two potential toxic compounds, emodin-8- O -glucoside and torachrysone- O -hexose, which could be selected as the toxic markers to evaluate different processing methods. The results indicated all processed PM samples could decrease the cytotoxicity on L02 cell. The best processing technology for PM process was to steam PM in black soybean decoction (BD-PM) for 24 h. [ABSTRACT FROM AUTHOR]

Polygonum multiflorum [PM, synonym Reynoutria multiflora (Thunb.) Moldenke.], a well-known and commonly used Traditional Chinese Medicine and herbal dietary supplement for nourishing the kidney and liver, etc., has aroused wide concern for its reported potential hepatotoxicity. Previous clinical cases and experimental studies have suggested that mild immune stress (MIS) may be one of the susceptibility-related factors of idiosyncratic drug-induced liver injury (IDILI) caused by PM. In this paper, we found that the same dose of PM caused abnormal liver biochemical indicators and liver tissue damage in MIS model rats, while it did not result in liver injury in normal rats, further confirming that MIS is a susceptibility factor for PM-IDILI. Plasma chemokine/cytokine profiling indicated that the MIS model group was significantly different from the other groups, showing a significant upregulation of plasma chemokines, while the MIS/PM group showed upregulated expression of chemokines or pro-inflammatory cytokines. Liver histopathological examination indicated a small amount of inflammatory cytokine infiltration in the MIS group, but no hepatocyte injury, consistent with the plasma profiles of increased chemokines and unchanged inflammatory cytokines. Notably, metabolomics characterization showed that MIS caused reprogramming of these metabolic pathways (such as phenylalanine and glutamate pathways), which was associated with acute phase reactions and inflammatory responses. These results suggested that MIS may promote an immune response to the initial cellular injury induced by PM in the liver, and MIS-induced upregulation of chemokines and metabolic reprogramming may an important mechanism that mediates the susceptibility to PM-IDILI. Furthermore, via receiver operating characteristic (ROC) curves analysis, we identified 12 plasma cytokines (e.g., IP-10, MCP-1 and MIP-1α) and nine metabolomics biomarkers (e.g., L-Phenylalanine, Creatinine, and L-glutamine) with differential capabilities (all ROC AUC > 0.9) of identifying susceptibility model animals from normal ones, which might be of referable value for the clinical recognition of PM-IDILI susceptible individuals. [ABSTRACT FROM AUTHOR]

Polyphenol is a valuable compound found in plants. Unfortunately, it is quite sensitive to heat, light and oxygen in the air. This is a disadvantage making the storage of these compounds for longer periods of time difficult. However, this problem can be overcome by encapsulation with carrier agents as maltodextrin, gum arabic, modified starch, etc. The efficiency of maltodextrin (MD, DE16-19) and gum arabic (GA) on spray drying of Polygonum multiflorum Thunb. root extract was investigated. The incorporation of gum arabic to the extract had the total polyphenol content (TPC) and antioxidant capacity (AC) higher than maltodextrin. The obtained powders from gum arabic and maltodextrin were analyzed for encapsulation yield, moisture content, color parameters, total phenolic content, antioxidant capacity, bulk density, wettability, hygroscopicity, water solubility index, particle size and microstructure. The results showed the types of carrier agents which significantly affected the physicochemical properties of powders produced by spray drying. [ABSTRACT FROM AUTHOR]

It is known that long-term excessive administration of glucocorticoid (GC) results in osteoporosis. The present study aimed to evaluate the protective effects of Polygonum multiflorm (PM) on the bone tissue of rats with GC-induced osteoporosis (GIO). A total of 90 6-month-old female Sprague Dawley rats (weight range, 190-210 g) were randomly divided into nine groups: Control (normal saline); prednisone (GC; 6 mg·kg-1·d-1; Model); GC plus PMR30 (the 30% ethanol eluent fraction of PM) (H) (400 mg·kg-1·d-1); GC plus PMR30 (M) (200 mg·kg-1·d-1); GC plus PMR30 (L) (100 mg·kg-1·d-1); GC plus PMRF (fat-soluble fraction of PM) (H) (400 mg·kg-1·d-1); GC plus PMRF (M) (200 mg·kg-1·d-1); GC plus PMRF (L) (100 mg·kg-1·d-1); GC plus calcitriol (CAL; 0.045 µg·kg-1·d-1; positive). Rats were administered intragastrically with prednisone and/or the aforementioned extracts for 120 days, and weighed once/week. The serum was collected for detection of biochemical markers. The left tibia was used for bone histomorphometry analysis. The right tibia was prepared for hematoxylin and eosin staining. The left femur was used to analyze the protein expression of dickkopf-1 (DKK1), WNT inhibitory factor 1 (WIF1) and secreted frizzled related protein 4 using western blotting. Long-term excessive treatment of prednisone inhibited the bone formation rate accompanied with a decrease in bone mass, growth plate, body weight, and the level of bone-specific alkaline phosphatase and hydroxyl-terminal propeptide of type I procollagen in the serum. Furthermore, a simultaneously increase in the level of tartrate resistant acid phosphatase-5b and cross-linked carboxy-terminal telopeptide of type I collagen in the serum, in addition to DKK1, and WIF1 protein expression, was observed. PMR30 (M and L) and PMRF (H) groups were able to reduce the negative effects of GC on the bones. PMR30 (M and L) and PMRF (H) dose demonstrated a protective effect of PM on bone tissue in GIO rats. The mechanism underlying the preventive effect of PM for the treatment of GIO may be associated with direct upregulation of the canonical Wnt/ß-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Polygonum multiflorum Thunb. is a highly important medicinal plant producing anthraquinones (emodin and physcion) and phenolic compounds which has pharmaceutical use. In vitro seedling explants such as roots, internodals, nodals and leaves were inoculated with A. rhizogenes strain KCTC 2703. Transformed roots were induced from internodals and leaf explants. Six transgenic clones of hairy roots were established and confirmed by polymerase chain reaction (PCR) and reverse transcription-PCR (RT-PCR) using rolC specific primers. Hairy roots cultured using MS liquid medium supplemented with 30 g/l sucrose showed highest accumulation of biomass (99.05 g/l FW [fresh weight] and 10.95 g/l DW [dry weight]) and highest production of anthraquinones content (emodin 211.32 μg/g DW and physcion 353.23 μg/g DW) were observed at 20 days. Nearly 9.5-fold increment of biomass was evident in suspension cultures at 20 days of culture and hairy root biomass produced in suspension cultures possessed 3.7- and 3.5-fold higher content of emodin and physcion, respectively, when compared with the untransformed control roots. MS basal liquid medium was superior for the growth of hairy roots and production of anthraquinones compared with other culture media evaluated (SH, B5 and N6), with MS-basal liquid medium supplemented with 30 g/l sucrose was optimal for secondary metabolite production. A total of 23 polyphenolic compounds were identified and quantified from P. multiflorum untransformed and hairy roots, which includes hydroxybenzoic acids, hydroxycinnamic acids, flavonols and other groups of phenolic compounds. The ultra-performance liquid chromatography (UPLC) analysis of the phenolic compounds profile revealed that pyrogallol, hesperidin, naringenin and formononetin were higher in hairy roots compared to untransformed roots. The total phenolics, flavonoids content, antioxidant and antimicrobial activity was high in hairy roots compared to untransformed roots. This is the first report for the production of anthraquinones (emodin and physcion), phenolic compounds and biological activities from hairy root cultures of P. multiflorum. [ABSTRACT FROM AUTHOR]

Polygonum multiflorum is a traditional Korean medicine that has been utilized widely in East Asian countries as a longevity agent. Clinical studies have demonstrated that Polygonum multiflorum improves hypercholesterolemia, coronary heart disease, neurosis and other diseases commonly associated with aging. However, scientific evidence defining the protective effects and mechanisms of Polygonum multiflorum against ischemic stroke is incomplete. In the present study, we investigated the cerebrovascular protective effects of Polygonum multiflorum against ischemic brain injury using an in vivo photothrombotic mouse model. To examine the underlying mechanism of action, we utilized an in vitro human brain microvascular endothelial cell (HBMEC) culture system. Hexane extracts (HEPM), ethyl acetate extracts (EAEPM) and methanol extracts (MEPM) of Polygonum multiflorum (100 mg/kg) were administered intraperitone-ally 30 min prior to ischemic insult. Focal cerebral ischemia was induced in C57BL/6J mice and endothelial nitric oxide synthase knockout (eNOS KO) mice by photothrombotic cortical occlusion. We evaluated the infarct volume, as well as neurological and motor function, 24 h after ischemic brain injury. Following ischemic insult, HEPM induced a significant reduction in infarct volume and subsequent neurological deficits, compared with EAEPM and MEPM. HEPM significantly decreased infarct size and improved neurological and motor function, which was not observed in eNOS KO mice, suggesting that this cerebroprotective effect is primarily an eNOS-dependent mechanism. In vitro, HEPM effectively promoted NO production, however these effects were inhibited by the NOS inhibitor, L-NAME and the PI3K/Akt inhibitor, LY-294002. Furthermore, HEPM treatment resulted in increased phosphorylation-dependent activation of Akt and eNOS in HBMEC, suggesting that HEPM increased NO production via phosphorylation-dependent activation of Akt and eNOS. In conclusion, HEPM prevents cerebral ischemic damage through an eNOS-dependent mechanism, and thus may have clinical applications as a protective agent against neurological injury in stroke. [ABSTRACT FROM AUTHOR]

Background: Polygonum multiflorum is an important medicinal plant. Hairy roots systems obtained by transforming plant tissues with the natural genetic engineer Agrobacterium rhizogenes can produce valuable biological active substances, which have immense potential in the pharmaceutical industry. Objective: To optimize the inductive and cultural conditions of P. multiflorum hairy roots and to identify the major active secondary metabolites in hairy roots. Materials and Methods: P. multiflorum hairy root were mediated with A. rhizogenes R1601 to induce hairy roots. Four combinations, including Murashige-Skoog (MS), 1/2 MS, B5, and White, were investigated to optimize the culture medium. MS medium was selected for the growth measurement. The qualitative and quantitative determinations of free anthraquinone in hairy roots were compared with the calli and aseptic plantlets using high-performance liquid chromatography. Results: The inductive rates of hairy roots by leaves were higher than for any other explants. The presence of agropine in the P. multiflorum hairy roots confirmed that they were indeed transgenic. MS medium was the most suitable of the four media for hairy root growth. Meanwhile, the growth kinetics and nutrient consumption results showed that the hairy roots displayed a sigmoidal growth curve and that their optimal inoculation time was 18-21 days. The determination of the anthraquinone constituents indicated that the rhein content of the hairy roots reached 2.495 μg g-1 and was 2.55-fold higher than that of natural plants. Conclusion: Transgenic hairy roots of P. multiflorum could be one of the most potent materials for industrial-scale production of bioactive anthraquinone constituents. [ABSTRACT FROM AUTHOR]

Background: Polygoni Multiflori Radix, He-Shou-Wu in Chinese, is a widely used traditional Chinese medicine. Clinically, water decoction is the major application form of He-Shou-Wu. Therefore, simultaneous determination of bioactive compounds in water extract is very important for its quality control. Results: A pressurized liquid extraction and short-end injection micellar electrokinetic chromatography (MEKC) were first developed for simultaneous determination of seven hydrophilic bioactive compounds in water extract of He-Shou-Wu. The influence of parameters, such as pH, concentration of phosphate, SDS and HP-ß-CD, capillary temperature and applied voltage, on the analysis were carefully investigated. Optimum separation was obtained within 14 min by using 50 mM phosphate buffer containing 90 mM SDS and 2% (m/v) HP-ß-CD (pH 2.5) at 15 kV and 20°C. All calibration curves showed good linearity (R2>0.9978) within test ranges. The overall LOD and LOQ were lower than 2.0 µg/mL and 5.5 µg/mL, respectively. The RSDs for intra- and inter-day of seven analytes were less than 3.2% and 4.6%, and the recoveries were 97.0%-104.2%. Conclusion: The validated method was successfully applied to the analysis of He-Shou-Wu samples, which is helpful for its quality control. [ABSTRACT FROM AUTHOR]

Abstract: Polygonum multiflorum is one of the most commonly used Chinese medicines. In this study, an effective pressurized water extraction and HPLC method was developed for first simultaneous determination of 8 hydrophilic compounds, including gallic acid, Hypaphorine, Catechin, Proanthocyanidin B1, Epicatechin, Proanthocyanidin B2, Emodin-8-O-β-d-glucopyranoside, stilbene glycosides, in P. multiflorum. The analysis was performed on a Zorbax SB-AQ column with gradient elution of 0.05% phosphoric acid aqueous solution and acetonitrile in 45min. All calibration curves showed good linearity (R 2 >0.9994) within test ranges. The LOD and LOQ were lower than 0.2 and 1.0μg/mL on column, respectively. RSD for intra- and inter-day of 8 analytes were less than 4.1% and 4.0%, respectively, and the overall recovery was 96.0–100.7%. The validated method was successfully applied to quantification of 8 hydrophilic compounds in samples of P. multiflorum from different locations of China. Chemometrics such as principal component analysis (PCA) and hierarchical clustering analysis (HCA) were used to evaluate homogeneity of P. multiflorum in China, which suggested that their quality homogeneity was good. [Copyright &y& Elsevier]

Abstract: Polygonflavanol A (1), a novel flavonostilbene glycoside with an unusual coupling pattern, together with five known stilbene glycosides (2–6), was isolated from the roots of Polygonum multiflorum. The structures were elucidated on the basis of extensive spectroscopic analysis and chemical evidence. The absolute configuration of 1 was further determined by CD analysis. Most of the compounds could inhibit nitric oxide (NO) secretion of RAW264.7 cells in respond to lipopolysaccharide (LPS) in a dose dependent manner. Among them, compound 2 displayed the highest inhibitory activity. [Copyright &y& Elsevier]

Context: Polygonum multiflorum is known as a medicinal plant. It has been used as a folk medicine which showed antioxidative property. Objective: Protective effects of the water extracts (w/v:1/10) from fresh P. multiflorum (WEP) on carbon tetrachloride (CCl4)-induced liver damage in rats were investigated. Materials and methods: CCl4 was used for inducing liver damage of SD rats, and WEP and emodin were fed for eight consecutive weeks. Results: We found that emodin levels in fresh WEP was higher than that in ripening WEP. Rats were administered WEP and emodin, the main active compound, for 56 consecutive days. WEP significantly lowered the serum levels of hepatic enzyme markers, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and reduced the generation of malonaldehyde. Treatment with WEP recovered glutathione S-transferase and catalase activity in rats as compared to treatment with CCl4 alone. In addition, serum tumor necrosis factor-α, an inflammatory marker, was found to decrease in rats treated with WEP. In histopathological evaluation, fatty degeneration and necrosis were found to be significantly decreased in the CCl4 plus WEP treatment group. Discussion and conclusion: WEP may be effective in attenuating liver damage by reducing lipid peroxidation as well as by positively modulating inflammation. [ABSTRACT FROM AUTHOR]

The leaf, stem and root of fresh Polygonum multiflorum plant were investigated. The contents of bioactive compounds and their antioxidant potential were studied by several radicals scavenging assay, and the antioxidative substances measured. The total phenolic contents were 179.0, 70.3 and 118.0 mg/g, whereas flavonoids contents were 7.3, 8.0 and 37.5 mg/g for water extracts from root (R), stem (S) and leaf(L), respectively. Further HPLC analysis revealed that the leaf and stem of this functional plant contained quercetin at 13,469 and 1,095 mg/kg, respectively. Furthermore, the root and stem contained rich emodin-related compounds that were 6,620 and 1,245 mg/kg, respectively. And different concentrations of emodin-related compounds and quercetin in root, stem and leaf showed different antioxidative ability. We observed that the DPPH scavenging activity, total antioxidant activity (TEAC), reducing power and NO scavenging ability of the three parts of the plant samples and found that the activities were R > L > S except that was S > L > R on superoxide anion scavenging effect. Our results indicated that the radical scavenging abilities of the three sample parts were more potent than that of emodin and quercetin. P. multiflorum contains rich emodin-related compounds and quercetin, indicating that these compounds played important roles in antioxidative effect. We suggested that the antioxidative effect of the fresh P. multiflorum plant correlate-well with emodin-related compounds and quercetin. [ABSTRACT FROM AUTHOR]

Polygonum multiflorum Thunb. (PM) has been used since ancient times as Chinese traditional medicine. 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside (THSG), a major active component in its extracts, has been reported to exhibit numerous bioactivities in cells and animals. Notably, anthraquinones, such as emodin and physcion, are of potential hazards when PM is sampled for composition analysis and application. Herein, molecularly imprinted polymers (MIPs) using emodin and physcion as templates were constructed to remove anthraquinones from PM extracts while fully reserved THSG. Through characterization analysis, MIPs were found to have looser scaffolds than non-molecularly imprinted polymers (NIPs). Static isothermal adsorption demonstrated that the absorption capacity best fitted to the Langmuir model and pseudo-first-order kinetics. The maximum absorption capacity for emodin and physcion was 48.87 and 32.00 μmol/g, respectively. Remarkably, highly selective absorption and removal towards merely targeted templates were noticed in the resulting MIPs, with no specific adsorption towards THSG. Tandemly connected emodin-MIPs and physcion-MIPs cartridges successfully removed emodin and physcion from PM extracts accompanied with > 90% recovery for THSG. Further, the MIPs cartridges displayed an excellent regeneration capacity in multiple cycles. This work pointed that MIPs can be introduced as an effective and accurate technique to obtain anthraquinones-free but THSG-rich crude PM extracts, thereby increasing the overall application of PM extracts. [Display omitted] • MIPs were synthesized using emodin and physcion as templates. • MIPs possessed highly selective absorption towards specific templates. • Selective removal of over 96% emodin and physcion in PM extracts was achieved. • Over 90% THSG in PM extracts was reserved after passing through MIPs cartridges. • MIPs cartridges showed excellent practicability and regeneration ability. [ABSTRACT FROM AUTHOR]

A rapid and effective ultra-high performance liquid chromatography (UHPLC) method was developed for the determination of five anthraquinones (emodin, physcion, aloe-emodin, rhein, and chrysophanol) in Polygonum multiflorum. The target compounds were ultrasonically extracted with 70% methanol, followed by dispersive solid-phase extraction (d-SPE) with HC-C18 and desorption with acetonitrile. The five anthraquinones were separated on an ACQUITY UPLC® HSS T3 column (2.1 × 100 mm, 1.8 μm) and detected by a photodiode array detector (PDA) at 254 nm. Under the optimized conditions, linear relationships were achieved in the range of 0.3~100 mg/L for emodin, 0.3~40 mg/L for physcion, 0.1~20 mg/L for aloe-emodin, and 0.05~20 mg/L for rhein and chrysophanol. The limits of detection of the five analytes ranged from 0.01 to 0.08 mg/L, and the recoveries were within the range of 82.8~118.4% with an RSD (n = 6) of 1.0~10.3%. The intra-day and inter-day precision (n = 5) of the five targets were in the range of 1.0~1.8% and 3.0~3.1%, respectively. Furthermore, this method was applied to analyses of Polygonum multiflorum samples collected from different regions in China with satisfactory results. All the results indicated that this method is suitable for the detection of five anthraquinones in Polygonum multiflorum. [ABSTRACT FROM AUTHOR]

The biotransformation of four 4-hydroxybenzen derivatives (1,4-benzenediol (compound 1), 4-hydroxybenzaldehyde (compound 2), 4-hydroxybenzyl alcohol (compound 3) and 4-hydroxybenzoic acid (compound 4)) by the hairy root cultures of Polygonum multiflorum Thunb. as a new biocatalyst was investigated. It was found that the substrates were transformed to their corresponding glucosides, 4-hydroxyphenyl β- D-glucopyranoside (arbutin, compound 1a), 4-hydroxymethylphenyl β- D-glucopyranoside (gastrodin, compounds 2a, 3a) and 4-carboxyphenyl α- D-glucopyranoside (compound 4a), respectively. In the meantime, the hairy roots of P. multiflorum were able to stereoselectively and regioselectively glucosylate phenolic hydroxyl groups of compounds 1–4, but the cultures could not glucosylate the aldehyde group of compound 2 or the benzylic hydroxyl group of compound 3, and no glucosyl esterification of carboxyl groups of compound 4 was detected. On the other hand, the result also showed that the hairy roots of P. multiflorum were able to reduce the 4-hydroxybenzaldehyde to its corresponding alcohol. This is the first report that substrate 4 has been converted into its α- D-glucopyranoside by a plant biotransformation system. [ABSTRACT FROM AUTHOR]

Abstract: High-speed counter-current chromatography methods, combined with solvent partition, were applied to the systematic separation and purification of chemical components from Chinese medicinal herb Polygonum multiflorum extract. The aim of this paper is summing up the rules of solvent system selection for diverse fractions of herbal extract, and establishing the systematic pattern to screen the bioactive constituents rapidly. Nine compounds including emodin, chrysophanol, rhein, 6-OH-emodin, emodin-8-β-d-glucoside, polygonimitin B, 2,3,5,4′-tetrahydroxystilbene-2-β-d-glucoside, gallic acid and an unkown glycoside, which differed in quantity and polarity remarkably, were obtained. The purities of them were all above 97% as determined by high-performance liquid chromatography (HPLC), and their structures were identified by 1H NMR and electrospray ionization mass spectrometry (ESI–MS). The results demonstrated that HSCCC is a speedy and efficient technique for systematic isolation of bioactive components from traditional medicinal herbs. [Copyright &y& Elsevier]

The protective effects of two Chinese herbs, Astragalus mongholicus, Polygonum multiflorum and Astragalus mongholicus-Polygonum multiflorum in combination against thymus injury induced by cyclophosphamide were evaluated by transmission electron microscopy, image analysis, DNA gel electrophoresis as well as flow cytometry. Results showed that mice pretreated with cyclophosphamide had degenerated thymus with less normal thymocytes; when those mice were treated with the herbs, thymus morphology improved. The apoptosis analysis showed the thymus treated with the herbs had fewer apoptotic thymocytes than the thymus pretreated with cyclophosphamide only. In conclusion, Astragalus mongholicus and Polygonum multiflorum have protective effects on the thymus against cyclophosphamide-induced injury. Their protective effects partly attribute to reduced apoptosis. Astragalus mongholicus-Polygonum multiflorum in combination has better effects than either of the two herbs. [ABSTRACT FROM AUTHOR]

The article discusses biosynthesis of various coumarin glycosides by transgenic hairy roots in Polygonum multiflorum plant species. It mentions that substrate specificity and regioselectivity of coumarin glycosyltransferases was investigated by utilization of coumarin derivatives esculetin and hydroxycoumarins as substrates. It reports that nine varieties of glycosides that involve four new compounds were obtained by transgenic hairy roots of plant species.

Abstract Herbal preparations are widely available and generally regarded by the public as harmless remedies for a variety of medical ailments. We report the first case in Australia of acute hepatitis associated with the Chinese herbal medicine Shou-Wu-Pian, prepared from Polygonum multiflorum. Cholestatic hepatitis developed in a Chinese woman taking this preparation for the greying of her hair, and liver biopsy was consistent with a toxic reaction. Clinical and biochemical resolution occurred following cessation of the drug. [ABSTRACT FROM AUTHOR]