Hongmei Lin

Traditional usages, botany, phytochemistry, pharmacology and toxicology of Polygonum multiflorum Thunb.: A review

Abstract Ethnopharmacological relevance Polygonum multiflorum Thunb., which is known as Heshouwu (何首乌 in Chinese) in China. It is traditionally valued and reported for hair-blacking, liver and kidney-tonifying and anti-aging effects as well as low toxicity. The aim of this review is to provide comprehensive information on the botany, traditional uses, phytochemistry, pharmacological research and toxicology of Polygonum multiflorum, based on the scientific literature. Moreover, trends and perspectives for future investigation of this plant are discussed. It will build up a new foundation for further study on Polygonum multiflorum. Materials and methods A systematic review of the literature on Polygonum multiflorum was performed using several resources, including classic books on Chinese herbal medicine and various scientific databases, such as PubMed, SciFinder, the Web of Science, Science Direct, China Knowledge Resource Integrated (CNKI). Results Polygonum multiflorum is widely distributed throughout the world and has been used as a traditional medicine for centuries in China. The ethnomedical uses of Polygonum multiflorum have been recorded in many provinces of China and Japan for nine species of adulterants in six families. More than 100 chemical compounds have been isolated from this plant, and the major components have been determined to be stilbenes, quinones, flavonoids and others. Crude extracts and pure compounds of this plant are used as effective agents in pre-clinical and clinical practice due to their anti-aging, anti-hyperlipidaemia, anti-cancer and anti-inflammatory effects and to promote immunomodulation, neuroprotection, and the curing of other diseases. However, these extracts can also lead to hepatotoxicity, nephrotoxicity and embryonic toxicity. Pharmacokinetic studies have demonstrated that the main components of Polygonum multiflorum, such as 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucopyranoside and emodin are distributed among many organs and tissues. Conclusion Therapeutic potential of Polygonum multiflorum has been demonstrated in the conditions like Alzheimer׳s disease, Parkinson׳s disease, hyperlipidaemia, inflammation and cancer, which is attributed to the presence of various stilbenes, quinones, flavonoids, phospholipids and other compounds in the drug. On the other hand, the adverse effects (hepatotoxicity, nephrotoxicity, and embryonic toxicity) of this plant were caused by the quinones, such as emodin and rhein. Thus more pharmacological and toxicological mechanisms on main active compounds are necessary to be explored, especially the combined anthraquinones (Emodin-8-O-β-d-glucopyranoside, Physcion-8-O-β-d-glucopyranoside, etc.) and the variety of stilbenes.

A novel method to analyze hepatotoxic components in Polygonum multiflorum using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry

Polygonum multiflorum, called Heshouwu in China, is a traditional Chinese medicine used to treat various diseases. However, the administration of P. multiflorum (PM) and P. multiflorum Praeparata (PMP) causes numerous adverse effects. This study sought to analyze the toxic components of PM using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), and their hepatotoxicity in L02 human liver cells. Toxicity was evaluated by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) leakage, and liver enzyme secretion (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) assays. Furthermore, UPLC-Q-TOF/MS, Progenesis QI, and Makerlynx XS software analyses were used to differentiate extracts and analyze the toxic components. The order of toxicity was P. multiflorum ethanol extract (PME)>P. multiflorum water extract (PMW)>P. multiflorum Praeparata ethanol extract (PMPE)>P. multiflorum Praeparata water extract (PMPW), which was determined by MTT assay, LDH leakage, and liver enzyme secretion levels. The analysis methods suggest that PM toxicity may be associated with anthraquinone, emodin-O-(malonyl)-hex, emodin-O-glc, emodin, emodin-8-O-glc, emodin-O-(acetyl)-hex, and emodin-O-hex-sulphate. The toxic mechanisms of these components require further study.

Types, principle, and characteristics of tandem high-resolution mass spectrometry and its applications

Tandem high-resolution mass spectrometry (THRMS) is an analytical technique that has arisen in recent years and is now widely used in pharmaceutical research and development (RD for example, for the identification of constituents in herbs and formulae, pharmacokinetics, omics, and drug degradation), food safety, environmental contamination and other research fields. Time of Flight (TOF) and Orbitrap are the most widely used mass analysers in THRMS, and the technical specifications vary among the different types of THRMS and even among the different manufacturers for a given type of analyser. In this article, we review the principle and functional characteristics of different types or models for THRMS and provide a brief description of its applications in the medical research, food safety, and environmental protection fields.

Simultaneous determination of 14 constituents of Radix polygoni multiflori from different geographical areas by liquid chromatography–tandem mass spectrometry

Radix polygoni multiflori (RPM) has antioxidative, anti-aging, liver-protective and antihuman cytomegalovirus activity. It has been proved to be hepatotoxic. Considering multiple ingredients to control RPM quality is essential. The aim of this study was to establish a simple, rapid method using resolution liquid chromatography coupled with a triple quadruple mass spectrometry to identify and quantify the major bioactive constituents in RPM. The method was applied to analyze 14 marker batches from manufacturers from the same province. The ultrasonic extracts of all samples were determined by LC-MS/MS, and assessed by hierarchical cluster analysis. The proposed method was applied to analyze 21 batches of samples with acceptable linearity (R(2) , 0.9930-0.9998), precision (relative standard deviation, RSD, 0.45-4.73%) repeatability (RSD, 1.14-9.41%), stability (RSD, 1.29-12.88%) and recovery (RSD, 1.80-12.15%) of the 14 compounds. Furthermore, the hierarchical cluster analysis was applied to classify 21 samples on the basis of characteristics of the 14 compound markers. The developed method was demonstrated to be simple, sensitive and reproducible, and has significant importance and comprehensive evaluation for quality control of RPM and related preparations. Hierarchical cluster analysis clearly indicated that the RPM from the same province was similar, whereas samples of RPM from different provinces were significantly different.

A New Perspective on Liver Injury by Traditional Chinese Herbs Such As Polygonum multiflorum: The Geographical Area of Harvest As an Important Contributory Factor

Herbal medicine has been widely used in the treatment of various diseases; however, the adverse reactions cannot be ignored. Most previous studies have ignored the relationship between the factors of geographical areas/batches and toxicity. This study used Polygonum multiflorum (PM) as an example to analyze the relationship between the geographical areas/batches and toxicity and speculated on the hepatotoxicity-inducing components in PM based on high content screening, UHPLC-Q-TOF/MS and Progenesis QI software analysis. The results of the study show that the toxicity of PM was obviously different among the different geographical areas, and the most toxic PM was from the Sichuan province. To obtain more accurate results and to reduce the false-positive rate, two methods were used to evaluate the speculative results. It was noteworthy that emodin was not the main hepatocyte toxicity constituent of PM. The analysis methods suggested that PM toxicity may be associated with tetrahydroxystilbene-O-(galloyl)-hex and emodin-O-hex-sulfate. The toxicity of these two components requires further study.

Characterization of the constituents in rat plasma after oral administration of radix polygoni multiflori extracts by ultra‐performance liquid chromatography/quadrupole time‐of‐flight mass spectrometry

An ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry method was established to detect as many constituents in rat plasma as possible after oral administration of Radix polygoni multiflori (RPM) extract. A C18 column (150 × 2.0 mm, 4 µm) was adopted to separate the samples, and mass spectra were acquired in negative modes. The fingerprints of RPM extract were established, resulting in 39 components being detected. Among these compounds, 29 were identified by comparing the retention times and mass spectral data with those of reference standards and relevant references, and eight compounds were separated and detected in RPM for the first time. In vivo, 23 compounds were observed in dosed rat plasma, 16 of 23 compounds were indicated as prototype components of RPM, and seven compounds were predicted to be metabolites of RPM. A high-speed and sensitive method was developed and was successfully utilized for screening and characterizing the ingredients and metabolites of RPM.

Application of iTRAQ-Based Quantitative Proteomics Approach to Identify Deregulated Proteins Associated with Liver Toxicity Induced by Polygonum Multiflorum in Rats

Background/Aims: Clinical reports on adverse reactions that result from Polygonum multiflorum (PM) and its preparations, especially regarding liver injury, have recently received widespread attention. This study aimed to investigate the mechanism of hepatotoxicity induced by different PM extracts through iTRAQ quantitative proteomics. Methods: The different PM extracts were orally administrated for 90 days to rats, and the hepatotoxicity effect was evaluated through measurement of biochemical indexes, oxidative damage indexes and hematoxylin-eosin (HE) staining. Then, the hepatotoxicity mechanism was investigated by iTRAQ quantitative proteomics. Results: The results of biochemical and histopathological analyses showed that liver injury occurred in all groups of rats given by various PM extracts, which proved all of the PM extracts could induce hepatotoxicity. The hepatotoxicity mechanism may differ between the total extract group and the other groups through the results of biochemical indicators. The iTRAQ proteomics study showed that hepatotoxicity resulting from PM was mainly related to the abnormal activity of mitochondrion function-related oxidative phosphorylation pathways. Conclusion: This iTRAQ proteomics study revealed that the hepatotoxicity induced by PM is primarily related to the oxidative phosphorylation pathways. NADH dehydrogenase family proteins and Slc16a2 could be potential biomarkers of hepatotoxicity resulting from PM.

Simultaneous determination and pharmacokinetic study of polygalaxanthone III, tenuifolin, tenuifoliside A and tenuifoliside C in rat plasma by LC-MS/MS after oral administration

For the first time, a rapid and specific LC-MS/MS method has been developed for the simultaneous analysis of polygalaxanthone III, tenuifolin, tenuifoliside A and tenuifoliside C in rat plasma, and was applied to the pharmacokinetics (PK) studies of those three compounds. The analysis was carried out on an Agilent Eclipse plus C18 reversed-phase column (100 × 4.6 mm, 3.5 μm) by gradient elution with methanol and ammonia (0.01%, v/v). The flow rate was 0.4 mL min−1. All analytes including internal standards (I.S.) were monitored by selected reaction monitoring with an electrospray ionization source. Linear responses were obtained for polygalaxanthone III and tenuifoliside A ranging from 1 to 2000 ng mL−1, and tenuifolin and tenuifoliside C ranging from 2.5 to 2000 ng mL−1. The intra-day and inter-day precisions (RSD) were less than 12.98% and 7.50% respectively. The extraction recovery ranged from 70.06 ± 6.33% to 86.95 ± 5.35%, and I.S. was 77.23 ± 3.68%. Stability studies showed that the accuracies of polygalaxanthone III, tenuifolin, tenuifoliside A and tenuifoliside C ranged from 93.18% to 106.70%. The matrix effects ranged from 91.72 ± 4.80 to 101.84 ± 5.04. The validated method was successfully used to determine the concentration–time profiles of polygalaxanthone III, tenuifolin, tenuifoliside A and tenuifoliside C.

Interpretation the Hepatotoxicity Based on Pharmacokinetics Investigated Through Oral Administrated Different Extraction Parts of Polygonum multiflorum on Rats

The liver injury induced by Polygonum multiflorum (PM) used for clinical treatment has recently received widespread attention. This study aimed to determine the hepatotoxicity of PM through pharmacokinetics studies. The extract of PM was separated to isolate the anthraquinone fraction, the tannin and polysaccharide fraction, the hydroxystilbene fraction, and the combined anthraquinone fraction. A rapid LC-MS/MS method was developed and validated to simultaneously analyze 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside (TSG), emodin-8-O-β-D-glucopyranoside (EDG), and emodin in rat plasma, and was applied to the pharmacokinetics (PK) studies. The hepatotoxicity of different extracted parts of PM was evaluated through the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBil), direct bilirubin (DBil), and indirect bilirubin (IBil) in rat serum. The results showed that liver injury occurred in all the treated groups and that the hepatotoxicity performance of the total extract was different from other groups. The pharmacokinetic studies showed that the Cmax, Tmax, AUC, t1/2, and MRT of the major compounds of different extracted parts were significantly different in rat plasma at same dosage. Emodin-O-hex-sulfate, tetrahydroxystilbene-O-(galloyl)-hex, emodin (original and generated through EDG deglycosylation), and other free anthraquinones might be responsible for the hepatotoxicity of PM in vivo. PM extracts produced inhibitory effects on drug metabolic enzymes, include CYP3A4, CYP2C19, CYP2E1, UGT1A1, etc. And these effects may be related to its hepatotoxicity and pharmacokinetic behavior different. This information on hepatotoxicity and the pharmacokinetic comparison may be useful to understand the toxicological effects of PM.

Simultaneous determination and pharmacokinetic study of P-hydroxybenzaldehyde, 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside, emodin-8-O-β-D-glucopyranoside, and emodin in rat plasma by liquid chromatography tandem mass spectrometry after oral administration of Polygonum multiflorum

A rapid and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous analysis of P-hydroxybenzaldehyde, 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside, emodin-8-O-β-D-glucopyranoside, and emodin in rat plasma, and it was applied to the pharmacokinetics (PK) studies of the four compounds from the herb Polygonum multiflorum. The analysis was carried out on a Phenomenex Hydro-RP C18 (150 × 2.0 mm, 4 μm) reversed-phase column by gradient elution with a flow rate of 0.4 mL min−1. All of the analytes including internal standards (I.S.) were monitored by selected reaction monitoring with an electrospray ionization source. Linear responses were obtained for P-hydroxybenzaldehyde, 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside, emodin-8-O-β-D-glucopyranoside, and emodin ranging from 1 to 1000 ng mL−1. The intra-day and inter-day precisions (RSD) were less than 8.61% and 8.75%, respectively. The extraction recovery ranged from 77.00 ± 5.54 to 91.30 ± 2.96, and the I.S. was 85.82 ± 3.58%. Stability studies showed that the accuracies of P-hydroxybenzaldehyde, 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside, emodin-8-O-β-D-glucopyranoside, and emodin ranged from 94.66 ± 3.54 to 106.84 ± 6.91; the matrix effects ranged from 92.14 ± 3.63 to 103.98 ± 8.71. The validated method was successfully used to determine the concentration–time profiles of P-hydroxybenzaldehyde, 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside, emodin-8-O-β-D-glucopyranoside, and emodin.