2. 云南省天然药物药理重点实验, 昆明医科大学, 昆明 650500
2. Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China
Traditional Chinese Medicine (TCM) plays a significant role in Chinese civilization and is widely used in western societies, Asia, Africa and the Middle East now. Pleuropterus multiflorum (hereinafter as PM), belonging to Pleuropterus genus and Polygonaceae family, is known as one of precious perennial Chinese traditional medicine, also called Heshouwu in China, which is dried root tuber of P. multiflorum. It is distributed mainly in provinces of Sichuan, Yunnan, Guizhou and southern Shanxi and Gansu in China. The PM utilization in traditional Chinese at the first time can be traced back to 973 A.D., recorded in Kaibao Bencao, an encyclopedia of medical plants. PM possesses variously pharmacological activities officially listed in the Chinese Pharmacopoeia. There are two forms of PM decoctions in the Chinese Pharmacopoeia (2015): Raw Radix P. multiflorum (RPM) and P. multiflorum Preparata (PMP). PM has been widely used for strengthening bones and muscles, preventing premature graying of the hair and treating seminal emission and menstrual complaints due to their multiple beneficial effects to human body in China. RPM contributes to detoxification and bowel relaxation, while PMP tonifies the liver and kidney, benefits essence of blood and black beard, and relieves hyperlipidemia, fatty liver, and osteoporosis. The modern studies indicated that PM can be used for liver injury, cancer, diabetes, alopecia, atherosclerosis, and neurodegenerative diseases as well. PM is also used in many Chinese medicinal supplements to improve general health. Along with the development of medical values of PM in recent years, it has been prepared as a tonic food and beverage and has become popular in Asia and many other countries. However, liver injuries caused by taking PM have been reported worldwide. More than 130 compounds, including anthraquinones, stilbenes, phenolic acid, phospholipids, flavones and dianthrone derivatives, have been isolated from PM. Anthraquinones and stilbenes might relate to the toxic components.
Therefore, this paper summarized the chemical constituents and pharmacological activities of PM to provide a complete overview for the information cur- rently available, which will facilitate further research and exploitation of PM and is beneficial for the strengthening standardization of clinical applications, basic science research, quality control in manufacturing.1 Chemical constituents 1.1 Anthraquinones
At present, more than 20 anthraquinones had been found from PM, including anthraquinone aglycones, anthraquinone glycosides and anthraquinone methyl ethers (Table 1).
Compound 1 is a possessing anti-cancer activity anthraquinone derived from PM and can dose-depen- dently inhibit the growth of HepG2 cells, perturb cell cycle progression, down-regulate the expression of genes and proteins related to glycolysis, and trigger intracellular ROS generation. Compound 2 is an active ingredient of Chinese herbs, such as Cassia occidentalis, Rheum palmatum, Aloe vera, and PM, which exhibits many pharmacological effects, including anticancer, antivirus, anti-inflammatory, antibacterial, antiparasitic, neuroprotective, and hepatoprotective activities. Therefore, it can be used to treat various diseases such as influenza virus, inflammation, sepsis, Alzheimer's disease, glaucoma, malaria, liver fibrosis, psoriasis, Type 2 diabetes, growth disorders, and several types of cancers. However, some adverse effects of compound 2 have been reported, especially hepato- toxicity and nephrotoxicity. A poor intestinal absorption, short elimination half-life and low bioavailability of compound 2 have been demonstrated by pharmaco- kinetic studies. Compound 4 is a major medicinal ingredient isolated from Rheum palmatum, Aloe barba- densis, Cassia angustifolia and PM, which has various pharmacological activities including anti-inflamema- tory, antitumor, antioxidant, antifibrosis, hepatopro- tective and nephroprotective activities.1.2 Dianthrone derivatives
There are 14 dianthrone derivatives had been found from PM[14–16] (Table 2). And 32 new dian- throne derivatives were tentatively characterized in PM using HPLC-UV/LTQ-FT-ICR-MS by Yang. Among of them, compounds 24-27 showed moderate cytotoxic effects against KB tumor cell lines. Compound 33 exhibited potential inhibitory effect on UGT1A1 activity.
Forty-two stilbenes (Table 3, 4, Fig. 1) have been isolated from PM[3–4, 6, 19–33]. Compound 38, 2, 3, 5, 4ʹ- tetrahydroxystilbene-2-O-β-d-glucoside (TSG), as the main component of PM was used as a standard compound for appraising PM in the Chinese Pharma- copoeia. Compound 38 is a bioactive natural pro- duction with anti-inflammatory and antitumor origin- nating. It might possess potent anti-breast cancer effect with adriamycin, which may exert a synergistic reduction of cell injury via the inhibition of vascular endothelial growth factor/phosphatidylinositol 3-kinase/ Akt pathway. The antioxidant and free radical- scavenging activities of compound 38 even are much stronger than resveratrol. Compound 38 also shown neuroprotective effect in various neurodegenerative diseases and cerebral ischemia such as Alzheimer's disease, Parkinson's disease and cerebral ischemia/ reperfusion injury. It can inhibit apoptosis and protect neuronal cells against injury through multifunctional cytoprotective pathways. Compound 38 also has the antiatherosclerosis, anti-inflammatory and anti- cardiac fibrotic effects[38–39]. Compound 38 could delay senescence and treat aging-related diseases, and even more effective than resveratrol in delaying sene- scence. The moderate inhibitory activities against NO production of compound 69 and 70 had been con- firmed by Li in LPS-stimulated RAW264.7 cells.
There are 26 flavones (Table 5, 6, Fig. 2), one group of important natural compounds, have been isolated from PM[6–7, 10, 19, 20, 31, 41–46], including rutin, kaempferol, quercetin and their derivatives. Modern medical research shows that flavones have multiple biological activities such as anti-diabetics, antioxidant, anti-cancer, anti-inﬂammatory activities.
Phospholipids were also isolated from PM. Pho- spholipids are one of the most important constituents of brain tissue and cranial nerve and the main materials of cytomembrane synthesized by erythrocyte and other cells of organisms. Phospholipids from PM included phosphatidyl choline, phosphatidyl ethanolamine, lysophosphatidyl choline, phosphatidiyl glycerol, 7- hydroxy-4-methyl coumarin-5-O-glucoside, 7-hydroxy- 3, 4-dimethyl coumarin-5-O-glucoside and phosphate- dylinositol. A new aliphatic ketone, 1, 2-dihydroxyno- nadecone-3, was confirmed from chloroform section of Radix Polygoni Multiflori Preparata. Two new phospholipids, 1-O-stearoyl-2-O-d-4ʹ, 7ʹ-dodecenoyl- 3-O-phosphatodic acid-O-β-d-glucoside and 1-O- stearoyl-2-O-d-4ʹ, 7ʹ-dodecenoyl-3-O-phosphatodic acid-O-(6ʹ-O--d-glucose)-β-d-glucoside were isolated from Radix Polygoni Multiflori Preparata. Other phospholipids from Radix Polygoni Multiflori Pre- parata, including dodecane, eicosane, hexanoic acid, hexadecanoic acid methyl ester, hexadecanoic acid ethyl ester, octadecanoic acid methyl ester, octade- canoic acid ethyl ester, ethyl oleate, docosanoic acid methyl ester, methyl palmitate, ethyl palmitate, tetra- decanoatic acid ethyl ester, diphosphatidiyl glycerol, copaene and squalene.1.6 Other chemical compounds
Additionally, β-sitosterol, gallic acid, torachry- sone-8-O-β-d-glucopyranoside, daucosterol, torachry- chrysone-8-O-(6ʹ-O-acetyl)-β-d-glucopyranoside, N- trans-feruloyl tyramine, N-trans-feruloyl-3-methyldo- pamine, schizandrin, indole-3-(l--amino--hydroxy- propionicacid)-methyl ester, 7-hydroxyl-4-methylcou- marin-5-O-β-d-glucopyranoside, 7-hydroxyl-3, 4-methyl- coumarin-5-O-β-d-glucopyrano-side, 1, 3-dihydroxyl- 6, 7-dimethyl xanthine-1-O-β-oxymethyl-7-hydroxyl-2- methyl chromone, β-amtrin were and 1, 2-dihydroxyl- nonadecanone-3, were isolated from PM[3, 14, 42].2 Pharmacological activities 2.1 Anti-aging and antioxidant activities
PM could significantly reduce the activities of malondialdehyde (MDA), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum from d-galactose induced acute senescence rats, while improve the activities of glutathione peroxidase (GSH- px), superoxide dismutase (SOD). PM shown a protective effect on skin aging of mice, which could relate to increasing the dermis thickness of aging mice, reducing the level of insulin and IGF-1, and pro- moting the expression of collagen fibers. Xu found that the extract of PM improved the activity of SOD in rat heart and brain tissues, reduced the content of lipid peroxide and lipofuscin and showed significant anti- oxidant effects and a protective effect on the peroxi- dation damage of heart and brain tissues.2.2 Improve immunity
The polysaccharide of P. multiflorum (PPM) sig- nificantly inhibited cyclophosphamide-induced weight loss of immune organs and the decrease in the number of blood cells in mice and potentiated the immune- logical function in immunosuppressed mice. It signi- ficantly increased the phagocytic percentage and phagocytic index, the contents of serum hemolysin, the esterase positive rate of T-lymphocytes and Con A-induced proliferation of splenic T-lymphocytes, which indicated that PPM had the function of enhancing immunity.2.3 Dyslipidemia regulation
The findings of a clinical study on 50 hyperlipi- demia patients demonstrated that the lipid-owering effect of PM may be related to regulating action of the genes involved in cholesterol synthesis and lipoprotein metabolism.2.4 Neuroprotective activity
The therapeutic effect of PM on neurodege- nerative diseases is quite obvious and widely recog- nized. An investigation about therapeutic activity of PM in Alzheimer's disease (AD) by Chen et al. shown that the scores for the Ability of Daily Living Scale and the Mini-Mental State Examination were signifi- cantly improved in the treatment group compared with the Chinese herb and western medicine control groups. In a randomized, piracetam-controlled, single- center clinical trial, PM was evaluated as monotherapy for vascular dementia (VaD). The results shown that the total clinical effective rate was 71.25% and that the herbal medicinal had obvious therapeutic effect on VaD, with no relative adverse drug reactions.2.5 Hepato-protective activity
In vitro and vivo models, the hepatoprotective effects of ethanolic extract of PM were related to regulating the redox state in liver injury through Nrf2 activation and controlling hepatic bile acid homeo- stasis in obstructive cholestasis, through bile acid transporter expression modulation. The study of P. multiflorum water extract (PMW) by Wei et al. suggested that PMW accelerated bile acid entero- hepatic circulation and changed the composition of intestinal Bas lead to activation of Fxr-Fgf15 signal in intestines and further inhibition of the expression of Cyp7a1 in the liver.2.6 Renal-protective activity
TSG from PM plays a concentration-dependent protective role in ameliorating the progression of an adriamycin (AD)-induced focal segmental glomerulo- sclerosis (FSGS) through activation of the Nrf2- Keap1 antioxidant pathway. TSG has the capacity of blocking angiotensin Ⅱ (ANG Ⅱ) signaling. In the streptozotocin (STZ)-induced diabetes model TSG was demonstrated the beneficial effect of therapy on renal damage though the inhibition of the RAS effectively to prevent renal injury in diabetic nephron- pathy.2.7 Cardiovascular system
Tetrahydroxystilbene glucoside could induce relaxation of the superior mesenteric artery through an endothelium-dependent pathway that involves the inhibition of COX-2 activity and decreased in TXA2
and through an endothelium-independent pathway via opening of a voltage-dependent K+ channel, blockade of Ca2+ influx and release of intracellular Ca2+. The cardioprotective effects of TSG have been demon- strated. TSG protected murine hearts against ischemia/ reperfusion injury in vivo and in vitro by activating the Notch1/Hes1 signaling pathway and attenuating ER stress-induced apoptosis.2.8 Anti-inflammatory and antibacterial activity
Lu et al. reported that ethanol extract of P. multiflorum (PME) had a significantly anti-inflame- matory effect. Chin et al.found that TSG of PM could reduce periodontitis, gene expression of TNF-α, interleukin-1 IL (IL-1) and IL-6, and inhibit the acti- vation of NK-kB in vivo and in vitro. Studies found that PM had the function of inhibiting human dysentery bacillus and mycobacterium tuberculosis. Especially, the anthraquinone derivatives of PM had inhibitory effect on bacteria, fungal influenza viruses and pathogens, such as paratyphoid rod 901, diph- theria bacillus, staphylococcus aureus, paratyphoid bacillus B, hemolytic streptococcus B and bacillus anthracis. Study confirmed that Raw Radix P. multi- florum had the effect of fighting staphylococcus aureus, while P. multiflorum preparata had the effect of fighting staphylococcus albicans. And steamed and wine P. multiflorum preparata had a better effect against diphtheria bacillus.2.9 Other effects
A study on diabetes-related bone loss in mice shown that PMW significantly alleviated mouse body weight loss and hyperglycemia, and elevated serum levels of insulin, osteocalcin and bone- alkaline phosphatase. PMW might relieve diabetes- related bone disorders through regulating osteoclast- related genes and PM may be used as a preventive agent for diabetes-induced bone loss. At the same time, tetra hydroxy stilbene glucoside from PM was also demonstrated the protected against diabetes- induced osteoporosis in mice with streptozotocin- induced hyperglycemia. A study on PME in high- fat diet-induced obese mice demonstrated that PME might relieve obesity by inhibition of adipogenesis and lipogenesis and lipolysis and fatty acid oxide- tion.3 Toxic effects
Although there are many reports referred to the toxicity of PM, especially for liver adverse reactions, mechanism of toxicity remains unclear. Liver injuries caused by PM have been reported and the incidences have increased in recent years[65–66]. Although the hepatotoxic chemicals attributing to the hepatic lesions of PM remain in dispute, the hepatotoxicity of emodin has been well documented in many studies[67–70]. Luteolin was reported to cause cytotoxicity in primary rat hepatocytes at dosages of 50 μmol/L or lower levels of concentration. Apigenin was found to can significantly increase the accumulation of lipid droplets and cause fatty liver disease. He et al.screen 25 ingredients in PM by a computational toxicology approach. Emodin, chrysophanol, rhein, danthron, aloe emodin, physcion, and apigenin could cause variable degrees of liver injury recorded in the literature. Emodin 8-glucoside, physcion-8-O-d-gluco- pyranoside, and luteolin were reported to possess potential hepatotoxicity. For the other 14 hepatotoxic ingredients, although direct evidence focused on their hepatotoxicity was not available, none of them was reported to be potential hepato-protector. Liu et al. hypothesized tannin, as another major component in PM, was one of the reasons for the induced liver damage. While the components of PM responsible for the hepatotoxic effects have not yet been identified now, even many of the reports are contradictory, and the mechanism involved in PM-induced liver damage are not comprehensive. Although many reports referring to toxicity of PM especially for liver adverse reactions have been reported, it might possible that PMW usage in TCM still keep safe currently, except high dose of HSW usage in a long term.4 Conclusions
PM is an important medical plant wildly used in traditional Chinese medicine. There are abundant anthraquinones, stilbenes, flavones, phospholipids and dianthrone derivatives from PM. At present these studies on PM mainly aimed at the medicinal effects, mechanisms and quality control. TSG, as the main component of PM, not only has many medicinal activities, but also has great potential exploitation for medicines. And with the concern about liver injury induced by PM, the model of safety monitoring and risk management of PM is very important based on quality control as one of the major safety problems in TCM drug safety concerns. The comprehensive know- ledge of PM by strengthening standardization of clinical applications, basic science research, quality control in manufacturing is significance. Measures should also be encouraged and implemented to promote healthy development of the TCM industry.
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