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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 21-49

A review of the pharmacology, application, ethnopharmacology, phytochemistry, quality control, processing, toxicology, and pharmacokinetics of Paridis Rhizoma


1 Key Laboratory of Chinese Materia Medica, Heilongjiang University of Chinese Medicine, Harbin, China
2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States

Date of Submission02-Oct-2020
Date of Acceptance28-Dec-2020
Date of Web Publication29-Apr-2021

Correspondence Address:
Liu Yang
Heilongjiang University of Chinese Medicine, Harbin, 150040
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_4_21

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  Abstract 


Paridis Rhizoma (PR) is also known as the flower with seven leaves and one branch, PR with golden thread, etc. It tastes bitter, numb, and slightly cold and has little poison. It is often used for the treatment of external skin infection, sore throat, snake bite, fall pain, frightening convulsion, and other diseases. PR has analgesic, sedative, anti-inflammatory, hemostatic, antitumor, antibacterial, antiviral, and renal and liver protective effects; inhibition of angiogenesis; immune regulation; and antioxidant and cardiovascular effects, and antifertility and anti-early pregnancy sperm killing effects. Steroidal saponins, β-ecdysone, polysaccharides, microelements, flavonoid glycosides, and amino acids were isolated from PR. In this paper, its pharmacology, application, ethnopharmacology, phytochemistry, quality control, toxicology, and pharmacokinetics were reviewed. This information suggests that we should focus on the development of new drugs related to PR, including specific ingredients, so as to make PR play a greater therapeutic potential. At the same time, attention should be paid to the rational use of PR resources to avoid excessive using, resulting in resource shortage. Therefore, we can carry out the research on the substitutes of PR, a large-scale planting of (Paridis Rhizoma) PR, and develop the same genus of PR and other resources. So far, great progress has been made in pharmacology and phytochemistry, especially in antitumor research, and many traditional uses have been confirmed and clarified by modern pharmacological research. However, there are few studies on the mechanism of its pharmacological action and few studies on processing. To develop new drugs in the future, more studies and experiments are still needed to prove the effect of PR and explore more new effects.

Keywords: Analytical methods;Paridis Rhizoma; pharmacokinetics; pharmacology; phytochemistry; toxicology


How to cite this article:
Liu ST, Yu H, Hou AJ, Man WJ, Zhang JX, Wang S, Wang XJ, Zheng SW, Su XL, Yang L. A review of the pharmacology, application, ethnopharmacology, phytochemistry, quality control, processing, toxicology, and pharmacokinetics of Paridis Rhizoma. World J Tradit Chin Med 2022;8:21-49

How to cite this URL:
Liu ST, Yu H, Hou AJ, Man WJ, Zhang JX, Wang S, Wang XJ, Zheng SW, Su XL, Yang L. A review of the pharmacology, application, ethnopharmacology, phytochemistry, quality control, processing, toxicology, and pharmacokinetics of Paridis Rhizoma. World J Tradit Chin Med [serial online] 2022 [cited 2022 May 18];8:21-49. Available from: https://www.wjtcm.net/text.asp?2022/8/1/21/336841




  Introduction Top


Paridis Rhizoma (PR) is derived from PR Smith var. yunnanensis (Franch.) Hand. Mazz. and PR Smith var. chinensis (Franch.) Hara. It is a traditional Chinese medicine (TCM) of antipyretic and antidote. It was originally recorded in Sheng Nong's Herbal Classic under the name of Zaoxiu. In Chinese Pharmacopoeia (2020 Edition), it has a long history of medicinal use and is a rare and endangered plant in China. PR was first published in Sheng Nong's Herbal Classic and listed as inferior. PR is also known as Huachonglou, Qiyelian, and Tiedengtai. It is mainly distributed in Sichuan, Yunnan, Guizhou, Fujian, and other areas. It can be mined all year round, but it is better to dig in autumn but remove fibrous roots and wash and dry in the sun. Angiosperms belong to liver meridian. It has the functions of clearing heat and detoxification, relieving detumescence and pain, cooling the liver, and calming convulsion.

PR is an important component of Yunnan Baiyao, Gongxuening capsule, antiviral particles, Jidesheng snake tablets, and Yizhihua ointment. PRs are often confused with a variety of plants of the same genus. Different factors such as origin and growth years will cause quality differences between genuine Paridis Rhizomas saponins (PRS). At present, the common breeding methods of PR plants include seed propagation, rhizome cutting propagation, and tissue culture. Pharmacological studies have proved that it has analgesic, hemostatic, sedative, anti-inflammatory, bacteriostatic, antiviral, antitumor, deworming, uterine contraction, and immune regulation effects. At the same time, PR, as a folk anticancer drug, is widely used in liver, lung, nasopharyngeal, ovarian, uterine, gastric, and other cancer diseases.[1] The picture of PR is shown in [Figure 1].
Figure 1: Paridis Rhizoma

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In this paper, the ethnopharmacology, phytochemistry, pharmacological activity, toxicology, quality control, toxicology, and pharmacokinetics of PR were comprehensively discussed. A more comprehensive understanding of PR was conducted to provide relevant information and basis for further research and development of PR.


  Ethnopharmacy Top


Traditional applications

Shennong's Classic of Materia Medica (《神农本草经》) is the earliest existing monograph on pharmacology. It is the first systematic summary of early clinical medication experience in China, and it has been praised as the classic work of traditional Chinese medicine. It was written during the Qin, Han, or Warring State periods. The main treatment of epilepsy shaking head and tongue bite. For the treatment of abdominal distension, epilepsy, ulcer evil sores, vulva malnutrition, can also remove intestinal worms, snake venom.

Ri Hua Materia Medica (《日华本草》) said, “Treatment of vomiting, restlessness, convulsions, coma.” This book is compiled by combining various herbs and medicines commonly used at that time. The character and function sequence of each drug are more comprehensive, but the exact date of compilation is uncertain.

“Compendium of Materia Medica” (《本草纲目》) included the name of Zaoxiu; it has the functions of clearing heat and detoxification, relieving swelling and pain, cooling the liver, and eliminating astonishment. Recording can treat fetal wind in children, hand and foot convulsions;“A layer of seven leaves, blooming in summer, a flower has seven petals; the venom of insects and snakes can be treated, so it has the names of Zaoxiu and Sting.” Written by Li Shizhen during the Ming Dynasty, the book covers a wide range of scientific fields, including medicine, pharmacology, biology, mineralogy, chemistry, environment and biology, genetics, and variation.

“Ben Cao Hui Yan” (《本草汇言》) record PR should not be used in the syndrome of heat injury, yin vomiting, and bleeding. This book is published by Shanghai Science and Technology Publishing House in 2005. The author is Ni Zhumo. The greatest value of this book is to record the medical theories of hundreds of medical experts in Zhejiang province in the late Ming Dynasty and also extract a large number of medical prescriptions in the Ming Dynasty.

 “Ben Jing Feng Yuan” (《本经逢原》) record is forbidden for those with deficiency of vital energy. This book is written by Zhang Lu, a famous doctor in The Qing Dynasty. There are many personal opinions and experiences in the discussion.

“An Illustrated Book of Plants” (《植物名实图考》) records, PR is a surgical medicine. It was written in the Qing Dynasty. One of its features is the combination of pictures and texts.

 “Tang Materia Medica” (《唐本草》) indicated, Grind the roots with vinegar. It's very effective for reducing swelling and snake venom. Commonly known as Xin Xiu Ben Cao (《新修本草》), it is compiled in the Tang Dynasty, it is the world's first state-issued pharmacopoeia.

Compound

According to Chinese Pharmacopoeia, it is compatible with honeysuckle and forsythia to treat heat toxin sores. It is the same as Bidens bipinnata to treat snakebite; it is compatible with Shijianchuan, Scutellaria barbata, and Prunella vulgaris to treat cancer. There are many compound prescriptions of PR [Table 1].
Table 1: Compound Paridis Rhizoma

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  Phytochemistry Top


PR has a variety of chemical components, including steroidal saponins, plant endophytes, polysaccharides, amino acids, trace elements, sterones, cholestanols, C21 steroids, phytosterols, plant ecdysone, flavonoids, triterpenoids, and fatty acids.

Steroidal saponins

Most studies have shown that PR contains steroidal saponins, which account for the majority of the chemical constituents and are the main active components. Steroidal saponins are a class of compounds formed by dehydration of steroidal aglycones with spirostane side chains and carbon hydroxyl groups on the end groups of sugars. It mainly includes diosgenin glycosides and Pennogenin.[20] It is found that these ingredients have many pharmacological effects, such as anticancer, sedative, hemostatic, anti-inflammatory, and antioxidant, vascular endothelial cell protection, and uterine contraction, and several of them (Paridis Rhizoma saponins I, II, VI, and VII) are taken as quality standards in Chinese Pharmacopoeia. The main components separated are shown in [Table 2]. The structure of steroidal saponins in PR is shown in [Figure 2].
Table 2: Steroidal saponins in Paridis Rhizoma

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Figure 2: Structure of steroidal saponins in Paridis Rhizoma

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Studies have shown that phytosterols have many advantages, such as abundant nutrients, abundant ingredients, and high physiological activity, which can reduce the risk of cardiovascular disease. At present, stigmasterol, carotene, β-sitosterol, stigmasterol-3-acetate, β-sitosterol-3-acetate, sitosterol-3-O-glucose, grape glycosides, Δ5-22-stigmasterol-3-O-β-D-glucopyranoside, etc., have been isolated and detected in PR.[51] The names of some phytosterols are shown in [Table 3], and the structures are shown in [Figure 3].
Table 3: Phytosteroids in Paridis Rhizoma

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Figure 3: Structure of phytosteroids in Paridis Rhizoma

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Ecdysone is a growth hormone of a class of invertebrates and is also an active ingredient of a variety of Chinese herbs. According to the present study, four kinds of β-ecdysone were isolated from Paris plants.[57] There are mainly ajugasterone, α-ecdysone, and paristerone.

Flavonoids

Flavonoids are widely distributed in plants of this genus, which are fat soluble and have certain biological activities. At present, 22 flavonoids have been isolated from this genus, and their configurations are mainly flavonols, bioflavonoids, and chalcones. They are usually linked to sugar chains in C-3 to form glycosides and widely exist in Yunnan PR, five-fingered Lotus, Mao PR, long-medicine PR and four-leafed PR.[53],[58],[59] The names of some flavonoids are shown in [Table 4], and the structures are shown in [Figure 4].
Table 4: Flavonoids in Paridis Rhizoma

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Figure 4: Structure of flavonoids in Paridis Rhizoma

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At present, the research on chemical constituents of Paris is mainly focused on steroidal saponins, in addition to phenyl propanoids, fatty acids, alkaloids, and quinones.[65],[66]

Pharmacological effects

Studies have shown that PR has pharmacological effects such as antitumor,[67] hemostasis,[68] bacteriostasis,[69] anti-inflammation,[70] analgesia,[71] sedation,[72] inhibition of angiogenesis,[73] immunomodulation,[74] antioxidant,[75] renal and liver protection,[76] antifertility and anti-early pregnancy spermicidal,[77] cardiovascular,[78] and antiviral.[79]

Antitumor

PR has a wide range of anticancer effects and is widely used in the treatment of liver cancer, lung cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, malignant lymphoma, nasopharyngeal cancer, brain tumors, and digestive system tumors. Its mechanism may be related to its own cytotoxic effect and its promotion of apoptosis, affecting the tumor cell cycle, inhibiting tumor angiogenesis, regulating immune function, and inducing cell autophagy. The effects of chemical constituents of PR on cancer cells are shown in [Table 5].
Table 5: The effects of chemical constituents of Paridis Rhizoma on cancer cells

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Antihepatoma

To investigate the effects of Paris saponin I (PSI) on the proliferation and apoptosis of human hepatoma SMMC-7721 cell line in vitro and the related mechanisms. Experiments using 1.25, 2.5, and 5 μmol/L PSI, respectively, deal with human liver cancer SMMC-7721 cells for 24 h. The results showed that SMMC-7721 cells after PSI intervention had chromatin concentration, nuclear fragmentation, apoptotic body formation, cell cycle arrest in G1 phase, and apoptotic peak formation, not only upregulated the expression of Fas and Bax, but also downregulated the expression levels of B-cell lymphoma-2 (Bcl-2), cyclin D1, and cyclin E proteins, and the effect was time–concentration dependent.[67] The blank control group was used to observe the morphological changes of the studied cells and the changes of the related proteins. In addition, the effects of PSI on the proliferation, cycle, and apoptosis of hepatoma MHCC97-H cells were studied. The results showed that PSI acts on human liver cancer cell MHCC97-H with a half maximal inhibitory concentration (IC50) of 5.7 μg/mL and PSI could inhibit S phase, block cells in G0/G1 phase, and significantly promote cell apoptosis.[80] However, its specific anticancer mechanism has not been elucidated.

The anticancer effects of four kinds of Paris saponins (PS1–PS4) on human cancer cells and normal cell lines were evaluated experimentally, and the potential mechanism of the selective anticancer effects of steroidal saponins was explored. Among them, PS1 and PS2 (Paris VII) could significantly induce apoptosis and G2/M arrest in HepG2 cells, and This study further demonstrated that this effect is related to cysteine protein-dependent and cysteine protein-independent mitochondrial pathways, dose-dependent reduction of CDK1 levels, activation of p38/MAPK and JNK/MAPK pathways, and inhibition of ERK1/2/MAPK and PI3K/Akt pathways. These results show that the anticancer effects of PS1 and PS2 are related to induction of apoptosis in HepG2 cells and blocking cell cycle progression through multiple targets.[81] The antitumor effects of PS1 and PS2 are comprehensively illustrated by the changes of multiple targets, but the lack of positive experiments may not well explain the strength of their anticancer effects. The study evaluated the mechanism of action of Paridon D (PD) in R-HepG2 and its parental cells; the mitochondrial apoptotic pathway was found to be involved in PD-induced apoptosis, which was speculated to be due to the depolarization of mitochondrial transmembrane potential induced by PD, the generation of H2O2, the release of cytochrome C, and the release of apoptosis-inducing factors. This experiment is the first to prove that PD becomes an effective anticancer drug by inducing apoptosis, and the results showed that PD could overcome the drug resistance of R-HepG2 cells and cause programmed cell death through mitochondrial dysfunction. In addition, inhibition of these mitochondrial functions can reduce the cytotoxic effects of PD, which also confirmed the conjecture that PD can cause mitochondrial damage to induce apoptosis of cancer cells, and found that its effects are significantly dose and time dependent.[82] The positive control group was used in the experiment, which can clearly illustrate the strength of resistance to this type of hepatocellular carcinoma cells. At the same time, it was found that this component can overcome the drug resistance of this type of cells, which can provide information for future research on the drug resistance of R-HepG2 cells. The experiment only elaborated the effect of PD on R-HepG2 cells, but the lack of effect on other cells is not stated.

The antitumor effect of total PR saponins was evaluated by establishing a diethylnitrosamine (DEN)-induced hepatocellular carcinoma rat model. The results showed that PRS inhibited the formation of malondialdehyde (MDA) and nitric oxide (NO), increased the production of superoxide dismutase (SOD), and upregulated the expression of glutathione S-transferase-α/μ/π to alleviate the level of liver injury. It was also found that PRS treatment significantly reduced the levels of alpha-fetoprotein (AFP) mRNA and protein, while the levels of AFP mRNA and protein are biological markers for the diagnosis of liver cancer. These results suggest that PRS can treat liver cancer. The study further illustrated the anticancer mechanism of PRS, including upregulation of DEN-induced liver tissue phase I and II enzymes and downregulation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and DNA damage.[83] The study illustrates the therapeutic effect of PRS from the changes of multiple molecules, discusses the anticancer mechanism of PRS, and illustrates the anticancer effect of PRS; however, the lack of a positive control group cannot better compare the strength of the anticancer effect between PRS and positive drugs, and there is still a lack of more basis for whether PRS can be applied in clinical practice. At the same time, the experiment only studied the effect of PRS on DEN-induced liver cancer model, lacking in in-depth study on liver cancer caused by other causes, which also provides ideas for future research directions.

To explore whether Paris saponin VII (PP7) can induce autophagy in HepG2 cells and its role in PP7-induced cell death, the autophagy inhibitor (chloroquine) was used to inhibit cell autophagy and eliminate PP7-induced cell death. The results showed that the cells were treated with 0.88, 1.32, and 1.98 M PP7 for 24 h, respectively. It is clearly observable that PP7 induced autophagic death of HepG2 cells, and C-Jun N-terminal kinase (JNK) was activated after PP7 treatment and pretreatment with inhibitor SP600125, reversing PP7-induced autophagy and cell death, suggesting that JNK plays an important role in PP7-induced autophagy. It was found for the first time that PP7 increased the phosphorylation of adenosine 5'-monophosphate-activated protein kinase and Bcl-2 and inhibited the PI3K, AKT, and mammalian target of rapamycin (mTOR). These results suggest that PP7 has antitumor effects.[84] Meanwhile, these pathways are dose dependent. However, these results are derived from cell-level studies, lacking the support of more research data and positive control to further support the conclusions.

Antilung cancer

To observe the effect of Yiqi Yang Yin Prescription (Chonglou Compound) on vascular endothelial growth factor (VEGF) in patients with nonsmall cell lung cancer (NSCLC), the serum VEGF value was measured. The VEGF value in the treatment group was 158.07 ± 75.82 μg/L before treatment and 110.00 ± 41.71 μg/L after treatment; there was a significant difference before and after treatment, which indicated that this compound could reduce the serum VEGF level of NSCLC patients and then treat NSCLC.[85] The experiment only explained the part of the antilung cancer effect of PR compound but did not explain whether the same effect would be produced by using PR alone, a lack of more data support. Later studies explored the effects of PSI combined with hyperthermia on a variety of NSCLC cells. The results showed that PSI combined with 43°C (IC50 = 1.21 µg/mL) hyperthermia significantly increased the inhibitory effect on NSCLC, leading to G2/M arrest, and significantly induced apoptosis to inhibit cell proliferation. Bcl-2 expression level decreased, while Bax expression increased. Caspase-3 protein expression significantly enhanced after combined treatment with 43°C and high temperature.[86] In summary, PSI combined with hyperthermia treatment for NSCLC has obvious enhancement effect. In the future, it can be studied from this direction to enhance the efficacy of Paris saponins, but the experiment did not use a positive control group, only compared with the treatment effect of PSI alone and hyperthermia group, which may lack clinical data.

Using uratan-induced C57BL/6 mouse lung cancer model, the antilung cancer effect of PRS was explored. It was found that PRS (50 mg/10 mL/kg) treatment reduced the histopathological severity of uratan-induced lung cancer in mice, and the antitumor mechanisms were found to include (1) alleviating oxidative stress injury by upregulating Nrf2 and heme oxygenase-1 (HO-1); (2) reducing the levels of inflammatory factors cyclooxygenase-2 (COX-2) and PGE2; (3) activating caspase-3 by downregulating antiapoptotic protein (Bcl-2) and upregulating proapoptotic protein (Bax); (4) decreasing the expression of PCNA and inhibiting the epidermal growth factor receptor (EGFR)/PI3K/Akt pathway. It indicated that PRS could inhibit and delay the occurrence of lung cancer through multiple pathways.[87] There are positive control group and negative control group. The effect of PRS on lung cancer cells can be observed obviously, but the effect of specific chemical components is not discussed, which provides ideas for future research direction. Moreover, only lung cancer induced by urethane was studied, but lung cancer caused by other reasons was not mentioned. Recently, some experiments have explored the effect of PRS on DEN-induced (100 mg/kg) lung cancer in mice. The results also found that PRS (100 mg/10 mL/kg) treatment reduced the severity of lung histopathology and found and summarized its antitumor mechanisms: (1) the oxidative stress injury was alleviated by up regulating the activities of CAT and SOD; (2) the levels of TNF-α, IL-6, COX-2 and PGE2 were downregulated; (3) caspase-3 was activated and Bax was upregulated; (4) the expression of PCNA was decreased; (5) the expression of tumor stem cell marker CD133 was inhibited; (6) the abnormal expression of cytokeratin 8 and 18 was inhibited; (7) EGFR/PI3K/Akt, EGFR/Ras/extracellular regulated protein kinase (ERK), and nuclear factor-κB (NF-κB) pathway were inhibited.[88] This is similar to the previous exploration of the mechanism of PRS on uratan-induced lung cancer. These results can further illustrate the anticancer mechanism of PRS and also show that PRS is not only effective for lung cancer induced by one cause but also has a wide range of applications. Other mechanisms of PRS on DEN-induced lung cancer have also been found, providing more reliable information for future experiments. However, no positive control was used in the experiment, which may have an impact on the scientificity of the data.

The metabolic profiles of PRS in Lewis pulmonary adenoma mice were studied using metabolomics. The results showed that treatment with PRS reduced most lipid compound levels and lactate concentrations and increased glutamate and glucose concentrations, by analyzing metabolic enzyme-related genes. The results also found that PRS regulated the p53/mTOR-c-Myc-HIF-1α network to reduce GLUT1, hexokinase 2, PKM2 and lactate dehydrogenase A (LDHA) genes, increased p53 mRNA, increased glutaminase levels, and inhibited ATP products, while PRS treatment decreased FASN mRNA levels to inhibit adipogenesis.[89] The changes of these factors suggest that PRS exerts anticancer effects by inhibiting the metastasis of lung adenocarcinoma in mice by inhibiting the metabolism of cancer cells.

The effect of PSI on the proliferation and apoptosis of circulating tumor cells (CTCs) of lung cancer was evaluated by in vitro experiments. The results showed that PSI could significantly inhibit the proliferation of CTC in a concentration-dependent manner, induce significant changes in the nuclear morphology of CTCs, and increase the proportion of apoptotic cells, and the cycle of CTCs was blocked in G0/G1 phase, which inhibited the transformation of cells into S phase, and its anticancer effect was dose dependent (the doses were 2, 3, and 5 mg/L, respectively).[90] However, the specific molecular mechanism has not been explained in the experiment, so its anticancer mechanism needs further study. The effect and mechanism of PSI on apoptosis of human lung cancer NCI-H661 cells were also studied. The results also showed that PSI inhibited the proliferation of NCI-H661 cells in a dose-dependent (the doses were 1, 5, and 10 μmol/L, respectively) and time-dependent manner and also induced apoptosis in a dose-dependent manner. After treatment with this drug, the expression of caspase-8, caspase-9, Bcl-2 gradually decreased; among them, Bcl-2 expression was most significantly attenuated, and the drug was found to rapidly lead to mitochondrial fragmentation, resulting in anticancer cell effects.[91] However, these experiments only studied the effect of PSI on individual lung cancer cell lines, which may lack scientific basis to support its effect. Moreover, the experiments are mainly cell experiments, and more in vivo and in vitro experiments are lacking.

Antinasopharyngeal carcinoma

CNE-2Z human nasopharyngeal carcinoma cells were used to investigate the effects of total saponins from PR on cell cycle and apoptosis. The experimental results showed that total saponins from PR could inhibit the proliferation of CNE-2Z cells. The effect was obviously time and dose dependent, but the cells that had obvious apoptotic characteristics were dose dependent. In the experiment, apoptosis was most obvious after 120 μg/mL of total saponins from PR and CNE-2Z cells would be blocked in S phase.[92] However, there is no study on its mechanism, Moreover, the lack of blank control group and positive control group in the experiment has a certain impact on the scientific nature of the explanation of this effect. The experiment also did not specify the specific chemical composition that produced the effect. Future research in this area can be carried out.

To investigate the effect of PP-22 purified from Yunnan Chonglou on nasopharyngeal carcinoma cell line CNE-2, the results showed that PP-22 could induce apoptosis of CNE-2 cells, activate p38 mitogen-activated protein kinase pathway, downregulate signal transducer and activator of transcription 3 (STAT3) pathway, and inhibit ERK. The changes of these pathways and cells indicated that PP-22 had an inhibitory effect on NPC cells.[93] However, it is not clear which pathway changes have a stronger inhibitory effect on cancer cells, and the specific mechanism is unclear.

Previous studies have found that the expression level of long noncoding RNA (lncRNA) reprogramming regulator (ROR) is high in nasopharyngeal carcinoma cell lines, and this experiment found that PR saponin I can significantly downregulate the expression level of lncRNA-ROR, in which lncRNA-ROR/P53 signal transduction is the basis of PR saponin I inhibiting the progression of nasopharyngeal carcinoma. These data suggest that PP-I can downregulate lncRNA-ROR and then upregulate P53 signal transduction, thereby inhibiting tumor growth and inducing apoptosis of nasopharyngeal carcinoma cells to play an antinasopharyngeal carcinoma role.[94] The research is mainly focused on the cell level, lacking animal experiments, which may provide obstacles for clinical application.

Ovarian cancer

SKOV3 cells related to ovarian cancer were used to study the effect of PSI on tumor cells. It was found that PSI treatment increased the number of cells in G2 phase, decreased the number of cells in G0/G1 and S phase, and inhibited the growth of SKOV3 cells in a dose-dependent manner; at the same concentration, PSI killed cells more effectively than the positive control group, and the level of cytochrome C increased after PSI treatment, mitochondrial cytochrome C level decreased, and Bcl-2 level decreased; these data suggest that PSI can induce cancer cell death through mitochondrial apoptotic pathway. PSI can also inhibit ERK1/2 activation, reduce phosphorylated ERK1/2 level, and reduce ERK activity, leading to a significant decrease in Akt phosphorylation level, resulting in antitumor effects.[95] This study not only studied one cell line related to ovarian cancer, lacking multitarget studies but also pointed out that Akt may be a potential target, which still needs further study.

The inhibitory and proapoptotic functions of the active ingredient PSI extracted from PR on the growth of human ovarian cancer cells (HO-8910PM cells) in vitro were studied. The results showed that PSI had a significant inhibitory effect on the proliferation of HO-8910PM cells in the concentration range of 0.5–5 μg/mL, showing a significant dose–time dependence, and its half inhibitory concentration was basically between 1 and 3.5 μg/mL; moreover, when the concentration of PSI was within 2 μg/mL, apoptosis of HO-8910PM cells could be induced at the early stage of drug administration, which also exerted antitumor effect in a time-dependent manner, and it was found that PSI mainly affected the pre-DNA synthesis stage (G0/G1) of HO-8910PM cells to cause apoptosis.[96] However, only this kind of cell line was studied, lacking of more data support and positive control drugs to illustrate the strength of its efficacy.

PSII can produce cytotoxicity and inhibit the growth of ovarian cancer cells. The formation of ovarian cancer is related to pathological angiogenesis (hereafter referred to as angiogenesis), so whether PSII affects angiogenesis was studied, and the molecular mechanism of PSII's action was discussed. The results showed that PSII significantly inhibited the growth of human umbilical vein endothelial cells (HUVECs) stimulated by VEGF in a dose–time-dependent manner; it also inhibited cell movement and interfered with the formation of renal tubules. In the mouse aortic ring experiment, PSII blocked the growth of microvessels and affected angiogenesis in SKOV3 and HOC-7 ovarian cancer models, suggesting that PSII has good therapeutic potential in the treatment of ovarian cancer.[97] The antiangiogenic effects of PSII and positive drugs were compared. The results showed that PSII (5, 10, 15, and 20 μM) was stronger than positive drugs. The experiment explored the tumor effect of PSII from a new angle and the effect was significant. After that, other antitumor mechanisms of PSII were studied, and the effect of PSII (5 μM) on NF-κB activity in SKOV3 tumor cells was evaluated. It was found that PSII inhibited NF-κB activation, thereby reducing the expression of downstream targets of NF-κB, such as VEGF, Bcl-2, and Bcl-xL. It was found that the effect was due to the decrease of IKKβ kinase activity and IKKβ expression on its substrate IκBα; These results suggest that PSII can significantly inhibit the growth of human ovarian cancer cells by inhibiting the activation of NF-κB and thereby inhibiting the expression of IKKβ.[98] Studies further illustrated that PSII affects other targets on ovarian cancer cells, and inhibition of NF-κB activation has a significant inhibitory effect on human ovarian cancer cell growth, but these studies are at the cellular level, lacking animal and clinical trials, and lacking data support for clinical application. At the same time, other antiovarian cancer mechanisms need to be further explored.

The inhibitory effect of the aqueous extract of Paris polyphylla (AEPP) on the epithelial–mesenchymal transition (EMT) and mitochondrial activity of human ovarian cancer cell line OVCAR-3 induced by high glucose (HG) was explored experimentally; the results showed that AEPP (100 µg/mL) significantly decreased the viability of OVCAR-3 cells by inducing apoptosis and EMT was also downregulated. Moreover, HG-induced elevation of estrogen-related receptor-α activator and peroxisome proliferator-activated receptor gamma-coenzyme activator-1α levels was inhibited after AEPP (100 µg/mL) treatment, which indicated that AEPP contributed to the treatment of ovarian cancer.[99] The anticancer effect and anticancer mechanism of the water extract of PR were explained in the experiment, which expanded the research scope for the application of PR in the future. However, the research was only at the cell level, lacking more animal experiments to provide clinical data.

Antigastric cancer

The inhibitory effect of total saponins from PR on the growth of gastric cancer cell line MGC-803 was studied. The results showed that the total saponins from PR could significantly inhibit the growth of MGC-803 cells in a time–dose-dependent manner when the concentration was 10–160 μg/mL, which could arrest the cells in S phase and induce apoptosis. It can also inhibit the expression of EPHA2 and survivin protein and upregulate the expression of caspase-3 protein, which are the reasons for inhibiting gastric cancer cells.[100] The experiment explored the inhibitory effect of total saponins of PR on gastric cancer cells from many aspects. However, there was no study on whether the single chemical component of PR had such effect. The research was only at the cell level, lacking positive control group and lacking more scientific basis to support the effect.

The synergistic effect of Chong Lou Fu Fang (CLFF) and 5-fluorouracil (5-FU) on gastric cancer cells in vitro was also explored. The results showed that CLFF and 5-FU produced better synergistic cytotoxicity to induce tumor cell apoptosis, and it was found that CLFF could downregulate thymidylate synthase gene expression.[5] In this study, we explored the combined treatment of PR compound and 5-FU. The results showed that the combined application could improve the effect of single drug, and the mechanism of influence was discussed, and the positive drug group was used to support the experimental data.

The effect of PPI on gastric cancer cell line SGC7901/DDP was studied; the results showed that PPI could significantly inhibit cell proliferation, invasion, and EMT.[101]

Breast cancer

In preliminary drug screening, it was found that Paris saponin D (similar to 17 β-estradiol structure) has antibreast cancer activity, so it was studied. After treating MCF-7 and MDA-MB-231 cells with Paris saponin D (2.73 mg/kg), the results showed that cell survival was inhibited, which could effectively reduce the weight and size of tumors and induce apoptosis, mechanistically. Paris saponin D dissipates mitochondrial membrane potential, induces downregulation of antiapoptotic Bcl-2 expression and upregulation of pro-apoptotic Bax expression, and activates caspase-9. These results indicate that Paris saponin D is apoptotic through mitochondrial dysfunction; in summary, Paris saponin D has inhibitory effects on breast cancer cells without significant cardiac and hepatotoxicity.[102] Starting from the cytotoxicity of Paris saponin D, the effects on two breast cancer-related cell lines were studied, which indicated that Paris saponin D could promote the apoptosis of breast cancer cells; however, only this aspect was studied while other aspects such as cell proliferation were lacked, and the specific mechanism of inhibiting cancer cells was also lacked.

Using PRS to treat MCF-7 cells. When PRS concentration increased in a dose-dependent manner (20, 40, 80 and 160 g/mL), cell viability decreased. Meanwhile, after PRS treatment, PARP, Caspase-3 and Caspase-9 were activated, while the ratio of Bax to Bcl-2 increased; at the same time, the disruption of mitochondrial membrane led to the release of cytochrome C into the cytosol in a dose-dependent manner. These results all indicate that PRS has an inhibitory effect on breast cancer cells.[103] The effects of total saponins from PR on MCF-7 cells were studied. Similar to previous studies, the cytotoxic effects of PR and the effects of mitochondria on cells were also studied. However, this experiment was a study of total saponins from PR, not a single chemical component from PR.

Colorectal cancer

The effects of different concentrations of total saponins from PR (PRTS) on apoptosis of colorectal cancer cells were observed, and the mechanism was explored. The results showed that typical apoptotic morphology, serum IL-6 secretion was significantly reduced (P < 0.05) and STAT3 level was decreased, indicating that PRTS could significantly promote apoptosis of SW480 colorectal cancer cells. The mechanism may be to inhibit the secretion of IL-6 and inhibit the IL-6/JAK-NF protein signaling pathway.[104] The experiment not only studied one kind of cell lacking more data to support but only studied the total saponins of PR lacking the discussion of single component, which can be further explored in these aspects in the future.

Esophageal cancer

The anticancer effect of PRS was evaluated by using N-nitrosomethylbenzylamine (NMBA)-induced esophageal cancer model in rats. The results showed that PRS could significantly reduce the size and number of esophageal tumors in NMBA-exposed rats and inhibit the survival, migration, and invasion of esophageal cancer cells EC9706 and KYSE150 in a dose-dependent manner (P < 0.01). PRS could also induce apoptosis and G2/M phase arrest. COX-2 and cyclin D1 expression in cancer cells was also significantly reduced (P < 0.01), in which disorders of COX-2 pathway were associated with digestive system cancer.[105] In addition, the release of prostaglandin E2, a downstream molecule of COX-2, was significantly reduced in a dose-dependent manner (P < 0.01). These results indicate that PRS can inhibit the generation and development of esophageal cancer.[106] This study demonstrated the effect of PRS against esophageal cancer cells, but the study only showed that PRS had an effect on NMBA-induced esophageal cancer, and whether PRS had an effect on esophageal cancer caused by other reasons still needs further study. The experimental results are one sided. In the future, the effect of PRS on other targets can be studied, as well as other levels of research, to study the specific mechanism.

It was found that polyphyllin VI (PPVI) had an effect on apoptosis and aerobic glycolysis of esophageal cancer cells. The specific effects on cells and the mechanism of action were studied. The results showed that PPVI (2.5 and 5 μmol/L) significantly inhibited the proliferation of esophageal cancer cells KYSE150 and EC109, and the apoptotic rate of cells also increased significantly, the expression of Bax, Bak, cleaved caspase-9, and cleaved PARP was significantly upregulated, the expression of Bcl-2 was significantly decreased, the phosphorylation level of JNK increased significantly, while the consumption of glucose and lactate production decreased significantly in esophageal cancer cells. The expression of GLUT1, HK II, and LDHA protein decreased. The phosphorylation level of ERK1/2 decreased significantly, and the expression of C-myc also decreased significantly, which indicated that PPVI induced apoptosis of esophageal cancer cells by activating mitochondrial apoptosis and the mechanism of action was related to the activation of JNK pathway.[107] The study illustrated the effects of Paris saponin VI on esophageal cancer cells from a variety of perspectives and elucidated one of the mechanisms but lacked a positive control, which may have an impact on elucidating the strength of its effects.

Cervical cancer

To investigate the growth inhibitory effect and molecular mechanism of Paris pilosa steroidal saponin (PS-VII) on human cervical cancer Hela cells, the results of various methods showed that the IC50 of PS-VII on the growth inhibition of Hela cells was 2.62 ± 0.11 μmol, and the treatment increased the expression of caspase-3, caspase-9, and Bax and decreased the expression of Bcl-2, which indicated that PS-VII may induce apoptosis through endogenous apoptotic pathway. In conclusion, PS-VII has anticervical cancer effects.[108] The lack of positive control in this study, the lack of explanation of the mechanism of action, and the lack of in vivo experiments make the data insufficient. But it was suggested that the effect was dose-dependent.

Hemostasis

By gavaging male Wistar rats with total saponins from PR (TSSP) solution, the results showed that total steroidal saponin solution could enhance ADP-induced platelet aggregation, while total steroidal saponin solution (100–300 μg/mL) could directly induce platelet aggregation in vitro, which was proportional to the dose and time of administration. TSSP can also directly activate platelets to cause deformation and release. In conclusion, TSSP has hemostatic effects.[68] This is the first time that TSSP can directly induce platelet aggregation in vitro. This study explores the hemostatic effect of total steroidal saponin solution in vivo and in vitro and finds the relationship between its effect and dose, which provides relevant basis and data for future research in this area. However, it was not stated which specific saponin component produced the effect.

Through the heart blood collection experiment of male Wistar rats, it was proved that Paris saponin H (Ps-H) can induce platelet aggregation and can directly induce platelet aggregation in rats, presenting a dose effect. Low and medium concentrations (5–20 μmol/L) of Ps-H solution can induce reversible platelet aggregation, while higher concentration of Ps-H (30 μmol/L) can induce irreversible platelet aggregation. The mechanism of Ps-H-induced platelet aggregation is dependent on the release of ADP and the production of TXA2 after platelet activation.[109] This study explored the effect of the concentration of saponin H on hemostasis and provided information for future experiments on the concentration of saponin. However, the study lacked blank group and positive control group, which may lack data to support its efficacy. Yun Nan Bai Yao, a hemostatic drug, is often used as a positive control group in the comparison of bleeding time and clotting time, to explain the possible mechanism of hemostasis of PR; the influence factors of its extracts on coagulation function were further studied, among which thrombin has important hemostatic and coagulation effects. The results showed that the hemostatic effect of Paris was mainly achieved by affecting exogenous and endogenous coagulation factors, reduced prothrombin time (PT), and activated partial thromboplastin time (APTT) but had no significant effect on the thrombin time; these phenomena indicate that PR has hemostatic effects.[110] However, this experiment did not explore the hemostatic effect of specific components in PR. In the future, we can explore the specific components that affect exogenous coagulation factors and endogenous coagulation factors in PR.

The hemostatic time and bleeding volume of mice were measured by gavage with different doses (5, 10, and 15 g/kg) of aqueous extract of PR and alcohol extract of PR. The results showed that both of them could significantly reduce the hemostatic time and bleeding volume of mice and alcohol extract showed more significant hemostatic effect than water extract in a dose-dependent manner. Among the platelet and blood agglutination indexes, the number of platelets, hematocrit, volume distribution width, and fibrinogen (FIB) were significantly increased, but PT and APTT were not significantly changed. The changes of these factors indicated that the extract of PR had a strong hemostatic effect.[111] The positive control group was used in the experiment, which can better illustrate its efficacy, but the specific mechanism remains to be further explored.

In the experiment, the tail hemorrhage time of mice was taken as an index, and the saponin of Paris could significantly shorten the tail hemorrhage time and clotting time and increase the FIB. It is presumed that PS-H binds specifically to thrombin to enhance the agglutination between thrombin and FIB and further promotes the occurrence of coagulation.[112] However, this experiment only speculated on the possible mechanism, without proof, and more experiments are needed to confirm this conjecture.

Antibacterial effect

Ten cariogenic bacteria and 11 common pathogenic bacteria such as pulp periapical inflammation and periodontal disease were treated with dian PR water extract, and the minimum inhibitory concentration values were 20 mg/mL. This indicates that the saponin components contained in dian PR have an inhibitory effect on the growth of common pathogenic bacteria in the oral cavity.[69] However, this study did not point out the antimicrobial effect of a specific component in saponins, which needs further exploration. There is no explanation of its bacteriostatic mechanism, and more experiments are still needed to explore its specific mechanism.

Early studies have shown that PR decoction has different degrees of inhibition on Staphylococcus aureus, hemolytic streptococcus, meningococci, dysentery bacilli, typhoid bacillus, paratyphoid bacillus, Escherichia coli, and Pseudomonas aeruginosa.[113] However, the experiment lacked positive control group and did not explain the mechanism of antimicrobial, so it is necessary to conduct more experiments to explore the antimicrobial active ingredients and their mechanism of action in the PR. Neither does it clarify whether the dose affects the efficacy, and the future research direction is also extensive.

In recent years, antimicrobial experiments have shown that the total saponins extracted from rhizomes have certain antifungal activity against Aspergillus fumigatus and Candida spp., among which four spirosteroid saponins (PSI, Paris saponin V, Dioscorea dioscin, and PSII) have obvious antifungal activity, and the minimum inhibitory concentration is stronger than that of the positive control drug voriconazole.[114] Positive control test was added to the study, and the specific components with antimicrobial activity in the PR were explained, but the test related to the missing dose and the antimicrobial components in the PR was studied, so it did not elaborate whether the dose affected the antimicrobial activity of the PR antimicrobial components, which provided ideas for future research directions.

Anti-inflammatory effect

In the course of inflammation, macrophage activation will be induced, which will cause the release of a large number of cytokines as mediators of inflammation; in the experiment, rat peritoneal macrophages activated by heat-inactivated E. coli were used as target cells. Experiment showed that the total saponin concentration of PR could significantly inhibit the release of inflammatory factors (TNF-α) in heat-inactivated E. coli-induced rats as long as it reached 5 μg/mL; with an increase of concentration, the effect is also enhanced. If the concentration is increased again, although it can increase the inhibitory effect of total saponins of PR, it may also increase the toxic side effects. However, the optimal inhibitory concentration of heat-inactivated E. coli-induced release of inflammatory factors (IL-1β) in rats was 10 μg/mL, and increasing the concentration did not increase the inhibitory effect.[70] However, there is no discussion on whether the specific components of PR saponins affect the effect, only a good description of the dose relationship. The results of multiple trauma rat model showed that total saponins of PR (2.5, 5, and 10 mg/kg) could significantly reduce the contents of TNF-α, IL-1β, and IL-6 cytokines in the serum of Wistar rats with multiple trauma.[115] This experiment increased the inhibitory effect of total saponins of PR on IL-6 inflammatory cytokines and also showed that the total saponins of PR has anti-inflammatory effect, which can inhibit the development of inflammation to the direction of deterioration.

Asthma is a chronic inflammatory reaction disease of the respiratory tract; IgE antibody plays an important role in the pathogenesis of asthma, to explore the effect of PR on the level of IgE in asthmatic rats. The results showed that high-dose PR could effectively reduce the serum IgE content of asthmatic rats, and its effect was similar to that of dexamethasone. Among them, low-dose group also has certain antiasthma effect, but the effect is weaker than high-dose group; eosinophils (EOS) is an index to evaluate anti-inflammatory drugs.[116] In the experiment, the effect of high-dose (50 g/kg) PR group on EOS level was similar to that of positive drugs, which indicated that PR could inhibit the increase of EOS caused by asthma.[117] The anti-inflammatory effect of PR has positive control group, which fully demonstrates the anti-inflammatory mechanism of PR. However, the experiment only explained the changes of the concentration of inflammatory factors. In future experiments, we can observe the changes of other inflammatory factors and explore the wider application of PR saponins.

Sedative and analgesic effects

The results of analgesia test by electric stimulation analgesia method showed that PR (36 g/kg) has obvious analgesic effect. The application of hot plate analgesia method showed that it also had analgesic effect and the analgesic effect was strong. The results of compound determination showed that PR saponin A had certain analgesic effect and that Dioscorea delicatea saponin also had analgesic effect; in the sedation experiment of mice, PR showed obvious sedative effect and the sedative effect was equivalent to a certain dose of diazepam injection, in which the sedative effect of PR saponin A was stronger than that of Dioscorea delicatea. At the experimental dose, the sedative effect of PR saponin A was weaker than that of the alcohol extract of PR crude drug, and its sedative intensity was not weaker than that of diazepam.[72] However, neither the specific mechanism of analgesia and sedation nor the optimal dose of analgesia and sedation has been explained, which can be further explored in the future. In the acetic acid writhing test, PR mixture can effectively reduce the writhing times, and the high-dose group (20 g/kg) can significantly inhibit the writhing reaction of mice induced by acetic acid, which indicates that PR mixture has certain analgesic effect.[71] There is no explanation on the mechanism of analgesia, but some explanations about dosage are given, which can provide information on dosage application in the future. Continuous injection of morphine resulted in acute morphine tolerance in rats with chronic pain, the analgesic tolerance was confirmed by tail flick test with warm water and the decrease of pain behavior score, and PRS could reduce the pain behavior score and increase the tail flick latency in morphine tolerant rats, indicating that PRS has a certain delay effect on acute morphine tolerance. The mechanism may be related to the antagonism of PRS on the decrease of adrenocorticotropic hormone level in hypothalamus during morphine tolerance.[118] This indicates that PR may produce analgesic and sedative effects through this mechanism, which provides a direction for the next exploration of the mechanism of this effect and further study on animal experiments or other experiments.

Inhibition of angiogenesis

HUVECs and human colon cancer LoVo cells were treated with PR saponins solution in vitro; in this study, angiogenesis was used as a target. The ethanol extract of PR (15–60 μg/mL) inhibited the number of lumens and lumen formation in a dose-dependent manner and also effectively inhibited angiogenesis in vitro. At the same time, the migration of endothelial cells decreased significantly after adding the ethanol extract of PR, and the inhibition of migration became more obvious with the increase of concentration. It was also found that the ethanol extract of PR could cause endothelial cell necrosis. It was speculated that the mechanism of this effect might be related to the inhibition of endothelial cell proliferation, migration, and lumen formation; induction of endothelial cell apoptosis; and inhibition of endothelial cell DNA synthesis.[73] The study discussed the mechanism of action and the application of dose, but only in vitro experiment data, lack of in vivo experiment, we can carry out further studies in this aspect in the future, also lack of research on the mechanism of the production of specific chemical components in PR, all of which provide ideas for future research direction.

The model of chick embryo chorioallantoic membrane is sensitive to antiangiogenic drugs; therefore, to explore whether steroidal saponins in PR have effect on chick embryo chorioallantoic membrane angiogenesis, experiments were carried out. The results showed that the experimental groups of PR saponin I, PR saponin V, fine diosgenin, and PR saponin II had less vascular growth and fewer vascular branches. Therefore, it was speculated that they might have the effect of inhibiting vascular growth; among them, Paris polyphylloside I had the best activity, the slender dioscin had the weakest activity, while Paris saponin V had no activity. Among them, PR saponin I is the only component containing arabinose, so it is speculated that arabinose has an important contribution to the inhibition of vascular growth, in the structure of PR saponin V and fine diosgenin. There is no sugar substitution on the fourth position of glucose which is directly connected with the aglycon, but the number of sugar in the structure of fine dioscin is more than that in the structure of PR saponin V. If the structure of diosgenin contains arabinose, or glucose is directly attached to the aglycones in the saponin structure and has a sugar substitution at position 4, is also important for the activity. In conclusion, if the structure of dioscin contains arabinose, it can inhibit the growth of blood vessels and enhance its activity. If the fourth position of glucose directly connected with aglycone in saponin structure is replaced by sugar, the vasoinhibitory activity will be enhanced. If the number of sugar in the structure is increased, the inhibitory vascular activity will be enhanced.[119] This study made a clear explanation of the specific chemical components in PR to inhibit angiogenesis and also explored the reasons for the inhibition of angiogenesis. However, there was no study on the optimal dose, only a single dose was used, and there was no study on whether the dose affected the effect.

As the target cells of antiangiogenesis, HUVECs are highly sensitive to the extract of PR extract (PRE), and the changes of HUVECs cells treated with PRE were observed experimentally. The results showed that the proliferation, differentiation, and migration ability of the cells were decreased, and apoptosis and cell cycle arrest were also induced in a dose-dependent manner. It was also found that PRE had selective cytotoxicity to HUVECs cells and significant antiangiogenesis effect in vivo. Meanwhile, the study showed for the first time that PRE could inhibit angiogenesis through various effects on HUVECs with little side effects. In addition, PRE has also been found to have an effect on cell cycle arrest and apoptosis induction of endothelial cells, speculating that this may be one of the mechanisms of PRE's antiangiogenesis effect. Experiments have also observed that PRE has an antitumor effect on human Lovo cancer transplantation tumors and an inhibitory effect on microvessel density; this reagent interferes with endothelial cell function, so this may be a potential antiangiogenesis therapy.[120] The study explained the dose effect and carried out experiments both in vivo and in vitro, with sufficient scientific basis, but did not elaborate the specific mechanism causing changes in cells, which still needs further exploration by researchers, as well as did not specify the specific components to extract the building, which needs further verification.

Immunomodulatory effects

The study on the effect of Rhizoma Paris compound on the immune function of H22-bearing mice showed that Paris saponin I–III could induce concanavalin A (ConA)-induced lymphocyte proliferation in mice and improve the immune function. Compared with the positive chemotherapeutic drug cyclophosphamide, PR compound can significantly improve the spleen index of H22-bearing mice, significantly increase the activity of cytotoxic lymphocyte (CTL), and promote the killing of target cells H22 by CTL cells in a dose-dependent manner, while CTL cells are the main effector cells of specific cellular immune response, indicating that PR compound has a certain effect on immune regulation.[74] The study explored the mechanism of PR on immune function and mentioned that the effect was dose dependent. There was a positive control group in the experiment, and the data had certain reliability but did not explore the optimal dose to produce the effect. Moreover, we only mentioned the effects of several saponins in PR on immune function. We can explore the specific chemical components of PR with this effect in the future.

Systemic lupus erythematosus (SLE) is a typical autoimmune disease with multiple organ damage. Immune dysregulation is the main cause of SLE, especially the imbalance of Th1/Th2. Lupus nephritis (LN) is the main clinical manifestation of SLE. The study used PSII to intervene in patients with LN and found that TGF-β and IL-10 levels were higher after treatment than before intervention. The change of TGF-β and IL-10 levels is one of the reasons for regulating Th1/Th2 imbalance. It suggested that PSII might treat LN and other immune diseases by increasing the levels of TGF-β and IL-10, regulating the Th1/Th2 imbalance, and improving the immunosuppressive function of CD4+CD25+Treg.[121] This study described the immunomodulatory effects of PR saponin II, but the absence of a positive control may affect the reliability of the data, and the absence of an explanation of whether dose affected the effect. More clinical trials or animal experiments are needed to support the immunomodulatory effect of the drug through this mechanism and more possible mechanisms may be found system.

Antioxidant effect

PR extract scavenged ROS and antioxidant activity in vitro. The results showed that PR extract had scavenging effect on hydroxyl radicals produced by Fenton reaction, and the maximum scavenging rate was slightly higher than that of the positive tea polyphenols. The scavenging rate reached the maximum when the mass concentration was more than 0.4 mg/mL. It was also found that the extract of PR could also scavenge the superoxide radical (O2−) produced by photoriboflavin, which was similar to the scavenging rate of O2 − produced by tea polyphenols, the total saponin extract of PR could continuously exert the scavenging effect on O2 − for a long time, and the scavenging rate reached the maximum when the mass concentration was more than 0.47 mg/mL; it also has a strong inhibitory effect on lipid peroxidation. When 0.4 mg/mL total saponin extract from PR was added, the inhibitory rate increased. It was found that the production of MDA analog decreased, DNA oxidative damage was inhibited, and the inhibitory rate was concentration dependent, and this was an indirect effect.[75] The antioxidant effect of total saponin extract of PR was elaborated from many aspects, but the specific components producing the effect were not explained. The data obtained from in vitro experiment in this experiment can be used for in vivo experiment, which provides more reliable scientific basis for clinical experiment. The optimal dosage of the effect is also described in the experiment, which provides the basis for the use of dose in the future.

In the experiment, a cell model of oxidative damage was established using human umbilical vein endothelial cell line ECV304 to study the antioxidant effect of PR, and the biological effects of the alcohol extract of PR (5, 50, and 500 ng/L) were found for the first time through this experiment. The results showed that the drug could effectively protect the oxidative damage of ECV304 induced by H2O2 mimicry in umbilical vein endothelial cells in vitro and inhibit the apoptotic pathway mediated by caspase-3 protein; the protective effect of this drug on oxidative damage of endothelial cells was preliminarily confirmed, indicating that its ethanol extract has certain antioxidant effect.[122] The research only explored at the cell level, not in vivo and in vitro experiments, lack of scientific basis for clinical application, but provides relevant ideas for the future research direction.

Renal and hepatoprotective effects

Membranous nephropathy (MN) rat model was used to investigate the effect of PR on the activity of NF-κB and the expression of type IV collagen in the kidney of MN rats; after treatment with PR, the expression of NF-κB p65 was low, the expression of ColIV was low, and the expression of NF-κB mRNA was decreased. These results suggested that the protective effect of PR (8 mg/kg) on the kidney of MN rats might be related to its inhibition of NF-κB activation, which in turn alleviated the expression of extracellular matrix (such as ColIV), alleviated the inflammatory response of rats, protected the kidney organs of rats, and inhibited the generation and development of MN in rats.[76] The renal protection mechanism of PR was elaborated, and the possible mechanism was proposed. The positive control was carried out, and the effect was obvious. However, there was a lack of dose description and the research on the effect of chemical components in PR, as well as the in vivo and in vitro experiments, which resulted in the lack of scientific basis to support clinical application.

Mice with acute liver injury induced by carbon tetrachloride were gavaged with water extract and alcohol extract of PR. The results showed that liver index and serum aspartate aminotransferase (AST) of mice in the alcohol extract group and water extract group were significantly decreased, high-dose ethanol extract group (3.9 g/kg) and water extract groups (7.2, 4.8, and 2.4 g/kg) also significantly reduced the activity of serum alanine aminotransferase (ALT), and the middle- and low-dose groups of alcohol extraction group slightly decreased the activity of ALT, and the effect of protecting liver and reducing enzyme of water extraction group was stronger than that of alcohol extraction group. The results showed that the levels of MDA and the activities of malondialdehyde (SOD) and GSH were significantly increased in the high-dose group of PR ethanol extract group. The effects of different doses of PR aqueous extract on SOD, GSH, and MDA levels in mice liver tissue were better in a dose-dependent manner. These results indicate that the water extract can better maintain the integrity of cell membrane structure and function and play a protective role in CCl4-induced chemical liver injury.[123] The optimal dose of the effect was described, and the difference between the ethanol extract and the water extract was compared. However, the target of drug action was not studied, and the specific mechanism of action was not mentioned. Only one cause of liver injury has been studied, which lacks universality.

Antifertility and anti-early pregnancy and spermicidal effect

In the experiment, mouse spermatozoa were incubated in vitro to determine their activity, and the effect of PR on sperm activity in vitro was studied. The results showed that pinosaponin (PHAC-A) and dioscin (PHAC-B) which could kill spermatozoa in a short time, and at low concentrations (final concentration of 4 μg/mL), most spermatozoa could also effectively lose their ability to swim quickly. When the final concentration of PHAC-B was 20 μg/mL, all the spermatozoa could lose their ability to swim quickly. When the final concentration of PHAC-B was 40 μg/mL, the spermatozoa could be basically killed, while some of the spermatozoa still survived at the same concentration of PHAC-A. It was also found that the antifertility activity (sperm survival rate) of PHAC-A and PHAC-B was better than that of the positive drug gossypol acetate, and there was a dose-dependent relationship. Further experimental studies showed that the effect of PHAC-B was significantly better than that of PHAC-A. It can be concluded that the antifertility active substances in total saponins of PR are mainly PHAC-B. Total saponins of PR and PHAC-A and PHAC-B obtained by separation and purification are steroidal saponins, which are strong surfactants, have strong emulsifying power, and can form complex with cholesterol on cell membrane, leading to destabilization of cell membrane.[77] In summary, the total saponins of PR and the inhibitory effects of PHAC-A and PHAC-B on sperm activity may be due to their surface activity, which causes the membrane of sperm cells to lose stability, resulting in the osmotic pressure change of sperm cells to lose their vitality or death, thus achieving the antifertility effect.[124] There is a positive control in the experiment, the scientific basis is more sufficient, and it shows that the effect is dose dependent. The effect of two chemical components is compared, and the optimal dose is explained. However, the experiment is only carried out in vitro, while the in vivo experiment is lacking, and the specific mechanism of the effect is not elaborated. Therefore, there is no scientific basis for clinical application. In addition, the effects of the alcohol extract of PR on the sperm of rats and mice were explored. The results showed that the 70% ethanol extract of PR had spermicidal ability on rat spermatozoa at a concentration of 3 mg/mL and spermicidal ability on mouse spermatozoa at a concentration of 1.5–3 mg/mL.[78] Experiments have explained the dosage of the effect of the alcohol extract of PR, but there is a lack of research on the mechanism, factors affecting it, more data support, and scientific basis.

Cardiovascular effects

Diosgenin in standard and low calcium medium can promote the increase of cardiomyocyte pulsation number and can significantly increase the calcium intake of cardiomyocyte, while pinosaponin has less effect. The experiment proved that the aqueous extract of PR could partially antagonize the death of mice caused by endothelin (ET) and had endothelium-dependent relaxation on the contraction of isolated rat aortic rings caused by ET, which had a certain preventive and therapeutic effect on cardiovascular diseases.[78] Researchers have done less research in this area.

Antiviral effect

Experiments of PR water or alcohol extract of the antiviral effect have carried on the exploration. Both extracts were found to have inhibitory effects on influenza A and Asian influenza A viruses. It was observed that the extract was still effective when diluted to 1∶10000 or 1∶10 parts. In mice using PR medicine droplet nose, after waiting for 5 h, the virus was inoculated; data showed that the mortality of PR group was lower than that of the control group. After waiting for 5 h, the virus was inoculated; data showed that the mortality of PR group was lower than that of the control group. The results showed that PR had certain antiviral effect.[79] There are few studies on the antiviral effect of PR. However, it has been recorded that there is an important relationship between the antiviral effect and the tannin contained in Dian-Chonglou.[125] This lays the foundation for the future research on the main components of antivirus in PR.

Compatibility

Combination of PR and Curcuma longa: The water extract of C. longa (CW) has a good synergistic effect on the antitumor activity of PRS, and the addition of CW also inhibits the gastric stimulation of PRS. The optimal ratio of curcumin compounds to PRS was also determined to be 16:500. It was found that the intestinal absorption of five major saponins in PRS was different in different intestinal segments (duodenum, jejunum, ileum, and colon). The results showed that the cumulative amount of ginsenosides in PRS was ileum > jejunum > duodenum > colon; PRS-0.4 mm curcumin increased the intestinal permeability of total saponins, and the cumulative amount was in the order of duodenum > jejunum > ileum > colon, especially duodenum, with no dose-dependent effect; only 0.4 mm curcumin can upregulate the absorption of PRS in the duodenum, and increasing or decreasing this concentration will reduce this effect. In the experiment, the antitumor effect of aqueous extract of turmeric and methanol extract on PRS was compared, and the adsorption effect of aqueous extract of turmeric was better than that of methanol extract. In conclusion, the combination of aqueous extract of turmeric and PRS is a good method to improve the antitumor effect of PRS.[126] In S180 tumor-bearing mice, PRS, Lou Huang preparation (LH), and CTX significantly inhibited gastric emptying, and the analysis data found that turmeric could reduce the toxicity of PRS, the weight of H22 tumor mice treated with PRS was reduced, and the growth of solid tumors was inhibited by LH at the dose of 20–100 mg/kg in a dose-dependent manner. The weight and volume of tumors in the LH treatment group were lower than those in the control group. In  Mouse Ascites cancer cells (EAC) tumor model, PRS reduced the relative weight of tumors, and LH 100 mg/kg could significantly reduce tumor growth and significantly inhibit tumor volume.[127] These experiments have explained the antitumor effect of PR combined with curcuma and have an impact on a variety of tumor cells, and the possible reasons for its enhancement effect were speculated, but the specific mechanism was not explained. Further research and experiment in this area can be carried out in the future.

Effects of chemical constituents of PR on other related factors of pharmacological action are shown  in [Table 6].
Table 6: Effects of chemical constituents of Paridis Rhizoma on other related factors of pharmacological action

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  Application Top


PR has a long history and has a variety of pharmacological effects, so it is often used in clinical practice. This literature[78] summarizes the clinical application of PR.

Common Paridis Rhizoma formula for cancer treatment

PR is often used in the treatment of cancers, such as esophageal, laryngeal, rectal, lung, and cervical cancer.

Treatment of pain and hemorrhage

PR is a TCM hemostatic medicine. Yun Nan Bai Yao, with PR as its main component, has been used for many years in various pain and blood diseases in internal, external, gynecology, and traumatology departments.

Treatment of pulmonary diseases

PR taste bitter, cold, can clear heat decrease internal heat; it not only has the effect of clearing heat and detoxification but also can relieve cough and asthma, promote blood circulation, and remove blood stasis.

Treatment of lymph node tuberculosis ulcer

Tuberculosis of cervical and axillary lymph nodes, known as murine ulcer in TCM, occurs mostly in children and young people, and the treatment is more difficult.

Treatment of Chlamydia infection in women

PR contains a variety of steroidal saponins; the main function is clearing heat and detoxification and relieving detumescence and pain. Observation after vaginal administration, no local adverse stimulation, no side effects were found; every other day after administration, the powder has been dissolved, no residual powder was noted, and cervical erosion can be quickly repaired.

Others

Rhizome of PR can be used to treat acute tonsillitis. At the end of PR, add rice vinegar to make a paste and apply it to the affected area, which can treat herpes zoster. In addition, it can also treat mumps and phlebitis.

Compatibility application

It can be used in combination with honeysuckle and forsythia to treat hot and toxic sores; it can be used with B. bipinnata to treat poisonous snake bite; it can be used with Shijianchuan, S. barbata, and P. vulgaris for cancer (Chinese Pharmacopoeia).

Some of the major applications are shown in [Table 7].
Table 7: Applications

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  Quality Control Top


TCM has the characteristics of multicomponent and multitarget, many kinds of TCM are complex, and its efficacy varies greatly. Due to different drug habits in different regions, the source of TCM on the market is confused, and the quality level is different, which seriously affects the safety and effectiveness of TCM clinical medication. The pharmacodynamics of TCM really depends on the group of chemicals it contains, and the quality standard is one of the indicators of the technical and advanced level of drug production and management. There are about 24 species, 13 varieties, and some forms in the world. There are 19 species and 10 varieties in China. Therefore, it is necessary to control the quality of PR.

In the Chinese Pharmacopoeia (2020 edition), TLC was used for qualitative identification of PR, and HPLC was used for quantitative evaluation. To PR saponins I, II, VII as quality control index, and provides three kinds of total saponins content shall not be less than 0.6%, also provides moisture should not exceed 12.0%, the total ash content must not exceed 6.0%, acid insoluble ash content should not exceed 3.0%. These are beneficial for good-quality control of PR. However, the use of these quantitative markers alone may not be sufficient to assess the quality of PR extracts with certainty.

Zhou et al. determined the contents of PR saponins I, II, VI and VII in Dian PR by high performance liquid chromatography, and found that the contents of PR saponins in different regions were different.[130] This method has high resolution, high speed, and high repeatability; HPLC column can be used over and over again but need a fast flow velocity; it will reduce the column efficiency. Han et al. used ultra-high performance liquid chromatography (UPLC)- evaporative light-scattering detector (ELSD) method of simultaneous determination of PR in PR saponins I, II, VI, VII. The UPLC method is characterized by good separation effect, good repeatability, simple operation and rapid operation, and it is superior to HPLC method. It can be used as quality control method of PR; ELSD is a general-purpose quality detector, its response is not dependent on the optical properties of the sample, as long as the volatile sample is lower than the mobile phase can be detected.[131] Using UPLC still can greatly reduce the cost. However, if the internal pressure of the instrument is too high, the instrument connection will age faster. Yang et al. used UPLC-tandem mass spectrometry (MS) method to simultaneously quantify nine major saponins identified from Paris polyphylla, including polyphyllin I, polyphyllin II, dioscin, progenin III, polyphyllin VI, polyphyllin VII, polyphyllin H, gracillin, and polyphyllin S and to establish a simple, rapid, precise, and sensitive method to quantify nine components of PR in rat plasma using LC–MS was developed and validated.[132] Compared with the previous UPLC method used alone, the UPLC-MS/MS method used in this experiment can largely solve the difficulty of the separation of TCM components. Polyphyllin I, II, VI, and VII were determined by UPLC-MS/MS and Fourier transform infrared spectrometer (FT-IR). Among them, FT-IR spectroscopy in combination with chemometrics has merits such as finer reproducibility, integrity, and higher sensitivity, consistent with the holistic theory and covering the whole message of herbal medicine (HM).[133] The combination of UPLC-MS/MS and FT-IR can capture more signals of chemical components, and the accuracy is significantly improved. Studies have shown that Paris saponin D has an antibreast cancer effect, polyphyllin H has a hemostatic effect, and polyphyllin VI has resistance to esophageal cancer. Therefore, the presence of these compounds may be a critical indicator of extract quality.

Hence, to better evaluate the quality of the PR, to explore more compounds, especially the saponin compounds in the PR is necessary, the spectrum–effect relationship method can be combined with network pharmacology effect relationship between chemical composition, and it is also necessary to predict the treatable diseases and disease targets, and to select the most effective instrument for quality detection. Therefore, more experiments and studies are needed to ensure the quality of medicinal materials and develop more effective drugs.


  Processing Top


The main processing methods are baking, canning, frying, washing, soaking, bleaching, steaming, boiling, and other methods of processing Chinese HM. The purpose is to eliminate or reduce the toxicity of drugs, strengthen the curative effect, facilitate preparation and storage, and make drugs pure. The results showed that PR decoction had antitussive effect on mice induced by sulfur dioxide, and its ethanol extract had obvious spermicidal effect. Through the processing of PR, the original toxicity of PR will be reduced, and the effect will be improved if the effective ingredients such as rhizome of PR are cleaned or cut to a moderate size, so its pharmacological effect will be better studied and applied in clinic. However, there are few reports on this aspect at present, and more studies on processing PRs can be carried out in the future. PR, Radix Sophorae Tonkinensis, P. vulgaris, etc., were used to study the fine powder and refine honey as pills to treat esophageal cancer.[128]

By processing PR, the primary toxicity of PR is reduced. In addition, cleaning or cutting the effective parts such as roots and stems of PR to a medium size will improve its efficacy, so as to better study its pharmacological effects and apply it in clinical practice. However, there are few reports on this aspect at present, and more research can be carried out on the processing of PR in the future.


  Toxicity and Pharmacokinetics Top


Toxicity

The Compendium of Materia Medica (本草纲目) records “The part of Paridis Rhizoma used as medicine is the root. It has a bitter taste, cold nature and is poisonous.

The toxicity of PR was studied, and the killing of Oncomelania by PRS was observed. It was found that the mortality rate of Oncomelania was 50%–100% when Oncomelania was immersed in PRS solution of 5–20 mg/L for 48 h. The eggs of Oncomelania were immersed in PRS solution of 12.5–50.0 mg/L for more than 24 h, and no young Oncomelania was incubated. Toxicity to other animals was also discussed, and it was found that when the PRS solution concentration was greater than 10 mg/L; all fish seedlings over 24 h died.[134] Jin et al. studied the toxic effect of PR on HepG2 cells of liver cancer and found that the killing effect of 250 and 500 μg/mL PR extract was similar to that of the positive drug, while the killing effect of 1000 and 2000 μg/mL PR extract was obviously higher. The results showed that PR extract had cytotoxic effect.[135] The dosage description is well stated in this study, which provides a basis for future research on toxic dosage.

There are also clinical cases that show that PR is toxic: 10–20 mL of PR medicine and wine were taken at 3 p.m., respectively, and poisoning symptoms appeared 2 h later; Case 1: A 65-year-old female presented with no past history, nausea, vomiting, diarrhea, headache after taking medicine and alcohol; Case 2: A 75-year-old presented with no past history, nausea, vomiting, diarrhea, headache at 5 pm after taking medicine and alcohol; Case 3: A 68-year-old female presented with a history of gastric ulcer perforation, partial gastrectomy, and toxic symptoms at 5 pm.[136] In vitro cytotoxicity test of Ps-H was carried out. The results showed that compared with cisplatin, Ps-H had significant cytotoxic effects on HepG2, A549, PRE, and L929 cells, and IC50 values were 5.93 ± 0.22 μg/mL, 1.53 ± 0.08 μg/mL, 5.90 ± 0.18 μg/mL, and 4.66 ± 0.62 μg/mL, respectively. The cytotoxic activities against A549 cells were significant (IC50 values were 1.53 ± 0.08).[37] The study not only studied the toxicity of one of the saponins but also studied the cytotoxicity of some cells, lacking the explanation of dosage. The positive control can accurately explain the strong cytotoxicity of this component.

The toxicity of PRS was studied experimentally. Binuclear cells, massive hepatocyte necrosis, diffuse necrosis cells, and inflammatory cell infiltration were occasionally observed in the liver treated with PRS, which may be due to drug toxicity, indicating that 90-day administration can lead to liver injury; meanwhile, the endogenous metabolites in the liver also changed significantly. Metabolomic results showed that the toxic dose of PRS changed the level of hepatic metabolites. PRS treatment can enhance the complex signals of lactic acid, succinic acid, glucose, threonine, sarcosine, creatine, and so on. PRS treatment caused inhibition of tricarboxylic acid cycle and glycolysis, and PRS treatment also interfered with glycine, serine, and threonine metabolism.[137] Compared with the normal group, the metabolites of PRS group changed a lot. PRS could significantly increase the lipid level but reduce the concentrations of fatty acids, glycerides, and even ketones, including acetic acid and 3-hydroxybutyric acid; these indicators were highly correlated with the degree of liver damage determined by histological examination. These results showed that chronic exposure to PRS was associated with liver injury, and the levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in the serum were analyzed. In the study, 90-day administration of PRS could significantly reduce the levels of TG, total cholesterol (T-CHO), and LDL-C, and the contents of TC and TG decreased significantly with PRS exposure, indicating that PRS caused hepatocyte injury, dysfunction, and transport of lipoproteins such as HDL-C and LDL-C; elevated serum ALT and AST levels indicate that 90-day administration can lead to liver injury; chronic exposure to PRS can significantly reduce the mRNA levels of CYP1A2, CYP2E1, and UGTs. In conclusion, 90-day administration can lead to liver injury.[138] The toxicity of 90-day administration of PRS was studied, and the cells and compounds affected by the toxicity were summarized. However, only the toxicity of PRS to the liver was described, and there was a lack of positive drug group and more data to support it. In the future, the toxicity of other organs could be studied and the positive control group could be increased.

The toxicity of PRS on other aspects was further studied. The results showed that the absolute weight of lung tissue in the PRS group was significantly higher than that in the normal group, mild chronic lymphocyte interstitial infiltration and fibrin exudate occupied the alveolar cavity after PRS treatment; under PRS treatment, ROS levels are overexpressed in liver and kidney tissues, 8-OHdG and MDA increased significantly after taking PRS, and PRS could significantly increase serum Trx and TXNIP levels and decrease renal GSH concentration. PRS adds clinical biochemical data, including liver function (ALT, AST, AKT, and g-GT) and renal function parameters (BUN and Cr), suggesting that PRS is toxic to the body, after 45 days of administration. PRS significantly upregulated acute inflammatory markers (COX-2 and IL-1b), as well as activated nuclear factors containing Nrf2 and NF-JB. In conclusion, PRS, as a low toxicity anticancer drug, causes liver and lung injury through overexpression of ROS and proinflammatory cytokines.[139] The toxicity characteristics of PRS and other organs such as lung and kidney were further illustrated, but there was still a lack of positive control, but the factors and cells affected by PRS were studied.

Pharmacokinetics

A rapid, specific, and sensitive PR-HPLC-DAD method was developed to determine the content of PSII in the plasma of beagle dogs, and the pharmacokinetics of oral PSII extract was studied by this method. The results showed that both the extract and the internal standard of PR saponin II were detected at excellent resolution with retention times of 12.11 (203 nm) and 34.52 (203 nm) min, and no interference peaks were observed, by plotting the peak area ratio of PR saponin II to the internal standard (y) and the ratio of PR saponin II (x) to plasma. A linear response could be obtained to the extract of PR II from 3.33 to 100 μg/mL. The experiment showed that the intraday precision was 4.55%–9.23%, the interday precision was 3.23%–9.24%, the intraday accuracy was 91.19%–105.03%, and the interday accuracy was 89.67%–107.25%. The precision and accuracy were within acceptable range, the average recovery of saponin II was 84.97%~90.35%, and this method had a high extraction recovery. PSII showed high stability in the dog plasma, which indicated that the samples were stable during preparation and analysis. The experiment also showed that the Area Under Curve (AUC) of PSII decreased when other components were added; therefore, a rapid and specific Reverse phase-High-performance liquid chromatography- Ultraviolet (RP-HPLC-UV) method was established for the determination of PSII in plasma of beagle dogs after oral administration of PSII extract; the method has high sensitivity, high recovery, and precision. The accuracy and reproducibility of plasma after oral administration of extract of PSII by beagle dogs are high, with high sensitivity, recovery, precision, accuracy, and reproducibility.[140] In this study, the pharmacokinetics of the extract of PR II orally was studied with good results.


  Summary and Prospect Top


As an important TCM, PR has a long history and has pharmacological effects such as analgesia, sedation, anti-inflammation, hemostasis, antitumor, bacteriostasis, antivirus, kidney and liver protection, inhibition of angiogenesis, immune regulation, antioxidation, cardiovascular effects, and antifertility and anti-early pregnancy spermicidal effects. It has a variety of chemical components, including steroidal saponins, plant endophytes, polysaccharides, amino acids, trace elements, sterones, cholesterols, C21 steroids, phytosterols, plant ecdysteroids, flavonoids, triterpenes, and fatty acids. It is toxic to liver, lung, kidney, and other organs. It has a variety of analytical methods to determine and study the composition and content of PR. However, there are still some deficiencies:

First, PR has a variety of pharmacological effects, mainly the study of antitumor effects, and relatively few studies on other aspects of pharmacological effects. In the antitumor research, the main research is on lung and liver cancer, possibly because PR has obvious toxicity to these two organs, but there are also studies on other cancers, but there are fewer involved areas and lack of in-depth research. Most of the studies on its antitumor effects are at the cellular and molecular levels, lacking animal-level and higher-level studies. Therefore, there will be a lack of clinical data and less research on the specific mechanism of their anticancer cells, possibly because of the complex structure of cancer cells and the complex composition of TCM, which increases the difficulty of the research. The study of the body mechanism is hindered; and only the effects of several chemical components in PR have been studied, among which the main ones are PR saponins, and few studies have been done on other chemical components. Besides the antitumor pharmacological effects, there are still relatively few studies. Later, more in-depth studies on these aspects can be carried out to provide a basis for the development of more effective drugs.

Second, PR and a variety of other Chinese medicines can be prepared into compounds, some of which have been marketed for production and have generated good response. For example, the studies on the synergistic antitumor effect of PR plus Curcuma longa L. showing good results, which provides a good idea for the future application of PR. There are many other examples of PR combining with other TCM to produce stronger effects. In the future, researchers can combine other TCM research and development drugs from this perspective and maximize the availability of PR.

Third, there are a lot of analysis and measurement method of PR for testing and analysis. However, there are some problems when some testing instruments are used alone, such as long analysis time and small sample size, etc. Therefore, some researchers have combined several testing instruments and achieved good results, which provides a reference for the selection of experimental instruments in the future.

Fourth, at present, there is less introduction to the processing experiment of PR. In the future, the effect and composition of PR can be studied after processing, so as to provide ideas and information for the research and development of new drugs in the future. Many processing methods are discussed, and the effects of several processing methods on PR are compared.

Fifth, the PR is slightly toxic, and there are clinical examples to prove the toxicity of the PR, but only the toxicity of PRS and Ps-H has been studied, while some studies also show some antitumor effects. Therefore, the research in the toxicity of PR needs to be further carried out, to better explore the pathways of toxic effects and the mechanism of toxicity, to provide the basis for reducing the toxic side effects of drugs in the future, and to clarify the mechanism.

Sixth, from the research progress of PR, it is found that there is a lack of pharmacokinetic experiments, which may be due to the fact that most of the studies on PR are at the cellular and molecular levels, which hinders its application in the clinic. Future studies can be biased toward this aspect to explore whether more factors have an impact on the effect of PR, to improve the medication compliance of medicated patients, and to expand medication. Expand the scope of application of drugs, etc.

As an important natural Chinese medicine, PR has many uses and great potential for development. This paper reviews the research progress in botany, ethnopharmacology, traditional uses, phytochemistry, analytical methods, quality control, processing, pharmacology, toxicology, and pharmacokinetics of PR in the past two decades. The purpose of this article is to further understand the role, ingredients, and deficiencies of PR and to analyze what aspects can be further studied in the future, to develop the PR to a greater extent, to provide information and ideas for the development of new drugs, and to better apply in clinical practice.

Acknowledgments

This work was supported by the Innovative Talents Funding of The Heilongjiang University of Chinese Medicine Doctoral Innovation Foundation [No. 2014bs05]; the Graduate Innovative Research Project Foundation of Heilongjiang University of Chinese Medicine [No. 2019yjscx013]; the Application Technology Research and Development Projects of Harbin Technology Bureau [No. 2014RFQXJ149]; the Natural Science Foundation of Heilongjiang Province [No. H2015037]; Heilongjiang University of Chinese Medicine [No. 2018RCD25]; the National Natural Science Foundation Matching Project [No. 2018PT02]; the National Natural Science Foundation Matching Project [No. 2017PT01]; Heilongjiang Postdoctoral Scientific Research Developmental Fund [No. LBH Q16210 and LBH-Q17161]; the National Natural Science Foundation of China (No. 81703684, 81803690, 81973604); the Postdoctoral Initial Fund of Heilongjiang Province, the University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province [No. UNPYSCT 2017219 and UNPYSCT 2017215].

Acknowledgements

This work was supported by the Innovative Talents Funding of The Heilongjiang University of Chinese Medicine Doctoral Innovation Foundation [No. 2014bs05]; the Graduate Innovative Research Project Foundation of Heilongjiang University of Chinese Medicine [No. 2019yjscx013]; the Application Technology Research and Development Projects of Harbin Technology Bureau [No. 2014RFQXJ149]; the Natural Science Foundation of Heilongjiang Province [No. H2015037]; Heilongjiang University of Chinese Medicine [No. 2018RCD25]; the National Natural Science Foundation Matching Project [No. 2018PT02]; the National Natural Science Foundation Matching Project [No. 2017PT01]; Heilongjiang Postdoctoral Scientific Research Developmental Fund [No. LBH Q16210 and LBH-Q17161]; the National Natural Science Foundation of China (No. 81703684, 81803690, 81973604); the Postdoctoral Initial Fund of Heilongjiang Province, the University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province [No. UNPYSCT 2017219 and UNPYSCT 2017215].

Conflicts of interest

There are no conflicts of interest.



 
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