Research progress on chemical composition, pharmacological effects of Forsythia suspensa (Thunb.) Vahl and predictive analysis on Q-marker

Hui Peng, Peng Lu, Yiting Liu, Chuanxin Liu, Yanquan Gao, EbukaOlisaemeka Nwafor, Yuelin Zhang, Zhidong Liu

REVIEW

Research progress on chemical composition, pharmacological effects ofand predictive analysis on Q-marker

Hui Peng1,2#, Peng Lu1,2#, Yiting Liu1,2, Chuanxin Liu3, Yanquan Gao1,2, EbukaOlisaemeka Nwafor1,2, Yuelin Zhang1,2, Zhidong Liu1,2

1Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China;2Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin, China;3School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.

Lianqiao (, Abbreviated as “below) is traditional Chinese medicine in China, widely distributed all over the country and also highly rich in resources. The Northwest Territories is a genuine producing area. There are many chemical components in, including lignans, phenylethanolic glycosides, flavonoids, C6-C2 natural alcohols and their glycosides, phenolic acids, terpenes and volatile oils. Among them, lignans and phenylethanolic glycosides are the main active components. Based on the review of chemical components or constituents and main pharmacological activities, according to the definition of quality marker, the components of quality marker ofwere predicted and analyzed from the aspects of plant genetics and chemical composition, traditional efficacy, traditional medicine, new efficacy, blood entering composition, measurable composition, effective composition in different compatibility, and the influence of storage conditions of extract. Further research on its medicinal active ingredients will provide scientific basis for the evaluation ofquality.

, Phenylethanol glycosides, Lignans, Quality control, Q-marker

Background

Lianqiao (, Abbreviated as “” below) is one of the traditional Chinese medicines (TCMs) in China, a plant of the genus Forsythia and its fruits widely used, well known in TCM as “Forsythiae Fructus”. Its fruit signifies TCM, and its shell as the medicinal part specified in the Pharmacopoeia [1].was first recorded in Shengnong Bencao Jing [2], a classic work of TCM in the Qin and Han Dynasties (100BC-200AD). In 2015 edition of the Chinese Pharmacopoeia,has the functions of clearing heat and detoxification, reducing swelling, dispersing and evacuating wind and heat [1] (also known as fever and common cold). It has also been used as an effective remedy for the treatment of ulcer, gonorrhea, flu, erysipelas and nephritis for thousands of years. Modern pharmacology [3, 4] showed thathad potential medicinal value in protecting nerves [5], protecting liver and choleretic, regulating immunity, antioxidant effects [6], diuretic and anti-hypertensive, anti-aging, anti-tumor, anti-viral [7], anti-bacterial, anti-inflammatory [8], etc.

The quality of TCM includes little or no adverse effect or reactions, safe and guaranteed efficacy or effectiveness in modern clinical applications. In this paper, the resources, chemical components and main pharmacological activities ofwere reviewed. On this basis, the quality standards and quality markers (Q-marker) ofwere studied potentially, providing a scientific basis for the establishment of quantitative standards of material components.

Resource distribution

In China,is mainly produced in Hebei, Shanxi, Shaanxi, Shandong, Western Anhui, Henan, Hubei, Sichuan and other provinces (regions). In addition, it also grows in Korea, Japan and Europe [9].

Chemical composition

More than 200 compounds have been isolated and identified from[10]Studies on the chemical constituents ofare mainly focused on phenylethanolic glycosides and lignans, followed by C6-C2 natural alcohols and their glycosides, terpenes, volatile oils, flavonoids, phenolic acids, sterols and alkaloids.Among them, phenylethanol glycosides and lignans, the main medicinal ingredients, have the highest content.

Phenylethanoid glycosides

Phenylethanoside is a kind of phenolic glycoside compound [11], which is composed of phenylethanol and sugar. The content of this component is high in, and it is one of the important Q-marker inIt mainly includes forsythiaside (forsythoside A) [12], forsythoside B [13], forsythoside D [14], forsythoside E [12, 15], forsythoside M [16], isoforsythiaside [17], forsythiaside G [12], forsythiaside I [14], forsythiaside J [12], lianqiaoxinside B [18], calceolarioside C [19], forsythenside K [20], plantainoside [21], calceolarioside A [22], calceolarioside B [12], etc. The specific compound names were shown in Supplemental data and the chemical structures of phenylethanolic glycosides 1-30 were shown in Figure 1.

Lignans

Lignans are a class of natural compounds polymerized by two molecules of phenylpropanoid derivatives, most of which are in free state, and a few of which are in the wood and resin of plants due to the synthesis of glycosides with sugar. There are three types of monomers that make up lignans: 1. Cinnamolic acid or cinnamaldehyde, 2. Cinyl alcohol, 3. Allylbenzene. Lignans are an important active component of, mainly including (+)-lariciresinol[28], isolariciresinol[29], (+)-phillygenin[27], (+)-phillyrin[27], (-)-arctiin[30], (-)-arctigenin[30], (-)-matairesinol[31], (-)-matairesinoside[31], (+)-pinoresinol[32], (+)-epipinoresinol [30, 33], (+)-pinoresinol-4-O-β-D-glucoside[34], (-)-dimethylmatairesinol[31], etc. The specific compound names were shown in Supplemental data and the chemical structures of lignans 31-75 were shown in Figure 2 and Figure 3.

C6-C2 natural alcohols and their glycosides

Currently, the separation products of C6-C2 natural alcohol and its glycosides are isorengyol [40], rengyol [47], rengyolone [47], rengyoxide [47], rengyoside A [48], rengyoside B [48], rengyoside C [48], suspenol [49], rengynic acid [52], forsythenside A [54], forsythenside B [54], etc. The specific compound names were shown in Supplemental data and the chemical structures of C6-C2 natural alcohol and their glycosides 76-99 were shown in Figure 4 and Figure 5.

Flavonoids

There are more than 20 flavonoids in, mainly including quercetin [25, 57], isoquercetin [30], astragalin [30], rutin [57], wogonin-7-O-β-D- glucuronide [30], cymaroside [43], luteolin [43], kaempferol [24], isorhamnetin [57], hesperidin [59], isorhamnetin-3-O-α-L-ranorhamnoside-(1→2)-β-D- glucopyranoside [43], potengriffioside A [43], hyperoside [59], etc. The specific compound names were shown in Supplemental dataand the chemical structures of flavonoids 100-120 were shown in Figure 6 and Figure 7.

Phenolic acids

So far, the phenolic acids isolated frommainly include caffeic acid [63], ferulic acid [25], p-hydroxyphenylacetic acid [25], palmitic acid [64, 65], vanillic acid [63], succinic acid [63], etc. The specific compound names were shown in Supplemental data and the chemical structures of phenolic acids 121-162 were shown in Figure 8and Figure 9.

Terpenoids and Volatile oils

The volatile oils inare monoterpenes, monoterpenols, sesquiterpenes, triterpenes, and cycloterpenoids. Among them, α-pinene [70], β-pinene [70], α-phellandrene[70],camphene [70], limonene [70], sabinene [70], p-cymene [70], linalool [70], terpinen-4-ol [70], (+)-carene[71], oleanolic acid [72], ursolic acid [27, 73], 2,3-hydroxyursolic acid[74, 75], etc. The specific compound names were shown in Supplemental data and the chemical structures of terpenoids and volatile oils 163-217 were shown in Figure 10, Figure 11 and Figure 12.

Other compounds

Other compounds were isolated and identified as well.Mainly including sterols and alkaloids such as suspensine A[76],(–)-7ʹ-O-methylegenine [76], (–)-egenine [76], (–)-bicuculline [76], taraxasterol [25], β-sitosterol [56], etc. The specific compound names were shown in Supplemental data and the chemical structures of other compounds 218-225 were shown in Figure 13.

Pharmaceutical effects

In recent years, there are more and more studies on the activity screening of some compounds in. Their pharmacological effects are also obvious, with antibacterial, anti-inflammatory, antiviral, anti-tumor, liver protection, nerve protection, anti-allergic, anti-oxidative effects and regulating body immunity, etc.

Antibacterial effects

Antibacterial activities ofcontribute to its detoxification effects in terms of traditional efficacy.is a kind of broad-spectrum antibacterial drug, which can inhibit many kinds of bacteria. It is mainly used in the treatment of upper respiratory tract infection and acute nephritis [78]. The results [38] showed that caffeoyl phenylethanoid glycosides, forsythiaside and isoforsythiaside were the main antibacterial components of. In addition, the volatile oil inhad a good antibacterial effect onStaphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans, Aspergillus niger and other sensitive microorganisms in vitro [70]. Shuanghuanglian Oral Liquid is a proprietary Chinese medicine, which consists of Rendongteng (), Huangqin (), and, and it is mainly used to treat colds and fevers, coughs and sore throats.The study of Bai YE [79] showed that compared with Shuanghuanglian Oral Liquid, water extract ofwas more sensitive to Staphylococcus aureus and Streptococcus pneumoniae, but it is not sensitive to Escherichia coli (E. coli) and Candida albicans. Han X and others [80]tested the antibacterial activity of 80% methanol extract ofon E. coli K88 (MIC=25.00mg/ml), Staphylococcus aureus (MIC=12.50mg/ml) and Salmonella (MIC=1.56mg/ml) in vitro by a well-diffusion assay procedure and a 2-fold dilution method. And in-vivo tests on 252 broilers for 42 days showed that the extract (100 mg/kg) could reduce the level of E. coli and was a potential antibacterial agent. Some researchers have pointed out that forsythiaside [81] could significantly reduce the mortality of model animals infected with Staphylococcus aureus, Pseudomonas aeruginosa, and E. coli through experiments. Meanwhile, the body temperature of the rabbit model of fever caused by endotoxin and the rat model of yeast fever were significantly reduced. Therefore, it can be confirmed that forsythiaside has antipyretic and anti-infective effects.

Anti-inflammatory effects

The anti-inflammatory activity ofranks first among many TCMs, and it is the most effective and promising anti-inflammatory drug for inhibiting inflammation [82]. The main anti-inflammatory components ofare phenylethanolic glycosides and lignans. Wang TT [83] have done the related in vitro bacteriostatic test and anti-inflammatory activity research, which showed that both forsythoside A and phillyrin have significant bacteriostatic effect. Modern pharmacology showed that the anti-inflammatory activity ofsupported traditional effects of heat-clearing and detoxifying, reducing swelling, dispersing, and evacuating wind and heat.

The anti-inflammatory effect ofhas been proved to play a role in various disease models, including edema [84], colitis [85] and peritonitis [86].Studies by Lee JJ and other studies [87] have shown that water extract of(mainly including forsythiaside A, lariciresinol, arctigenin, etc.) activated Nrf2 (Nrf2, important transcription factors that regulate cellular oxidative stress) and inhibited NF-κB activity (NF-κB, a transcription factor that regulates the expression of key cytokine genes that promote inflammation) and induced A20 [88](A20, a negative regulator of NF-κB signaling pathway) expression to play an anti-inflammatory effect. Ethanol extract of(such as phillyrin, phillygenin, forsythoside A, pinoresinol, suspensaside, caffeic acid, etc.) could reduce the production of inducible nitric oxide synthetase (iNOS), prostaglandin E2 (PGE2) and cyclooxygenase-2 [89]. It has been reported that the anti-inflammatory effect of forsythiaside A on BV-2 microglia (mouse microglioma cells) and primary microglia in vitro was studied at different concentrations. And the inhibitory effect [90] of was recognized to inhibit NF-κB signaling pathway and higher levels of Nrf2 and heme oxygenase 1 (HO-1). From the number of neutrophils and the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in the peritoneal cavity, it was confirmed that forsythiaside A [86] could significantly reduce peritonitis. In a mouse model of acute lung injury [91], phillyrin could inhibit the pathological changes of lung tissue, alveolar hemorrhage and neutrophil changes in mice. It protected lung injury by inhibiting TNF-α, interleukin-1β (IL-1β), IL-6 and peroxidase.

Lee S [92] has shown that arctiine could reduce the production of NO and pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and PGE2, and reduce gene and protein levels detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. In addition, arctiin [93] could inhibit the expression of costimulatory molecules (such as B7-1, B7-2), and the NF-κB signaling pathway in macrophages to achieve anti-inflammatory purposes. Arctiin has a good anti-inflammatory biological activity.

Antiviral effects

Antiviral activities ofalso contribute to its detoxification effects[94]. Studies [95] have shown that in mice inoculated with H1N1 in vivo, the administration of phillyrin (20 mg/kg/day) for three consecutive days significantly prolonged the average survival time, and it was determined that the virus titer, IL-6 and influenza hemagglutinin production were significantly reduced, and lung tissue damage was reduced. Forsythiaside A [96] could reduce the content of influenza A virus M1 protein in model mice infected with influenza virus, prevent the generation and spread of new virions, and improve the survival rate of mice infected with influenza virus in vivo. More importantly, forsythiaside A [97] could control influenza A virus infection by inhibiting influenza A virus replication and improve the prognosis of influenza A virus infection. Yang Y [98] evaluated the anti-swine influenza virus effect of. Experiments have shown that it had antiviral effects, mainly by resisting virus adsorption, interfering with virus replication, and direct killing.

Anti-cancer effects

Anti-cancer activity ofalso supports its detoxification and antioxidant effects.has multiple therapeutic effects [99] on lung cancer, colon cancer, liver cancer, leukemia, oral epidermoid cancer, gastric cancer, breast cancer, colorectal cancer, melanoma, esophageal cancer, lung adenocarcinoma, melanoma, etc. Bao J et al [100] tested the anti-proliferative effect ofwater extract on mouse melanoma B16-F10 cells in vitro. In vivo transplantation of B16-F10 melanoma in mice, the extract (10000 mg/kg) significantly inhibited tumor growth, cell proliferation and angiogenesis. Its anti-tumor effect was related to the anti-inflammatory and anti-oxidation properties regulated by mitogen-activated protein kinase (MAPKs)/Nrf2/ HO-1.

Hepatoprotective effect

Pan CW [101] reported that forsythiaside A (15, 30, 60 mg/kg) at a certain concentration could be alleviated inflammatory response and had hepatoprotective effect in a model of lipopolysaccharide (LPS)/D-galactosamine (GalN) induced acute liver injury. It could reduce the production of malondialdehyde (MDA) and the levels of alanine aminotransferase in serum and aspartate aminotransferase. And it could also activate Nrf2 and inhibit the NF-κB signaling pathway. Similarly, forsythiaside A, forsythiaside B, forsythiaside N, and forsythiaside O all showed survival rates with strong liver cells.

Antioxidant effect and regulating body immunity

Isoforsythiaside was isolated fromby Qu H [102] and its pharmacological test showed that isoforsythiaside had high antioxidant and antibacterial activity. In vitro, isoforsythiaside and forsythiaside had a strong scavenging effect on DPPH free radicals. And the strong antioxidative effect of isoforsythiaside was related to the ortho substitution of the hydroxyl group in the phenol structure. Forsythiaside B, forsythiaside H, and calceolarioside B [18] also showed free radical scavenging activity in vitro. Lu T [103] used DPPH and ABTS free radical scavenging experiments to confirm the antioxidant capacity of 80% ethanol extract ofin vitro.

Phillygenin, 8-hydroxypinoresinol, forsythialan and forsythialan B obviously protected the renal tubular epithelial cells LLC-PK1 in vitro [104]. Forsythiaside could enhance the expression of antioxidant enzymes in H2O2-treated neurons cultured in vitro [105]. It has been reported that phenolic constituents also had strong antioxidant properties and were stronger than ascorbic acid, such as methyl caffeate, rutin and quercetin [106].

Anti-allergic effects

Sung YY [107] studied that forsythiaside, phillyrin, lariciresinol, and phillygenin can reduce the production of thymus activation regulating chemokine, macrophage-derived chemokine and rantes. In a mouse in vivo model, the ethanol extract ofcould alleviate the symptoms of allergic dermatitis induced by the crude extract of dust mites. The methanol extract ofcould reduce the allergic symptoms caused by β-companion soybean globulin in weaned piglets. Hao Y [108] believed that the mechanism may be related to inhibiting allergic antibodies, hindering mast cell degranulation, T lymphocyte proliferation, histamine production and interleukin-4 synthesis.

Neuroprotective effects

It was reported that forsythiaside and phillyrin [109] were considered as promising drugs for the treatment of cognitive impairment and Parkinson's disease, and were candidates for the treatment of amnesia. Zhang S [110] studied the inhibitory effect of 75% ethanol extract of(mainly including forsythoside A, suspensaside, rutin, etc.) on rotenone induced neurotoxicity in SD male rats. It could improve the behavior of rats, protect dopamine neurons from loss and restore dopamine level. The results showed that its potential function is by relieving pro-inflammatory molecules of Parkinson's disease and regulating phosphatidylinositol 3-kinase, protein kinase B, NF-κB and MAPK pathways.

Kim JM [111] found that phillygenin could shorten the escape latency, reduce the level of thiobarbituric acid reactive substances assay (TBARS) in rats and protect the nerves in the scopolamine-induced mouse memory impairment model. Its mechanism was that phillygenin could express its anti-inflammatory activity through forsythia lipoproteins by inducing a decrease in glial cell activation and expression levels of IL-1β and tumor necrosis factor-α, thereby achieving a neuroprotective effect.

By processing the mouse brain homogenate in the Wang’s model group [109], the levels of IL-1β, NO, MDA and norepinephrine (NE) were significantly decreased, and the activities of total superoxide dismutase and glutathione peroxidase and the levels of glutamate and acetylcholine were significantly increased. Therefore, this study indicated that forsythiaside had a herapeutic effect on amnesia and neuroprotection.

Other pharmacological effects

In addition to the above effects,could also promote gastric emptying, lower blood lipids and relax blood vessels. It was reported that phillyrin [112] had vasodilating effect on vasoconstriction caused by NE. The mechanism was that it protected the aorta of isolated rats by limiting the inflow of calcium ions in vitro. Hao FF [113] studied that compared with the blank group, the water extract ofadministration group had no effect on gastric emptying and small intestinal advancing of mice under normal physiological conditions. However, it had a good two-way regulation and improvement effect on gastric emptying and small intestine models of mice under pathological conditions caused by dopamine, adrenaline, atropine and neostigmine.

Predictive analysis of Q-marker

The chemical composition types ofin different provinces, different places of origin, different growth years and different harvest periods are generally similar, but the contents are different. Q-marker [114, 115] was a new concept put forward by academician Liu Changxiao [116, 117] (Researcher of Tianjin Institute of Pharmaceutical Research, academician of Chinese Academy of Engineering) in 2016, which closely linked the “effectiveness – material basis – quality control landmark components” of TCM. Q-marker systematically expounded the relationship between the quality and efficacy of TCM with new perspectives, improved the quality standard of TCM in China, and improved the scientificity, rationality and operability of the standard [118]. It referred to chemical substances that were inherent in TCM and TCM products (Chinese herbal extracts, TCM decoction pieces, TCM preparations, etc.) were formed during processing and were closely related to the functional properties of TCM, as a reflection of the safety of TCM and quality control of effectiveness. Since academician Liu Changxiao put forward, scholars have conducted preliminary discussions on some Chinese medicines [119, 120] and TCM Patent Prescriptions [121, 122]. In order to evaluate the quality ofobjectively and scientifically, according to the definition of Q-marker, the Q-marker ofis predicted, which is helpful to establish a scientific quality control method of.

Predictive analysis of Q-marker based on plant genetics and chemical component-specific evidence

According to herbal research [123, 124], the TCM “Forsythia” mostly used Hyperic ascyron L. as the basis in the Song Dynasty. After the Song Dynasty,was used as the basis of the TCM “Forsythia” and has been used ever since.is derived from Forsythia of Oleaceae. Forsythia species include Lianqiao ()Jinzhonghua(), and Qinqiao() in China. Studies on other breeds have been scarce.is mainly distributed in Hebei, Shanxi, Shaanxi, Shandong, Western Anhui, Henan, Hubei, Sichuan and other provinces in China. There are many chemical constituents isolated from, including 36 phenylethanolic glycosides, 55 lignans, 58 terpenes and volatile oils, 25 C6-C2 natural alcohols and their glycosides, 23 flavonoids, more than 50 sterols, alkaloids and phenolic acids. Among them, phenylethanol glycosides and lignans are the main active ingredients and important chemical markers ofThese two kinds of effective components are selected as the quality indicators of

Predictive analysis of Q-marker based on traditional efficacy

has the functions of clearing heat and detoxification, reducing swelling and dispersing, and evacuating wind and heat. In modern pharmacological studies, the traditional efficacy ofis based on the anti-inflammatory and anti-oxidation properties of phenylethanolic glycosides (forsythiaside A, B, C, D, E, etc.) and lignan compounds (phillygenin, phillyrin, etc.) in. In modern pharmacology, the traditional efficacy of “clearing away heat and detoxification” is mainly reflected in the pharmacological effects of antipyretic, cooling, antibacterial and anti-inflammatory; The traditional effect of “swelling and dispersing the wind and dispersing wind and heat” is mainly reflected in anti-virus, swelling and anti-inflammatory.

Hu NH [125] studied the inflammation model and fibrosis model of human hepatic stellate cells (LX2) induced by different concentrations of lipopolysaccharide (LPS), and then given high, medium and low doses of phillygenin for intervention. The results showed that phillygenin could inhibit LPS-induced LX2 cell activation and inflammation of the TLR4/MyD88/NF-κB signaling pathway. Phillygenin could also inhibit LX2 cell activation and fibrotic cytokine expression by inhibiting the LPS-induced proinflammatory response. Zou SS [126] intravenously and orally administered forsythiaside to rabbit models infected with parainfluenza virus, and tested to significantly reduce the contents of the heating medium protein kinase C and cyclic adenosine monophosphate (cAMP) in the hypothalamus. Experiments showed that forsythia could reduce the body temperature of rabbits after parainfluenza virus infection, and its antipyretic mechanism may be related to the down-regulation of cAMP content in rabbit hypothalamus. Forsythiaside A [127] could prevent cigarette smoke-induced lung tissue damage in mice with chronic obstructive pulmonary disease by activating Nrf2 and inhibiting the NF-κB signaling pathway and this experiment also demonstrates that forsythiaside A can attenuate the penetration of inflammatory cells.

Phenylethanol glycosides and lignans correspond to the traditional efficacy of, which were the main medicinal substance basis of traditional efficacy of, and also the main way and important basis for screening Q-marker of.

（4）提高球化能力 将球化温度控制在1450℃左右，球化剂上覆盖0.2%硅钡孕育剂，球化能力刚好合适，既不会太强也不会太弱。球化完毕后铁液中的渣易于浮出，便于除渣，可保证铁液纯净。

Predictive analysis of Q-marker based on traditional medicinal properties

The classic taste of TCM [128] is the basic attribute of TCM, and it is also an important basis for the treatment of clinical symptoms and formulating prescriptions. It should also be used as one of the bases for determining Q-marker.possesses related properties: it has a bitter taste and cold attribute to lung, heart and small intestine. The important material foundation of “bitter taste” should first have the taste characteristics and functional properties of bitterness. The taste of the medicine has a corresponding relationship with its chemical components or constituents used in formulation. The glycosides and alkaloids are the main sources of the bitter taste possessed by the cold medication [129]. Based on the above, it can be concluded that the chemical components of phenylethanol glycosides and lignans inshould be the main material basis of its “sexual taste” and the main choice of Q-marker.

Predictive analysis of Q-marker based on new pharmacodynamic uses

The phenylethanolic glycosides contained inhave an effect of protecting the liver and eliminating jaundice, and the aglycone caffeic acid and its structural analog chlorogenic acid also have the effect of protecting the liver and promoting gall [101]. Cheng Y [130] reported that phillyrin and forsythiaside A had different induction effects on cytochrome P450 in rat liver microsomal incubation system. Both phillyrin and forsythiaside A can potentially induce cytochrome oxidase activity. Zhang YY [131] studied that the ethyl acetate extract of(EAF) could reduce the content of serum triglyceride and total cholesterol in streptozotocin induced diabetic mice model. And it also increased the content of high-density lipoprotein, and significantly reduced blood glucose levels in diabetic mice treated with EAF. In addition, EAF may have anti-diabetic effects by regulating gene expression and pancreatic function. Leng W [132] explored the effects of phillyrin on renal function, inflammatory response and oxidative stress in diabetic nephropathy rats by establishing a diabetic nephropathy rat model, and the results showed that phillyrin can protect renal damage in diabetic nephropathy.

It can be concluded that phenylethanolic glycosides and lignans are the main material foundations forto protect the liver and lower blood sugar, which should be taken as the Q-marker of

Predictive analysis of Q-marker based on blood-introducible chemical components

The chemical composition of TCM is very complicated, and its complexity is manifested in the fact that TCM contains a large number of different structural types of chemical components, and each type has a large number of chemical components. The complexity of TCM ingredients is the basis for its multiple functions and multiple pharmacological effects. Although the chemical composition of TCM is complex, the chemical ingredients must be absorbed into the blood and reach a certain blood concentration in the body before they can play a pharmacological effect directly or indirectly (except for a few components that directly affect the intestine). By analyzing the components of the prototype and their metabolites after administration, analyzing the markedly effective ways based on the compound-target-pathway, and combining the tissue distribution of the blood-injecting components with the pathological site of the disease and the drug intervention method, the effective ingredients ofwere screened and used as an important basis for predicting the Q-marker of

The oral bioavailability of phenylethanolic glycosides is low, but the efficacy is significant, which means that the mixture of prototypes and metabolites may be the group of active ingredients that play the role of efficacy. The main reactions of phenylethanolic glycosides in vivo are hydrolysis, reduction, dehydrogenation, methylation, sulfation, etc. Bai Y [133] was used to study the pharmacokinetics ofmethanol extract ofin rats. The liquid chromatography, electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) was established and validated for the determination of 9 selected components (forsythiaside A, forsythiaside B, rutin, astragaloside, phillyrin, kaempferol, quercetin, iaorhamnetin and arctiin) in rat plasma. The experimental results showed that only three forsythiasides A, rutin and phillyrin are detected in the plasma after oral administration ofmethanol extract in rats. Li C studied the antiviral evaluation of phillyrin and its metabolites [134]. Phillyrin is converted to aglycone forsythiaside by hydrolysis, and then converted to other metabolites mainly through a series of metabolic processes in the blood such as methylation, demethylation, dehydroxylation, and ring opening. The results showed that phillyrin and four metabolites had inhibitory effects on the H3N2 influenza virus, indicating that phillygenin were the main components of phillyrin in rat plasma.

Based on the above analysis, the blood components ofare mainly phenylethanol glycosides and lignans, which are closely related to medicinal effects, and are likely to be the basis of the main pharmacodynamic substances, which serve as an important reference for screeningQ-marker.

Predictive analysis of Q-marker based on changes in chemical composition content of extracts under different storage conditions

The clinical efficacy of Chinese medicine is related to its quality, which is related to the effective active ingredients. After the TCM is harvested and processed for clinical applications, it is also extracted and stored. At this time, temperature, humidity, and light will affect the effective active ingredient content in it. Selecting a suitable storage method is of great significance to ensure the quality and stability of the TCM. During the packaging and storage of, the contents of forsythiasides A,phillyrin and phillygenin showed a decreasing trend [135]. In addition, different morphological conditions have different effects on their chemical composition content.

Conclusions and future perspectives

is a TCM commonly used in China. It has a wide range of physiological activities and has a long history of extensive application, accurate curative effects, and abundant sources of medicine. There are many new clinical applications, such as reducing blood sugar, lowering blood pressure, regulating blood lipids, and protecting the liver. The composition system ofis complex, and the single index component has been used as the standard to meet the entire forsythia industry chain. However, to establish a scientific and reasonable quality evaluation method, the quality ofis evaluated comprehensively and accurately, to guide the rational utilization of forsythia species, is of great practical significance for healthy development ofindustry.

On the basis of summarizing the research status ofchemical composition and modern pharmacological effects, this paper takes the Q-marker of TCM as the core concept. As shown in Figure 14, the relationship between traditional efficacy and modern pharmacological effects need be fully understood. According to the chemical components and pharmacological effect of, relevant literature of sexual taste, its measurable components, blood composition, etc., and combined with chemical composition analysis and some related researches on effectiveness, the literature analysis and demonstration of the selection and determination of. Q-markers were carried out, and a feasible path and a reference model method for Q-marker analysis of TCM were put forward. It will lay a foundation for the prediction and analysis of the Q-marker ofin the future, so as to establish the quality control and quality traceability system of.

Figure 1 Chemical structures of phenylethanoid glycosides (No. 1-30)

Figure 2 Chemical structures of lignans (No. 31-75)

Figure 3 Chemical structures of lignans (No. 31-75)

Figure 4 Chemical structures of C6-C2 natural alcohol and their glycosides (No. 76-99)

Figure 5 Chemical structures of C6-C2 natural alcohol and their glycosides (No. 76-99)

Figure 6 Chemical structures of flavonoids (No. 100-120)

Figure 7 Chemical structures of flavonoids (No. 100-120)

Figure 8 Chemical structures of phenolic acids (No. 121-162)

Figure 9 Chemical structures of phenolic acids (No. 121-162)

Figure 10 Chemical structures of terpenoids and volatile oils (No. 163-217)

Figure 11 Chemical structures of terpenoids and volatile oils (No. 163-217)

Figure 12 Chemical structures of terpenoids and volatile oils (No. 163-217)

Figure 13 Chemical structures of other compounds (No. 218-225)

Figure 14 Inductive summary of the mechanism of drug effect

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The new quality evaluation system takes traditional Chinese medicine (TCM) quality markers as its core concept, and lays foundation for the future analysis of the quality markers of Lianqiao (, Abbreviated as “” below), in order to establish aquality control and quality traceability system.

is a common medicinal plant in China, and it grows in hillside shrubs, underwoods, grasses, or in valleys. It can effectively improve immune functions, and have obvious curative effects in protecting nerves, anti-inflammatory, anti-virus, delaying aging, and reduce tumorigenesis.

Abbreviations: Q-marker, Quality marker;,; TCM, traditional Chinese medicine; MIC, minimum inhibitory concentration; cAMP, Cyclic adenosine monophosphate; RT-PCR, Reverse Transcription-Polymerase Chain Reaction; LPS, Lipopolysaccharide; TARC, Thymus activation regulating chemokine; MDC, Macrophage-derived chemokine; MAPK, Mitogen-activated protein kinase; IC50, half maximal inhibitory concentration; iNOS, inducible nitric oxide synthetase; PGE2, prostaglandin E2; HO-1, heme oxygenase 1; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; IL-1β, interleukin-1β; E. coli, Escherichia coli; MDA, malondialdehyde; GalN, D-galactosamine; DPPH, 1,1-diphenyl-2-picrylhydrazyl; ABTS, 2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); EAF, the ethyl acetate extract of F. suspensa; MyD88, Myeloid differentiation primary response gene 88; TLR-4, toll like receptor-4; NE, norepinephrine.

Competing interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Online: 6March 2020.

:Peng H, Lu P, Liu YT, et al. Research progress on chemical composition, pharmacological effects of Forsythia suspensa (Thunb.) Vahl and predictive analysis on Q-marker. TMR Modern Herbal Medicine 2020, 3(2):86-112.

Executive Editor: Chaoyong Wu

Submitted: 16 February 2020,

28 February 2020,

*Correspondence to: Zhidong Liu, Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. Tel: +86-22-59596170; Email: liuzhidong@tjutcm.edu.cn

#These authors contributed equally to this work.