Research Progress of Paederia scandens (Lour.) Merr in Modern Pharmacy

TANG Chao-ling, HAN Dong-miao, SUN Wan-ying, HUANG Zi-bao, WANG Rui-qi,ZHANG Xiao-po✉

1. Department of Pharmacy, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, China

2. Hainan Simcere Pharmaceutical Co., Ltd, Haikou 571000, China

3. School of Pharmacy, Hainan Medical University, Haikou 571199, China

Keywords:

ABSTRACT Paederia scandens (Lour.) Merr.is a traditional Chinese medicine, which mainly has the functions of analgesia, detoxification, anti-inflammatory and anticonvulsant.Modern studies show that the main chemical constituents of this plant are iridoids and volatile oil, which have biological activities such as analgesia, anti-inflammatory, hepatoprotection, renoprotection and antibacterial.This review highlights the chemical constituents and biological activities of P.scandens based on studies published in last decades and provides the references for the further development and utilization of this medicinal plant.

1.Chemical composition

It was found that PSM mainly contains volatile oil, iridoid glycosides, flavonoids and other chemical components, among which iridoid glycosides have attracted more attention due to their remarkable activity and unique structure, especially the sulfur atoms and dimers in their structures.

1.1 Volatile oil

Volatile oil is an important active ingredient in PSM.The main ingredients are thymol, dimethyl disulfide, quinoline, dimethyl phthalate, hexadecanoic acid, dibutyl phthalate, nonanal,diisobutyl phthalate[4], ethyl palmitate, chlorophyllin, palmitic acid, phenylacetaldehyde, ligustilide, ethyl linoleic acid, dimethyl trisulfide, pentadecanoic acid, 2-n-pentylfuran[5], methyl salicylate,isoamyl acetate Methylmethylmethylthiosulfonate, isoamyl hexanoate, benzyl acetate, benzaldehyde, eugenol, 4,5-dimethyl octane, ethyl hexanoate, 5-methyl-2 heptanone, ethylenedioxy pentane, ethoxypentane, hexyl acetate, amyl isovalerate, benzyl formate, isoamyl octanoate, camphor, dodecane, 2-phenylethyl acetate, bornyl acetate, dimethyl sulfone β-Propanolactone,isobutyl nitrite, butyric anhydride, methylamine, ketene, metamizole,propane, 3-Hexen-1-ol, pyrrole, trans-2-hexenol, furfural, linalool,linalool oxide, n-hexadecane, isophorone, Longifolene, n-heptane,acetic acid, oleic acid, linoleic acid[6].

1.2 Iridoid glycoside

Iridoids and their glycosides are abundant in PSM, which are the main active ingredients in PSM.Such components isolated from them mainly include paederoside, asperuloside, paederosidic acid[7],scandoside[8, 9], geniposide, caryophyllic acid, deacetylasperulosidic acid methyl ester, daphylloside, paederosidic acid methyl ester,deacetylasperulosidic acid and feretoside[10].Dang NQ[11] isolated three sulfur-containing dimers of iridoid glycosides from PSM,including the dimer of paederosidic acid and paederosidic acid,the dimer of paederoside and paederosidic acid, and the dimer of paederosidic acid methyl ester and paederosidic acid.

1.3 Flavone

Flavonoids isolated from PSM include astragaloside, Isoquercitrin,quercetin-3-o-rutose-7-o-glucoside, rutin, quercetin-3-o-glucose-7-o-xyloside[7], daidzein, quercetin, kaempferol-7-o-glucoside,kaempferol-3-o-rutinoside[12], kaempferol, gossypioside, and smectin[13].

1.4 Triterpene

The triterpenoids isolated from PSM were xylenone, epixylitol,ursolic acid, 2α-hydroxyursolic acid, oleanolic acid, oleanolic acid 3-acetate, taraxerol, 3-O-β-D-glucopyranoseursolic acid,2 ,3β,13β-hydroxy-11-en-28-oic acid, 3β,13β- hydroxy-11-en-28-oic acid and 3-oxours-12-en-28-oic acid[14, 15].

1.5 Steroidal glycoside

The steroidal glycoside isolated from PSM mainly include borassoside E, rapeseed sterol, stigmasterol, γ-sitosterol,β-sitosterol, (24R)-stigmast-4-en-3-one, stigmast-5-ene-3,7-diol,carotenoid[14].

1.6 Other ingredients

Phenylpropanoids from PSM include anisodamine, 1-caffeic acid-6-ferulic acid-glucoside, syringin diglycoside, 5-hydroxy-8-methoxypyranocoumarin, etc; Aliphatic alkanes include pentadecane, heptadecane and octadecane; Fatty alcohols include thirty-one alkanols and twenty-six alkanols; Fatty acids include palmitic acid, propionic acid, myristic acid and lauric acid[14].There are also amino acid components such as glutamic acid and aspartic acid[15].In addition, there are also polysaccharide components in the PSM, which mainly include glucose, rhamnose, L-arabinose,galactose[16].

2.Pharmacological activity

Modern pharmacological studies have shown that PSM has a wide range of pharmacological activities.Pharmacological activities mainly focus on pain relief, anti-inflammatory, sedation,antibacterial, antioxidant, liver protection, kidney protection, antitumor and so on.

2.1 Analgesic effect

As a kind of analgesic, PSM has a long history of medicinal use.It was pointed out in the Qing Dynasty’s “seeking the origin of Materia Medica” that it has the effect of relieving pain[17].The folk commonly use PSM water and wine decoction to treat traumatic pain and injury.PSM can significantly increase the pain threshold of mice caused by hot plate, which is the highest at 4 h, reduce the frequency of writhing reaction caused by acetic acid, and also have obvious analgesic effect on the pain caused by chemical stimulation[18,19].Iridoid glycosides, which are abundant in PSM, can play an analgesic role by antioxidant and scavenging superoxide free radicals.However, the iridoid glycosides of PSM play an obvious analgesic role by inhibiting the production of nitric oxide, and there is no addiction to continuous medication[20].Iridoid glycosides of PSM have analgesic effect on neuropathic pain rats by inhibiting NO/cGMP/PKG signaling pathway[21].Wang Tongchao[22] used mouse formalin test and hot plate test to study the analgesic effect of 20 mg/kg and 40 mg/kg paederosidic acid and methyl paederosidate dimer at different concentrations, and found that it has peripheral and central analgesic effects, and found that its maximum effective concentration for analgesia is 40 mg/kg.

2.2 Anti-inflammatory effect

Iridoid glycosides and polysaccharides from PSM have significant anti-inflammatory effects, and have good effects on a variety of inflammation.Fu Xiaopeng[23] found that the decoction of PSM can inhibit the inflammatory factor tumor necrosis factor (TNF-α)and interleukin-1β (IL-1β), it can significantly improve the infiltration of inflammatory cells and vascular proliferation in the joint tissue of rheumatoid arthritis mice.Li Xiang[24] through network pharmacology research found that there are multi-target and multi-channel characteristics in the treatment of rheumatoid arthritis with extracts of PSM, including affecting inflammatory response,apoptosis, angiogenesis and other signaling pathways.Wang Yongchang[25] found that PSM oral liquid can improve the primary pathogenesis of complete adjuvant arthritis in rats by reducing the production of prostaglandin E2 (PGE2) in inflammatory tissues and the content of inflammatory mediator nitric oxide.Hu Han[26] found that the extract of PSM can significantly reduce TNF-α And IL-1β in rats with acute gouty arthritis, it can also improve the pathological damage of its joints and play an anti-inflammatory role.Man[27]and Ma[28] found that the extract of PSM can reduce the TNF-α and IL-1β in the serum of mice, and regulating the production of proinflammatory mediators and reducing nuclear factors κB(NFκ B) in rat synovium, so as to play an anti rheumatoid arthritis role.

2.3 Sedative effect

Paederosidic acid (10 mg/kg 20 mg/kg and 40 mg/kg) can increase the brain of rats and mice by γ-aminobutyric acid,reduce brain glutamate and up regulate the expression of glutamate decarboxylase-65 (GAD65), thus exerting anticonvulsant and sedative effects[29].Extract of PSM (0.02 mL/g) can inhibit some passive and spontaneous activities of mice, and does not affect the sleep efficacy promoted by barbiturates[30].In addition, the extract of PSM could partially antagonize the activity of strychnine without affecting the effect of hydroxyecdysone.Low dose PSM extract (5 mg/kg～10 mg/kg) can prolong the latency of rats and cats in defensive motor conditioning, and has a significant effect on pentylenetetrazole convulsion, which is similar to phenobarbital sodium.However, in the larger dose (45 mg/kg～95 mg/kg) of PSM extract, it shows obvious sedative effect[31].

2.4 Antibacterial effect

Through the study of the components of the volatile oil of PSM,it was found that it contains phenol, aldehyde, ketone and other components such as eugenol, borneol, camphor, methyl salicylate,etc.these compounds have antibacterial effects[32].The establishment of in vivo antibacterial model was used to explore the antibacterial activity of the polysaccharide components of PSM, and it was found that the single polysaccharide component, crude polysaccharide component and polysaccharide fractionation component of PSM all have antibacterial effect in vivo, and the single polysaccharide component has the strongest antibacterial activity[16].Through the bacteriostatic experiment, it was found that the water extract of PSM can inhibit escherichia coli and staphylococcus aureus, and the minimum inhibitory concentration (MIC) was 0.25 g/mL[33].Mao Caiyan[34] found that the antibacterial strength of PSM in different seasons was different.The water extract of the root of PSM in Yunnan in spring and autumn had antibacterial and bactericidal effects on pseudomonas aeruginosa, escherichia coli, dysentery bacillus and staphylococcus aureus.Therefore, we should select the roots of PSM collected in different seasons to treat diseases caused by different pathogenic bacteria.In addition, the antibacterial strength of the PSM at different growth stages varies greatly.The antibacterial activity of the ethanol extract of the young PSM stem against staphylococcus aureus is significantly higher than that of the old PSM, with MIC of 0.625 g/mL and 5 g/mL respectively, while the antibacterial activity against pseudomonas aeruginosa is slightly lower than that of the old PSM[35], with MIC of 5 g/mL and 2.5 g/mL respectively.

2.5 Antioxidation

Xian Jingchun[36, 37] studied the best extraction method, time and antioxidant activity of total alkaloids and total flavonoids of PSM by ethanol extraction method, and found that total alkaloids and total alkaloids of PSM have significant scavenging effect on hydroxyl free radicals.When alkaloid concentration is 0.35 mg/mL and total flavone concentration is 0.4 mg/mL, the scavenging rate of hydroxyl radicals is the best, and the scavenging rate can reach 40%～50%.

2.6 Hepatoprotection

Zhu Ning[38] used liver cancer cell line (HepG2.2.15) to study the anti hepatitis B virus activity of the volatile oil of PSM.At the maximum non-toxic concentration (500 mg/L), the maximum inhibition rate on hepatitis B surface antigen (HBsAg) was 72.49%,and the maximum inhibition rate on hepatitis e antigen (HBe Ag)was 23.64%.The extract of PSM also has an anti liver fibrosis effect, and its mechanism of action is related to the inhibition of osteopontin (OPN) and transforming growth factor-β (TGF-β)and Smad3 mRNA expression, as well as promoting Smad7 mRNA expression[39, 40].Total iridoid glycosides of PSM can reduce AST and ALT levels, increase glutathione (GSH) and superoxide dismutase (SOD) activities, and reduce malondialdehyde (MDA)levels in acute liver injury rats induced by carbon tetrachloride[41].Tian Jingtao[42] found that the combination of PSM and tea polyphenols can reduce the damage of endotoxin to hepatocytes and can be used for the treatment of enterogenous fatty liver.The volatile oil of PSM can significantly reduce the levels of reactive oxygen species (ROS) and MDA in chicken liver in the model of nonalcoholic fatty liver, and downregulate heat shock protein(HSP7C), showing good antioxidant activity[43].

2.7 Renoprotection

Wu Jianxia[44] found that the total iridoid glycosides of PSM had a certain therapeutic effect on adenine induced uric acid nephropathy in rats, which can effectively reduce the levels of uric acid, urea nitrogen and creatinine in rats with uric acid nephropathy,and improve the kidney damage of rats to a certain extent.Zhu Wenjing[45] found that the total iridoid glycosides of PSM (70, 140,280 mg/kg) have preventive and therapeutic effects on rats with uric acid nephropathy, and the mechanism of action may be related to the reduction of blood uric acid, the downregulation of the expression of cyclooxygenase (COX-2) and the upregulation of the expression of nitric oxide synthase (NOS-1) in kidney tissue.It was found that iridoid glycosides from PSM could block transmembrane signal transduction of NF-κBp65 pathway, downregulation -Smooth muscle actin(α-SMA) and monocyte chemoattractant protein 1(MCP-1), up regulating NOS-1 expression and down regulating TNF-α And TGF-β1 expression, reduce the production of proinflammatory mediators in nephrotic tissues, thereby improving renal fibrosis in rats with uric acid nephropathy, and exert antiinflammatory and immunomodulatory effects on the kidneys of rats with uric acid nephropathy[46,47].Wang Shaojun[48] found that the extract of PSM can effectively reduce the blood glucose level of mice with diabetes nephropathy, significantly reduce the content of MDA and advanced glycation end products (AGE) in kidney tissue,increase the activities of SOD and glutathione peroxidase (GSHPx),improve kidney function, and have obvious renal protection.

2.8 Antitumor activity

Kapadia[4] found that the iridoid glycosides of PSM such as feretoside, paederoside, 7-deoxynormethanol, geniposide,scandoside, asperuloside and 7-deoxyloganic acid, all have obvious antitumor activities, of which paederoside has the most significant activity.Iridoid glycosides from PSM play a role by inducing apoptosis of tumor cells, and the mechanism is closely related to the inhibition of p53/MDM2 protein and its mediated signal pathway;At the same time, the anti-tumor activity of these components is also related to the inhibition of the expression of pro apoptotic protein (Bax) and apoptotic protein (Bcl-2), which in turn affect the dynamic balance of apoptotic factors in cells[14].Li Hongxia[49] studied the cytotoxic activity of iridoid glycosides from PSM by using tetramethylazozole blue method (MTT), and found that iridoid glycosides have inhibitory effects on the proliferation of human gastric adenoma cell (SGC7901), human colon cancer cell(COLO205), cervical cancer cell (Hela), human breast cancer cell(MCF7), human colon cancer cell (HCT-116) and human breast cancer cell (BT-549), The inhibitory effect on SGC7901 cells was the strongest and the IC50 was 156.6 ug/mL.

3.Conclusion and Discussion

PSM is a traditional Chinese medicinal plant and a good medicine for relieving fever and pain.Modern scientific research has further discovered the pharmacological activities of different chemical components in PSM.Through consulting relevant literature, it was found that there were rich types of chemical components in the PSM, and the research mainly focused on the extraction and analysis of the active components of the volatile oil and iridoid glycosides of the PSM.In terms of pharmacological research, PSM has a wide range of pharmacological activities, and has significant effects on a variety of pain, without drug resistance, addiction and other side effects; In addition to the analgesic effect, PSM also has anti-inflammatory, sedative, antioxidant, liver protecting, kidney protecting, antibacterial and other pharmacological activities.In recent years, with the continuous expansion of the research on PSM,its clinical application has also achieved certain efficacy, especially in pain relief and anti-inflammatory[50, 51].However, at present, the relevant research of PSM mainly focuses on the activity of total iridoid glycosides, and the research on other types of chemical components and the mechanism of their efficacy is less.Therefore, it is very necessary to carry out systematic and integral research on the active ingredients and related mechanisms of action of PSM, so as to provide scientific basis for the development of PSM and the basic research of its pharmacodynamics.

Author’s contribution

Tang Chaoling: topic selection and writing; Han dongmiao and Sun Wanying: paper structure design and literature collection; Huang Zibao and Wang Ruiqi: collection and collation of literature; Zhang Xiaopo: topic selection and design.