Abstract
Lonicerae Japonicae Caulis is the aboveground stem part of the Lonicera Japonica Thunb, which belongs to the medicine food homology species in China. It has the effects of clearing away heat, toxic material, dredging wind and unblocking collaterals. Modern research shows that it contains various active metabolites and a wide range of pharmacological effects, which is of great research and clinical application value. It mainly contains organic acids, volatile oils, flavonoids, triterpenes, triterpene saponins and other active metabolites. Its pharmacological effects mainly include anti-inflammatory, antibacterial, antitumor, antioxidant, and repairing bone and soft tissue. Based on the literature reports in recent years, the active metabolites, pharmacological effects and mechanisms of Lonicerae Japonicae Caulis were sorted out and summarized. It lays a foundation for explaining the efficacy material basis and application value of Lonicerae Japonicae Caulis. It aims to provide a reference for the in-depth research, development and utilization of Lonicerae Japonicae Caulis.
1 Introduction
Lonicerae Japonicae Caulis is also known as Laowengxu, Salicylus vine, Psychic grass, Qianjin vine, etc. It is a medicinal and food homologous Chinese medicinal material. Traditional Chinese medicine theory believes that its nature is sweet flavor and cold. It has been mainly treated for warm-disease fever, sore carbuncle and swollen toxin, heat toxin and blood dysentery, beriberi pyretic arthralgia, arthralgia and myalgia, etc. It was initially published in the Famous Doctors and recorded in the Compendium of Materia Medica. The Chinese (veterinary) medical theory believed that Lonicerae Japonicae Caulis had effects of clearing away heat, toxic material, dredging wind and unblocking collaterals. Traditional Chinese medicine health cultivation known as Medicine comes from food, food has medicinal properties, and medicine has food habits. With the change in lifestyle and diet structure, it has entered the public’s field of vision and attracted widespread attention. Lonicerae Japonicae Caulis, a medicinal and edible dual-use Chinese medicinal material, has significant advantages in anti-inflammatory, antioxidant, antitumor and inhibition of pathogenic microorganisms and other aspects. In clinical practice, it can to treat acute fever, headache, sore throat, respiratory infections and arthritis (). Lonicerae Japonicae Caulis contains organic acids, volatile oils, flavonoids, triterpenes, triterpene saponins and other active metabolites, of which chlorogenic acid (CGA) is one of the characteristic active metabolites of Lonicerae Japonicae Caulis. By reviewing the literature on Lonicerae Japonicae Caulis in recent years, this paper reviews and analyzes the active metabolites, pharmacological effects and mechanisms of Lonicerae Japonicae Caulis. It aims to provide a reference for the subsequent research, development and utilization of Lonicerae Japonicae Caulis and to look forward to its research prospects.
2 Main active metabolites of Lonicerae Japonicae Caulis
The main active metabolites of Lonicerae Japonicae Caulis include organic acids, volatile oils, flavonoids and triterpenes, triterpene saponins, etc.
2.1 Organic acids
Lonicerae Japonicae Caulis is rich in organic acid metabolites, mainly including chlorogenic acid derivatives and cinnamic acid derivatives. Chlorogenic acid derivatives mainly include chlorogenic acid (CGA) and neochlorogenic acid, etc. (; ; ; Yang et al., 2015; ; ; Wang et al., 2020; ). Cinnamic acid derivatives mainly include caffeic acid (CA), 1-caffeoylquinic acid (cryptochlorogenic acid), trans-cinnamic acid, trans-ferulic acid, and methyl caffeate (; Yang et al., 2015; ; ). In terms of the inhibitory effect on human platelet aggregation, caffeic acid methyl ester, 3,4-di-O-caffeoyl quinic acid and 3,4-di-O-caffeoyl quinic acid methyl ester have strong effects. In addition, the protective effect of various phenolic acids on hydrogen peroxide-induced cell damage suggests that polyphenol metabolites may play a role in maintaining vascular homeostasis. Among them, chlorogenic acid and caffeic acid are the phenolic acids that are more studied at present, which belong to the essential active metabolites in Lonicerae Japonicae Caulis, and have anti-inflammatory and antioxidant effects at the same time (; ; ). In addition, chlorogenic acid also has significant antitumor and hepatoprotective effects and is one of the most abundant organic acids in Lonicerae Japonicae (Caulis) (; Zhang et al., 2016; Yu et al., 2013; Tzeng et al., 2014; ). There is a high correlation between total phenolic content and antioxidant activity and phenolic metabolites have a significant contribution to the antioxidant capacity of traditional Chinese medicine. The organic acid content in Lonicerae Japonicae Caulis can be analyzed and determined with the Waters Symmetry C18 column (Tian et al., 2018). However, when establishing quantitative analysis of multi-metabolites by single marker (QAMS), there are differences in the mixing method, mixing position, and accuracy of mobile phases among different liquid chromatography systems, which may lead to differences in peak positioning. Therefore, when establishing QAMS, it is necessary to explore a more efficient and accurate approach. The specific information is shown in Table 1 and the structures of the main organic acid metabolites are shown in Figure 1.
TABLE 1
| No. | Compound Name | Formula | Ref. |
|---|---|---|---|
| 1 | chlorogenic acid | () | |
| 2 | neochlorogenic acid | (Wang et al., 2016) | |
| 3 | isochlorogenic acid C | (Wang et al., 2016) | |
| 4 | caffeic acid | (Zhang et al., 2009) | |
| 5 | cryptochlorogenic acid | (Wang et al., 2016) | |
| 6 | 3-O-caffeoylquinic acid | (Wang et al., 2016) | |
| 7 | 4-O-caffeoylquinic acid | (Wang et al., 2016) | |
| 8 | 3,4-Di-O-caffeoylquinic acid | () | |
| 9 | 3,4-Di-O-caffeoylquinic acid methyl ester | () | |
| 10 | ethyl 3,4-Di-O-caffeoylquinine | () | |
| 11 | 3-O-caffeoylquinic acid methyl ester | (Wang et al., 2016) | |
| 12 | 3-O-caffeoylquinic acid ethyl ester | (Wang et al., 2016) | |
| 13 | 4-O-E-caffeoylquinic acid methyl ester | (Wang et al., 2016) | |
| 14 | 4,5-Di-O-caffeoylquinic acid | (Wang et al., 2016) | |
| 15 | 4,5-Di-O-caffeoylquinic acid methyl ester | (Wang et al., 2016) | |
| 16 | 5-O-caffeoylquinic acid methyl ester | () | |
| 17 | 5-O-caffeioyl quinine butyl ester | (Wang et al., 2016) | |
| 18 | 1,3-Di-O-caffeoylquinic acid | () | |
| 19 | 3,5-Di-caffeoylquinic acid | () | |
| 20 | 3,5-Di-caffeioyl quinine butyl ester | (Wang et al., 2016) | |
| 21 | ethyl 3,5-Di-caffeoylquinate | (Wang et al., 2016) | |
| 22 | 1,5-Di-caffeoylquinic acid | () | |
| 23 | 3,4,5-O-triformylquinic acid | (Wang et al., 2016) | |
| 24 | caffeic acid-4-O- β- D-glucoside | () | |
| 25 | trans-Cinnamic acid | (Wang et al., 2016) | |
| 26 | ferulic acid | () | |
| 27 | trans-ferulic acid | (Wang et al., 2016) | |
| 28 | caffeic acid methyl ester | () | |
| 29 | ethyl caffeate | () | |
| 30 | vanillic acid | (Wang et al., 2016) | |
| 31 | syringic acid | (Wang et al., 2016) | |
| 32 | loganic acid | (Wang et al., 2016) | |
| 33 | protocatechuic acid | (Zhang et al., 2009) | |
| 34 | cinerea caprifolia G | (Zhang et al., 2009) | |
| 35 | methyl p-hydroxycinnamate | () | |
| 36 | ethyl laurate | (Wang et al., 2016) | |
| 37 | 2(E)-3-ethoxyacrylic acid | (Wang et al., 2016) | |
| 38 | abscisic acid | (Wang et al., 2016) | |
| 39 | 3-(3,4-Di-hydroxyphenyl) propionic acid | (Wang et al., 2016) | |
| 40 | cinnamic acid | (Wang et al., 2016) | |
| 41 | 4-hydroxycinnamic acid | (Wang et al., 2016) | |
| 42 | methyl 4-hydroxycinnamate | (Wang et al., 2016) | |
| 43 | p-coumaric acid | (Zhang et al., 2009) | |
| 44 | 3,4-Di-hydroxybenzoic acid | (Zhang et al., 2009) |
Composition of organic acid compounds in Lonicerae Japonicae (Caulis).
FIGURE 1
2.2 Volatile oils
The volatile oils are the main active metabolites of Lonicerae Japonicae, mainly including acids, aldehydes, alcohols, ketones and their esters, which are present in the flowers, leaves and stems of Lonicerae Japonicae. In addition, it should be noted that different parts contain different volatile oil metabolites (). Li Huijun isolated and identified the volatile oil metabolites in Lonicerae Japonicae Caulis, and confirmed that palmitic and linoleic acid had the highest content (). Wang Shuyan found that esters are the highest content of Lonicerae Japonicae Caulis volatile oil (Wang et al., 2011). Nenad Vukovic prepared essential oils from different parts of Lonicerae Japonicae and then carried out metabolite identification research with gas chromatography and mass spectrometry to. As a result, the researcher found that linalool was the primary volatile oil metabolite in honeysuckle flower buds, palmitic acid and linalool in honeysuckle leaves were the main volatile oil metabolites and palmitic acid in the stem was the primary volatile oil metabolite (Vukovic et al., 2012). However, there are also differences in the types and metabolites of volatile oils contained in Lonicerae Japonicae (Caulis) from different regions (). At present, qualitative and quantitative analysis among various studies shows that the metabolite composition of plants is greatly influenced by the environment and sample state. Therefore, when determining the content of metabolites in plants, it is necessary to consider the conditions of origin and the state of plant samples. The volatile oil in Lonicerae Japonicae (Caulis) is an edible natural flavour, which is currently mainly used in cosmetics, cigarettes, spices and food industries (; ; Zhang et al., 2020). The volatile oils have certain activities in antibacterial, anti-inflammatory, and anti-tumor aspects. The main metabolites in the volatile oils, such as linolenic acid, palmitic acid and oleic acid, can affect the inflammatory factors nitric oxide (NO) and tumor necrosis factor (TNF)-α. And then inhibit the proliferation of breast cancer MCF-7 cells. In addition, it can effectively alleviate the occurrence of breast cancer and the inflammatory response in the early and late stages (Yang et al., 2018). Guo Fengyu et al. found that linalool accumulated on the cell membrane due to hydrophobic interactions. This phenomenon will cause the surface of the cell membrane to shrink, cause the formation of pores in the cell membrane and wall and lead to the leakage of small molecules. Therefore, it interferes with the regular operation of the ATP generation system inside bacteria and inhibits cell functional characteristics. And as the action time prolongs, the degree of damage increases with the increase in drug concentration (). The specific information is shown in Table 2 and the structures of the main volatile oils metabolites are shown in Figure 2.
TABLE 2
| No. | Compound Name | Formula | Ref. |
|---|---|---|---|
| 45 | palmitic acid | () | |
| 46 | linoleic acid | () | |
| 47 | ethyl linoleate | () | |
| 48 | linalool | () | |
| 49 | cyclohexanone | (Wang et al., 2016) | |
| 50 | cyclohexane | (Wang et al., 2016) | |
| 51 | 2-Nonanol | (Wang et al., 2016) | |
| 52 | lauric acid | (Wang et al., 2016) | |
| 53 | benzyl benzoate | (Wang et al., 2016) | |
| 54 | undecane | (Wang et al., 2016) | |
| 55 | tridecanal | (Wang et al., 2016) | |
| 56 | tetradecanal | (Wang et al., 2016) | |
| 57 | pentadecanal | (Wang et al., 2016) | |
| 58 | myristate | (Wang et al., 2016) | |
| 59 | pentadecanoic acid | (Wang et al., 2016) | |
| 60 | cetyl alcohol | (Wang et al., 2016) | |
| 61 | margaric acid | (Wang et al., 2016) |
Volatile oil compound components in Lonicerae Japonicae (Caulis).
FIGURE 2
2.3 Flavonoids
The flavonoids are the secondary metabolites prevalent in many natural plants (; ; ). The structure is diversified, which include the circular matrix structure and O-and-C-glycosylated derivatives (). Currently, the flavonoids isolated from Lonicerae Japonicae can be divided into two categories: flavonoids and flavonols (). Among them, flavonoids include cinaroside, luteolin, witch hazel 7-O-neohesperidin, witch hazel 7-O-glucoside, cloxacillin and traxine, etc. (; ; ). Flavonols mainly include rutin, quercetin, isoquercetin, baicalein and quercetin 3-O-hexosideetc (; ). The specific information is shown in Table 3. The main pharmacological effects include antioxidant, bacteriostatic and antitumor activities. The flavonoids not only have an excellent preventive effect on cancer, but also have a certain effect on chronic diseases such as diabetes, cardiovascular and cerebrovascular diseases and liver diseases, etc. Among them, luteolin has anti-angiogenic effects on retinal microvessels, positive effects on inhibiting retinopathy in premature infants, and anti-inflammatory activity. With its ability to inhibit the oxidation of low-density lipoprotein, flavonoids exhibit unique cardioprotective effects and have a certain role in the prevention of cardiovascular diseases (; ; ; Park et al., 2012; ; ; ; ; Wan et al., 2019; ). The main metabolite types are shown in Table 3; The metabolites structures are shown in Figure 3.
TABLE 3
| No. | Compound Name | Formula | Ref. |
|---|---|---|---|
| 62 | quercetin | (Zhang et al., 2012) | |
| 63 | isoquercetin | (Wang et al., 2016) | |
| 64 | rutin | (Zhang et al., 2012) | |
| 65 | naroside | (Wang et al., 2016) | |
| 66 | luteolin | () | |
| 67 | tricine | ———— | (Wang et al., 2016) |
| 68 | baicalein | (Wang et al., 2016) | |
| 69 | 9-α-Hydroxy terpineol | ———— | () |
| 70 | quercetin 3-O-α-L-arabinopyranoside | ———— | () |
| 71 | quercetin-7-O-β-D-glucopyranoside | () | |
| 72 | quercetin 3-O-β-D-glucopyranoside | ———— | () |
| 73 | chrysanthemulin | () | |
| 74 | 3-methoxycarvacrol | ———— | () |
| 75 | luteolin-7-O-neohesperidin | () | |
| 76 | luteolin-7-galactoside | ———— | () |
| 77 | nivolumab-6-O-neohesperidin | ———— | () |
| 78 | syringin | () | |
| 79 | rhoifolin | () | |
| 80 | apigenin | (Zhang et al., 2009) | |
| 81 | luteolin-7-O- β- D-glucopyranoside | (Zhang et al., 2009) | |
| 82 | isorhamnetin-7-O-β-D-glucopyranoside | (Zhang et al., 2009) | |
| 83 | geranylgeranyl-7-O-β- D-glucopyranoside | (Zhang et al., 2009) | |
| 84 | flavonoid lignans hydrocarpin D | ———— | (Zhang et al., 2009) |
| 85 | diosmin | () | |
| 86 | hypodatin | () | |
| 87 | lariciresinol | () | |
| 88 | pear wood flavonoids 7-O-β-D-glucopyranoside | () | |
| 89 | pear wood flavonoids | () | |
| 90 | medicksativa | () | |
| 91 | 5,7,4 '- trihydroxy-8-methoxyflavonoid | ———— | () |
| 92 | naphthol 7-O-β-D-glucopyranoside | () | |
| 93 | apigenin-7-O-β-D-glucopyranoside | () | |
| 94 | diosmetin7-O-β-D-glucopyranoside | () | |
| 95 | diosmetin | () | |
| 96 | alfalfa-7-O-β-D-glucopyranoside | ———— | () |
| 97 | quercetin 3-O-β-D-glucopyranoside | () | |
| 98 | flavonolignan | ———— | (Wang et al., 2016) |
| 99 | eriodictyol | (Wang et al., 2016) | |
| 100 | chrysoeriol | (Wang et al., 2016) | |
| 101 | dioscorea grosvenorii biflavone A | (Wang et al., 2016) | |
| 102 | cypress bisflavonoid | (Wang et al., 2016) |
Flavonoid compound components in Lonicerae Japonicae (Caulis).
FIGURE 3
2.4 Triterpenoids and triterpene saponins
Lonicerae Japonicae Caulis contains many terpene metabolites, including triterpenoids, triterpene saponins, etc. A large number of studies have shown that the terpenoids contained in Lonicerae Japonicae (Caulis) have anti-inflammatory and antitumor activities (; ; ; ). As an essential triterpene saponin, aescin can significantly inhibits lung cancer cell proliferation by downregulating protein kinases such as AKT, mTOR, MEK, and ERK. It also can induce cytotoxic autophagy-mediated cell apoptosis withthe downregulation of AKT mTOR. In addition, aescin downregulates the expression of the HIF-1α and VEGF gene to reduce the migration and invasion ability of cells. Based on this, further research and exploration can be considered on the interaction between aescin and macromolecular compounds with migration ability in the future. In addition, the preclinical DEN-induced lung cancer model successfully monitored the expression of EGFR gene, improved the lung histology, and regulated the biochemical parameters. However, the above findings have not been further validated so far. So it is necessary to conduct the studies in vivo on xenograft or genetic animal models (Singh et al., 2023). Sweroside isolated from Lonicera japonica can regulate the expression of MAP kinase and melanogenesis enzyme, which may be an effective skin-whitening agent, which can be used as raw materials for cosmetics and fragrances (). The specific metabolite information is shown in Table 4, and the main metabolites structures are shown in Figure 4.
TABLE 4
| No. | Compound Name | Formula | Ref. |
|---|---|---|---|
| 103 | loganin | () | |
| 104 | cyclosporin | ———— | (Mehrotra et al., 2004) |
| 105 | sweroside | () | |
| 106 | cyclosporin dimethyl acetal | ———— | () |
| 107 | secologanin | ———— | () |
| 108 | deoxidized loganin | (Wang et al., 2016) | |
| 109 | strychnoside semialdolactone | (Wang et al., 2016) | |
| 110 | secologanin | (Wang et al., 2016) | |
| 111 | sanguisorba saponin II | (Wang et al., 2016) | |
| 112 | pine resin phenol 4-O-β-D-glucopyranoside | ———— | (Wang et al., 2016) |
| 113 | 2-methoxyhydroquin-4-O-β-D-glucoside | ———— | () |
Triterpenoids and triterpene saponins in Lonicerae Japonicae (Caulis).
FIGURE 4
2.5 Other metabolites
The chemical metabolites of Lonicerae Japonicae Caulis are complex, diverse, and have multiple effects. In addition to the four main chemical substances mentioned above, it includes numerous other metabolites. Chen Ling et al. isolated inositol, uracil nucleoside, 2-methoxyhydroquinone 4-O- β- D-glucoside, and (+) turpentin-4-O- β- D-glucoside from Lonicera japonica vine (). Expect the above active metabolites, Lonicerae Japonicae (Caulis) also contains some amino acids, such as Alanine (Ala), Serine (Ser), Proline (Pro), Valine (Val), Threonine (Thr), Isoleucine (Lle), Leucine (Leu), Aspartic acid (Asn), Glutamic acid (Gln), Lysine (Lys), Histidine (His), Phenylalanine (Phe), and Arginine (Arg), as well as trace elements such as Iron (Fe), Magnesium (Mg), Copper (Cu), Chromium (Cr), Manganese (Mn), Zinc (Zn), Nickel (Ni), Arsenic (Se), Molybdenum (Mu), Selenium (Xi), Cadmium (Cd), Mercury (Hg) and Lead (Pb) (Yu et al., 2013; Zhao et al., 2018; ). In addition, it contains four nucleosides, Cytidine, Uridine, Adenosine, and Inosine. The specific composition information is shown in Table 5, and the main metabolites structures are shown in Figure 5.
TABLE 5
| No. | Compound Name | Formula | Ref. |
|---|---|---|---|
| 114 | honeysuckle alcohol | (Zhao et al., 2007) | |
| 115 | esculetin | (Zhang et al., 2009) | |
| 116 | glucose | () | |
| 117 | N-29 alcohol | () | |
| 118 | inositol | () | |
| 119 | β-Sitosterol | (Wang et al., 2016) | |
| 120 | β-Sitosterol glucoside | () | |
| 121 | daucosterol | () | |
| 122 | (22E, 24R)ergoste-7,22-diene-3 β, 5 α, 6 β- Triol | ———— | () |
| 123 | camptothecin alkaloid | () | |
| 124 | scopolamine | () |
The other active ingredients in Lonicerae Japonicae (Caulis).
FIGURE 5
3 Pharmacological action and mechanism of Lonicerae Japonicae Caulis
The crude extract and the monomer metabolites contained in Lonicerae Japonicae Caulis have pharmacological effects such as the inhibition of pathogenic microorganisms, anti-rheumatism, anti-inflammatory, bone and soft tissue repair, antitumor, anti-oxidation, anti-allergic reaction, and immune regulation function.
3.1 Anti-pathogenic microbial effect
The main bacteriostatic active metabolites in Lonicerae Japonicae Caulis are chlorogenic acid and flavonoids, and the bacteriostatic effect of flavonoids is more significant than that of chlorogenic acid (Xiong et al., 2013; Yang et al., 2016; ; Yan et al., 2020). Lonicerae Japonicae Flos is superior to Lonicerae Japonicae Caulis in the prevention and treatment of respiratory diseases, and Lonicerae Japonicae Caulis is better than Lonicerae Japonicae Flos in the treatment of infectious hepatitis and infectious mumps (Zhao et al., 2016). 214 cases of chronic hepatitis B patients were collected, and the dialectical treatment with Lonicerae Japonicae Caulis powder was carried. The results showed that the level of endothelin (ET) in the treated patients decreased significantly, confirmed that Lonicerae Japonicae Caulis had the effect of repairing endothelial cells and had a specific effect on the chronic hepatitis B cases caused by hepatitis B virus (Zhou and Yu, 2002). Luo Mingjing found that Lonicerae Japonicae Caulis injection could reduce the expression level of α-hemolysin and its related regulatory genes, reduce the secretion of α-hemolysin, reduce the damage of Staphylococcus aureus to lung epithelial cells and reduce the fatality rate of Staphylococcus aureus pneumonia, suggesting that Lonicerae Japonicae Caulis injection has an inhibitory effect on Staphylococcus aureus (Figure 6) (). This experiment analyzed the secretion of α-hemolysin and the mechanism of Lonicerae Japonicae Caulis’s anti-staphylococcus aureus pneumonia effect from the perspective of virulence factors. It laid the foundation for further exploring the complex mechanism of action of Lonicerae Japonicae Caulis in staphylococcus aureus pneumonia. Although the research has shown that Lonicera japonica injection has a significant therapeutic effect on pneumonia caused by staphylococcus aureus, relevant data has not yet been obtained in the clinical practice, and further research results on the clinical application need to be followed up. Zuo Huifen et al. compared the specific effects of Lonicerae Japonicae Caulis, Plum and Lonicerae Japonicae Flos on Steurophila maltophila by Mueller-Hinton Agar dilution method, and the results showed that they all had different degrees of bacteriostatic effects on this bacterium (Zuo et al., 2020). The specific antibacterial metabolites of the three traditional Chinese medicines against Stenotrophomonas maltohilia have not been identified here. This can be considered as the next research content. Chen Weiyan prepared the four kinds of extracts from the traditional Chinese Medicine of Hemibranch, Mutong, Lonicerae Japonicae Caulis and Forsythia by microwave, and analyzed their inhibitory effects on Citrus anthracnose, Cotton wilt and Wheat Total Eclipsing Bacteria (). The results showed that Lonicerae Japonicae Caulis had a strong bacteriostatic effect under the extraction of ethanol, acetone and ethyl acetate, and the bacteriostatic effect could reach 100% under the condition of acetone solvent, which confirmed the excellent effect of Lonicerae Japonicae Caulis in inhibiting pathogenic microorganisms. Some studies have shown that Lonicerae Japonicae can significantly promotes the colonization of beneficial bacteria and inhibits the reproduction of harmful bacteria (Wang et al., 2014; ). The defense mechanisms against bacteria, such as the activation of neutrophils, lymphocytes and complement systems, require further research.
FIGURE 6
3.2 Anti-inflammatory effect
Inflammation refers to a normal protective response when the body is damaged and infected. In the research and response of traditional Chinese Medicine, Lonicerae Japonicae (Caulis) is often combined with other traditional Chinese Medicines to treat inflammation and has significant anti-inflammatory effects in vivo and in vitro (; ; Zhou et al., 2021). Gout is an inflammatory joint disease, and studies have found that the use of fire-needle therapy for bloodletting and the oral Lonicerae Japonicae Caulis soup for the treatment of gout patients can improve the level of inflammatory factors, promote inflammatory absorption, and relieve pain (Zhao and Chen, 2019). Another study found that using Lonicerae Japonicae Caulis granules to intervene in gouty arthritis rats, the results showed that the blood uric acid (BUA) level, liver xanthine oxidase (XO) activity, interleukin-1β (IL-1β), matrix metallo proteinase-3 (MMP-3), lipoprotein phospholipase A2 (LP-PLA2) and tumor necrosis factor-α (TNF-α) levels in gouty arthritis rats were significantly reduced, confirming that Lonicerae Japonicae Caulis has anti-inflammatory and analgesic effects (Wang, 2016). The specific action mechanism is shown in Figure 7. For the sake of comparability of experimental data, male rats were used in this study. Considering the gender differences in clinical practice, this study lacks a certain degree of objectivity. Although the mechanism in treating gout is becoming clear increasingly, due to the complex metabolites contained in traditional Chinese medicine. It is difficult to observe a single variable and locate precise targets. Therefore, further exploration is needed for the deeper mechanism study. Lonicerae Japonicae Caulis decoction was used to treat patients with humid heat and the connotation of uric acid nephropathy. The observation symptoms showed that the symptoms of joint burning pain and lower limb edema were significantly reduced. Renal function was improved, and blood uric acid and blood β2 microglobulins were significantly reduced, indicating that Lonicerae Japonicae Caulis has anti-inflammatory activity and a specific effect on the humid heat connotation of uric acid nephropathy (). Chen Hening et al. used the water-extracted of Astragalus, Angelica and Lonicerae Japonicae Caulis freeze-dried powderon the rat synovial cells, observed and monitored the morphological changes and apoptosis rate of synovial cells, as well as the expression levels of criticalproteins in NF-κB and JAK/STAT pathways. The results showed that the extract might increase the apoptosis rate of synovial cells by inhibiting NF-κB and JAK/STAT signaling pathways, in the end ultimately inhibit the synovial cell proliferation and alleviate the inflammatory symptoms (). The water decoction of Astragalus, Angelica and Lonicerae Japonicae Caulis dry powder were prepared respectively to intervene in inflammatory injury model rats by Meng Xiaoying. The results showed that the content of T-cells increased, the mobility decreased and the chemokine-2 (CCL2) increased. The mechanism was related to the inhibition of synovial cell inflammatory proliferation in rats, which positively affected the prevention and treatment of rheumatoid arthritis (). Lan Huangqi et al. used Litsea pungens Hemsl and Lonicerae Japonicae Caulis extracts on asthma model mice and found that its mechanism of action was reducing the levels of IgE, IL-4, IL-5, and IL-10 contained in the serum, increase the level of IFN-γ, and weaken the expression of GATA-3 protein, confirming that Lonicerae Japonicae Caulis can be used to improve airdoritis in the asthmatic mice (). Dou Yuyu et al. used Litsea pungens Hemsl and Lonicerae Japonicae Caulis in asthma model mice based on the experimental research of Lan huangqi, and found that the drug could reduce the levels of IGF-β1, IL-4, IL-13, VEGF, PDGF and the expression levels of related proteins Cyclin D1 and ERK1/2, thereby inhibiting the proliferation of airway smooth muscle cells and achieving anti-inflammatory effects (). Another study has shown that Lonicera japonica can exert anti-inflammatory effects on the LPS-induced lung inflammation, improve lung morphology, and reduce pulmonary edema. Lonicerae Japonicae Caulis increases the nuclear Sp1 binding activity through incremental phosphorylation of ERK, thereby enhancing IL-10 expression. Simultaneously, it can reduce nuclear NF-κB binding activity by suppressing the phosphorylation of IκB, p38, and JNK, thereby inhibiting the expression of TNF-α, IL-1β and IL-6 in the lungs (). The above studies have shown that Lonicerae Japonicae Caulis can play a good role in treating inflammatory diseases. However, further research is needed to confirm the specific effects of natural metabolites contained in Lonicerae Japonicae Caulis on macrophages under in vitro conditions.
FIGURE 7
3.3 Repair bone and soft tissue
Modern research has shown that Lonicerae Japonicae Caulis has a definite role in the repairing of the bone and soft tissue. Jia Haiyan found that Lonicerae Japonicae Caulis had a significant effect on the content of calcium and alkaline phosphatase in the serum of fractured rabbits, and had a positive effect on the repair of fractures (). The specific mechanism of action is shown in Figure 8. Huang Xin used a self-formulated prescription including Rhubarb (30 g), Bitter ginseng (30 g), Lonicerae Japonicae Caulis (30 g), and Bai Zhi (20 g) to treat soft tissue sprain patients (), and the results showed that the total effective rate was as high as 97% in 200 patients, which proved that Lonicerae Japonicae Caulis had a good effect on dissipating local bruising and repairing soft tissues. In addition, Lonicerae Japonicae Caulis is effective in treating chronic osteomyelitis (COM). In summary, Lonicerae Japonicae Caulis positively can positively indeed promote the repair of bone and soft tissue.
FIGURE 8
3.4 Antitumor effect
The flavonoids and saponins in Lonicerae Japonicae Caulis also have certain antitumor pharmacological effects. Shan Yu et al. found that macranthoside B (MB), a saponin metabolite, could block the proliferation of human ovarian cancer A2780 cells and induce apoptosis and autophagy (). Yan Baofei et al. found that Lonicerae Japonicae Caulis could achieve the purpose of apoptosis of human osteosarcoma cells (HOS) through mitochondrial apoptosis (Yan et al., 2021). Lonicerae Japonicae Caulis extract can reduce the mitochondrial membrane potential and Bcl-2 protein expression levels of HOS, and increase the expression level of Bax and cleaved Caspase-9 protein, thereby inhibiting the survival rate of HOS and 143B cells. The specific mechanism were shown in Figure 9. This study conduct a comprehensive and rapid qualitative analysis of the chemical metabolites of Lonicerae Japonicae Caulis based on UPLC-Q-TOF/MS. In the later study, it can be considered to start further elucidating the anti-tumor mechanism of Lonicerae Japonicae Caulis with the interaction between specific metabolites. There are also studies using the rough alcohol extraction of Lonicerae Japonicae Caulis extraction to carry out tumor suppression experiments in vivo and tumor-killing experiments in vitro. Its tumor inhibition rate is 30% higher, which confirms the antitumor effect of Lonicerae Japonicae Caulis (). Chen Ling et al. used the Lonicerae Japonicae Caulis extract on the colon cancer cells. Some Researchers detected the proliferation of colon cancer cells after medication and tested the change of mitochondrial membrane potential of cancer cells. Besides, the expression level of cell-related proteins was measured. Some researchers detected the effects of Lonicerae Japonicae Caulis extract and a kind of p53 inhibitor (PFT-α) on the apoptosis of cancer cells. The results showed that Lonicerae Japonicae Caulis extract could induce apoptosis in p53-dependent mitochondria and had the anti-colon cancer effects (). Researchers isolated and identified four flavonoids from Lonicerae Japonicae, all of which exhibited anti-liver cancer activity in vitro experiments and had a protective effect on the liver. At present, in the clinical treatment of liver cancer, the common chemotherapy drugs doxorubicin (Dox), lipiodol, and cisplatin all have serious adverse reactions (). The protective effects of flavonoids from the flowers, leaves, and stems of Lonicera japonica on liver cancer may indicate the potentiality of Lonicerae Japonicae Caulis as being a health food resource during chemotherapy for liver cancer.
FIGURE 9
3.5 Antioxidant effect
The antioxidant effect is one of the important biological activities of Lonicerae Japonicae (Caulis) (; ; Wan et al., 2019; Zhang et al., 2020). found that Lonicerae Japonicae Caulis had antioxidant activity in vivo and in vitro. Its antioxidant activity is closely related to the polyphenols and polysaccharides rich in Lonicerae Japonicae, including various phenolic acids and flavonoid metabolites (; ). Xiang Jiqian et al. used 3 micro-models of 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) and ferric reducing antioxidant power (FRAP) as indicators to detect the effects of different flavonoid extraction processes on the extraction of total flavonoids in Lonicerae Japonicae Caulis and their antioxidant effect in vitro (Xiang et al., 2017). The results showed that total flavonoids of Lonicerae Japonicae Caulis had high antioxidant capacity in vitro. Chlorogenic acid (CGA) and caffeic acid (CA), which belong to phenolic acids, have significant antioxidant activity in vitro and in vivo and are potent antioxidants (Wang et al., 2009; ; ). Chen Liangmian et al. used DPPH, ABTS and FRAP to determine that Lonicerae Japonicae Caulis, Lonicerae Japonicae Flos and Folium Lonicerae all had different degrees of antioxidant effects (). In addition, the anthocyanins rich in Lonicerae Japonicae Caulis have significant anti-inflammatory and antioxidant activities. Denis Golubev et al. studied the antioxidant and anti-aging activities of Lonicerae Japonicae extract with the model of drosophila melanogaster. The results showed that for male and female fruit flies, supplementation with 100 uM concentration of Lonicerae Japonicae extract (LE) and anthocyanins could better improve the life span of fruit flies ().
3.6 Immunomodulatory effect
Lonicerae Japonicae Caulis also has a regulatory effect on the body’s immune function. Meng Xiaoying used Lonicerae Japonicae Caulis, Astragalus and Angelica to regulate the T-cell immune system, thereby inhibiting the expression of CCL2 and further reducing the inflammatory response of the rat synovial cells (). Lan Huangqi et al. applied the ethanol extract of Litsea pungens Hemsl and Lonicerae Japonicae Caulis to treat the asthma model mice. It was found that the levels of IgE, IL-4, IL-5, and IL-10 in mice were significantly reduced, while IFN- γ level significantly increased and the expression level of GATA-3 protein was also improved. The above results suggest that Lonicerae Japonicae Caulis has a regulatory effect on the immune function in the body. But there is currently no specific explanation for its upstream mechanism of regulating GATA-3 expression (). In addition, the flavonoid substances in Lonicerae Japonicae Flos can enhance immunity by removing superoxide ion free radicals in the body (Yang et al., 2017). Lonicerae Japonicae Caulis is widely used in clinical applications. Lonicerae Japonicae Caulis decoction affects immune infertility caused by anti-sperm antibody (AsAb) positive (). And Lonicerae Japonicae Caulis can be combined with Caulis spatholobi to treat the autoimmune diseases, such as systemic lupus erythematosus, allergic purpura, and thrombocytopenic purpura, etc. Besides, it has achieved good clinical efficacy, and the addition of Lonicerae Japonicae Caulis to broiler feed can improve the conversion rate of broiler feed, increase the phagocytosis of broiler thymus, spleen index, and macrophages (Wu et al., 2007; Sun et al., 2010). It is also suggested that Lonicerae Japonicae Caulis can enhance the immune function of the animal body.
4 Summary and research prospect
Lonicerae Japonicae Caulis has the effect of clearing away heat, toxic material, dredging wind and unblocking collaterals in the theory of traditional Chinese Medicine. It is mainly used clinically for the prevention and treatment of warm fever. Its various traditional uses have now been confirmed by modern pharmacology, and its various active metabolites have been confirmed by some researches. Due to the abundant content and pharmacological effects of the active metabolite CGA, it has been used as a marker to characterize the chemical properties of Lonicerae Japonicae Caulis, and Lonicerae Japonicae Flos. Still, CGA is not specific, and further research is needed to determine whether the quality of the drug is entirely appropriate when used to determine whether the quality is entirely appropriate.
It is precisely because of the various pharmacological activities of Lonicerae Japonicae Caulis that it plays an increasingly important role in treating various a variety of diseases. At the same time, because Lonicerae Japonicae Caulis belongs to the homologous resources of medicine and food, and it has the characteristics of medicine and food. It has natural advantages in safety and tonics, so the public loves it. In addition, the research and exploration of the pharmacological activity of Lonicerae Japonicae Caulis can also help develop and prepare new drugs from Lonicerae Japonicae Caulis. In recent years, many studies have been on the chemical metabolites and pharmacological activities of Lonicerae Japonicae Caulis. However, it is unclear whether there are interactions between the various chemical metabolites. In addition, the impact of environmental factors on the types and contents of chemical metabolites that Lonicerae Japonicae Caulis contains is currently not fully understood. The differences in the effect mechanisms of various single metabolites and metabolites groups on the various diseases have not been fully explored and studied. It is possible to explore the pharmacological effects of classic prescriptions. Although many studies have confirmed the various pharmacological activities of Lonicera japonica vine, there is still a lack of research on its clinical application. Therefore, in future research and exploration, the scope of material foundation research and the depth of pharmacological activity research should be expanded, and clinical practice research should be emphasized.
In summary, the active metabolites contained in Lonicerae Japonicae Caulis are complex, the pharmacological effects are diverse. It has a positive effect in the prevention and treatment of respiratory diseases, cancer, cardiovascular and cerebrovascular diseases, liver diseases, etc., which confirms that the potential application value of Lonicerae Japonicae Caulis is outstanding, which is worthy of follow-up in-depth research.
Statements
Author contributions
Y-XC: Writing–original draft. PJ: Writing–review and editing. F-LW: Supervision, Writing–review and editing. J-QD: Supervision, Writing–review and editing. C-CL: Supervision, Writing–review and editing. TM: Supervision, Writing–review and editing. H-CY: Supervision, Writing–review and editing. Y-MW: Project administration, Writing–review and editing. Y-LH: Project administration, Writing–review and editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Key R&D Projects of Ningxia Science and Technology Department (2023BCF01039), the National Nature Science Foundation of China (No. 32260899, U21A20262), A University-level Fuxi Talent Project (No. Gaufx-02Y05), China's Modern Agricultural Industrial Technology System (No. CARS-37), the Lanzhou Talent Innovation and Entrepreneurship Project (No. 2021-RC-57).
Acknowledgments
The authors would like to express our gratitude and appreciation to those who helped with this study at the College of Veterinary Medicine, Gansu Agricultural University, and appreciation to the experimental platform provided by Gansu Agricultural University.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
AsAb, Anti-sperm Antibody; BUA, Blood Uric Acid; CCL2, Chemokine-2; COM, Chronic osteomyelitis; CA, Caffeic Acid; CGA, Chlorogenic Acid; ET, Endothelin; HOS, Human osteosarcoma cell; IL-1β, Interleukin-1β; LE, Lonicerae Japonicae Caulis extract; LP-PLA2, Lipoprotein Phospholipase A2; LPS, Limpopolysaccharide; MMP-3, Matrix Metalloproteinase-3; MB, Macranthoside B; TNF-α, Tumor Necrosis Factor-α; XO, Xanthine oxidase.
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Summary
Keywords
Lonicerae Japonicae Caulis, active metabolites, pharmacological effects, mechanism of action, research progress
Citation
Cao Y-X, Ji P, Wu F-L, Dong J-Q, Li C-C, Ma T, Yang H-C, Wei Y-M and Hua Y-L (2023) Lonicerae Japonicae Caulis: a review of its research progress of active metabolites and pharmacological effects. Front. Pharmacol. 14:1277283. doi: 10.3389/fphar.2023.1277283
Received
14 August 2023
Accepted
10 October 2023
Published
25 October 2023
Volume
14 - 2023
Edited by
Yi Wu, Nanjing Agricultural University, China
Updates
Copyright
© 2023 Cao, Ji, Wu, Dong, Li, Ma, Yang, Wei and Hua.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Peng Ji, jip@gsau.edu.cn; Yan-Ming Wei, weiym@gsau.edu.cn
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