A systematic review on the chemical constituents of the genus consolida (ranunculaceae) and their biological activities.
* Corresponding authors
a Zhuhai Key Laboratory of Fundamental and Applied Research in Traditional Chinese Medicine, Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, China
b Functional Molecules Analysis and Biotransformation Key Laboratory of Universities in Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China E-mail: [email protected] , [email protected]
For centuries, species of the genus Consolida (Ranunculaceae) have been extensively utilized for their extremely high ornamental and medicinal values. Phytochemical investigations of Consolida species have revealed the presence of multiple active ingredients, including diterpenoid alkaloids, flavonoids, phenolic acids, phytosterols, fatty acids, and volatile constituents. These chemical constituents are of great research significance due to their novel structures and broad biological activities. This review addresses, for the first time, the chemical constituents of Consolida plants and the biological activities of these compounds to facilitate future research.
- This article is part of the themed collection: 2020 Reviews in RSC Advances
T. Yin, L. Cai and Z. Ding, RSC Adv. , 2020, 10 , 35072 DOI: 10.1039/D0RA06811J
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Research Progress on Chemical Constituents of Zingiber officinale Roscoe
1 School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
2 School of Chemical and Chemical Engineering, Shandong University of Technology, Zibo 255049, China
Zingiber officinale Roscoe is commonly used in food and pharmaceutical products but can also be used in cosmetics and daily necessities. In recent years, many scholars have studied the chemical composition of Zingiber officinale Roscoe; therefore, it is necessary to comprehensively summarize the chemical composition of Zingiber officinale Roscoe in one article. The purpose of this paper is to provide a comprehensive review of the chemical constituents of Zingiber officinale Roscoe. The results show that Zingiber officinale Roscoe contains 194 types of volatile oils, 85 types of gingerol, and 28 types of diarylheptanoid compounds, which can lay a foundation for further applications of Zingiber officinale Roscoe.
Zingiber officinale Roscoe (ZOR, also Shengjiang in Chinese) is a perennial herb from the Zingiberaceae family, native to the Pacific Islands. It can be found in the Chinese provinces of Shandong, Henan, Hubei, Yunnan, Guangdong, Sichuan, and Jiangsu. ZOR is the fresh root of ginger, which is not only an important condiment but also one of the most commonly used Chinese medicines in clinical practice. Traditional Chinese medicine believes that ZOR has effects of releasing exterior and dissipating cold, arresting vomiting, resolving phlegm, and relieving coughs and can be used to treat fish and crab poison, stomach colds and vomiting, and cold sputum cough [ 1 ]. Modern pharmacological studies have shown that ZOR can promote digestion, improve blood circulation, lower blood lipids, lower blood sugar, relieve vestibular stimulation, and provide anti-inflammatory, antitumor, antimicrobial, and antioxidant effects [ 2 – 5 ]. Due to its rich active constituents, ZOR has been used in cosmetics [ 6 ], toothpaste [ 7 ], and health foods [ 8 – 10 ].
All development and utilization of ZOR are based on its material composition. The chemical composition of ZOR is complex, includes more than 300 types of species, and can be broadly divided into three categories: volatile oils, gingerol, and diarylheptanoids [ 11 – 13 ]. In this paper, the existing research literature of ZOR is systematically summarized, and each chemical composition and its chemical structure are listed in detail, with a view to providing references for quality control, cultivation production, and further development of ZOR.
2.1. volatile oils.
Volatile oils, also known as ginger essential oils, are generally composed of terpenoids [ 14 ]. Ginger essential oils give ZOR a unique aromatic smell [ 11 ]. The volatile oil composition varies based on where the ZOR is harvested. Currently, the ingredients identified in the volatile oils of ZOR and their chemical structures are shown in Table 1 .
Volatile oils in ZOR.
Gingerol is the spicy component of ZOR. It is a mixture of various substances, all of which contain the 3-methoxy-4-hydroxyphenyl functional group. Gingerols can be divided into gingerols, shogaols, paradols, zingerones, gingerdiones, and gingerdiols, according to the different fatty chains connected by this functional group [ 28 , 29 ]. The structural formulas are given in Table 2 .
Gingerols in ZOR.
Diarylheptanoid is a group of compounds with 1,7-disubstituted phenyl groups and heptane skeletons in its parent structure. Currently, it can be divided into linear diphenyl heptane and cyclic diphenyl heptane compounds with antioxidant activity [ 53 ]. The structural formulas are shown in Table 3 .
Diarylheptanoids in ZOR.
2.4.1. proteins and amino acids.
ZOR contains a variety of amino acids, including glutamate, aspartic acid, serine, glycine, threonine, alanine, cystine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine, arginine, proline [ 22 , 60 ], and tryptophan [ 51 ].
ZOR also contains polysaccharides [ 44 ], cellulose, and soluble sugar.
2.4.3. Organic Acids
ZOR contains oxalic acid, tartaric acid, lactic acid, acetic acid, citric acid, succinic acid, formic acid, and malonic acid [ 61 ].
2.4.4. Inorganic Elements
ZOR has been shown to contain more than 20 inorganic elements such as K, Mg, Ga, Mn, P, Al, Zn, Fe, and Ba [ 44 ].
Various gingers have different regions and chemical compositions. Jolad [ 30 ] conducted quantitative analysis on the extracts of dichloromethane from Chinese white ginger and Japanese turmeric and found that the highest content of 6-gingerol was 28% and 34%, respectively. The next highest concentrations were 8-gingerol and 10-gingerol, and the lowest content of 6-shogaol was only 0.35%. Onyenekwe [ 62 ] determined that the main components of the volatile oils of Nigerian ginger were terpenoids such as zingiberene (29.5%) and β- sesquiphellandrene (18.4%), which were quite different from those of ginger grown in other regions. Another study showed the volatile oil content of ginger grown in five different areas of China (Shandong Laiwu, Anhui Tongling, Shandong Anqiu, Guangdong Guangzhou, and Hunan Rucheng) was 0.13%, 0.23%, 0.30%, 0.14%, and 0.17% [ 63 ], respectively. 6-Gingerol is often the quality standard for ginger, where the ginger found in Qianwei, Sichuan Province, shows a higher effective content of 6-gingerol than that of the pharmacopoeia standard of the People's Republic of China [ 64 , 65 ]. The concentrations of 6-gingerol and 6-zingiberol of ginger grown in different regions of China vary greatly, which may be related to the growth environment [ 66 ]. Mature and fresh ginger extracts contain the same chemical components, but the difference is in the relative content of each component. Ginger oleoresin in mature ginger is significantly higher than that in fresh ginger. In aromatic terpenoids, the contents of 2-acetoxy-1,8-cineole, β- citronellal, citral, geraniol, geranyl acetate, and zingiberene in mature ginger are lower than those in fresh ginger. The relative content of α -curcumene in mature ginger was higher than that in fresh ginger. In spicy gingerol compounds, the relative content of gingerol in mature ginger is higher than that in fresh ginger, which may be the result of further synthesis and accumulation of gingerol components in the process of continued growth of mature ginger in the second year [ 48 ]. The varieties of ginger with the highest oil content are Laiwu ginger, Japanese ginger, Shannong 1 ginger, Shannong 2 ginger, and Anqiu big ginger, with concentrations of 4.56%, 4.42%, 4.52%, 4.50%, and 4.35%, respectively. Average oil contents of 3.45% and 3.16% were found in Jinchang ginger and Chinger, respectively. The lowest oil extraction rates were found in Anqiu small ginger, Fangzhou ginger, and Jinshi ginger, which were 2.95%, 2.60%, and 1.55%, respectively [ 48 ].
Ginger, as a kind of food and medicine, has many functions, such as antioxidant, anti-inflammatory, antimicrobial, anticancer, antiobesity, antidiabetic, antinausea, antiemetic, antiallergic, neuroprotective, hepatoprotective, cardiovascular protective, and respiratory protective activities [ 67 ]. Currently, most studies of the bioactive components of ginger focus on ginger volatile oil, gingerol, shogaol, and zingerone compounds. Ginger essential oil can effectively improve the antioxidant capacity of the liver, reduce inflammatory response, and protect against fatty liver [ 68 ]. The antioxidant compounds in ginger are primarily gingerol and diarylheptanoid. Substituents on alkyl chains contribute to free radical scavenging and oxidation inhibition of lipids [ 69 ]. Antioxidant activity is typically derived from gingerols, shogaols, and some related phenolic ketone derivatives [ 70 ]. Gingerols are spicy ingredients in which 6-gingerol shows the highest biological activity, so 6-gingerol is often used as an indicator of ginger quality [ 71 ]. 6-Gingerol has been used to inhibit angiogenesis in vivo and in vitro [ 72 ]. It has been shown to have anticancer and antigastric ulcer properties while suppressing central nervous stimulation and various pharmacological activities [ 73 , 74 ]. 6-Gingerol has been used to treat tumors by regulating the apoptosis gene by reversing the abnormal expression of tumor cell genes. It can also affect the apoptosis signal transduction pathway and induce apoptosis [ 75 ]. 8-Gingerol and 10-gingerol have good inhibitory effects on the activity of various tumor cells, where the inhibitory effects are somewhat different. The two may affect the phosphorylation level of the MAPK pathway proteins ERK and P38, leading to G1 phase arrest of breast cancer cells, thus applying inhibitory effects on the proliferation of tumor cells [ 76 ]. The main components of strong heart are gingerol and 6-shogaol [ 77 ]. The effects of 6-gingerol and 6-shogaol on blood pressure have been shown to induce a hypotensive effect at low doses, while high doses have shown a three-phase reaction. Initially, blood pressure drops rapidly, then rises, and then provides a hypotensive effect at later stages [ 78 ]. Ginger polysaccharide has biological activities such as antitumor, hypoglycemic, lipid-lowering, immune regulation, antivirus, and antifatigue [ 79 ].
ZOR is a widely used drug and food in clinical and daily life and has been used in the prevention and treatment of the digestive, circulatory, respiratory, and central nervous system diseases and other diseases. In this paper, the chemical constituents found in ZOR in recent years are summarized, and the results show that more than 300 chemical constituents are identified from the extracts of ZOR, including 194 types of volatile oil, 85 types of gingerol, and 28 types of diarylheptanoids compounds. From this, it can be clearly observed that ZOR has a complex chemical composition. The interactions between the components provide the clinical effects; therefore, it is necessary to further study the chemical composition and pharmacological action of ginger, for further applications. Exploring the mechanism by which different components perform the same effects is a new way to develop drugs in the future; for example, 4-terpineol and beta-sitosterol can act on the two targets of the 5-hydroxytryptamine receptor 3A and the mu-type opioid receptor, respectively, and provide corresponding therapeutic effects on diarrhea and dysentery. This can provide ideas for the research and development of new drugs and lay a foundation for further applications of ZOR.
This work was financially supported by the Key Research and Development Technology of Shandong Province (Industry Key Technology) (2016CYJS08A01).
Conflicts of Interest
The authors declare that they have no conflicts of interest.
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A study of the chemical composition and antioxidant properties of products of wild berries processing
L Nilova 1 , S Malyutenkova 1 and R Ikramov 1
Published under licence by IOP Publishing Ltd IOP Conference Series: Earth and Environmental Science , Volume 337 , Efficient waste treatment - 2018 13–14 December 2018, Congress Center of Peter the Great, St. Petersburg Polytechnic University Citation L Nilova et al 2019 IOP Conf. Ser.: Earth Environ. Sci. 337 012025 DOI 10.1088/1755-1315/337/1/012025
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1 Institute of Industrial Management, Economics and Trade, Peter the Great St. Petersburg Polytechnic University, 195251, Saint-Petersburg, Russia
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The article presents the results of studies of the chemical composition and composition of individual antioxidants of bilberries and lingonberries and their marc, which are waste products after squeezing the juice from the berries. The yield of juice from berries averaged 64%. Dry substances, acidity, composition of sugars, pectin substances and individual antioxidants - total phenolic compounds, total flavonoids, total anthocyanins were determined in berries and in the marc. During squeezing of the juice, a redistribution of chemical components was occurred with a predominance of total phenolic compounds, total flavonoids and total anthocyanins in the marc. As a result, the marc showed higher antioxidant properties than juices, which were investigated using the DPPH and FRAP methods. The antioxidant properties of the marc are due to the transition in them of anthocyanins, which make up 64% and 59%, respectively, of their total amount in bilberries and lingonberries. The correlation between DPPH and FRAP tests for anthocyanins was more than 0.952.
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Advances in Research on Chemical Constituents and Their Biological Activities of the Genus Actinidia
- Open access
- Published: 30 September 2021
- volume 11 , pages 573–609 ( 2021 )
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- Jin-Tao Ma 1 ,
- Da-Wei Li 2 ,
- Ji-Kai Liu 1 &
- Juan He 1
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Kiwi, a fruit from plants of the genus Actinidia , is one of the famous fruits with thousand years of edible history. In the past twenty years, a great deal of research has been done on the chemical constituents of the Actinidia species. A large number of secondary metabolites including triterpenoids, flavonoids, phenols, etc. have been identified from differents parts of Actinidia plants, which exhibited significant in vitro and in vivo pharmacological activities including anticancer, anti-inflammatory, neuroprotective, anti-oxidative, anti-bacterial, and anti-diabetic activities. In order to fully understand the chemical components and biological activities of Actinidia plants, and to improve their further research, development and utilization, this review summarizes the compounds extracted from different parts of Actinidia plants since 1959 to 2020, classifies the types of constituents, reports on the pharmacological activities of relative compounds and medicinal potentials.
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With the development of natural product research, a huge number of chemical constituents have been identified from natural resources. There is no doubt that the research on the chemical composition of fruits, including trace elements, has greatly improved the application prospects of these fruits. With no exception, it is the same to kiwifruit, one of the most prestigious fruits with a long history of eating [ 1 , 2 ]. Kiwi belongs to plants of the genus Actinidia comprising more than 70 species around the world [ 3 ]. Some of these plants are proven to have a wide range of medicinal activities. For example, A. valvata , whose root is known as ‘‘Mao-Ren-Shen” in traditional Chinese medicine, exhibits antitumor and anti-inflammatory activities and has been used for the treatment of hepatoma, lung carcinoma and myeloma for a long time [ 4 , 5 ]. The roots of A. chinensis Planch, called “Teng-Li-Gen” usually, were used as a traditional Chinese medicine for the treatment of various cancers, such as esophagus cancer, liver cancer, and gastric cancer [ 6 ]. In the past two decades, great research had been accomplished about exploring the chemical composition of Actinidia plants. These studies have greatly promoted the understanding of the chemical components and functions of the Actinidia plant. According to literature survey, 12 Actinidia species including A. valvata , A. chinensis, A. argute , A. polygama , A. kolomikta , A. eriantha , A. macrosperma , A. deliciosa , A. chrysantha , A. rufa , A. indochinensis , and A. valvata were reported for their natural products. This review systematically summarizes the chemical components and their biological activities from different parts of 12 Actinidia species from 1959 to 2020. According to structure types, a total of 325 molecules have been collected including terpeniods, phenols, and other small groups (Fig. 1 ). Names and isolation information were listed in the tables, while the biological activities of the extracts or compounds were discussed in the text.
Constituents proportion of 12 Actinidia plants
2 Chemical Constituents
In recent years, a large number of terpenoids were isolated from many Actinidia species. Among them, triterpenes account for the vast majority that are mainly composed by several normal frameworks including ursane-type, oleanane-type, and lupane-type. Of the total 325 compounds in this review, 104 are triterpenoids. From the literature review, ursolic acids and their saponins are undoubtedly the most abundant in Actinidia species.
2.1.1 Ursane Triterpenoids
Ursane-type triterpenes are characterized of ursolic acid and its saponins, possessing a 6/6/6/6/6-fused carbon skeleton. A total of 76 ursane-type triterpenoids ( 1 – 76 ) have been identified from plants of the genus Actinidia (Fig. 2 , Table 1 ). Ursolic acid (3 β -Hydroxyurs-12-en-28-oic acid 1) [ 7 ], is one of the most frequently obtained compound in many kinds of kiwifruit plants with unique flavor. Great attention had been paid on biological activities about ursolic acid, attracting much interest in recent years. Ursolic acid exhibits different pharmacological activities, including anti-cancer, amylolytic enzyme inhibitors, cytotoxicity, downregulating thymic stromal lymphopoietin and others [ 7 , 8 , 9 , 10 , 11 ].
Structures of ursane triterpenoids 1 ‒ 76 from Actinidia plants
Compounds 2 ‒ 7 are ursane triterpenoids featuring with two hydroxyl groups. Compound 3 (2 α -Hydroxyursolic acid) was tested for its antiproliferative activity and cytotoxicity in MDA-MB-231 human breast cancer cells through the methylene blue assay. It significantly down-regulated expressions of TRAF2, PCNA, cyclin D1, and CDK4 and up-regulated the expressions of p-ASK1, p-p38, p-p53, and p-21. Furthermore, it induced apoptosis in MDA-MB-231 cell by significantly increasing the Bax/Bcl-2 ratio and inducing the cleaved caspase-3 [ 12 ]. Compound 4 exhibited inhibitory activity on pancreatic lipase with an IC 50 value of 20.42 ± 0.95 μM [ 13 ]. It also showed cytotoxicity to human lung adenocarcinoma (A549), ovarian cancer (SK-OV-3), skin melanoma (SK-MEL-2), and colon cancer (HCT-15) cell lines with IC 50 values ranging from 11.96 to 14.11 μM [ 14 , 15 , 16 , 17 ].
Compounds 7 ‒ 14 are trihydroxy-ursolic acid derivatives. In early 1992, Sashida et al. reported the isolation of 8 ‒ 10 . Compounds 8 and 9 were evaluated for their cytotoxicity against A549 cells, LOVO cells, and HepG2 cells with IC 50 values of 32.9, 31.6, 35.7 μg/mL respectively for 8 and 34.6, 13.9, 34.5 μg/mL respectively for 9 [ 18 , 19 ]. Compounds 17 ‒ 26 are ursolic acids with four or five hydroxy groups. Xu et al. reported 17 from roots of A. valvata , this compound exhibited weak cytotoxicity against A549, LOVO and HepG2 cell lines with IC 50 values of above 100 μg/mL [ 20 ]. 2 α ,3 α ,19 α ,24-Tetrahydroxyurs-12-en-28-oic acid 20 was separated from the leaves of A. valvata which showed cytotoxicity against PLC, Hep3B, HepG2, HeLa, SW480, MCF-7 and Bel7402 in vitro [ 21 ]. A new polyoxygenated triterpenoid (2 β ,3 α ,6 α )-2,3,6,20,23,30-hexahydroxyurs-12-en-28-oic acid 26 was obtained from the roots of A. valvata DUNN, it exhibited moderate cytotoxic activity against BEL-7402 and SMMC-7721 tumor cell lines in vitro [ 22 ].
Compound 30 (3 β -O-acetylursolic acid) was isolated from the fruit galls of A. polygama and the structure was elucidated on the basis of chemical and spectral evidence. It was reported to be a mixed-type protein tyrosine phosphatase 1B (PTP1B) inhibitor with an IC 50 value of 4.8 ± 0.5 μ Μ [ 23 , 24 ]. Isolation of the antiviral active ingredient of A . chinensis root bark gave fupenzic acid 40 , which showed moderate inactivity under the concentration of 100 μg/mL [ 25 ]. Callus tissue from the stems of A. arguta (Actinidiaceae) produced three ursane-type triterpenes including ursolaldehyde 41 , α -amyrin 42 , and uvaol 43 [ 26 ]. Of them, compound 43 showed anti-inflammatory, anticancer, and wound healing activities [ 27 , 28 , 29 ]. Anti-inflammatory properties of 43 on DSS-induced colitis and LPS-stimulated macrophages have been explored detailly and completely. It showed excellent potential of NO production inhibition. It could attenuate disease activity index (DAI), colon shortening, colon injury, and colonic myeloperoxidase activity in DSS-induced colitis mice. What’s more, studies on LPS challenged murine macrophage RAW246.7 cells also revealed that uvaol reduces mRNA expression and production of pro-inflammatory cytokines and mediators. These results indicating that uvaol is a prospective anti-inflammatory agent for colonic inflammation [ 27 ]. Guided by the hepatoprotective activity, the phytochemical study on the roots of A. chinensis led to the isolation of two new compounds 2 α ,3 β -dihydroxyurs-12-en-28,30-olide 46 , 2 α ,3 β ,24-trihydroxyurs-12-en-28,30-olide 47 and 3 β -hydroxyurs-12,18-dien-28-oic acid 50 [ 30 ]. Compounds 52 ‒ 54 showed antifungal activity against C. musae at 3 μg/mL [ 31 ]. A new compound 2 α ,3 α ,23,24 -tetrahydroxyursa-12,20(30)-dien-28-oic acid 55 was isolated from the roots of A. chinensis Planch. It exhibited moderate antitumor activities against five human cancer cell lines (HepG2, A549, MCF-7, SK-OV-3, and HeLa) with IC 50 values of 19.62 ± 0.81, 18.86 ± 1.56, 45.94 ± 3.62, 62.41 ± 2.29, and 28.74 ± 1.07 μM, respectively [ 32 ].
Compounds 59 ‒ 63 are actinidic acid derivatives with a phenylpropanoid unit that were identified as 3-O- trans-p -coumaroylasiatic acid 59 , 23-O- trans-p -coumaroylasiatic acid 60 , actiniargupene E 61 , actiniargupene F 62 , and actiniargupene G 63 from the leaves of A. arguta . All the compounds showed inhibitory effects on α -glucosidase activity. Among them compound 59 showed most potentially inhibitory activity on α -glucosidase with an IC 50 of 81.3 ± 2.7 μM, equal to that of the positive control (acarbose, 72.8 ± 3.1 μM) [ 33 ]. The structure–activity relationship suggested that triterpenoids with a phenylpropanoid moiety exhibited more potent effects than those without such a unit [ 34 ]. Compound 71 showed potent cytotoxic activity against human SKVO3 and TPC-1 cancer cell lines with IC 50 values of 10.99 and 14.34 μM, respectively [ 19 , 35 ]. Compound 74 exhibited moderate cytotoxic activity against BEL-7402 and SMMC-7721 tumor cell lines [ 22 ]. Compounds 75 and 76 were isolated from roots of A. valvata Dunn. They exhibited moderate cytotoxic activity in vitro against BEL-7402 and SMMC-7721 tumor cell line [ 36 ].
2.1.2 Oleanane Triterpenoids
Oleanane-type triterpenoids also possessed a 6/6/6/6/6 pentacyclic carbon skeleton. Unlike ursane triterpenes, oleanane-type triterpenoids have two methyl groups at the C-20 position instead of each one at the C-19 and C-20, respectively. So far, a total of 24 oleanane-type triterpenoids have been identified from Actinidia plants ( 77 ‒ 100 , Fig. 3 , Table 2 ). The most representative compound is oleanolic acid 77 . It was found from callus tissue from the stems of A. arguta , together with 2 α ,3 β -dihydroxyolean-12-en-28-oic acid 78 [ 26 ]. Oleanolic acid 77 is abundant in nature and exhibits a wide range of biological activities including anti-inflammatory [ 54 ], anti-hypertension [ 55 ], anti-tumor [ 56 , 57 ], neuroprotection [ 58 ], and anti-cholesterol activities [ 59 ]. Oleanolic acid was performed to test the effect on apoptosis and autophagy of SMMC-7721 Hepatoma cells. It can significantly inhibit the growth of liver cancer SMMC-7721 cells and induce autophagy and apoptosis [ 57 ]. Compound 78 also showed anti-tumor and anti-inflammatory activities [ 60 , 61 ]. Lim et al. have demonstrated that 78 showed very strong anti-tumor-promoting activity with an IC 50 of 0.1 mg/mL [ 60 ].
Structures of oleanane triterpenoids 77 ‒ 100 from Actinidia plants
Bioassay- and 1 H NMR-guided fractionation of the methanol extract afforded two oleanolic acids of 2 α ,3 β ,23-trihydroxyolean-12-en-28-oic acid 80 and 2 α ,3 α ,24-trihydroxyolean-12-en-28-oic acid 81 , showing antifungal activity against C. musae at 3 μg/mL [ 31 ]. The EtOAc extract of the roots of A. eriantha Benth exhibited potent growth inhibitory activity against SGC7901 cells, CNE2 cells and HUVECs cells. From which, compound 87 (3 β ,23,24-trihydroxyl-12-oleanen-28-oic acid) was identified [ 62 ]. Compound 88 was extracted from the roots bark of A. chinensis , which showed anti-viral activity [ 25 ]. A new triterpenoid 12 α -chloro-2 α ,3 β ,13 β ,23 -tetrahydroxyolean-28-oic acid-13-lactone 89 was extracted from the roots of A. chinensis Planch (Actinidiaceae). It was tested for cytochrome P450 (CYPs) enzyme inhibitory activity in later years, which could significantly inhibit the catalytic activities of CYP3A4 to < 10% of its control activities [ 19 , 52 ].
3 β -(2-Carboxybenzoyloxy) oleanolic acid 93 and spathodic acid-28-O- β - d -glucopyranoside 94 were extracted from the root bark of A. chinensis . The anti-phytoviral activity test indicated that 94 showed potent activity on TMV, and CMV with inactivation effect of 46.67 ± 1.05, and 45.79 ± 2.23 (100 mg/L), compared to ningnanmycin with inactivation effect of 30.15 ± 1.16 and 27.18 ± 1.02 (100 mg/L) respectively [ 25 ]. 3 β ,23-Dihydroxy- -30-norolean-12,20(29)-dien-28-oic acid 98 , 3 β ,23-dihydroxy-1-oxo-30-norolean-12,20(29)-dien-28-oic acid 99 , and 2 α ,3 α ,23,24-tetrahydroxy-30-norolean-12,20(29)-dien-28-oicacid 100 are three one-carbon-degraded oleanane triterpenoids that were identified from A. chinensis Radix for the first time [ 50 ].
2.1.3 Lupane Triterpenoids
Lupane triterpenoids possess a 6/6/6/6/5-fused carbon skeleton. Compared with ursane and oleanane triterpenoids, the number of lupane triterpenoids in the Actinidia plants is much smaller, only four related compounds have been identified ( 101 ‒ 104 , Fig. 4 , Table 3 ). Three of them ( 101 ‒ 103 ) were identified from the rhizomes of A. kolomikta [ 51 ]. Betulinic acid 101 is one of the most representative compound of lupane triterpenes, it has been extensively studied in recent years based on the wide biological activities including anti-inflammatory, antitumor, anti-HIV, anti-diabetic and antimalarial activities [ 68 , 69 , 70 , 71 , 72 , 73 ]. Much attention as a molecular target about protein tyrosine phosphatase 1B had been paid to the treatment of insulin resistance diseases because of its critical roles in negatively regulating insulin- and leptin-signaling cascades. Betulinic acid showed significant PTP1B inhibitory activity, with IC 50 values of 3.5 μM [ 24 ].
Structures of lupane triterpenoids 101 ‒ 104 from Actinidia plants
2.1.4 Other Terpenoids
A total of 19 other terpenoids including iridoids, diterpenoids, and their glycosides have been found from Actinidia plants ( 105 − 123 , Fig. 5 , Table 4 ). None of these compounds have good biological activities, only compound 120 showed certain anti-angiogenesis activity [ 77 ].
Structures of other terpenoids 105 ‒ 123 from Actinidia plants
β -Sitosterol 124 is a very normal phytosterol almost distributed in all plants. Eight phytosterols have been obtained from the Actinidia plants ( 124 ‒ 131 , Fig. 6 , Table 5 ). Pharmacological studies on these steroids have demonstrated that β -sitosterol showed various bioactivities including anti-inflammatory, anti-cancer, antimicrobial and anti-diabetic properties [ 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. A study suggested that β -sitosterol may serve as a potential therapeutic in the treatment of acute organ damages [ 82 ].
Structures of steroids 124 ‒ 138 from Actinidia plants
In addition to phytosterols, seven normal ergosterols ( 132 ‒ 137 , Fig. 6 , Table 5 ) were obtained from peel or rhizomes of kiwifruit plants. It is well known that ergosterols should be fungal products. Compounds 132 ‒ 137 may be produced by fungal infected kiwifruit plants.
2.3.1 catechins and epicatechins.
A total of 16 related compounds ( 139 ‒ 154 ) have been obtained from kiwifruit plants (Fig. 7 , Table 6 ). Compounds 148 and 149 possessed a novel structure featuring with a pyrrolidin-2-one substituent at C-6 and C-8, respectively. Compounds 152 and 153 were two sulfur-containing catechins that was rare in nature. Pharmacological studies have revealed that (+)-catechin 139 and (−)-epi-catechin 140 showed nitric oxide inhibitory activity in LPS stimulated RAW 264.7 cell with IC 50 values of 26.61 and 25.30 μg/mL, respectively [ 53 , 91 ]. Compound 147 showed moderate radical scavenging and antioxidant capabilities by measuring their capacity to scavenge DPPH and anion superoxide radical and to reduce a Mo(VI) salt [ 89 ]. Two new flavan-3-ols, 6-(2-pyrrolidinone-5-yl)-(−)-epicatechin 148 and 8-(2-pyrrolidinone-5-yl)-(−)-epicatechin 149 , as well as proanthocyanidin B-4 150 , were isolated from an EtOAc-soluble extract of the roots of A. arguta . The isolates were tested in vitro for their inhibitory activity on the formation of advanced glycation end products (AGEs). All of them exhibited significant inhibitory activity against AGEs formation with IC 50 values ranging from 10.1 to 125.2 μM [ 92 ].
Structures of catechins and epicatechins 139 ‒ 154 from Actinidia plants
2.3.2 Flavones, Isoflavones, and Flavonols
A total of 48 flavone derivatives have been identified from kiwifruit plants, most of which are glycosides ( 155 ‒ 202 , Fig. 8 , Table 7 ). Pharmacological studies indicated that these compounds, particularly kaempferol and its derivative, had a wide range of biological activities including antiproliferation, antioxidation, anti-inflammation, anticancer, anti-free radical, and neuroprotection activities [ 96 , 97 , 98 , 99 ]. Kaempferol 157 was found to prevent neurotoxicity by several ways which was able to completely block N -methyl-D-aspartate (NMDA)-induced neuronal toxicity and potently inhibited MAO (monoamine oxidase) with the IC 50 of 0.8 μM [ 99 ]. Two novel flavonoids 171 and 172 were separated from the leaves of A. valvata Dunn. They exhibited dose-dependent activity in scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, superoxide anion radicals, and hydroxyl radicals, and inhibited lipid peroxidation of mouse liver homogenate in vitro [ 100 ]. Compounds 178 [ 101 ] and 179 [ 102 ] were two new compounds obtained from the leaves of A. kolomikta . The latter was screened for its protective effect on human erythrocytes against AAPH-induced hemolysis, which could slow the hemolysis induced by AAPH [ 102 ]. Eerduna et al. evaluated the effects of compound 182 on acute myocardial infarction in rats, the groups treated with 182 showed a dose-dependent reduction in myocardial infarct size model, markedly inhibited the elevation of the activity of creatine kinase, troponin T level, and the content of malondialdehyde induced by AMI [ 103 ]. Compound 182 also showed a capacity to increase the activities of superoxide dismutase, catalase, and endothelial nitric oxide synthase [ 104 ]. Lim et al. tested the DPPH radical scavenging activity and nitric oxide production inhibitory activity in IFN- γ , LPS stimulated RAW 264.7 cell of quercetin 185 , quercetin-3-O- β - d -glucoside 186 , and quercetin 3-O- β - d -galactoside 193 with IC 50 value of 20.41, 18.23, and 30.46 μg/mL, respectively [ 91 ].
Structures of flavones, isoflavones, and flavonols 155 ‒ 202 from Actinidia plants
Three xanthones were isolated from n-butyl alcohol fraction of A. arguta (Sieb. & Zucc) Planch. ex Miq and identified as 2- β - d -glu-1,3,7-trihydrogen xanthone 203 , 7-O-[ β - d -xylose-(1 → 6)- β - d -glucopyranoside]-1,8-dihydroxy-3-methoxy xanthone 204 , and 1-O-[ β - d -xylose-(1 → 6)- β - d -glucopyranside] -8-hydroxy-3,7-dimethoxy xanthone 205 (Fig. 9 , Table 8 ). They were isolated from this plant for the first time [ 108 ]. Compound 203 showed extensive biological activities, including inhibiting α -Glycosidase, NO production inhibition and NF- κ B inhibition and PPAR activation [ 116 , 117 ]. It has been demonstrated the inhibitory effects on NF- κ B transcriptional activation in HepG2 cells stimulated with TNF α with an IC 50 value of 0.85 ± 0.07 μM, which was more potent than the positive control of sulfasalazine (IC 50 = 0.9 μM) [ 118 ].
Structures of xanthones, isoflavones, and flavonols 203 ‒ 219 from Actinidia plants
Five anthocyanins were obtained from the flesh of larger fruit of A. deliciosa and A. chinensis and identified as delphinidin 3-galactoside 206 , cyanidin 3-galactoside 207 , cyanidin 3-glucoside 208 , delphinidin 3-[2-(xylosyl)galactoside] 209 , and cyanidin 3-[2-(xylosyl)galactoside] 210 , respectively (Fig. 9 , Table 8 ) [ 119 ]. Cyanidin 3-glucoside 208 exhibited a wide range of pharmacological activities including anti-inflammatory, neuroprotective, anti-cancer, and antioxidant activities [ 120 , 121 , 122 , 123 , 124 ].
A total of nine emodin derivatives were obtained ( 211 ‒ 219 , Fig. 9 , Table 8 ). Three emodin constituents were isolated from EtOAc fraction of the roots of A. deliciosa for the first time, and their structures were identified to be aloe-emodin 211 , 11-O-acetyl-aloe-emodin 212 , and aloe-emodin 11-O- α - l -rhamno -pyranoside 213 [ 125 ]. Compound 211 exhibited intriguing biological activities including inflammatory, antifungal, and anticancer activity [ 126 , 127 , 128 ]. Lipoxygenases (LOXs) are potential treatment targets in a variety of inflammatory conditions, enzyme kinetics showed that aloe emodin inhibited lipoxygenase competitively with an IC 50 of 29.49 μM [ 126 ]. Compound 215 was reported to possess wide biological activities including anti-inflammatory, neuroprotection, anti-cardiovascular and α -glucosidase inhibitory activity [ 129 , 130 , 131 , 132 ]. It exhibited potent inhibition of α-glucosidase with an IC 50 value of 19 ± 1 μM and lower cytotoxicity to the Caco-2 cell line [ 132 ].
2.3.6 Phenylpropionic Acids
A total of 38 phenylpropionic acid derivatives have been identified from kiwifruit plants ( 220 ‒ 257 . Fig. 10 , Table 9 ), while most of them were glycosides or quinic acid derivatives. Phytochemical examination of the fruits of A. arguta led to the isolation of two organic acids including caffeic acid 220 and caffeoyl- β - d -glucopyranoside 221 , which were tested for their nitric oxide production inhibitory activity in LPS-stimulated RAW 264.7 cells and DPPH radical scavenging activities. Compared with positive control (L-NMMA), they were potently reduced nitric oxide productions and showed anti-oxidative activities [ 135 ]. Nine succinic acid derivatives ( 228 ‒ 236 ), eleven quinic acid ( 245 ‒ 255 ) derivatives and two shikimic acid derivatives ( 256 and 257 ) were isolated from the fruits of A. arguta . The NF- κ B transcriptional inhibitory activity of the compounds was evaluated using RAW 264.7 macrophages cells induced by lipopolysaccharide. Among the groups of different organic acid derivatives, the quinic acid derivatives inhibited NF- κ B transcriptional activity with an IC 50 value of 4.0 μM [ 136 ].
Structures of phenylpropionic acids 220 ‒ 257 from Actinidia plants
Coumarins are rarely identified from kiwifruit plants, and only eleven members have been reported ( 258 ‒ 267 , Fig. 11 , Table 10 ). Umbelliferone 258 was obtained from the leaves of A. polygama (Sieb. et Zucc.) Miq [ 109 ]. A number of studies demonstrate the pharmacological properties of 258 including antitumor, anti-inflammatory, antioxidant, antidiabetic, and immunomodulatory activities [ 143 , 144 , 145 , 146 , 147 , 148 , 149 ]. It showed cytotoxicity against MCF-7 and MDA-MB-231 cell lines with IC 50 values of 15.56 and 10.31 μM, respectively [ 148 ]. Phytochemical examination of the fruits of A. arguta led to the isolation of esculetin 259 [ 135 ]. Two coumarins were isolated from the roots of A . deliciosa and identified as fraxetin 260 and isoscopoletin 261 [ 150 ]. Compound 260 showed potent inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation with an IC 50 value of 10.11 ± 0.47 µM [ 151 ]. Esculin 263 and fraxin 264 were characterized from the stems and fruits of A . deliciosa (kiwifruit) and A . chinensis [ 152 ]. Compound 264 showed inhibitory activity towards HepG2 with an IC 50 value of 14.71 μM [ 153 ].
Structures of coumarins 258 ‒ 268 from Actinidia plants
Lignans also had a narrow distribution in kiwi plants, only six members have been identified from Actinidia plants ( 269 ‒ 274 , Fig. 12 , Table 11 ). (+)-Pinoresinol 271 , (+)-medioresinol 272 , and (−)-syringaresinol 273 were partitioned from the fraction of the roots of A. arguta [ 53 ]. Compound 271 is a biologically active lignan and widely found in many dietary plants. It was reported to possess antifungal, anti-inflammatory, antioxidant, hypoglycemic, and antitumor activities [ 158 , 159 , 160 , 161 , 162 ]. A study on this compound suggested that 271 displayed significant inhibition of fMLP/CB-induced superoxide anion generation and elastase release, with an IC 50 value of 1.3 ± 0.2 μg/mL [ 159 ]. The 50% ethanol extract of A . arguta showed strong inhibitory effect on α -glucosidase (32.6%), while a bio-guided isolation on the extract gave a bioactive compound pinoresinol diglucoside 274 [ 138 ].
Structures of lignans 269 ‒ 274 from Actinidia plants
2.3.9 Simple Phenols
Simple benzene derivatives including glycosides and isoprenylated benzene products from Actinidia plants were collected ( 275 ‒ 298 , Fig. 13 , Table 12 ). Phytochemical examination of the fruits of A. arguta led to the isolation of protocatechuic acid 279 [ 135 ]. It showed anti-inflammatory [ 163 ], antioxidant [ 163 ], neuroprotective [ 164 ], and anti-proliferative activities [ 165 ]. Protocatechuic acid exhibited significant (p < 0.05) anti-inflammatory (83% and 88% inhibition for egg-albumin induced and xylene induced oedema, respectively), analgesic (56% inhibition and 22 s of pain suppression for acetic acid-induced and hot plate-induced pain, respectively), and antioxidant effects (97% inhibition and absorbance of 2.516 at 100 μg/mL for DPPH and FRAP assay, respectively) in the models [ 166 ]. Extraction of leaf tissue from the golden-fleshed kiwifruit cultivar A. chinensis “Hort16A” expressing genotype-resistance against the fungus Botrytis cinerea , a new phenolic compound, 3,5-dihydroxy-2-(methoxycarbonylmethyl)phenyl 3,4-dihydroxybenzoate 278 was therefore obtained [ 167 ].
Structures of simple phenols 275 ‒ 298 from Actinidia plants
Four novel skeleton phenolic compounds planchols A‒D ( 291 ‒ 294 ) were isolated from the roots of A. chinensis Planch. Their structures were elucidated by spectroscopic analysis and chemical evidence. The structure of 291 was further confirmed by the single-crystal X-ray diffraction. Moreover, it was found that 291 and 292 showed remarkable cytotoxic activity against P-388 with IC 50 of 2.50 and 3.85 μM, respectively, and against A-549 with IC 50 of 1.42 and 2.88 μM, respectively [ 94 ].
Three alkaloids ( 299 ‒ 301 ), eleven fatty acids and derivatives ( 302 ‒ 312 ), and other thirteen small molecules ( 313 ‒ 325 ) were obtained from Actinidia plants (Fig. 14 , Table 13 ). Actinidine 299 and boschniakine 300 were isolated from the leaves and galls of A . polygama and also isolated from A. arguta which might be converted from iridoids [ 174 , 175 ]. A bioassay-guided fractionation of the fruits of A. polygama led to the separation and identification of a polyunsaturated fatty acid, α -linolenic acid (ALA) 305 [ 176 ]. This compound was found to possess a broad biological properties including anti-inflammatory [ 177 ], anti-tumor [ 178 ], anti-hyperlipidemic [ 179 ], anti-diabetic [ 180 ], and anti-fungal [ 181 ] activities. By a bio-guided fractionation, a ceramide namely actinidiamide 312 was identified as an anti-inflammatory component from the EtOAc fraction of A. polygama Max. It potently inhibited nitric oxide production (30.6% inhibition at 1 μg/mL) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and β -hexosaminidase release (91.8% inhibition at 1 μg/mL) in IgE-sentized RBL-2H3 cells [ 182 ].
Structures of other molecules 299 ‒ 325 from Actinidia plants
In summary, this review focused on the biological components and related pharmacological activities of various parts of Actinidia plants, including triterpenoids, steroids, flavonoids, catechins, coumarins, lignans, phenols, and other small organic molecules. A total of 325 molecules have been collected in this review. Most of the active molecules are derived from the roots of Actinidia plants, while triterpenes and flavonoids are the most important types regardless of the number of compounds and their biological activity significance. The stems, leaves, fruit galls, and other parts of kiwi are mainly rich in flavonoids, phenylpropionic acids, and other small molecule compounds. Currently, these chemical components are not structurally novel. In addition, there are few in-depth researches on pharmacological activities of the bioactive compounds. Therefore, research on the chemical constituents of Actinidia plants is still promising. We hope that this review can provide positive information for the further exploration of the chemical components and their biological activities of Actinidia plants.
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This work was financially supported by the National Natural Science Foundation of China (22177139) and the Scientific Research Program of Hubei Provincial Department of Education, China (D20183001).
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Jin-Tao Ma, Ji-Kai Liu & Juan He
Center of Economic Botany, Core Botanical Gardens, Chinese Academy of Sciences, Wuhan, 430074, People’s Republic of China
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Ma, JT., Li, DW., Liu, JK. et al. Advances in Research on Chemical Constituents and Their Biological Activities of the Genus Actinidia . Nat. Prod. Bioprospect. 11 , 573–609 (2021). https://doi.org/10.1007/s13659-021-00319-8
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DOI : https://doi.org/10.1007/s13659-021-00319-8
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Original research article, qualitative and quantitative determination of chemical constituents in jinbei oral liquid, a modern chinese medicine for coronavirus disease 2019, by ultra-performance liquid chromatography coupled with mass spectrometry.
- 1 Traditional Chinese Medicine Research Institute, Shandong Hongjitang Pharmaceutical Group Co., Ltd., Jinan, China
- 2 Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkvile, VIC, Australia
- 3 Institute of Optical Physics and Engineering Technology, Qilu Zhongke, Jinan, China
- 4 The first Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan, China
- 5 Yinan County People’s Hospital, Linyi, China
Introduction: Traditional Chinese medicine (TCM) has the advantages of syndrome differentiation and rapid determination of etiology, and many TCM prescriptions have been applied to the clinical treatment of coronavirus disease 2019 (COVID-19). Among them, Jinbei Oral Liquid (Jb.L) has also shown an obvious curative effect in the clinic, but the related material basic research is relatively limited.
Methods: Therefore, in this process, a systematic data acquisition and mining strategy was established using ultra-high- performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry (UPLC-Q-TOF-MS).
Results and Discussion: With the optimized conditions, a total of 118 peaks were tentatively characterized, including 43 flavonoids, 26 phenylpropanoids, 14 glycosides, 9 phthalides, 8 alkaloids and others. To determine the content of relevant pharmacological ingredients, we firstly exploited the ultra-performance liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry (UPLC-QqQ-MS/MS) method for simultaneous detection of 31 active ingredients within 17 min, and the validation of methodology showed that this method has good precision and accuracy. Moreover, analyzing the pharmacology of 31 individual of the medicinal material preliminarily confirmed the efficacy of Jb.L and laid a foundation for an in-depth study of network pharmacology.
In December 2019, many cases of viral pneumonia were found in Wuhan City, Hubei Province. By February 2020, more than 20,000 cases of coronavirus disease 2019 (COVID-19) were confirmed nationwide, and 425 patients had died. For this outbreak, it is difficult for western medicine to carry out targeted treatment without identifying the pathogen, but traditional Chinese medicine (TCM) can quickly determine the cause through syndrome differentiation and treatment ( Zeng et al., 2020 ).
COVID-19 belongs to the category of “epidemic disease” in TCM, and its pathological changes first appear in the interstitial lung ( Yang and Fan, 2021 ). The main symptoms are fever, dry cough, and fatigue. In severe cases, lung consolidation may occur ( Miao et al., 2020 ; Xiong, 2020 ; Zhan et al., 2020 ). In view of these symptoms, many prescriptions were applied, such as Jinhua Qinggan granules, Shufeng Jiedu capsules, Jingfang granules, and Jinbei oral liquid (Jb. L), and showed an obvious curative effect in the clinic. Among them, Jb. L was listed in the Chinese Medicine Diagnosis and Treatment Plan of novel coronavirus pneumonia in Shandong Province (Second Edition) in February 2020, and our subsequent clinical data analysis showed that the effect of Jb. L combined with chemical drugs was better than the single chemical therapy group ( Li et al., 2021 ). Jb. L is composed of Astragali radix , Codonopsis radix , Angelica sinensis , Glehniae radix , Scutellariae radix , Fritillariae cirrhosae bulbus , Chuanxiong rhizoma , Salvia miltiorrhiza radix , Pinelliae rhizoma praeparatum cumalumine , Lonicerae japonicae flos , Forsythiae fructus , and Glycyrrhizae radix . It has the effect of replenishing qi and nourishing yin, expelling blood stasis, and removing phlegm.
Although TCM prescriptions have a certain theoretical and clinical application basis, the material basis of compound TCM prescriptions is complex, and the action mechanism is diverse, which brings considerable difficulty to the basic material research into the efficacy of TCM. In recent years, hyphenated techniques have been powerful tools for rapid online qualitative analysis of unknown compounds in complex matrices, especially ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS), which benefits due to its high resolution and sensitivity. These methods have been proven to be efficient and highly sensitive tools for the rapid analysis of TCM preparations ( Gao et al., 2014 ; Zhang et al., 2017a ; Li et al., 2018 ; Wang et al., 2018 ; Sun et al., 2021 ). In addition, UPLC coupled with triple quadrupole mass spectrometry (UPLC-QqQ-MS/MS) can be well applied to quantitative analysis of multiple chemical components of TCM through the multiple reaction monitoring (MRM) mode, which has great significance in the modernization of TCM ( Wu et al., 2019 ; Liu et al., 2020 ; Zheng et al., 2021 ).
Studying the material basis of the efficacy of TCM is the prerequisite to solving the principle of the effective action of TCM, and the determination of the effective components of TCM is the primary task. Therefore, in this experiment, the chemical composition of Jb. L was qualitatively determined by UPLC-Q-TOF-MS/MS, and the main functional components were quantitatively analyzed by UPLC-MS/MS. This is the first report on the systematic analysis of the chemical components of Jb. L, which provides the basis for quality control and an in-depth study of its pharmacodynamics.
2 Materials and methods
2.1 instruments and reagents.
An Agilent 1290 UPLC system was coupled with an Agilent 6530C Q-TOF-MS/MS (Agilent Technologies, USA); A Waters ACQUITYTM I-Class UPLC (Waters Technologies, USA) was coupled with a SCIEX Triple Quad 5,500 (AB SCIEX, USA); an XS105 analytical balance was purchased from METTLER TOLEDO (Shanghai, China); a KQ-800VSM Bench ultrasonic cleaner was purchased from Kunshan Ultrasonic Instrument Co., Ltd. (Jiangsu, China); LC-MS-grade acetonitrile was purchased from Merck KGaA (Darmstadt, Germany); HPLC-grade formic acid was purchased from Kermel (Tianjin, China); ultra-pure water was purchased from Watsons (Guangzhou, China).
A total of 31 reference standards (adenosine, guanosine, chlorogenic acid, loganin, caffeic acid, schaffetaside, rutin, forsythoside A, ferulic acid, sibemine, fritillin B, isochlorogenic acid A/B/C, quercitrin, rosmarinic acid, salvianolic acid B, liquiritin, lindenaza, baicalin, genistein, forsythin, liquiritigenin, mullein isoflavones, bergamot esters, baicalein, formononetin, glycyrrhizic acid, glycyrrhetinic acid, wogonin, and ligustilide) were purchased from the National Institutes for Food and Drug Control, Jiangsu Yongjian Pharmaceutical Technology, Ltd., and Shandong WoDeSen Bioscience Technology, Ltd. The purities of all the reference standards were over 96.0%. Samples of Jb. L were produced by Shandong Hongjitang Pharmaceutical Group, Ltd.
2.2 Preparation of reference standards and sample solutions
Individual reference standards were prepared by accurately weighing the required amounts and dissolving the in LC-MS-grade methanol. Samples were stored at 4 °C before being analyzed.
The Jb. L sample (20 mL) was extracted ultrasonically for 30 min once with 60 mL of methanol. After it was cooled to room temperature, the weight was supplemented. The sample was filtered through a 0.22 μm nylon membrane filter before being analyzed.
2.3 Method of qualitative analysis by UPLC-Q-TOF-MS/MS
The research was performed on a Poroshell 120 SB-C18 column (2.1 mm *150 mm, 2.7 μm) at a flow rate of 0.2 mL/min, and the injection volume was 2 μL. To obtain good chromatographic separation and appropriate ionization, the UPLC-Q-TOF-MS/MS conditions were optimized systemically. Similarly, the column, temperature, and elution profile were optimized for LC. Different sheath gases and collision energies were investigated for MS. The mobile phase was composed of 0.1% (v/v) formic acid (A) and acetonitrile (B) with gradient elution, and the elution program was as follows: 0–2.7 min, 4% B; 2.7–6.6 min, 4%–7% B; 6.6–20.6 min, 7%–14% B; 20.6–30.7 min, 14%–19% B; 30.7–43.9 min, 19%–30% B; 43.9–54.3 min, 30%–50% B; 54.3–64 min, 50%–70% B; 64–75 min, 70%–80% B.
Mass spectrometric conditions were as follows: both positive and negative electrospray ionization (ESI) modes were applied to this analysis. The capillary voltage was 3.5 kV (negative ion mode) and 4.0 kV (positive ion mode), and the collision energy range of the secondary mass spectrum was 20–60 eV. MS scan and auto MS/MS modes were adopted, the scanning range of mass spectrometry was 100–1,200 Da, and the data acquisition was centroid mode.
2.4 Method of quantitative analysis by UPLC-QqQ-MS/MS
The analysis was performed on an ACQUITY UPLC BEH C18 column (2.1 mm *100 mm, 1.7 μm). The mobile phase was 0.1% formic acid (A) and acetonitrile (B) with gradient elution (0–1.0 min,10% B; 1.0–3.0 min, 10%–20% B; 3.0–5.0 min, 20%–30% B; 5.0–7.0 min, 30%–40% B; 7.0–9.0 min, 40%–55% B; 9.0–11.0 min, 55%–70% B; 11.0–14.0 min, 70%–80% B; 14–15 min, 80%–85% B; 15.0–16.1 min, 85%–10% B; 16.1–17 min, 10% B); the flow rate was 0.3 mL/min. Mass spectrometric conditions were as follows: ionization of analytes was carried out using positive/negative mode electrospray ionization (ESI) with the multiple reaction monitoring (MRM) mode. The ion source spray voltage was 4500 V, the curtain gas was 20.0 psi, the ion source gas was 50 psi, the entrance potential was ±10 V, and the collision cell exit potential was ±5.5 V. The MS analysis parameters of 31 detected compounds are shown in Table 1 , and the extracted ion chromatograms of each component are shown in Supporting Information Figure S2. The data acquisition and processing software was MultiQuant 3.0.2 Workstation.
TABLE 1 . MS analysis parameters of 31 detected compounds.
We herein report the qualitative and quantitative analysis of the chemical constituents of Jb. L using both UPLC-Q-TOF-MS/MS and UPLC-QqQ-MS/MS. The research diagram is shown in Figure 1 .
FIGURE 1 . Research strategy for identifying the components of Jinbei oral liquid See Supplementary Figure S1 .
3.1 Identification of chemical compositions by UPLC-Q-TOF-MS/MS
The total ion chromatograms (TIC) of Jb. L samples were obtained under chromatographic and mass spectrometry conditions described in Section 2.3. These chromatograms are shown in Figure 2 . First, according to the chromatographic peak information, the molecular formula was generated by the Compound Identification function in Agilent Qualitative Workflows B.08.00 software. The compounds contained in Jb. L were preliminarily identified by comparison with the relevant literature on the chemical constituents of 12 TCMs ( Zhang and Ye, 2009 ; Song et al., 2014 ; Su et al., 2015 ; Xia et al., 2016 ; Zhang et al., 2017b ; Huang et al., 2018 ; Jiang et al., 2020 ; Luo et al., 2020 ; Wang and Su, 2020 ; Yao et al., 2020 ; Zhang et al., 2020 ; Zhao and Xia, 2020 ). Second, the corresponding fragment ions of the compound were obtained by secondary mass spectrometry of collision-induced dissociation (CID). As a result, 118 compounds were detected and tentatively identified in Jb. L by comparing the retention time and mass spectrometry and retrieving the reference literature. These compounds included 43 flavonoids, 26 phenylpropanoids, 14 glycosides, 9 phthalides, 8 alkaloids, and others. The quality deviation was controlled within 15 ppm. The structures of these compounds are summarized in Figure 3 . Information on the t R (min), molecular formula, theory mass ( m/z ), observed mass ( m/z ), mass error (in ppm), fragment ions, and category is summarized in Supporting Information Table S1. Among them, 31 components, such as chlorogenic acid, caffeic acid, salvianolic acid B, baicalin, glycyrrhizic acid, cryptotanshinone , imperialine, forsythin, calycosin, schaftoside , rutin, and so on, were compared with the corresponding reference standards.
FIGURE 2 . UPLC-Q-TOF-MS total ion chromatogram of Jinbei oral liquid in negative (A) and positive (B) ion mode See Supplementary Figure S2 .
FIGURE 3 . Potential chemical structures investigated in Jinbei oral liquid See Supplementary Figure S3 .
Flavonoids are secondary plant metabolites with various pharmacological effects. They are a series of compounds with 2-phenylchromone as the basic parent nucleus and mainly have anti-inflammatory, antioxidant, cardiovascular protection, and other effects. For example, rutin can significantly inhibit the activity of cardiac inflammation and can play a protective role against cardiac inflammation ( Dai et al., 2013 ; Alara et al., 2018 ). It is abundant in Chinese herbal medicinal plants, such as Astragalus , Scutellaria , Glycyrrhiza , and Forsythia . In this study, the 45 identified flavonoids can be divided into four classes (flavonoids, dihydroflavonoids, isoflavones, and pterocarpoids). The compounds include schaftoside (12), hesperidin (13), liquiritin (14), and liquiritigenin-7-O-D-apiosyl-4’-O-D-glucoside (15), and luteoloside (17), baicalin (29), calycosin (36), wogonoside (38), rutin (69), hyperoside (70), quercitrin (73), pratensein 7-O- β -D-glucopyranoside (78), genistin (84), methylnissolin-3-O-glucoside (90), baicalein (100), isoastragaloside IV (101), formononetin (106), and so on. The mass spectra information is shown in Supporting Information Table S1.
The identification process of flavonoids is illustrated by taking schaftoside and kumatakenin as examples. Schaftoside produced ion m/z 563.1400 [M-H] - in negative source mode. In its secondary mass spectrometry, molecules of H 2 O (18 Da) and Glc (162 Da) were removed to produce a fragment ion fragment m/z 383.0770, followed by either the removal of a CH 2 O (30 Da) molecule to produce fragment ion m/z 353.0665 or the removal of a C 4 H 8 O 4 (120 Da) molecule to produce fragment ion m/z 443.0960. The possible fragmentation pathway (FP) is shown in Figure 4A . In the positive ion mode, kumatakenin exhibited an [M + H] + ion at m/z 315.0866 (1.27 ppm, C 17 H 14 O 6 ), then neutral elimination of a CH 3 (15 Da) residue produced the ion at m/z 299.0571 ([M + H-15] - , C 16 H 11 O 6 ). The ion at m/z 243.0642 ([M + H-56] - , C 14 H 11 O 4 ) came from the neutral elimination of a C 2 O 2 residue. In addition, C 1 -C 3 of the A-ring directly underwent RDA cleavage to produce fragment ion m/z 167.0317 ([M + H-C 9 H 7 O 2 ] - , C 8 H 7 O 4 ). The possible FP is shown in Figure 4B .
FIGURE 4 . (A) The FP of schaftoside in negative ion mode. (B) The FP of kumatakenin in positive ion mode. (C) Mass spectrometric fragmentation of dihydroflavones. (D) The FP of liquiritin in negative ion mode. (E) The FP of formononetin in positive ion mode. (F) The FP of calycosin-7-O-glucoside in positive ion mode. (G) The FP of methylnissolin-3-O-glucoside in positive ion mode.
In the positive source mode, the parent C-ring of dihydroflavonoids generally undergoes a ring-opening rupture with break sites at the C2- O and C3-C4 bonds, generating ions retained at the A-ring end (RDA cleavage). In the negative source mode, break sites at the C2- O and C4-C10 bonds also occur at the same time, generating ions with charge retained at the A-ring end, sometimes with the loss of the B-ring, as shown in Figure 4C . The identification process of dihydroflavonoids is illustrated taking liquiritin as an example. Liquiritin underwent glycosidic bond breakage in both positive and negative ion modes, and one molecule of the glucose group was removed to obtain a fragment ion with m/z 255.0662 [M-H-Glc] - . Then, RDA cleavage occurred in the C-ring to produce fragment ion m/z 135.0085. The FP is shown in Figure 4D .
For isoflavones, in positive ion mode, the primary mass spectra were obtained with [M + H] + peaks, and the other fragments were formed by the absence of neutral units such as CO, CH 3 , and CHO or the occurrence of RDA cleavage. The identification process of isoflavones is illustrated by the example of formononetin and calycosin-7- O -glucoside. In the positive source mode, formononetin produced excimer ion m/z 269.0807 [M + H] + . Fragment ions m/z 137.0238 and m/z 133.0643 were generated after RDA cleavage, and then neutral elimination of CHO (29 Da) and CH 3 (15 Da) produced the ions at m/z 108.0211 and m/z 118.0409, respectively. Formononetin may also remove one molecule of CH 3 (15 Da) and then remove one H atom to obtain fragment ions of m/z 253.0469. The possible cleavage pathway is shown in Figure 4E . The fragment ion m/z 285.0766 was found in the positive ion mode because the oxyglycoside bond was prone to break and one molecule of the glycosyl group was removed, to obtain the fragment ion m/z 285.0766, and then one molecule of CH 3 (15 Da) or CH 4 O (32 Da) was also lost to produce the fragment ion m/z 270.0532 or m/z 253.0481. The m/z 270.0532 fragment ion underwent RDA cleavage to yield a fragment ion of m/z 137.0232, and its possible FP is shown in Figure 4F .
Pterocarpins are second only to isoflavones in the isoflavone family. The basic skeleton is a tetracyclic system synthesized by the 4-position and 2′-position of isoflavones through ether bond rings. Pterocarpin has two asymmetric carbon atoms, C-6a and C-11a. The identification process of pterocarpoids is illustrated by taking methylnissolin-3- O -glucoside as an example. In the positive ion mode, methylnissolin-3- O -glucoside produced an [M + H] + ion at m/z 463.1601 (0.65 ppm, C 23 H 26 O 10 ); the fragment ion m/z 301.1086 showed an ionized peak corresponding to the ion m/z 463.1601 losing a glucose group. Meanwhile, it showed 162 Da more than compound 89, indicating more glycosyl (Glc, 162 Da) than medicarpin. Finally, the fragment ion at m/z 167.0711 was generated after removing substituents (C 8 H 6 O 2 , 144 Da), and its possible FP is shown in Figure 4G .
Obviously, for flavonoids, the fragmentation of MS is mainly the cleavage of sugar residues or small molecules and the cleavage of RDA in the ring.
Phenylpropanol is a naturally occurring compound composed of a benzene ring and three straight-chain carbon groups (C6-C3 groups) and can be divided into phenylpropionic acids, coumarins, and lignans.
188.8.131.52 Phenylpropionic acids and derivatives
The structure of phenylpropionic acid is characterized by a C6-C3 structure and aromatic carboxylic acid substituted by a phenolic hydroxyl group. Danshensu (1), 5- O -caffeoylquinic acid (3), 1-O-caffeoylquinic acid (7), chlorogenic acid (9), cryptochlorogenic acid (10), caffeic acid (11), lithospermic acid (19), 3,4-dicaffeoylquinic acid (20), 3,5-dicaffeoylquinic acid (21), rosmarinic acid (24), 4,5-dicaffeoylquinic acid (25), salvianolic acid B (31), salvianolic acid E (33), and salvianolic acid A (35) were the main phenylpropionic acids in Jb. L. They can be divided into three types according to the different substituents of compounds: caffeoyl substituents, salvianolic acids, and other organic acids ( Zhang et al., 2006 ; Lin et al., 2017 ; Cao et al., 2021 ). For example, compounds 20, 21, and 25 are three typical caffeoyl-substituted phenolic acids that produced similar precursor ions at m/z 515.1194 and fragment ions at m/z 353.0873 [M-H-Caff] - in negative ion mode, and m/z 191.0551 [M-H-2Caff] - , m/z 179.0350 [M-H-Caff-C 7 H 10 O 5 ] - , m/z 173.0450 [M-H-2Caff-H 2 O] - , and m/z 135.0462 [M-H-Caff-C 7 H 10 O 5 -CO 2 ] - the identification of the last four fragment ions is based on literature and mass spectrometry analysis. Taking 4,5-dicaffeoylquinic acid as an example, the main FP of caffeoyl-substituted phenolic acids is summarized in Figure 5A . Salvianolic acid compounds are the main water-soluble compounds in Salvia miltiorrhiza , among which the two components with the highest content, salvianolic acid A and B, have the strongest activity. Salvianolic acids A and B are compounds with danshensu as the parent nucleus. In the negative ion mode, salvianolic acid B exhibited an [M-H] - ion at m/z 717.1459 (0.84 ppm, C 36 H 30 O 16 ), then split in the CID mode and lost danshensu to produce fragment ions at m/z 519.0928, m/z 339.0505, and m/z 321.0402 corresponding to [M-H-C 9 H 10 O 5 ] − , [M-H-C 9 H 10 O 5 -C 9 H 8 O 4 ] − and [M-H-2C 9 H 10 O 5 ] − , respectively. The secondary mass spectra are shown in Figure 5B . The FP was inferred as shown in Figure 5C . Rosmarinic acid is used as an example of other organic acids. Rosmarinic acid is a diploid synthesized by caffeic acid and danshensu condensation, and the most unstable one is the intermediate ester bond. As shown in Figure 5D , fragment ions m/z 161.0240 and m/z 197.0449 were formed when the bond was broken, and fragment ion m/z 179.0346 was formed when the charge was broken by the b bond. The final structure was the same whether the charge was on the caffeic acid or danshensu. The inferred cleavage law was also confirmed according to the secondary mass spectra of rosmarinic acid and its standard ( Figure 5E ). Other types of acids tend to lose stable small molecules or free radicals. For example, lithospermic acid has a phenylpropionic acid unit, which is triploid, and the unstable part of the structure is lactone and carboxyl groups on the benzodihydrofuran ring. The FP is shown in Figure 5F .
FIGURE 5 . (A) MS/MS spectrogram of salvianolic acid B in negative ion mode. (B) The FP of salvianolic acid B in negative ion mode. (C) MS/MS spectrogram of rosmarinic acid in negative ion mode (A-sample, B-reference standard). (D) The FP of rosmarinic acid in negative ion mode. (E) The FP of lithospermic acid in negative ion mode. (F) The FP of terpineol in negative ion mode. (G) The FP of7-hydroxycoumarin in positive ion mode.
Lignans are defined as a class of natural products formed by the connection of two structures with a phenylpropane skeleton by the β,β′ or 8,8-carbons, mainly including forsythin (85), sylvatesmin (86), and terpineol (95). Taking terpineol as an example, the molecular fragment peak mainly comes from the benzene ring and the cyclic alkyl group. In positive ion mode, terpineol is produced an [M + H] + ion at m/z 359.1489 (1.39 ppm, C 20 H 22 O 6 ), then neutral elimination of H 2 O (18 Da), 2 OCH 2 (60Da), and C 6 H 4 (76 Da) to produce the ion at m/z 205.0842. Similarly, after the loss of a small molecule, fragment ions at m/z 151.0375 and m/z 137.0605 were also obtained. The possible FP is shown in Figure 5G .
Coumarin is a lactone compound synthesized by intramolecular dehydration cyclization of cis-o-hydroxycinnamic acid. It has the basic core nucleus of benzopyranone and has been found in Angelica sinensis radix and Glycyrrhiza radix . Variants include liquiritigenin (31), 7-hydroxy coumarin (51), hydroxymethyl couman (57), scopoletin (58), fraxidin (62), bergapten (96), 8-methoxypsoralen (107), phellopterin (110), and so on. In the positive source mode, the excimer ion was at m/z 163.0391 [M + H] + , and a molecule of CO (28 Da) was removed successively to form characteristic fragments at m/z 135.0449 [M + H-CO] + , m/z 107.0500 [M + H-2CO] + , and m/z 79.0545 [M + H-3CO] + , respectively. The FP is shown in Figure 5H .
Glycosides, also known as glycoplasts, are compounds formed by connecting the terminal carbon atoms of sugars or sugar derivatives with another kind of non-sugar substance (called aglycone, ligand or aglycone). Fourteen glycosides were identified in Jb. L, including phenylethanol glycosides such as forsythoside A (16), forsythoside E (52), salidroside (53), and desrhamnosyl isoacteoside (64); nucleosides, such as adenosine (46) and guanosine (47); saponins, such as astragaloside II (42), astragaloside VI (93), astragaloside IV (101), licoricesaponin G 2 (105), glycyrrhizic acid (108), 18 β -glycyrrhetinic acid (109), and so on. Generally, it is difficult to observe molecular ions in these compounds, and sometimes only molecular ions with extremely low abundance can appear. However, the fragment ions produced by continuous dehydration of molecular ions or dehydration after deglycosylation, as well as fragment ions from the aglycone and glycosyl parts, can be clearly seen.
The glycyrrhizic acid in triterpene saponins is used as an example. There is a double glucuronic acid (-GluA) in its structure. In the positive ion mode, the m/z 647.3776 was a fragment that lost a molecule of dehydrated glucuronic acid. Then, the charge was on the 11-position carbonyl of glycyrrhetinic acid, and the dehydrated diglucuronic acid was lost to obtain m/z 471.3464 [M + H-2GluA] + . There were hydrogen atoms on both sides of the sugar and aglycone of the 3-position glycosidic bond, so, in addition to m/z 471.3464, one molecule of H 2 O can also be lost to form m/z 453.3357 [M + H-2GluA-H 2 O] + . Its secondary mass spectrum is shown in Figure 6A , and the possible FP is shown in Figure 6B .
FIGURE 6 . (A) MS/MS spectrogram of glycyrrhizic acid in positive ion mode; (B) the FP of glycyrrhizic acid in positive ion mode; (C) the FP of astragaloside IV in positive ion mode; (D) MS/MS spectrogram of forsythoside A in negative ion mode; (E) the FP of forsythoside A in negative ion mode.
The structure of astragaloside IV contains a glucose group (-Glc) and a xylose group (-Xyl). In the positive ion mode, the fragment ion m/z 491.3694 [M + H-Glc-Xyl] + was obtained after removing the sugar group, then neutral elimination of H 2 O (18 Da) produced m/z 455.3518 [M + H-Glc-Xyl-2H 2 O] + and m/z 437.3395 [M + H-Glc-Xyl-3 H 2 O] + . After the removal of 3 H 2 O, the C-C bond between the two five-membered rings breaks to form fragment ion m/z 143.1067 [M + H-Glc-Xyl-3H 2 O-C 22 H 30 ] + with a spiroketal structure, and its possible FP is shown in Figure 6C .
Taking forsythoside A with high content in Forsythia suspensa as an example: in negative ion mode, the [M-H] - m/z 623.1965 ion produced fragment ions representing m/z 461.1683, m/z 443.1536, and m/z 179.0346 due to the successive losses of C 9 H 6 O 3 (162 Da), H 2 O (18 Da), and C 13 H 12 O 6 (264 Da), respectively. The secondary mass spectrum is shown in Figure 6D , and the possible FP is shown in Figure 6E .
Phenylphthalide, also known as o-hydroxymethylbenzoic acid lactone, is structurally characterized as a bicyclic fusion of γ -lactone (A-ring) and benzene (B-ring), a lactone formed by the loss of one molecule of H 2 O from γ -hydroxy carboxylic acid. It has antibacterial, analgesic, and anti-inflammatory biological activities, with significant therapeutic effects in calming asthma, lowering blood pressure, and improving the immune system ( Zhang et al., 2017c ). Angelica sinensis and Chuanxiong rhizoma are rich in phenanthrenes. In this study, a total of nine phenanthrenes were identified, including senkyunolide J/I/F/H/G/A (65, 77, 79, 80, 103, 113) and 3-butylphthalide (102), E -ligustilide (114), and Z -ligustilide (116). In the positive ion mode, the senkyunolide J/I/H/G excimer ion was dominated by [M + Na] + , and the senkyunolide F/A excimer ion was dominated by [M + H] + followed by the loss of small molecules H 2 O, CO, CO 2 to produce fragment ions. Compounds 104, 116, and 118 have the same excimer ion at m/z 191 [M + H] + and have the same fragment ion m/z 173 [M + H-H 2 O] + , presumably with a similar cleavage pattern ( Lin et al., 1998 ). Among them, E -ligustilide and Z -ligustilide are cis-trans isomers with significantly different retention times according to the relevant literature, and the peak of E -ligustilide is earlier. E -ligustilide is used as an example to illustrate the identification process of phenylpeptides: it yielded an ion at m/z 191.1065 [M + H] + in the positive ion mode, and the molecular formula was estimated to be C 12 H 14 O 2 by mass spectrometry software. After removing small molecules of H 2 O (18 Da) and CO (28 Da), respectively, fragment ions were produced at m/z 173.0961, m/z 163.1138, and m/z 145.1015, and the possible FP is shown in Figure 7 .
FIGURE 7 . The FP of E-ligustilide in positive ion mode.
Alkaloids are a class of nitrogenous organic compounds originating from the biological world (mainly the plant world), most of which have a more complex ring structure with nitrogen atoms bound within the ring. Alkaloids have protective effects on the cardiovascular system. For example, the alkaloid fraction in the Chinese herbal medicine maidenhair has pharmacological effects such as lowering blood pressure, slowing heart rate, and anti-tumor, in addition to its cough suppressing, asthma calming, and expectorant effects. Eight alkaloids were identified in this study, corresponding to compounds such as phenylalanine (49), tryptophan (50), mussel methycin (61), imperialine (67), perlolyrine (72), peimine (74), peiminine (76), and 1-acetyl-carboline (104). Imperialine is used as an example to illustrate the identification process of alkaloids. The m/z displayed in positive ion mode was 430.3320 [M + H] + . In its secondary mass spectrum, the excimer ion lost one molecule of H 2 O (18 Da) to yield m/z 412.3214 fragment ion, followed by a retro Diels–Alder (RDA) reaction that produced a fragment ion at m/z 138.1266 ([M + H-C 18 H 26 O 2 ] + , C 19 H 16 N), and its possible FP is shown in Figure 8 .
FIGURE 8 . The FP of imperialine in positive ion mode.
3.1.6 Other compounds
Many other substances were also found in Jb. L, such as tanshinones, including tanshinone I (118), cryptotanshinone (117), and dihydrotanshinone I (115), iridoid terpenoids, including sweroside (56), loganin (57), and secoxyloganin (60), and triterpenes, including ursolic acid (98) ( Wang et al., 2020 ). Cryptotanshinone is used as an example. In ESI + mode, the excimer ion was m/z 297.1490 [M + H] + (1.68 ppm,C 19 H 20 O 3 ) with fragments at m/z 279.1375 [M + H-18] + and m/z 251.1411 [M + H-46] + , corresponding to [M + H-H 2 O] + and [M + H-H 2 O-CO] + , respectively. Cryptotanshinone might also direct shed C 2 H 5 (29 Da) to form a fragment ion m/z 268.1120. The possible FP is shown in Figure 9A . Taking sweroside as an example, the m/z displayed in the ESI + mode was 359.1340 ([M + H] + ). After CID cleavage, the fragment ion m/z 197.0809 corresponding to excimer ion losing a glucose group, then neutral elimination of H 2 O/CO/C 4 H 4 residue produced the ions at m/z 179.0691 ([M + H-Glc-18] + ), m/z 151.0747 ([M + H-Glc-18-28] + ), and m/z 127.0392 ([M + H-Glc-18-52] + ). The possible FP is shown in Figure 9B .
FIGURE 9 . (A) The FP of cryptotanshinone in positive ion mode; (B) the FP of sweroside in positive ion mode.
3.2 Quantitative analysis by UPLC-QqQ-MS/MS
3.2.1 preparation of reference standards.
Adenosine, guanosine, chlorogenic acid, loganin, caffeic acid, schaffetaside, rutin, forsythoside A, ferulic acid, sibemine, fritillin B, isochlorogenic acid A/B/C, quercitrin, rosmarinic acid, salvianolic acid B, liquiritin, lindenaza, baicalin, genistein, forsythin, liquiritigenin, mullein isoflavones, bergamot esters, baicalein, formononetin, glycyrrhizic acid, glycyrrhetinic acid, wogonin, and ligustilide reference substances were accurately weighed in appropriate amounts, dissolved in methanol and diluted to make a mass concentration of 100 ppm of the reference stock solution. A 0.1 mL aliquot of each of the above-mentioned reference substances was added to a 10 mL volumetric flask. Methanol was added to dilute to scale, and the flask was shaken well to obtain the No. 1 mixed reference substance solution. The No. 1 mixed reference solution was diluted 2, 4, 5, 10, and 20 times to prepare mixed reference solutions Nos. 2–6.
3.2.2 Methodological investigation of quantitative detection methods
184.108.40.206 investigation of extraction methods.
Five samples of Jb. L were selected at random and fully mixed. A 10 mL aliquot of the mixed solution was precisely measured and dissolved into 30 mL of 50% (V/V) methanol-water solution and shaken.
The samples were treated separately by the following methods: ultrasonic extraction for 30 min (250 W, frequency 40 kHz); reflux for 30 min. Then, the sample was allowed to cool to room temperature. The sample was weighed, and the weight loss reduction was made up with the 50% (v/v) methanol-water solution. The sample was shaken well and filtered through a 0.22 μm microporous filter. The early filtrate was abandoned, and the subsequent filtrate was taken as the sample solution. The total ion chromatograms of different extraction methods are shown in Figure 10 . It can be seen from the figure that ultrasonic and reflux extraction have no significant effect on the chromatographic peak response of the components in the sample. In view of the stable baseline of the chromatographic peaks produced by ultrasonic extraction, ultrasonic extraction was determined to be more appropriate.
FIGURE 10 . Total ion chromatograms of Jinbei oral liquid by different extraction methods. (A) Ultrasonic; (B) reflux See Supplementary Data Sheet 2 .
220.127.116.11 Investigation of extraction solvents
A 10 mL sample of Jb. L was extracted with 30% methanol, 50% methanol, and 80% methanol as extraction solvents, respectively. The sample solution was prepared according to the ultrasonic extraction method described in Section 18.104.22.168, and the sample was injected for analysis. The TIC diagrams of the samples with different extraction solvents are shown in Figure 11 . The chromatographic peak response of the components extracted by 50% methanol was high, and the baseline was relatively stable, so 50% methanol was selected as the extraction solvent.
FIGURE 11 . Total ion chromatograms of Jinbei oral liquid by different extraction solvents. (A) 30% methanol; (B) 50% methanol; (C) 80% methanol See Supplementary Data Sheet 3 .
22.214.171.124 Investigation of extraction time
A 10 mL sample of Jb. L was precisely measured, and 50% methanol was used as the extraction solvent. The sample was ultrasonically extracted for different durations (20, 30, 40 min) to prepare the test solution, which was then injected and analyzed. The TIC of the sample under different extraction times is shown in Figure 12 . Considering the response value of the chromatographic peak and the stability of the baseline, the extraction time was selected as 30 min.
FIGURE 12 . Total ion chromatograms of Jinbei oral liquid by different extraction times. (A) 20 min; (B) 30 min; (C) 40 min See Supplementary Data Sheet 4 .
126.96.36.199 Confirmation of sample preparation method
According to the above investigation results, it was determined that the sample solution preparation method was as follows: 10 mL of Jb. L was accurately measured and transferred to a stoppered conical flask; 30 mL of 50% methanol was accurately added. The sample was precisely weighed and subjected to ultrasonic extraction for 30 min. After cooling to room temperature, the weight was made up, the solution was filtered, and the filtrate was used for analysis.
188.8.131.52 Stability test
The sample solution of Jb. L was injected after 0, 2, 6, 12, and 24 h. The results (Supporting Information Figure S3) showed that the RSD values of 31 compounds were in the range of 1.62%–4.70%, which indicated that the content of the test solution was stable within 24 h, and it was appropriate to inject samples for analysis within this time range.
184.108.40.206 Repeatability test
The same batch of Jb. L was weighed in parallel with six portions, and the sample solution was prepared according to the method described in Section 220.127.116.11. The contents of 31 compounds were analyzed and calculated (Supporting Information Figure S3). The RSD was in the range of 2.49%–5.59%, indicating that the method has good repeatability.
18.104.22.168 Precision test
The 31 compounds in Jb. L were divided into three groups. The mixed reference substance A containing peiminine, bergapten, 18β-glycyrrhetinic acid, imperialine, quercetin, genistin, and formononetin was prepared with a concentration of 250 ng/mL. Mixed reference solution B containing calycosin, liquiritigenin, loganin, schaftoside, rutin, wogonin, luteoloside, ferulic acid, and guanosine was prepared with a concentration of 2.5 μg/mL. Mixed reference solution C containing baicalein, ligustilide, adenosine, rosmarinic acid, forsythin, caffeic acid, isochlorogenic acid A/B/C, liquiritin, glycyrrhizic acid, chlorogenic acid, baicalin, salvianolic acid B, and forsythoside A was prepared with a concentration of 10 μg/mL. Three 5-mL samples were taken from the same batch of Jb. L. A 1 mL sample of the reference solutions A, B, and C was added to each, respectively. The results showed that the recovery rate was in the range of 91.2%–109.4%, indicating that the accuracy of the method was good.
22.214.171.124 Durability test
The durability was investigated in two aspects: column temperature and chromatographic column. The setting of column temperature was varied by ±2 °C (33 °C and 37 °C), and different batches of the same brand of column material were selected for the chromatographic column. The results showed that the durability of the system meets the requirements, and the RSD of the measured concentration was less than 4.5%.
126.96.36.199 Linear relationship and sample determination
A 2 μL sample of each of the six reference solutions No. 1 to No. 6 mentioned in Section 3.2.1 was injected. Taking the peak area as the ordinate (y) and the mass concentration (μg·L −1 ) as the abscissa (x), a standard curve was drawn to obtain the regression equation and correlation coefficient (r) of each component. The result is shown in Table 2 and indicates that all components have a good linear relationship and high sensitivity.
TABLE 2 . Calibration curves and determination of 31 compounds detected in Jinbei oral liquid.
Three batches of Jb. L samples were prepared according to the method described in Section 188.8.131.52 and analyzed within 24 h, and the contents of adenosine, guanosine, chlorogenic acid, and 31 other components in the samples were calculated as shown in Table 2 . The results show that the components with the highest concentrations were forsythoside A, which has bacteriostatic and anti-inflammatory effects; flavonoids with antioxidant effects, such as calycosin, baicalin, liquiritin, rutin; salvianolic acid B, chlorogenic acid, rosmarinic acid, and other organic acids with anti-inflammatory and antibacterial effects; and adenosine, guanosine, and other nucleosides with immune regulation functions. Alkaloids with antitussive, expectorant, and anti-inflammatory effects, such as imperialine and peiminine, were found with the next-highest concentrations.
The material basis for prevention and treatment within TCM is an organic whole composed of multiple components, which is a prerequisite for elucidating the active substances, pharmacological action, mechanism, and clinical efficacy of TCM. Therefore, in the process of research and development for new TCM drugs, it is necessary to strengthen basic research, discover clinical characteristics and comparative advantages, focus on clinical positioning, and improve clinical efficacy.
In this study, UPLC-Q-TOF-MS was used to qualitatively analyze various chemical components in Jb. L, and a total of 118 compounds were detected and tentatively identified, including 43 flavonoids, 26 phenylpropanoids, 14 glycosides, 9 phthalides, 8 alkaloids, and others. Among them, 31 compounds were analyzed and compared with reference materials by mass spectrometry. Other components were analyzed by comparing the mass spectrometry and retrieving the reference literature. It may also be necessary to further analyze and verify with reference materials. We developed a UPLC-QqQ-MS/MS method for the simultaneous determination of 31 effective constituents in Jb. L. Formononetin, calycosin, and genistin from Astragali radix are flavonoids and important antioxidant active substances. Ligustilide, bergapten, and ferulic acid are the main active ingredients in Angelica sinensis and Chuanxiong rhizoma and have many physiological activities such as spasmolysis, asthma relief, sedation and analgesia, and myocardial protection. Baicalin, baicalein, and luteoloside are the main active substances in Scutellariae radix and have antiviral effects in vivo and in vitro . Liquiritin, liquiritigenin, glycyrrhizic acid, 18 β -glycyrrhetinic acid, and schaftoside are the main active ingredients in Glycyrrhizae radix . From the perspective of network pharmacology reported in the literature, liquiritin can inhibit the expression of IL-17 inflammatory factors and has an anti-inflammatory effect. Liquiritigenin can regulate the Th1 immune response, and glycyrrhizic acid can inhibit the proliferation of fibroblasts, induce cell cycle arrest and promote cell apoptosis. 18β-Glycyrrhetinic acid can inhibit the production of the coronavirus by interfering with the early stage of virus replication. Schaftoside has the effects of protecting the liver, resisting inflammation, clearing heat, and eliminating dampness. Salvianolic acid B and rosmarinic acid are derived from Salvia miltiorrhiza radix . Salvianolic acid B can inhibit inflammatory cell infiltration, alveolar structure destruction, and collagen deposition in animal experiments. Rosmarinic acid has strong anti-inflammatory, antibacterial, and antiviral activities. Forsythin, forsythoside A, and quercitrin are from Forsythiae fructus and have good anti-inflammatory effects. The main antiviral components of Lonicerae japonicae flos are flavonoids and organic acids, such as chlorogenic acid, isochlorogenic acid A/B/C, caffeic acid, and rutin, which are quantitatively analyzed in this study, and they are the main markers of Lonicerae japonicae flos ’s heat-clearing and detoxification effects. Imperialine and peiminine are derived from Fritillariae cirrhosae bulbus and have the effects of relieving cough, eliminating phlegm, and blocking the production of pro-inflammatory mediators. Adenosine and guanosine are alkaloids commonly contained in twelve TCMs and have the effect of regulating immunity.
The above ingredients confirmed the material basis of Jb. L’s pharmacological activities of invigorating qi, nourishing yin, removing blood stasis, and resolving phlegm. However, we can only infer from the pharmacology reported in the literature, and further research is needed.
In this paper, 118 compounds from Jb. L were identified and analyzed, and a quantitative analysis method for 31 active ingredients was established. Moreover, the verification results of the methodology prove that the quantitative analysis method has good specificity, high sensitivity, and short analysis time, providing a powerful means for the rapid and accurate analysis of the complex system of a Chinese patent medicine preparation. We expect that this strategy may provide a good basis for future research on the metabolomics and network pharmacology of Jb. L and other TCM prescriptions.
Data availability statement
The original contributions presented in the study are included in the article/ Supplementary Material ; further inquiries can be directed to the corresponding author.
AZ: conceptualization, methodology, investigation, software, formal analysis, writing—review and editing. QX: conceptualization, methodology, investigation, software, formal analysis, writing—original draft. JuJ: data curation. ZZ: investigation. LZ: validation. KT: resources. GC: methodology. JiZ: supervision. LD: project administration. ZM: funding acquisition. WD: conceptualization. CW: formal analysis, resources.
The National Science and Technology Major Project for “Significant New Drugs Development” (2014ZX09509001), the Key R & D Program of Shandong Province (2020CXGC010505), the Shandong Natural Science Foundation Joint Fund Project (ZR202209170013), and the Shandong Province Technical Innovation Center of Traditional Chinese Medicine Treatment of Respiratory Diseases provided financial support during the literature search and experimental stages of this project.
Conflict of interest
AZ, QX, JuJ, LZ, KT, GC, JiZ, and ZM were employed by Shandong Hongjitang Pharmaceutical Group Co., Ltd.
The remaining 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.
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.
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2023.1079288/full#supplementary-material
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Keywords: Jinbei oral liquid, quadrupole time-of-flight mass spectrometry, qualitative analysis, triple quadrupole mass spectrometry, quantitative analysis
Citation: Zhang A, Xu Q, Jiang J, Zhao Z, Zhang L, Tao K, Cao G, Zhang J, Ding L, Meng Z, Dong W and Wang C (2023) Qualitative and quantitative determination of chemical constituents in Jinbei oral liquid, a modern Chinese medicine for coronavirus disease 2019, by ultra-performance liquid chromatography coupled with mass spectrometry. Front. Chem. 11:1079288. doi: 10.3389/fchem.2023.1079288
Received: 25 October 2022; Accepted: 11 January 2023; Published: 07 February 2023.
Copyright © 2023 Zhang, Xu, Jiang, Zhao, Zhang, Tao, Cao, Zhang, Ding, Meng, Dong and Wang. 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: Chunxia Wang, [email protected]
† These authors have contributed equally to this work
This article is part of the Research Topic
Advances in Drug discovery and Quality Evaluation