Next Article in Journal
Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay
Previous Article in Journal
Molecular Dynamic Analysis of Hyaluronic Acid and Phospholipid Interaction in Tribological Surgical Adjuvant Design for Osteoarthritis
Article Menu
Issue 9 (September) cover image

Export Article

Molecules 2017, 22(9), 1466; doi:10.3390/molecules22091466

Review
Forsythiae Fructus: A Review on its Phytochemistry, Quality Control, Pharmacology and Pharmacokinetics
Zhanglu Dong, Xianyuan Lu, Xueli Tong, Yaqian Dong, Lan Tang * and Menghua Liu *
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
*
Correspondence: Tel.: +86-20-6164-8597 (M.L.); Fax: +86-20-6164-8533 (M.L.)
Received: 18 July 2017 / Accepted: 24 August 2017 / Published: 4 September 2017

Abstract

:
Forsythiae Fructus, as a traditional Chinese medicine, has been widely used both as a single herb and in compound prescriptions in Asia, mainly due to its heat-clearing and detoxifying effects. Modern pharmacology has proved Forsythiae Fructus possesses various therapeutic effects, both in vitro and in vivo, such as anti-inflammatory, antibacterial and antiviral activities. Up to now, three hundred and twenty-one compounds have been identified and sensitive analytical methods have been established for its quality control. Recently, the pharmacokinetics of Forsythiae Fructus and its bioactive compounds have been reported, providing valuable information for its clinical application. Therefore, this systematic review focused on the newest scientific reports on Forsythiae Fructus and extensively summarizes its phytochemistry, pharmacology, pharmacokinetics and standardization procedures, especially the difference between the two applied types—unripe Forsythiae Fructus and ripe Forsythiae Fructus—in the hope of providing a helpful reference and guide for its clinical applications and further studies.
Keywords:
Forsythiae Fructus; phytochemistry; quality control; pharmacology; pharmacokinetics

1. Introduction

Forsythiae Fructus, the dried fruit of Forsythia suspensa (family Oleaceae), known as lianqiao in China, was first recorded in Shennong Bencao Jing, a prestigious monograph on traditional Chinese medicine (TCM) [1], and subsequently listed in the pharmacopoeias of the People’s Republic of China, Japan and Korea [2,3,4]. It has been used as a heat-clearing and detoxifying TCM for the treatment of infectious diseases, such as acute nephritis, erysipelas and ulcers, for over 2000 years [5,6]. Modern pharmacological studies have confirmed that Forsythiae Fructus possesses anti-inflammatory, antioxidant, antiviral, antivomiting and antitumor activities, as well as hepatoprotective, neuroprotective and cardiovascular protective effects [7,8,9,10,11,12]. Nowadays, more than forty Chinese medicinal preparations containing Forsythiae Fructus are included in the Chinese Pharmacopoeia, Volume I [2]. For example, Forsythiae Fructus is used as a principal drug in Yinqiao Jiedu tablet exerting effects of expelling wind, relieving the exterior, clearing heat and detoxifying [2].
In the clinic two types of Forsythiae Fructus are used, namely the unripe Forsythiae Fructus (Qing qiao, UFF) and ripe Forsythiae Fructus (Lao qiao, RFF). Due to the different harvest times, they are distinguished as UFF and RFF collected at early September and October, respectively [6]. Although both of them have been listed as Forsythiae Fructus in the Chinese Pharmacopoeia, previous studies have found that the harvest time could affect the qualitative profile and relative contents of compounds in Forsythiae Fructus, which might further influence its pharmacological activities. For instance, Jia et al. [6] found a higher antioxidant activity for UFF than for RFF, but no significant difference in antibacterial activities was shown, indicating the differences between UFF and RFF should be considered for their clinical efficacies.
Up to now, a large number of studies focusing on the chemical compounds, pharmacology and quantitative analysis of Forsythiae Fructus have been published. In 2012, a mini review [13] naming chemical constituents of plants from the genus Forsythia reported only one hundred and twenty-one chemical constituents in Forsythiae Fructus, which was much less than those we summarize herein (three hundred and twenty-one compounds). New pharmacological activities and quality control methods have been discovered, so a systematic and updated review is very necessary, as well as a comprehensive comparison between UFF and RFF. Therefore, this review aims to extensively summarize the phytochemistry, quality control data, pharmacology and pharmacokinetics of Forsythiae Fructus, thus providing evidence for further research and clinical applications of this plant.

2. Phytochemistry

With the analysis technologies of nuclear magnetic resonance (NMR), liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS) and infrared spectroscopy (IR), a total of three hundred and twenty-one compounds were identified from Forsythiae Fructus, including fifty-one phenylethanoid glycosides, fifty lignans, nineteen aliphatic alcohols with the C6-C2 skeleton, two iridoids, nineteen diterpenoids, twenty-seven triterpenoids, six sterols, nineteen flavonoids, fifty-two volatiles, seven alkaloids, twenty-eight organic acids, six amino acids, nine sugar derivatives, two allylbenzene glycosides and twenty-four others. Most of them were not mentioned whether obtained from UFF or RFF. The detailed information for these compounds is summarized in Table 1.

2.1. Phenylethanoid Glycosides

Phenylethanoid glycosides are the major bioactive constituents of Forsythiae Fructus with verified anti-inflammatory, antioxidant, antibacterial and antiviral effects [27,28,76,77]. Since forsythoside A (1) was reported by Endo et al. [20] in 1984, fifty-one phenylethanoid glycosides have been isolated from Forsythiae Fructus and their structures were shown in Figure 1. Except for (R)-suspensaside (3), (S)-suspensaside (4), (S)-suspensaside methyl ether (5), β-methoxyforsythoside E (11), acteoside (16), forsythoside B (17), forsythoside G (18), (S)-β-hydroxycalceolarioside C (22), (R)-β-hydroxycalceolarioside C (23), (S)-β-methoxycalceolarioside C (24), (R)-β-methoxycalceolarioside C (25), derhamnosyl suspensaside (27), β-methoxylacteoside (28), caffeoyl calceolarioside C (29), β-methoxyferruginoside B (31), β-methoxylipedoside A (32), suspensaside A isomer (40) and demethyl suspensaside A (41) tentatively identified by a HPLC/MSn method [17,18,22], the remaining compounds were isolated from the 50%, 60%, 70%, 75% or 85% ethanol extract of Forsythiae Fructus and then comfirmed by NMR [11,15,16,21,23,24,25,26,27,28,30]. In addition, forsythoside A (1) is recommended as the marker compound for the quality control of this plant in the Chinese Pharmacopoeia [2].

2.2. Lignans

The lignans are another major bioactive constituents in Forsythiae Fructus and their structures are shown in Figure 2. They are mainly classified into six groups: seven dibenzylbutyrolactones (5258), nineteen furofurans (5977), four arylnaphthalenes (7881), five benzylfurans (8287), nine tetrahydrofurans (8891,95100) and one dibenzylbutane (benzenebutanoic acid, 34). Structures of these compounds were confirmed by NMR after isolation from the methanol or 50% ethyl acetate extract of Forsythiae Fructus. Compounds, such as arctigenin (52), arctiin (53), matairesinoside (54), matairesinol (55), 2′,5′-dihydroxy-4′′-caffeoyl matairesinol (56), 3′,4′,5′-trihydroxy-3′′-methoxy-4′′-caffeoyl lignin (57), caffeoyl phillygenin (61), pinoresinol diglucoside (71), caffeoyl pinoresinol (72), 3′,4′,5′-trimethoxy-4′′-hydroxyllignan O-glucoside (76) and 3-furanone-2-(3-methoxy-4-hydroxy-phenyl)-4-veratryl (97) were tentatively identified by molecular weight and fragmentations by a HPLC-MSn method [17,22]. Among these compounds, phillyrin (60) is also recommended as the marker compound for Forsythiae Fructus in the Chinese pharmacopoeia [2].

2.3. Aliphatic C6-C2 Alcohols

To date, eighteen natural alcohols with the C6-C2 skeletons have been isolated from Forsythiae Fructus, since rengyol (103), rengyolone (110) and rengyoxide (111) were first reported in 1984 by Endo et al. [20]. Subsequently, they identified isorengyol (102), rengyoside A (106) and rengyoside C (107) in 1987 and 1989 [29,40]. Compounds cornoside (113), forsythenside A (114), forsythenside B (115), forsythensides G-J (118120), togerther with rengyolester (105) were obtained from 60%, 70% or 75% ethanol extract of Forsythiae Fructus [23,42,45], whereas suspenol (104), rengynic acid-1′-O-β-d-glucopyranoside (109) and forsythenside F (116) were isolated from methanol extract, aqueous extract and 50% acetone extract respectively [41,44,46]. The structures of these compounds are shown in Figure 3.

2.4. Iridoids, Diterpenoids and Triterpenoids

As shown in Figure 4, two iridoids (121122), nineteen diterpenoids (123141) and twenty-seven triterpenoids (142168) have been confirmed in Forsythiae Fructus. Most of them were reported by Kuo et al. [38] in 2017. The triterpenoid fraction contains eleven tetracyclic triterpenoids (142152) and sixteen pentacyclic triterpenoids (136151). Compounds such as ocotillone (142), ocotillol monoacetate (143) and oleanolic acid (153) were obtained from the 70% ethanol extract of Forsythiae Fructus [49,52]. Rouf et al. [50] found two new triterpenoids, namely 3β-acetyl-20,25-epoxy-dammarane-24α-ol (145) and 3β-acetyl-20,25-epoxydammarane-24β-ol (146) and confirmed their anti-inflammatory activities. Xue et al. [47] revealed dammar-24-en-3β-acetoxy-20-ol (147), 3β-acetoxy-20S,24R-dammarane-25-ene-24-hydroperoxy-20-ol (149) and 3-acetylisofouquierol (152) possessing strong anti-proliferative effect on MKN-45, BGC-823 and SGC-9701 cells in the 95% ethanol extract of Forsythiae Fructus.

2.5. Sterols

Six sterols, namely β-sitosterol (169), daucosterol (170), taraxasterol acetate (171), stigmasterol (172), ψ-taraxasterol (173) and (6′-O-palmitoyl)-sitosterol-3-O-β-d-glucoside (174), have been isolated from Forsythiae Fructus and identified by 1H- and 13C-NMR [48,49,56,57]. Their structures are shown in Figure 5.

2.6. Flavonoids

Flavonols, represented by quercetin (177) and its derivatives (178179), are the main types of flavonoids identified in Forsythiae Fructus. Forsythoneosides A−D (190193), four unusual condensation products of flavonoids and phenylethanoid glycosides isolated from the 75% ethanolic extract, displayed neuroprotective effects on rotenone-injured PC12 cells [11]. One rutin derivative (176), two quercetin derivatives (178179) and two kaempferol derivatives (183184) were extracted by 50% aqueous methanol and identified by HPLC-MS, but the exact attachment positions of the saccharides were unknown [22]. In addition, wogonin-7-O-glcoside (187) and baicalin (188), belonging to flavones, were also found in Forsythiae Fructus [58,60]. Their chemical structures are presented in Figure 6.

2.7. Volatiles

Forsythiae Fructus is also rich in volatiles. A total of fifty-two compounds with anti-inflammatory, anti-oxidant and antimicrobial effects were identified in the oil by GC-MS [61,62,63,64,65,66]. β-pinene (195, 45.88%), myrtenol (196, 13.86%), (+)-α-pinene (197, 13.09%), (−)-trans-pinocarveol (198, 7.34%), sabinene (199, 6.64%) and pinocarvone (200, 4.13%) were the major volatiles of Forsythiae Fructus [61]. Zhai et al. [63] compared five methods, including ionic liquid microwave extraction, hydrodistillation, microwave hydrodistillation, solvent-free microwave extraction and improved solvent-free microwave extraction to extract volatiles, but no significant difference in the oil composition was found. Jiao et al. [64] developed an enzyme-assisted microwave hydro-distillation method, which reached a maximum extraction yield of 3.27%.

2.8. Alkaloids

Alkaloids represent a relatively small class of compounds in Forsythiae Fructus. To date, seven alkaloids, namely rutaecarpine (246), suspensine A (247), (−)-egenine (248), (−)-7′-O-methylegenine (249), (−)-bicuculline (250), bis-2-(4-aminophenyl)ethyl-β-d-glucopyranoside (251) and choline (252) were obtained from the ethanolic extract of Forsythiae Fructus [6,57,67,68]. Their chemical structures are presented in Figure 7.

2.9. Others

Moreover, other compounds, including twenty-eight organic acids (253280), six amino acids (281286), nine sugar derivatives (287295), two allylbenzene glycosides (296297) and some miscellaneous compounds (298321) were also obtained from Forsythiae Fructus [6,14,18,23,30,36,45,48,56,58,60,69,70,71,72,73,74]. Their structures are shown in Figure 8.

3. Quality Control

Quality control is very important for the use of TCMs. Many rapid, sensitive and stable technologies, such as HPLC–ESI-MS/MS, LC–MS/MS and HPLC-ESI-MS have been applied for quantitative analysis of Forsythiae Fructus [18,31,58,66,78,79,80,81,82,83,84,85,86,87,88,89,90,91]. A total of twenty-nine compounds: forsythoside A (1), (R)-suspensaside (3), (S)-suspensaside (4), (S)-suspensaside methyl ether (5), forsythoside E (10), forsythoside B (17), suspensaside A (39), arctigenin (52), matairesinol-4′-O-glucoside (58), phillygenin (59), forsythin (60), phillyrin (60), (+)-epipinoresinol (62), (+)-epi-pinoresinol-4′-O-β-d-glucoside (64), pinoresinol (68), (+)-pinoresinol-β-d-glucoside (69), rutin (175), quercetin (177), hyperin (182), baicalin (188), hesperidin (189), chlorogenic acid (258) anchoic acid (259), 4-hydroxy-4-isopropylcyclohex-1-ene carboxylic acid (260), p-coumaric acid (261) p-hydroxy-benzoic acid (264), cafferic acid (268), p-hydroxyphenylethanol (314) and p-hydroxybenzyl alcohol (315) have been quantified by HPLC or HPLC-MS by different research groups [18,58,78,79,80,81,82,83,84,85,86,87,88,89,90]. The volatile substances, such as β-pinene (194), camphene (202), myrcene (203), α-pinene (212), α-terpineol (236), p-cymene (244) and limonene (245) were detected by GC [66]. Interestingly, the contents of forsythoside A (1), phillygenin (59), phillyrin (60), (+)-epipinoresinol (62), (+)-epi-pinoresinol-4-O-β-d-glucoside (64), (+)-pinoresinol-β-d-glucoside (69) and rutin (175) were 0.85–15.71%, 0.02898–2.16%, 1.08–1.27%, 1.11–2.10%, 0.91–1.64%, 0.52–1.44% and 0.05–0.36%, respectively, in UFF and 0.02968–10.59%, 0.02148–2.5%, 0.08–0.54%, 0.16–0.64%, 0.22–0.58%, 0.12–0.48% and 0.0556–0.0583%, respectively, in RFF. Jia et al. [6] revealed that RFF contained much more forsythoside A, forsythoside C, rutin and phillyrin (5.07 times, 2.78 times, 2.62 times, 1.35 times, respectively) than UFF, whereas the amino acid content in the UFF was higher than that in the RFF. In addition, the volatile compounds of α-pinene and β-pinene were 0.102–0.337% and 0.342–1.024% in the UFF, respectively, which were higher than the levels in the RFF [66,91]. The harvest times could affect the contents of active compounds in Forsythiae Fructus, which should be considered when assessing their clinical efficacies. The quantitative analysis of Forsythiae Fructus are listed in Table 2.

4. Pharmacology

Forsythiae Fructus has long been used in China, Korea, Japan and other Southeast Asian countries because of its various pharmacological effects. The bioactivities of the active constituents of Forsythiae Fructus, including phenylethanoid glycosides, lignans and flavonoids, have been studied, but these constituents also exhibit new pharmacological activities. The pharmacological effects of this herb are listed in Table 3.

4.1. Anti-Inflammatory Effect

The anti-inflammatory effect of Forsythiae Fructus is its most common clinical use. According to Taiwan’s nationwide prescription database, Forsythiae Fructus has been listed in the top 10 most commonly used single herbs for the treatment of atopic dermatitis (15.9%), urticaria (11.49–13.4%) and acne (22.3%) [5,156,157]. Recently, numerous studies have found that ethanol, methanol and aqueous extracts of Forsythiae Fructus exhibited significant anti-inflammatory effects in vitro and in vivo [92,93,94,95,96,97,98]. In addition, its volatiles showed an anti-inflammatory effect in models of mouse ear-swelling, mouse celiac capillary permeability, rat paw-swelling, rat hind paw edema, oleic acid-stimulated acute lung injury and rat cotton pellet granuloma by inhibiting the release of prostaglandin 2 (PGE2), histamine and serotonin [99]. Forsythoside A (1), arctigenin (52), arctiin (53), matairesinol (55), phillyrin (60), forsythin (60), suspensine A (247), (−)-egenine (248), 7′-O-methylegenine (249) and (−)-bicuculline (250) were active compounds isolated from Forsythiae Fructus and exhibited anti-inflammatory effects [67,100,101,103,104,106,109]. Forsythoside A (1) decreased the levels of pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO) and PGE2 in lipopolysaccharide (LPS)-stimulated BV2 microglia cells, RAW264.7 cells, human bronchial epithelial cells (BEAS-2B), acute liver injury mice and bursa of Fabricius of chicken, as well as in a mouse model of cigarette smoke-induced lung damage, through influencing the nuclear factor-κB (NF-κB), mitogen activated protein kinase (MAPK) and nuclear related factor 2/heme oxygenase 1(Nrf2/HO-1) signaling pathways [76,100,102,105,107,110]. Phillyrin (60) at 20 mg/kg showed an ameliorative effect on LPS-induced alveolar hemorrhage and neutrophil infiltration in lung injury mice by decreasing the production of TNF-α, IL-1β and interleukin-6 (IL-6) through MAPK and NF-κB signaling pathways [103].
Forsythin (60), a novel PDE4 inhibitor, inhibited the expression of PDE4 and production of NO, inducible nitric oxide synthase (iNOs), Toll-like receptor 4 (TRL4), TNF-α, IL-1β in LPS-induced lung injury mice, LPS-stimulated BV2 microglial cells and Staphylococcus aureus-induced monocyte-macrophages [94,95,99,111]. Arctiin (53) exhibited an anti-inflammatory effect in LPS-damaged macrophage cells by inhibiting the production of NO, PGE2, TNF-α, IL-1β, IL-6 and the expression of COX-2 [104]. Four alkaloids, namely suspensine A (247), (−)-egenine (248), 7′-O-methylegenine (249) and (−)-bicuculline (250), demonstrated an anti-inflammatory effect at a concentration of 10 μM by inhibiting the release of β-glucuronidase from polymorphonuclear leukocytes in the range of 34.8% to 39.6% [67]. In a word, the anti-inflammatory effects of Forsythiae Fructus and its constituents are closely related to the inhibition of pro-inflammatory mediators through activation of the Nrf2/HO-1 signaling pathway and downregulation of the NF-κB, JAK-STAT and p38 MAPK signaling pathways [101,104,107,110].

4.2. Antibacterial Effect

In vitro, the volatiles of Forsythiae Fructus exhibited good antibacterial effects against S. pneumoniae, Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), Haemophilus influenza, a beta-group Streptococcus, Yersinia enterocolitica, Klebsiella pneumonia, F’s dysentery bacillus, Salmonella typhi and Pseudomonas aeruginosa, with MICs of 172.90, 172.90, 172.90, 172.90, 172.90, 86.45, 172.90, 345.80, 518.70 and 864.50 μg/mL, respectively [112,113]. The mechanism might be closely related to the disruption of the cell membrane and degradation of bacterial proteins [112]. Ethanol, methanol and aqueous extracts of Forsythiae Fructus also exhibited antibacterial activity [114,115,116]. Li et al. [114] found that the ethanol extract remarkably decreased secretion of α-hemolysin in S. aureus at a concentration of 16–128 mg/L. Han et al. [115] demonstrated that the aqueous extract inhibited growth of E. coli, S. aureus and Salmonella in a dose-dependent manner, indicating its uses in broiler chickens as a substitute antibiotic in vivo. The active compounds of Forsythiae Fructus were assessed for their antibacterial activities by E. coli, Pseudomonas aeruginosa, S. aureus, Helicobacter pylori and Klebsiella pneumoniae. As a result, the MIC values of forsythoside A (1), isoforsythoside A (30), phillyrin (60), 3β-hydroxyanticopalic acid (124), agatholic acid (125), β-amyrin acetate (155), 3β-acetoxy-20α-hydroxyursan-28-oic acid (159), betulinic acid (160) and ψ-taraxasterol (173) for E. coli were 38.33, 40.83, 3.94, 3.42, 2.62, 5.00, 4.55, 1.20 and 1.20 μg/mL, respectively [27,48]. The MIC values of forsythoside A (1) and isoforsythoside A (30) were 38.33 and 40.83 μg/mL, respectively, for Pseudomonas aeruginosa and 76.67 and 81.66 μg/mL for S. aureus [27]. In addition, some studies indicated that the antibacterial effect of Forsythiae Fructus was related to its inhibitory effect on the efflux pump of bacteria, but these studies are still in a primary stage [116].

4.3. Antiviral Effect

The antiviral effect of Forsythia Fructus mainly focused on influenza A (H1N1) virus, respiratory syncytial virus (RSV) and infectious bronchitis virus (IBV). Previous studies suggested that the 80% ethanol extract of Forsythia Fructus protected H1N1-infected MDCK cells with a minimal inhibitory concentration (MIC) of 1:8192 mg/mL [8]. Ko et al. [117] found that the 95% ethanol, 50% ethanol and aqueous extracts exhibited a dual regulatory effect on H1N1-infected human bronchial epithelial cells with IC50 values of 42 ± 6, 117 ± 15 and 232 ± 28 g/mL, respectively. Four compounds from Forsythia Fructus, namely forsythoside A (1), calceolarioside B (33), phillyrin (60) and rengynic acid (108), also demonstrated significant antiviral activity. In vivo, forsythoside A (1) at 20 ug/kg was able to control H1N1 infection and relieved the symptoms by inhibiting expression of Toll-like receptor 7 (TLR7), MyD88, tumor necrosis factor receptor-associated factor 6 (TRAF6), interleukin-4 receptor-associated kinase (IRAK4) and NF-kB p65 mRNA and H1N1 replication in C57BL/6j mice [77]. Phillyrin (60) inhibited H1N1 expresstion by down-regulating the gene of the H1N1 nucleoprotein in vitro and in vivo [118,119]. Meanwhile, forsythoside A (1), calceolarioside B (33) and rengynic acid (108) exhibited good anti-RSV effects in multiple different cell lines [23,43,120]. In addition, forsythoside A (1) was able to inhibit IBV in primary chicken embryo kidney cells at a concentration of 0.16 to 0.64 mm and in HD11 cells at a concentration from 10 uM/L to 20 uM/L, suggesting its potential for preventing IBV infection [121,122].

4.4. Antioxidant Effect

Recently, some studies revealed the anti-oxidative effect of the Forsythia Fructus extract and its compounds in the 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and ferric reducing antioxidant power (FRAP) assays in vitro [25,27,28,123,124,125]. The results indicated that forsythoside A (1), isoforsythoside A (30), phillygenin (59), phillyrin (60), forsythialan A (88) and polysaccharides exhibited strong antioxidant effects, with the DPPH IC50 values of 0.43, 2.74, 53.64, 351.14, 29.86 μg/mL and 0.08 mg/mL, respectively [27,123,124]. Calceolarioside C (21), forsythoside H (38) and lianqiaoxinoside B (43) were tested by the ABTS test and exhibited IC50 values of 22.7, 17.7 and 15.6 μg/mL, respectively [25,28]. Additionally, the ethyl acetate extract of Forsythia Fructus showed a strong antioxidant activity by the DPPH and FRAP assays [125]. Phillygenin (59) and 8-hydroxypinoresinol (73) at 50 μM were confirmed to reverse a LLC-PK1 cell damage induced by 3-morpholinosydnonimine, an ONOO-generator [126]. In addition, eight lignans—phillygenin (59), 7′-epi-8-hydroxypinoresinol (63), pinoresinol (68), 8-hydroxypinoresinol (73), isolaraciresinol (78), cedrusin (82), olivil (94) and lariciresinol (98) exerted inhibitory effects against lipid peroxidation of high-density lipoprotein (HDL) induced by AAPH (a thermo-labile radical generator), with IC50 values ranging from 12.1 to 51.1 μM [32]. In vivo, pretreatment with a CH2Cl2 fraction of Forsythia Fructus 80% ethanol extract inhibited oxidative stress in diquat-treated rats. The mechanism was associated with an increase in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well as the levels of GSH in plasma, liver and kidney, whereas a reduction in the level of malondialdehyde (MDA) was observed in plasma and the kidney [124]. Yan et al. [127] found that the anti-aging effect of phillyrin (60) is closely related to the antioxidant effect in aging model mice. Interestingly, the Forsythia Fructus extract has been used as an animal feed additive in weaned piglets and Arbor Acre broilers, mainly due to the improvement in growth performance via the modulation of some endogenous antioxidant molecules and oxidative stress biomarkers (SOD, GSH-Px and MDA) [128,129,130].

4.5. Neuroprotective Effect

The neuroprotective effect is a newly established research direction for Forsythiae Fructus. Zhang et al. [131] found that the Forsythiae Fructus ethanol extract reduced rotenone toxicity and protected PC12 cells. Further in vivo study demonstrated that Forsythiae Fructus (50 and 200 mg/kg) exhibited a protective effect in rotenone-stimulated rats through down-regulating inflammatory and oxidation factors. Forsythoside A (1) was the main compound with neuroprotective effects reported in Forsythiae Fructus. It ameliorated the physiology of senescence-accelerated mouse prone (SAMP8) mice and scopolamine-induced memory deficit mice, with significant increase in total superoxide dismutase (T-SOD), choline acetyl transferase (ChAT) and GSH-Px activities; significant decrease in MDA and NO levels; inhibition of AchE activity and increase of p-ERK expression, indicating that its mechanism might be to regulate the cholinergic system and antioxygenation [132,133,134]. Furthermore, cognitive functions of gerbils with transient cerebral global ischemia were ameliorated after treatment with forsythoside A (1) at 10 mg/kg due to the inhibition of activated microglia and astrocytes [135]. In vitro, forsythoside A (1) significantly inhibited the cell apoptosis induced by Aβ25-35 in PC12 and HT22 cells, which are closely related to Alzheimer’s disease [136,137]. Moreover, phillyrin (60) protected SH-SY5Y neuroblastoma cells against MPP+ [138], while forsythoneoside B (191) and forsythoneoside D (193) at 0.1 μM significantly inhibited PC12 cell damage induced by rotenone and increased cell viability [11], indicating their potential toward Parkinson’s disease.

4.6. Antitumor Effect

Forsythiae Fructus aqueous extract treatment of B16-F10 melanoma-transplanted C57BL/6 mice inhibited cancer cell proliferation and angiogenesis and prolonged their survival time, indicating a noticeable antitumor activity. The results revealed that this effect has a close relationship with antioxidant and anti-inflammatory activities via the MAPKs/Nrf2/HO-1 pathway [7]. The LQ-4 extract (which contains at least twelve types of compounds) showed antitumor actions on Hela and SGC-7901 cells by inhibiting cell proliferation and inducing apoptosis, which were probably related to the decomposition of caspase-8 protease [139,140,141]. Phillyrin (60) exhibited an antitumor effect on Lewis lung carcinoma in vivo at three doses of 5, 10 and 20 g/kg/d by decreasing vascular endothelial growth factor (VEGF) expression and increasing endostatin expression [142]. In addition, (+)-8-hydroxyepipinoresinol-4-O-β-d-glucopyranoside (65) showed significant cytotoxicity to A549, Colo205, Hep-3B, HL60 and KB cancer cell lines with IC50 values of 9.48, 7.75, 0.59, 4.06 and 38.38 μM, respectively [34]. Moreover, dammar-24-en-3β-acetoxy-20-ol (147) and ambrolic acid (163) from Forsythiae Fructus were tested against SGC-7901 and PC-3 cells. Both of them induced apoptosis of SGC-7901 cells dose-dependently by down-regulating the expression of caspase proteins (caspase 3, 6, 8 and 9) and up-regulating the levels of Bax [51,55], whereas, dammar-24-en-3β-acetoxy-20-ol (147) might also inhibit the activities of telomerases in PC-3 cells, thus enhancing the radiosensitivity of PC-3 cells [143].

4.7. Hepatoprotective Effect

The active compound phillygenin (59) in Forsythiae Fructus has been shown to exhibit a protective effect against acute liver injury induced by CCl4 in rats at the dosages of 0.05, 0.15, 0.5 mg/kg. It increased the activities of SOD, GSH-Px and GSH; decreased MDA and reduced the levels of TNF-α and IL-8 in liver tissue [10]. Wang et al. [144] reported that Lian qiao gan yuan (phillygenin) protected against hepatic fibrosis induced by bovine serum albumin in rats. However, the author considered forsythoside A (1) to be Lian qiao gan yuan in Chinese. Forsythin (60) showed a protective capability against alcohol-induced liver injury by suppressing expression of apoptosis factors (PARP and caspase 3) [145]. Moreover, the aqueous extract of Forsythiae Fructus excerted a hepatoprotective effect in liver injured rats with acute pancreatitis at three dosages of 1.25, 2.5 and 5.0 g/kg. This was associated with inhibition of mRNA expression of NF-κB and Foxp3, subsequently reducing activation of the NF-κB signaling pathway, which plays an important role in the pathogenesis of severe acute pancreatitis [146].

4.8. Cardiovascular Protective Effect

The cardiovascular protective activity of Forsythiae Fructus and its compounds has been reported in recent years. In an in vivo study, oral administration of ethyl acetate extract at dosages of 50, 100 and 200 mg/kg improved pathological damage and increased the serum level of insulin as well as expression of pancreatic function genes (PDX-1, INS-1 and INS-2) in streptozotocin-induced diabetic mice, indicating its potency as an antihyperglycemic and antihyperlipidemic agent [147]. Treatment with 150 mg/kg phillyrin (60) for ten weeks in an atherosclerosis (AS) model noticeably reduced the area of AS plaques, improved the function of arterial condensation and inhibited expression of sodium hydrogen exchange protein 1 (NHE-1), intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VACM-1), IL-1 and IL-6 [12]. Moreover, forsythoside A (1) exhibited a vasorelaxant effect against norepinephrine-stimulated vasocontraction in rats by decreasing calcium influx from the extracellular space [148].

4.9. Others

The aqueous extract of Forsythiae Fructus reduced the serum gastrin content and promoted gastrointestinal movement, demonstrating an anti-vomiting effect in mice exposed to chemotherapy [9]. Phillyrin (60) was shown to exert a remarkable antiobesity effect in high glucose-induced lipid accumulation in HepG2 cells and 3T3-L1 adipocytes, as well as in obese mice [149,150,151]. The mechanism of action was possibly due to inducing the liver kinase B1 (LKB1) phosphorylation and activating AMP-activated protein kinase (AMPK), thus reducing expression of sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase. Interestingly, forsythoside A (1) exhibited antiandrogenic alopecia activity in dihydrotestosterone-stimulated mice by suppressing the apoptosis of hair cells [152]. Forsythoside A (1) also exhibited an immune regulation effect in endotoxemia mice by down-regulating mRNA expression of Foxp3 and decreasing the secretion of IL-10 and TNF-α [153]. Moreover, in yeast-stimulated pyrexia mice, forsythoside A (1) increased the expression of temperature-sensitive transient receptor potential A1 (TRPA1), thereby taking antipyretic effect [154]. Furthermore, a study demonstrated that forsythoside A inhibited P-gp ATPase activity, thus influencing the efflux of drugs [155].

5. Pharmacokinetics

Pharmacokinetic studies have provided a scientific basis for the clinical application of Forsythiae Fructus and the data were presented in Table 4. When Sprague Dawley (SD) rats were orally administrated UFF and RFF extract, the main active compounds of forsythoside A (1), phillyrin (60), rutin (175), quercetin (177) and isorhamnetin (180) showed very different pharmacokinetic parameters, including Cmax, AUC0–24 h and Tmax. Generally, the AUC0–24 h and Cmax were much higher in the UFF group than in the RFF group. The absorption was faster after oral administration of UFF, as reflected by Tmax, whereas quercetin (177) and isorhamnetin (180) couldn’t be detected after RFF treatment. The pharmacokinetic properties after multiple-dose treatment had significantly increased than those after single-dose treatment, indicating that the harvest times affected the contents and bioavailability of active compounds in Forsythiae Fructus [59]. Liu et al. [31] developed an HPLC-ESI-MS/MS method for the quantification of matairesinol-4′-O-glucoside (58), phillygenin (59), phillyrin (60), (+)-pinoresinol-β-d-glucoside (69) and hyperin (182) in rat bile after oral administration of 75% methanol extract of Forsythiae Fructus, revealing that bile was the major pathway for the excretion of lignans in Forsythiae Fructus. Forsythoside A (1), phillygenin (59) and phillyrin (60) were the three most studied compounds in Forsythiae Fructus for pharmacokinetics. After oral administration of forsythoside A, the absorption was fast with a Tmax of 20 min, but the bioavailability was only 0.5% [158]. Furthermore, Chen et al. [159] revealed that most of forsythoside A (1) was excreted through bile due to the bile-to-blood distribution ratio was 0.32 ± 0.06 after intravenous administration. Phillyrin (60) was absorbed into plasma through passive diffusion and could be influenced by P-gp, thus exhibiting a low bioavailability [160]. After oral administration, a total of thirty-four metabolites of phillyrin (60) were found in rat bile, urine and feces by UPLC-Q-TOF-MS, providing a basis for the pharmacological activities of phillyrin in vivo, and the results also revealed that deglucosidation was the main metabolic reaction for phillyrin [161]. Absorption of phillygenin (59) was linear at three dosages of 1.4, 2.8, and 5.6 mg/kg, but it showed a rapid elimination rate of approximately 6 min [162]. In addition, forsythoside A induced the activities of CYP1A2 and CYP2C11, while phillyrin induced the activities of CYP1A2 and CYP2D1, which provided very useful information about interactions in the combination drug therapy [163].

6. Conclusions

In Asia, Forsythiae Fructus is widely used in the clinic as a single drug or compound prescription. Modern pharmacology showed that it has a variety of bioactivities, including anti-inflammatory, antibacterial, antiviral, antioxidant, antitumor, antidiabetic, antihyperlipidemic, antiandrogenic alopecia, antivomiting, antiaging and anti-obesity activities, as well as neuroprotective, hepatoprotective and vasorelaxant effects. In the past few years, many sensitive analysis technologies have been used for research of this herb. Three hundred and twenty-one compounds have been identified, including fifty-one phenylethanoid glycosides, fifty lignans, nineteen aliphatic alcohols with the C6-C2 skeleton, two iridoids, nineteen diterpenoids, twenty-seven triterpenoids, six sterols, nineteen flavonoids, fifty-two volatiles, seven alkaloids, twenty-eight organic acids, six amino acids, nine sugar derivatives, two allylbenzene glycosides and twenty-four others. Among them, forty-five were from the UFF, twenty-two were from the RFF, twenty-one were from the UFF and RFF and the remaining compounds have not been mentioned from UFF or RFF.
Moreover, phenylethanoid glycosides (forsythoside A), lignans (phillyrin, arctiin) and flavonoids (rutin, forsythoneoside D) are the major constituents and exerted various bioactivities, such as anti-inflammatory, antiviral, and neuroprotective effects. Additionally, the different harvest times not only affected the contents but also the bioavailabilities of the active compounds, especially forsythoside A and phillyrin. However, few studies have reported the difference in pharmacological activities between UFF and RFF. Altogether, this review extensively summarized the phytochemistry, quality control, pharmacology and pharmacokinetics of Forsythiae Fructus, especially the UFF and RFF, and provided evidence for its further research and clinical applications.

Acknowledgments

The project was financially supported by the National Natural Science Foundation of China (81503376) and applied science and technology research Foundation of Guangdong Province (2016B020237005).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Xu, L.G.; Huang, R.Q. Textual research on “Lianqiao” whose other name be “Lanhua” (cymbidium) in Shen Nong’s Herbal. Lishizhen Med. Mater. Med. Res. 2000, 11, 358–359. [Google Scholar]
  2. International Pharmacopoeia Commission. Pharmacopoeia Commission of the People’s Republic of China. In Pharmacopoeia of People’s Republic of China; Chemical Industry Press: Beijing, China, 2015; Volume 1, pp. 1–1750. ISBN 978-7-5067-7337-9. [Google Scholar]
  3. The Japan Drug Editional Commission of Administration. Japanese Pharmacopoeia; Ministry of Health, Labour and Welfare: Tokyo, Japan, 2011; pp. 1–2131.
  4. Korea Food and Drug Administration. South Korean Pharmacopoeia; Monografs Part II; Ministry of Health and Welfare: Se jong, Korean, 2015; pp. 1004–1241.
  5. Chen, H.Y.; Lin, Y.H.; Huang, J.W.; Chen, Y.C. Chinese herbal medicine network and core treatments for allergic skin diseases: Implications from a nationwide database. J. Ethnopharmacol. 2015, 168, 260–267. [Google Scholar] [CrossRef] [PubMed]
  6. Jia, J.P.; Zhang, F.S.; Li, Z.Y.; Qin, X.M.; Zhang, L.W. Comparison of Fruits of Forsythia suspensa at Two Different Maturation Stages by NMR-Based Metabolomics. Molecules 2015, 20, 10065–10081. [Google Scholar] [CrossRef] [PubMed]
  7. Bao, J.L.; Ding, R.B.; Zou, L.D.; Zhang, C.; Wang, K.; Liu, F.; Li, P.; Chen, M.W.; Wan, J.B.; Su, H.X.; et al. Forsythiae Fructus Inhibits B16 Melanoma Growth Involving MAPKs/Nrf2/HO-1 Mediated Anti-Oxidation and Anti-Inflammation. Am. J. Chin. Med. 2016, 44, 1043–1061. [Google Scholar] [CrossRef] [PubMed]
  8. Su, W.; Xu, H.F.; Huang, H. Effects of the extract of Forsythia suspensa on influenza A H1N1 infection in vitro. J. Med. Plants Res. 2010, 4, 1455–1458. [Google Scholar]
  9. Zuo, T. Study on the Mechanism of Forsythia Suspensa Preventing Vomiting Effect on Chemotherapy Mice. China J. Chin. Med. 2015, 30, 1400–1404. [Google Scholar]
  10. Feng, Q.; Xia, W.K.; Wang, X.Z.; Song, H.Y.; Yao, J.C. Protective effects of phillygenin against CCl4 induced hepatic injury in rat. Chin. Pharmacol. Bull. 2015, 31, 426–430. [Google Scholar]
  11. Zhang, F.; Yang, Y.N.; Song, X.Y.; Shao, S.Y.; Feng, Z.M.; Jiang, J.S.; Li, L.; Chen, N.H.; Zhang, P.C. Forsythoneosides A–D, Neuroprotective Phenethanoid and Flavone Glycoside Heterodimers from the Fruits of Forsythia suspense. J. Nat. Prod. 2015, 78, 2390–2397. [Google Scholar] [CrossRef] [PubMed]
  12. Zhou, N.Q.; Li, P.; Shi, W.D.; Bai, S.P. The effects and mechanism of Forsythia suspensa on Atherosclerosis Rats Model. Pharm. Clin. Chin. Mater. Med. 2016, 32, 28–33. [Google Scholar]
  13. Zhang, Q.; Jia, C.H.; Xu, H.Y.; Wang, Y.F.; Zhang, M.L.; Huo, C.H.; Shi, Q.W.; Yu, S.H. Chemical Constituents of Plants from the Genus Forsythia. Mini Rev. Org. Chem. 2012, 9, 303–318. [Google Scholar]
  14. Yan, X.J.; Bai, X.Y.; Liu, Q.B.; Liu, S.; Gao, P.Y.; Li, L.Z.; Song, S.J. Two new glycosides from the fruits of Forsythia suspense. J. Asian Nat. Prod. Res. 2014, 16, 376–382. [Google Scholar] [CrossRef] [PubMed]
  15. Kuang, H.X.; Xia, Y.G.; Yang, B.Y.; Liang, J.; Zhang, Q.B.; Li, G.Y. A New Caffeoyl Phenylethanoid Glycoside from the Unripe Fruits of Forsythia suspensa. Chin. J. Nat. Med. 2009, 7, 278–282. [Google Scholar] [CrossRef]
  16. Ming, D.S.; Yu, D.Q.; Yu, S.S. Two New Caffeyol Glycosides from Forsythia suspensa. J. Asian Nat. Prod. Res. 1999, 1, 327–335. [Google Scholar] [CrossRef] [PubMed]
  17. Ni, Y.N.; Zhuang, H.; Kokot, S. A High Performance Liquid Chromatography and Electrospray Ionization Mass Spectrometry Method for the Analysis of the Natural Medicine, Forsythia Suspensa. Anal. Lett. 2014, 47, 102–116. [Google Scholar] [CrossRef]
  18. Cui, Y.; Wang, Q.; Shi, X.W.; Zhang, X.W.; Sheng, X.N.; Zhang, L.T. Simultaneous Quantification of 14 Bioactive Constituents in Forsythia Suspensa by Liquid Chromatography-Electrospray Ionization-Mass Spectrometry. Phytochem. Anal. 2010, 21, 253–260. [Google Scholar] [CrossRef] [PubMed]
  19. Guo, H. Studies on the Chemical Constituents of Forsythia suspensa. Ph.D. Thesis, Peking University, Beijing, China, May 2006. [Google Scholar]
  20. Endo, K.; Hikino, H. Structures of rengyol, rengyoxide, and rengyolone, new cyclohexylethane derivatives from Forsythia suspensa fruits. Can. J. Chem. 1984, 62, 2011–2014. [Google Scholar] [CrossRef]
  21. Wang, F.N.; Ma, Z.Q.; Liu, Y.; Guo, Y.Z.; Gu, Z.W. New phenylethanoid glycosides from the fruits of Forsythia suspensa (Thunb.) Vahl. Molecules 2009, 14, 1324–1331. [Google Scholar] [CrossRef] [PubMed]
  22. Guo, H.; Liu, A.H.; Ye, M.; Yang, M.; Guo, D.A. Characterization of phenolic compounds in the fruits of Forsythia suspensa by high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Rapid Commun. Mass Spctrom. 2007, 21, 715–729. [Google Scholar] [CrossRef] [PubMed]
  23. Li, C.; Dai, Y.; Zhang, S.X.; Duan, Y.H.; Liu, M.L.; Chen, L.Y.; Yao, X.S. Quinoid glycosides from Forsythia suspensa. Phytochemistry 2014, 104, 105–113. [Google Scholar] [CrossRef] [PubMed]
  24. Li, C.; Dai, Y.; Duan, Y.H.; Liu, M.L.; Yao, X.S. A new lignan glycoside from Forsythia suspensa. Chin. J. Nat. Med. 2014, 12, 697–699. [Google Scholar] [CrossRef]
  25. Xia, Y.G.; Yang, B.Y.; Liang, L.; Kuang, H.X. Caffeoyl Phenylethanoid Glycosides from Unripe Fruits of Forsythia Suspensa. Chem. Nat. Compd. 2015, 51, 656–659. [Google Scholar] [CrossRef]
  26. Liu, D.L.; Zhang, Y.; Xu, S.X.; Xu, Y.; Wang, Z.X. Phenylethanoid Glycosides from Forsythia suspensa Vahl. J. Chin. Pharm. Sci. 1998, 7, 103–106. [Google Scholar]
  27. Qu, H.H.; Zhang, Y.M.; Chai, X.Y.; Sun, W.J. Isoforsythiaside, an antioxidant and antibacterial phenylethanoid glycoside isolated from Forsythia suspensa. Bioorg. Chem. 2012, 40, 87–91. [Google Scholar] [CrossRef] [PubMed]
  28. Kuang, H.X.; Xia, Y.G.; Liang, J.; Yang, B.Y.; Wang, Q.H. Lianqiaoxinoside B, a novel caffeoyl phenylethanoid glycoside from Forsythia suspensa. Molecules 2011, 16, 5674–5681. [Google Scholar] [CrossRef] [PubMed]
  29. Seya, K.; Endo, K.; Hikino, H. Structures of rengyosides A, B, and C, three glucosides of Forsythia suspensa fruits. Phytochemistry 1989, 28, 1495–1498. [Google Scholar] [CrossRef]
  30. Yan, X.J.; Wen, J.; Xiang, Z.; Cai, D.; Lv, C.N.; Zhao, Y.; Qu, Z.Y.; Liu, Y.J.; Qu, J.L. Two new phenolic acids from the fruits of Forsythia suspense. J. Asian Nat. Prod. Res. 2016, 19, 254–259. [Google Scholar] [CrossRef] [PubMed]
  31. Liu, X.Z.; Yu, S.H.; Huo, H.L.; Li, F.G.; Sheng, N.; Zhang, L.T. Hplc-Esi-Ms/Ms Quantitative Method for Simultaneous Analysis of Five Bioactive Constituents of Forsythia Suspensa in Rat Bile After. J. Liq. Chromatogr. Relat. Technol. 2013, 36, 44–60. [Google Scholar]
  32. Chang, M.J.; Hung, T.M.; Min, B.S.; Kim, J.C.; Woo, M.H.; Choi, J.S.; Lee, H.K.; Bae, K.H. Lignans from the fruits of Forsythia suspensa (Thunb.) Vahl protect high-density lipoprotein during oxidative stress. Biosci. Biotechnol. Biochem. 2008, 72, 2750–2755. [Google Scholar] [CrossRef] [PubMed]
  33. Fang, Y.; Zhou, G.A.; Liu, M.W. Chemical Constituents from Forsythia suspense. Chin. J. Nat. Med. 2008, 6, 235–236. [Google Scholar] [CrossRef]
  34. Yan, X.J.; Peng, Y.; Liu, Z.X.; Wen, J.; Liu, Q.B.; Li, L.Z.; Song, S.J. Three new lignan glycosides from the fruits of Forsythia suspense. J. Asian Nat. Prod. Res. 2014, 16, 602–610. [Google Scholar] [CrossRef] [PubMed]
  35. Liu, D.L.; Xu, S.X.; Wang, W.F. A Novel Lignan Glucoside from Forsythia suspensa Vahl. J. Chin. Pharm. Sci. 1998, 7, 49–51. [Google Scholar]
  36. Feng, W.S.; Li, K.K.; Zheng, X.K. Studies on Chemical constituents in Forsythia suspensa (Thunb.) Vahl. Chin. Pharm. J. 2009, 44, 490–492. [Google Scholar]
  37. Piao, X.L.; Jang, M.H.; Cui, J.; Piao, X.S. Lignans from the fruits of Forsythia suspensa. Bioorg. Med. Chem. Lett. 2008, 18, 1980–1984. [Google Scholar] [CrossRef] [PubMed]
  38. Kuo, P.C.; Hung, H.Y.; Nian, C.W.; Hwang, T.L.; Cheng, J.C.; Kuo, D.H.; Lee, E.J.; Tai, S.H.; Wu, T.S. Chemical Constituents and Anti-inflammatory Principles from the Fruits of Forsythia suspensa. J. Nat. Prod. 2016, 12, 14–22. [Google Scholar] [CrossRef] [PubMed]
  39. Takizawa, Y.; Suzuki, E.; Mitsuhashi, T. Naturally occurring antioxidant. (I). Isolation and determination of natural phenolic antioxidants from Forsythia suspensa Vahl. In Tokyo Gakugei Daigaku Kiyo, Dai-4-bumon: Sugaku, Shizen Kagaku; Tokyo Gakugei Daigaku: Tokyo, Japan, 1981; Volume 33, pp. 119–123. [Google Scholar]
  40. Endo, K.; Seya, K.; Hikino, H. Stereostructure of rengyol and isorengyol, phenylethanoids of Forsythia suspensa. Tetrahedron 1987, 43, 2681–2688. [Google Scholar] [CrossRef]
  41. Endo, K.; Seya, K.; Hikino, H. Structure and enantioselective synthesis of suspenol, a new polyol of Forsythia suspensa. In Proceedings of the Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, Sapporo, Japan, 26–28 August 1987; Volume 29, pp. 660–667. [Google Scholar]
  42. Wang, W.F.; Liu, D.L.; Xu, S.X.; Xiao, F.H. Rengyolester isolated from Forsythia suspensa Vahl. J. Shenyang Pharm. Univ. 1999, 16, 138. [Google Scholar]
  43. Zhang, G.G.; Song, S.J.; Ren, J.; Xu, S.X. A New Compound from Forsythia suspensa (Thunb.) Vahl with Antiviral Effect on RSV. J. Herb. Pharmacother. 2002, 2, 35–40. [Google Scholar] [CrossRef] [PubMed]
  44. Liu, Y.; Song, S.J.; Zhang, G.G.; Xu, S.X. A new compound from the fruit of Forsythia suspensa (Thunb.) Vahl. J. Shenyang Pharm. Univ. 2003, 20, 48–49. [Google Scholar]
  45. Dong, S.M. New quinoid glycosides from Forsythia suspensa. J. Nat. Prod. 1998, 61, 377–379. [Google Scholar]
  46. Wang, Y.Z.; Ma, Q.G.; Zheng, X.K.; Feng, W.S. A new forsythenside from Forsythia suspensa. Chin. Chem. Lett. 2008, 19, 1234–1236. [Google Scholar] [CrossRef]
  47. Xue, J.; Xie, L.; Liu, B.R.; Yu, L.X. Triterpenoids from the Fruits of Forsythia suspensa. Chin. J. Nat. Med. 2010, 8, 414–418. [Google Scholar] [CrossRef]
  48. Kuo, P.C.; Chen, G.F.; Yang, M.L.; Lin, Y.H.; Peng, C.C. Chemical Constituents from the Fruits of Forsythia suspensa and Their Antimicrobial Activity. BioMed Res. Int. 2014, 2014, 1–7. [Google Scholar]
  49. Ming, D.S.; Yu, D.Q.; Yu, S.S.; Liu, J.; He, C.H. A new furofuran mono-lactone from Forsythia suspensa. J. Asian Nat. Prod. Res. 1999, 1, 221–226. [Google Scholar] [CrossRef] [PubMed]
  50. Rouf, A.S.S.; Ozaki, Y.; Rashid, M.A.; Rui, J. Dammarane derivatives from the dried fruits of Forsythia suspensa. Phytochemistry 2001, 56, 815–818. [Google Scholar] [CrossRef]
  51. Sun, J.; Zhang, B. Study on the apoptotic induction mechanism of triterpenes isolated from Forsythia suspense in human gastric cancer cell line SGC-7901. Chin. J. Clin. Pharmacol. Ther. 2010, 15, 851–855. [Google Scholar]
  52. Shin, S.J.; Park, C.E.; Baek, N.I.; Chung, I.S.; Park, C.H. Betulinic and oleanolic acids isolated from Forsythia suspensa VAHL inhibit urease activity of Helicobacter pylori. Biotechnol. Bioprocess Eng. 2009, 14, 140–145. [Google Scholar] [CrossRef]
  53. Yin, J.; Guo, L.G. Modern Research and Clinical Application of Chinese Medicine (I); Academy Press: Beijing, China, 1993; pp. 356–358. [Google Scholar]
  54. Lee, J.S.; Min, B.S.; Bae, K.H. Cytotoxic Constituents from the Forsythiae Fructus against L1210 and HL60 cells. Yakhak Hoeji 1996, 40, 462–467. [Google Scholar]
  55. Shi, J.M.; Sun, J.; Zhang, G.D.; Yu, L.X.; Qian, X.P.; Liu, B.R. Inhibitory effects of Ambrolic Acid on cell proliferation in human gastric carcinoma cell line SGC-7901. Acta Univ. Med. Nanjing Nat. Sci. 2009, 29, 445–449. [Google Scholar]
  56. Chen, Y.J.; Xiang, J.; Xu, M.J.; Tao, L.; Gu, W. Studies on Chemical Constituents of Forsythia suspensa (Thunb.) Vahl. Chin. J. Chin. Mater. Med. 1999, 24, 296. [Google Scholar]
  57. Guo, Q.; Wang, Z.M.; Lin, L.M.; Xia, B.H.; Deng, X.L. Researches on chemical constituents in medicinal plants in genus Forsythia. Chin. J. Exp. Tradit. Med. Form. 2009, 15, 74–79. [Google Scholar]
  58. Qu, J.L.; Yan, X.J.; Li, C.Y.; Wen, J.; Lu, C.N.; Ren, J.G.; Peng, Y.; Song, S.J. Comparative Evaluation of Raw and Ripe Fruits of Forsythia suspensa by HPLC–ESI-MS/MS Analysis and Anti-Microbial Assay. J. Chromatogr. Sci. 2017, 55, 451–458. [Google Scholar] [PubMed]
  59. Bai, Y.; Li, J.; Liu, W.; Jiao, X.C.; He, J.; Liu, J.; Ma, L.; Gao, X.M.; Chang, Y.X. Pharmacokinetic of 5 components after oral administration of Fructus Forsythiae by HPLC-MS/MS and the effects of harvest time and administration times. J. Chromatogr. B 2015, 993–994, 36–46. [Google Scholar] [CrossRef] [PubMed]
  60. Liu, Y.; Song, S.J.; Xu, S.X.; Fu, X.H. Study on the chemical constituents of the fruits of Forsythia suspensa (Thunb.) Vahl. J. Shenyang Pharm. Univ. 2003, 20, 101–103. [Google Scholar]
  61. Lee, H.W.; Lee, H.S. Acaricidal Abilities and Chemical Composition of Forsythia suspense Fruit Oil against Storage and Pyroglyphid Mites. J. Appl. Biol. Chem. 2015, 58, 105–108. [Google Scholar] [CrossRef]
  62. Yang, J.J.; Wei, H.M.; Teng, X.N.; Zhang, H.Q.; Shi, Y.H. Dynamic Ultrasonic Nebulisation Extraction Coupled with Headspace Ionic Liquid-based Single-drop Microextraction for the Analysis of the Essential Oil in Forsythia suspensa. Phytochem. Anal. 2014, 25, 178–184. [Google Scholar] [CrossRef] [PubMed]
  63. Zhai, Y.J.; Sun, S.; Song, D.Q.; Sun, Y.; Zhang, Y.P.; Liu, H.; Zhang, H.Q.; Yu, A.M. Rapid Extraction of Essential Oil from Dried Cinnamomum cassia Presl and Forsythia suspensa (Thunb.) Vahl by Ionic Liquid Microwave Extraction. Chin. J. Chem. 2010, 28, 2513–2519. [Google Scholar] [CrossRef]
  64. Jiao, J.; Fu, Y.J.; Zu, Y.J.; Luo, M.; Wang, W.; Zhang, L.; Li, J. Enzyme-assisted microwave hydro-distillation essential oil from Fructus forsythia, chemical constituents, and its antimicrobial and antioxidant activities. Food Chem. 2012, 134, 235–243. [Google Scholar] [CrossRef]
  65. Sun, Y.N.; Ban, R.M.; Deng, Y.H.; Wang, Z.; Ni, Y. Comparative Study on the Chemical Constitutions of Volatile Oli in Forsythia suspensa and Old F. suspensa. China Pharm. 2016, 27, 2087–2089. [Google Scholar]
  66. Wei, S.; Wu, T.; Li, M.; Zhang, S.R. Analysis of Major Components and Antibacterial Activity of Volatile Oil from Forsythiae Fructus in Different Origins. Chin. J. Exp. Tradit. Med. Form. 2016, 22, 69–74. [Google Scholar]
  67. Dai, S.J.; Ren, Y.; Shen, L.; Zhang, D.W. New alkaloids from Forsythia suspensa and their anti-inflammatory activities. Planta Med. 2009, 75, 375–377. [Google Scholar] [CrossRef] [PubMed]
  68. Liu, Y.; He, J.M.; Sun, R.X.; Liu, C.; Zhang, R.P.; Shi, J.G. Simultaneous Structural Identification of Constituents in Active Herbal Extract of Forsythia Suspensa Using Nuclear Magnetic Resonance/Liquid Chromatography-Mass Spectrometry Parallel Dynamic Spectroscopy. Chin. J. Anal. Chem. 2011, 39, 323–329. [Google Scholar]
  69. Cai, Q.; Liu, Y.Q.; Feng, X. Studies on the Chemical Constituents from the Seed of Forsythia suspense. J. Chin. Med. Mater. 2009, 32, 1691–1693. [Google Scholar]
  70. Ming, D.S. Studies on the Chemical Constituents and Pharmacological Activities on Forsythia suspensa and Valeriana jatamansi Jones. Ph.D. Thesis, Peking Union Medical College, Beijing, China, May 1998. [Google Scholar]
  71. Chen, X.; Beutler, J.A.; McCloud, T.G.; Loehfelm, A.; Yang, L.; Dong, H.; Chertov, O.Y.; Salcedo, R.; Oppenheim, J.J.; Howard, O.M.Z. Tannic Acid Is an Inhibitor of CXCL12 (SDF-1)/CXCR4 with Antiangiogenic Activity. Clin. Cancer Res. 2003, 9, 3115–3123. [Google Scholar] [PubMed]
  72. Sun, W.J.; Sheng, J.G. Concise Manual of Natural Active Ingredients; Chinese Medical Science and Technology Press: Beijing, China, 1998. [Google Scholar]
  73. Wang, S.C.; Shi, S.S.; Lian, H.; Zhu, C.; Wang, H.J.; Liu, R.M.; Bligh, S.W.A. Structural Features and Anti-Complement Activity of an Acidic Polysaccharide from Forsythia suspensa. J. Glycom. Lipidom. 2016, 2, 1–8. [Google Scholar]
  74. Wang, Y.Q.; Guo, Z.M.; Jin, Y.; Zhang, X.L.; Li, W.; Liang, X.M. Selective enrichment with “click oligo (ethylene glycol)” column and TOF–MS characterization of simple phenylpropanoids in the fruits of Forsythia Suspensa. J. Sep. Sci. 2009, 32, 2958–2966. [Google Scholar] [CrossRef] [PubMed]
  75. Kuang, H.X.; Zhang, N.; Lu, Z.B. The chemical constituents of green Forsythia suspensa. Inform. Tradit. Chin. Med. 1985, 8, 25. [Google Scholar]
  76. Cheng, G.D.; Zhao, Y.L.; Li, H.; Wu, Y.; Li, X.X.; Han, Q.; Dai, C.S.; Li, Y.H. Forsythiaside attenuates lipopolysaccharide-induced inflammatory responses in the bursa of Fabricius of chickens by downregulating the NF-κB signaling pathway. Exp. Ther. Med. 2014, 7, 179–184. [Google Scholar] [CrossRef] [PubMed]
  77. Deng, L.; Pang, P.; Zheng, K.; Nie, J.; Xu, H.C.; Wu, S.Z.; Chen, J.; Chen, X.Y. Forsythoside A Controls Influenza A Virus Infection and Improves the Prognosis by Inhibiting Virus Replication in Mice. Molecules 2016, 21. [Google Scholar] [CrossRef] [PubMed]
  78. Chen, J.; Chen, Q.; Yu, F.; Huang, H.; Li, P.; Zhu, J.; He, X. Comprehensive Characterization and Quantification of Phillyrin in the Fruits of Forsythia suspensa and Its Medicinal Preparations by Liquid Chromatography–Ion Trap Mass Spectrometry. Acta Chromatogr. 2016, 28, 145–157. [Google Scholar] [CrossRef]
  79. Lei, J.L.; Li, Y.T.; Nie, H.S.; Du, S.Q.; Li, F. Determination of Phillyrin in Fructus Forsythiae from Different Habitats by HPLC. Chin. Artic. Tradit. Chin. Med. 2012, 30. [Google Scholar] [CrossRef]
  80. Yan, Y.L.; Liu, M.J.; Yan, H.R.; Li, X.; Xu, J.H.; Yang, J.X. Determination of phillyrin and forsythosideA in Forsythia suspensa from different localities by HPLC. China Pharm. 2015, 26, 37–39. [Google Scholar]
  81. Xia, H.; Liu, F.Q.; Zhou, Y.P.; Zhang, S.L.; Zhou, X.; Han, J. Simultaneous Determination of Phillyrin and Forsythoside A in Forsythiae Fructus by HPLC. Pharm. J. Chin. PLA 2014, 30, 60–62. [Google Scholar]
  82. Li, X.J.; Zhang, Y.P.; Yuan, Z.B. Determination of Rutin and Forsythin in Fruit of Forsythia Suspensa (Thunb.) Vahl by Capillary Electrophoresis-Electrochemical Detection. Chromatographia 2002, 56, 171–174. [Google Scholar] [CrossRef]
  83. Zhang, S.R.; Pei, X.P.; Yan, Y.; Wang, J.J. Content Comparison of Active Components in the Fruit and Folium of Forsysia suspensa in Different Harvesting Time. Chin. Pharm. 2011, 22, 2940–2942. [Google Scholar]
  84. Ye, L.H.; Gong, X.H.; Li, Y.X.; Peng, C. Comparison of the contents of multiple components derived from qingqiao and laoqiao. Pharm. Clin. Chin. Mater. Med. 2013, 4, 6–8. [Google Scholar]
  85. Xia, B.H.; Zhu, J.J.; Wang, Z.M.; Lin, L.M.; Gao, H.M. Quantitative determination of forsythiaside in Forsythia suspensa. Chin. J. Chin. Mater. Med. 2010, 35, 2110–2112. [Google Scholar]
  86. Qu, H.H.; Li, B.X.; Li, X.; Tu, G.Z.; Lü, J.; Sun, W.J. Qualitative and quantitative analyses of three bioactive compounds in different parts of Forsythia suspense by high-performance liquid chromatography-electrospray ionization-mass spectrometry. Microchem. J. 2008, 89, 159–164. [Google Scholar] [CrossRef]
  87. Xia, Y.G.; Yang, B.Y.; Wang, Q.H.; Liang, J.; Wei, Y.H.; Yu, H.D.; Zhang, Q.B.; Kuang, H.X. Quantitative analysis and chromatographic fingerprinting for the quality evaluation of Forsythia suspensa extract by HPLC coupled with photodiode array detector. J. Sep. Sci. 2009, 32, 4113–4125. [Google Scholar] [CrossRef] [PubMed]
  88. Zhang, Y.J. Studies on the main chemical constituents of Qinqiao and Laoqiao, And the Activity of Phillyrin and Forsythiaside A. Ph.D. Thesis, Shanxi University of Chinese Medicine, Tai Yuan, Shanxi, China, June 2015. [Google Scholar]
  89. Fu, Y.F.; Li, Q.; Bi, K.S. Determination of seven components in Forsythia suspensa by RP-HPLC. Chin. Tradit. Herb. Drugs 2013, 44, 1043–1046. [Google Scholar]
  90. Guo, H.; Liu, A.H.; Li, L.; Guo, D.A. Simultaneous determination of 12 major constituents in Forsythia suspensa by high performance liquid chromatography-DAD method. J. Pharm. Biomed. Anal. 2007, 43, 1000–1006. [Google Scholar] [CrossRef] [PubMed]
  91. Zhang, S.R.; Pei, X.L.; Wang, H.Y. Comparison of the Contents of α-pinene and β-pinene in Volatile Oil of Forsythia suspensa in Different Harvest Periods. Chin. Pharm. 2013, 24, 4469–4471. [Google Scholar]
  92. Zhao, P.F.; Piao, X.S.; Pan, L.; Zeng, Z.K.; Li, Q.Y.; Xu, X.; Wang, H.L. Forsythia suspensa extract attenuates lipopolysaccharide-induced inflammatory liver injury in rats via promoting antioxidant defense mechanisms. Anim. Sci. J. 2016. [Google Scholar] [CrossRef] [PubMed]
  93. Lee, S.E.; Lim, C.; Kim, H.; Cho, S. A Study of the Anti-Inflammatory Effects of the Ethyl Acetate Fraction of the Methanol Extract of Forsythiae Fructus. Afr. J. Tradit. Complement. Altern. Med. 2016, 13, 102–113. [Google Scholar] [PubMed]
  94. Sohn, S.H.; Ko, E.; Kim, Y.; Shin, M.; Hong, M.; Bae, H. Genomewide expression profile of Forsythia suspensa on lipopolysaccaride-induced activation in microglial cells. Mol. Cell. Toxicol. 2008, 4, 113–123. [Google Scholar]
  95. Wang, Y.; Zhao, H.F.; Lin, C.X.; Ren, J.; Ye, Y.Y.; Ji, Z.H.; Zhang, S.Z. The inhibitory effect of forsythin on inflammation in LPS-induced BV2 microglia cells. J. Apoplexy Nervous Dis. 2016, 33, 338–341. [Google Scholar]
  96. Hao, Y.; Li, D.F.; Piao, X.L.; Piao, X.S. Forsythia suspensa extract alleviates hypersensitivity induced by soybean β-conglycinin in weaned piglets. J. Ethnopharmacol. 2010, 128, 412–418. [Google Scholar] [CrossRef] [PubMed]
  97. Sung, Y.Y.; Yoon, T.; Jang, S.; Ho, K.K. Forsythia suspensa Suppresses House Dust Mite Extract-Induced Atopic Dermatitis in NC/Nga Mice. PLoS ONE 2016, 1–17. [Google Scholar] [CrossRef] [PubMed]
  98. Yuan, A.; Luo, L.; Gong, X.H.; Li, Y.; Zhao, M.J.; Zhang, R.Q.; Li, Y.X. Effect of Forsythia Extract on Paw Edema Induced by Carrageenan and Fresh Egg White in Rats. Liaoning Tradit. Chin. Med. Mag. 2016, 43, 2200–2202. [Google Scholar]
  99. Guo, J.; Shen, Y.J.; Xie, Y.H. The experimental study inflammation of Essential Oil from Fructus forsythia. Sichuan Physiol. Sci. Mag. 2005, 27, 136–137. [Google Scholar]
  100. Pan, C.W.; Zhou, G.Y.; Chen, W.L.; Zhuge, L.; Jin, L.X.; Zheng, Y.; Lin, W.; Pan, Z.Z. Protective effect of forsythiaside A on lipopolysaccharide/d-galactosamine-induced liver injury. Int. Immunopharmacol. 2015, 26, 80–85. [Google Scholar] [CrossRef] [PubMed]
  101. Pan, X.L.; Cao, X.; Li, N.; Xu, Y.M.; Wu, Q.Y.; Bai, J.; Yin, Z.M.; Luo, L.; Lan, L. Forsythin inhibits lipopolysaccharide-induced inflammation by suppressing JAK-STAT and p38 MAPK signalings and ROS production. Inflamm. Res. 2014, 63, 597–608. [Google Scholar] [CrossRef] [PubMed]
  102. Zeng, X.Y. Experimental Study on The Effect of Anti-endotoxin of Forsythoside A through HMGB1/TLR4/NF-κB Signaling Pathway. Ph.D. Thesis, Nanchang University, Nanchang, China, June 2016. [Google Scholar]
  103. Zhong, W.T.; Wu, Y.C.; Xie, X.X.; Zhou, X.; Wei, M.M.; Soromou, L.W.; Ci, X.X.; Wang, D.C. Phillyrin attenuates LPS-induced pulmonary inflammation via suppression of MAPK and NF-κB activation in acute lung injury mice. Fitoterapia 2013, 90, 132–139. [Google Scholar] [CrossRef] [PubMed]
  104. Lee, S.; Shin, S.; Kim, H.; Han, S.; Kim, K.; Kwon, J.; Kwak, J.H.; Lee, C.K.; Ha, N.J.; Yim, D.; Kim, K. Anti-inflammatory function of arctiin by inhibiting COX-2 expression via NF-κB pathways. J. Inflamm. 2011, 8, 1–9. [Google Scholar] [CrossRef] [PubMed]
  105. Liu, J.Z.; Zhang, L.W. Anti-inflammatory Activity of Forsythia suspensa Extract on Human Airway Epithelial Cells Inflammation Model. Nat. Prod. Res. Dev. 2015, 27, 1248–1253. [Google Scholar]
  106. Sung, Y.Y.; Lee, A.Y.; Kim, H.K. Forsythia suspensa fruit extracts and the constituent matairesinol confer anti-allergic effects in an allergic dermatitis mouse model. J. Ethnopharmacol. 2016, 187, 49–56. [Google Scholar] [CrossRef] [PubMed]
  107. Cheng, L.; Li, F.; Ma, R.; Hu, X.P. Forsythiaside inhibits cigarette smoke-induced lung inflammation by activation of Nrf2 and inhibition of NF-κB. Int. Immunopharmacol. 2015, 28, 494–499. [Google Scholar] [CrossRef] [PubMed]
  108. Coon, T.A.; McKelvey, A.C.; Weathington, N.M.; Birru, R.L.; Lear, T.; Leikauf, G.D.; Chen, B.B. Novel PDE4 Inhibitors Derived from Chinese Medicine Forsythia. PLoS ONE 2014, 9, 1–14. [Google Scholar] [CrossRef] [PubMed]
  109. Kang, H.S.; Lee, J.Y.; Kim, C.J. Anti-inflammatory activity of arctigenin from Forsythiae Fructus. J. Ethnopharmacol. 2008, 116, 305–312. [Google Scholar] [CrossRef] [PubMed]
  110. Wang, Y.; Zhao, H.F.; Lin, C.X.; Ren, J.; Zhang, S.Z. Forsythiaside A Exhibits Anti-inflammatory Effects in LPS-Stimulated BV2 Microglia Cells Through Activation of Nrf2/HO-1 Signaling Pathway. Neurochem. Res. 2016, 41, 659–665. [Google Scholar] [CrossRef] [PubMed]
  111. Wang, J.H.; Wang, X.X.; Liu, D. Inhibitory effect of forsythin on the inflammatory responses of monocyte-macrophage induced by Staphylococcus aureus. J. Xinxiang Med. Univ. 2016, 6, 466–468. [Google Scholar]
  112. Guo, N.; Gai, Q.Y.; Jiao, J.; Wang, W.; Zu, Y.G.; Fu, Y.J. Antibacterial Activity of Fructus forsythia Essential Oil and the Application of EO-Loaded Nanoparticles to Food-Borne Pathogens. Foods 2016, 5, 1–13. [Google Scholar] [CrossRef] [PubMed]
  113. Xiao, H.M.; He, Y.; Wang, S.W.; Wang, J.B.; Xie, Y.H. Experimental stydy on the antibacterial activity of the Essential Oil from Forsythiae Fructus in vitro. Inner Monog. Med. 2011, 15, 99–100. [Google Scholar]
  114. Li, H.; Dai, X.H.; Tian, W.L.; Zhang, H.L. Chinese herbal medicine Fructus forsythia extract inhibits Staphylococcus aureus alpha-hemolysin secretion activity. Chin. J. Vet. Sci. 2013, 33, 404–408. [Google Scholar]
  115. Han, X.; Piao, X.S.; Zhang, H.Y.; Li, P.F.; Yi, J.Q.; Zhang, Q.; Li, P. Forsythia suspensa Extract Has the Potential to Substitute Antibiotic in Broiler Chicken. Asian Australas. J. Anim. Sci. 2012, 25, 569–576. [Google Scholar] [CrossRef] [PubMed]
  116. Huang, R.Y.; Mu, X.P.; Bo, C.P.; Zhang, D.C.; Deng, W.Y. Effect of Forsythia suspensa on the adeb gene of the active efflux system of multidrug-resistant Acinetobacter baumannii. J. Pathog. Biol. 2016, 6, 111–114. [Google Scholar]
  117. Ko, H.C.; Wei, B.L.; Chiou, W.F. Dual regulatory effect of plant extracts of Forsythia suspense on RANTES and MCP-1 secretion in influenza A virus-infected human bronchial epithelial cells. J. Ethnopharmacol. 2005, 102, 418–423. [Google Scholar] [CrossRef] [PubMed]
  118. Qu, X.Y.; Li, Q.J.; Zhang, H.M.; Zhang, X.J.; Shi, P.H.; Zhang, X.J.; Yang, J.; Zhou, Z.; Wang, S.Q. Protective effects of phillyrin against influenza A virus in vivo. Arch. Pharm. Res. 2016, 39, 998–1005. [Google Scholar] [CrossRef] [PubMed]
  119. Duan, L.J.; Zhang, Q.; Wang, N.R.; Yang, B.; He, S.Q.; Sun, J. Effect of Phillyrin on Gene Expression of Influenza A Virus Nucleoprotein. Res. Tradit. Chin. Med. West. Med. 2012, 15, 2082–2084. [Google Scholar]
  120. Yang, M.; Lu, Y.; Ma, Y.Y.; Wu, G.Y.; Beier, R.R.; Hou, X.L.; Wu, G.J. Inhibition of porcine reproductive and respiratory syndrome virus in vitro by forsythoside A. Int. J. Pharmacol. 2015, 11, 394–399. [Google Scholar]
  121. Li, H.W.; Wu, J.F.; Zhang, Z.W.; Ma, Y.Y.; Liao, F.F.; Zhang, Y.; Wu, G.J. Forsythoside A inhibits the avian infectious bronchitis virus in cell culture. Phytother. Res. 2011, 25, 338–342. [Google Scholar] [CrossRef] [PubMed]
  122. Zhang, T.; Liu, B.H.; Yang, X.L.; Lv, A.; Zhang, Z.C.; Gong, P.; Li, D.Y.; Hou, X.L. Effect of forsythoside A on expression of intracelluar receptors and antiviral gene in IBV-infected cells. J. Beijing Univ. Agric. 2017, 32, 37–41. [Google Scholar]
  123. Huang, C.Y.; Huang, T.Z.; Zhang, H.; Cheng, S.J.; Qi, L.Y.; Xiao, G.; Huang, S.Y. Study on Optimization of Orthogonal Design of Enzyme Extraction Craft and Antioxidant Activity of Forsythia suspense Polysaccharide. Chem. World 2017, 1, 38–42. [Google Scholar]
  124. Lu, T.; Piao, X.L.; Zhang, Q.; Wang, D.; Piao, X.S.; Kim, S.W. Protective effects of Forsythia suspensa extract against oxidative stress induced by diquat in rats. Food Chem. Toxicol. 2010, 48, 764–770. [Google Scholar] [CrossRef] [PubMed]
  125. Huang, C.Y.; Zheng, H.J.; Ling, X.L.; Liang, H.Y.; Huang, C.J.; Huang, S.Y. Study of Antioxidant Property of the Extract from Forsythia suspense Ethyl Acetate. Chin. Wild Plant Res. 2017, 36, 15–17. [Google Scholar]
  126. Piao, X.L.; Cho, E.J.; Jang, M.H.; Cui, J. Cytoprotective effect of lignans from Forsythia suspensa against peroxynitrite-induced LLC-PK1 cell damage. Phytother. Res. 2009, 23, 938–942. [Google Scholar] [CrossRef] [PubMed]
  127. Yan, L.Y.; Liu, M.J.; Yan, H.R.; Li, X.; Xu, J.H.; Yang, J.X. Study on Anti-aging Effects of Phillyrin on Aging Model Mice. Chin. Pharm. 2015, 26, 37–39. [Google Scholar]
  128. Hao, P.F.; Piao, X.S.; Zeng, Z.K.; Li, P.; Xu, X.; Wang, H.L. Effect of Forsythia suspensa extract and chito-oligosaccharide alone or in combination on performance, intestinal barrier function, antioxidant capacity and immune characteristics of weaned piglets. Anim. Sci. J. 2016. [Google Scholar] [CrossRef]
  129. Zeng, Z.K.; Li, Q.Y.; Piao, X.S.; Liu, J.D.; Zhao, P.F.; Xu, X.; Zhang, S.; Niu, S. Forsythia suspensa extract attenuates corticosterone-induced growth inhibition, oxidative injury, and immune depression in broilers. Poult. Sci. 2014, 93, 1774–1781. [Google Scholar] [CrossRef] [PubMed]
  130. Zhang, H.Y.; Piao, X.S.; Zhang, Q.; Li, P.; Yi, J.Q.; Liu, J.D.; Li, Q.Y.; Wang, G.Q. The effect of Forsythia suspensa extract and berberine on growth performance, immunity, antioxidant activities, and intestinal microbiota in broilers under high stocking density. Poult. Sci. 2013, 92, 1981–1988. [Google Scholar] [CrossRef] [PubMed]
  131. Zhang, S.; Shao, S.Y.; Song, X.Y.; Xia, C.Y.; Yang, Y.N.; Zhang, P.C.; Chen, N.H. Protective effects of Forsythia suspense extract with antioxidant and anti-inflammatory properties in a model of rotenone induced neurotoxicity. Neuro Toxicol. 2016, 52, 72–83. [Google Scholar] [CrossRef] [PubMed]
  132. Xiong, Y.P.; Tian, Y.J. Ameliorative Effect and Its Mechanism of Forsythiaside on Learning and Memory of Composite Alzheimer’s Disease Model Mice. J. Int. Transl. Med. 2016, 4, 51–57. [Google Scholar]
  133. Wang, H.M.; Wang, L.W.; Liu, X.M.; Li, C.L.; Xu, S.P.; Farooq, A.D. Neuroprotective effects of forsythiaside on learning and memory deficits in senescence-accelerated mouse prone (SAMP8) mice. Pharmacol. Biochem. Behav. 2013, 105, 134–141. [Google Scholar] [CrossRef] [PubMed]
  134. Yang, J.S.; Sun, X.P.; Wang, Y.H.; Wang, L.W.; Liu, X.M. Effect of Forsythiaside on Scopolamine-induced Learning and Memory Impairment in Mice. Chin. J. Exp. Tradit. Med. Form. 2016, 22, 177–181. [Google Scholar]
  135. Kim, J.M.; Kim, S.; Kim, D.H.; Lee, C.H.; Park, S.J.; Jung, J.W.; Ko, K.H.; Cheong, J.H.; Lee, S.H.; Ryu, J.H. Neuroprotective effect of forsythiaside against transient cerebral global ischemia in gerbil. Eur. J. Pharmacol. 2011, 660, 326–333. [Google Scholar] [CrossRef] [PubMed]
  136. Lin, L.X.; Zhang, L.W.; Du, H.Z. Improvement of Forsythoside A on Neuroinflammation Iuduced by Aβ25–35 Oligomer. Nat. Sci. Educ. 2016, 39, 631–638. [Google Scholar]
  137. Sun, X.P.; Wang, Y.H.; Wang, L.W.; Qin, C.; Liu, X.M. Neuroprotective Effects of Forsythiaside on Glutamate, Low-glucose and Low Serum, Aβ25–35-induced Neurotoxicity in PC 12 Cell. Chin. J. Exp. Tradit. Med. Form. 2013, 19, 197–200. [Google Scholar]
  138. Zhang, M.R.; Wei, S.R.; Wu, Y.C.; Sun, F.L.; Ai, H.J.; Zhang, L.; Wang, W. Effects of Phillyrin on MPP+-induced Injury in SH-SY5Y Neuroblastoma Cells. Acta Neuropharmacol. 2011, 1, 12–15. [Google Scholar]
  139. Qu, X.; Li, X.; Cai, P.P.; Shang, X.Y.; Guo, D.B.; You, N.; Li, H.Y. In vitro induction of apoptosis caused by bioactive compounds extracted from Forsythia suspensa and its mechanisim in HeLa cells. Chin. J. Public Health 2013, 29, 397–399. [Google Scholar]
  140. Cai, P.P.; Li, X.; Qu, X.; Shang, X.Y.; Li, Y.K.; Li, H.Y. In vitro induction of apoptosis by the forsythia ethanol extract LQ-4 in human cervical cancer Hela cells. Chin. J. Clin. 2015, 7, 9235–9238. [Google Scholar]
  141. Guo, D.B.; Li, X.; Pu, Y.A.; You, N.; Zhong, E.D.; Cai, P.P.; Qu, X.; Li, H.Y. Research on forsythia anti-tumor component (LQ-4) effect on apoptosis of SGC-7901 cells in vitro. Chin. J. Clin. 2011, 5, 4345–4349. [Google Scholar]
  142. Zheng, M.; Jiang, Z.M. Effects of phillyrin on VEGF and endostatin expression in Lewis lung carcinoma. Chin. J. Pathophysiol. 2016, 32, 167–171. [Google Scholar]
  143. Wang, C.L.; Yan, H.T.; Liu, B.R. Effects of antiproliferation and radiosensitivity on PC-3 cell of prostate cancer induced by triterpenes component. Shangdong Med. 2011, 51, 25–27. [Google Scholar]
  144. Wang, E.L.; Yao, J.C.; Liu, Z. Effect of forsythiaside on immunological hepatic fibrosis of rats. Drug Eval. Res. 2015, 38, 161–164. [Google Scholar]
  145. Liu, Y.H.; Qi, Z.L.; Xu, G.X.; He, L.; Yang, J.H. Protective effect of forsythin on alcoholic liver injury. Chin. Clin. Pharmacol. Ther. 2016, 21, 6–9. [Google Scholar]
  146. Fan, X.B.; Li, W.X.; Chen, B.H.; Xiong, Z.Y.; Duan, J.M. Effect of Forsythia suspensa on expression of NF-κB and Foxp3 during liver injury in rats with severe acute pancreatitis. J. Clin. Hepatol. 2013, 29, 503–507. [Google Scholar]
  147. Zhang, Y.Y.; Feng, F.; Chen, T.; Li, Z.W.; Shen, Q.W.W. Antidiabetic and antihyperlipidemic activities of Forsythia suspensa (Thunb.) Vahl (fruit) in streptozotocin-induced diabetes mice. J. Ethnopharmacol. 2016, 192, 256–263. [Google Scholar] [CrossRef] [PubMed]
  148. Iizuka, T.; Nagai, M. Vasorelaxant effects of forsythiaside from the fruits of Forsythia suspensa. Yakugaku Zasshi 2015, 125, 219–224. [Google Scholar] [CrossRef]
  149. Do, M.T.; Kim, H.G.; Choi, J.H.; Khanal, T.; Park, B.H.; Tran, T.P.; Hwang, Y.P.; Na, M.K.; Jeong, H.G. Phillyrin attenuates high glucose-induced lipid accumulation in human HepG2 hepatocytes through the activation of LKB1/AMP-activated protein kinase-dependent signaling. Food Chem. 2013, 136, 415–425. [Google Scholar] [CrossRef] [PubMed]
  150. Kong, P.; Zhang, L.L.; Guo, Y.L.; Lin, D.P. Phillyrin, a Natural Ligands, Attenuates Tumor Necrosis Factor α-Mediated Insulin Resistanceand Lipolytic Acceleration in 3T3-L1 Adipocytes. Nat. Planta Med. 2014, 80, 880–886. [Google Scholar]
  151. Xiao, H.B.; Sui, G.G.; Lu, X.Y. Phillyrin lowers body weight in obese mice via the modulation of PPAR/-ANGPTL 4 pathway. Obes. Res. Clin. Pract. 2017, 2, 1–9. [Google Scholar] [CrossRef] [PubMed]
  152. Shin, H.S.; Park, S.Y.; Song, H.G.; Hwang, E.; Lee, D.G.; Yi, T.H. The Androgenic Alopecia Protective Effects of Forsythiaside A and the Molecular Regulation in a Mouse Model. Phytother. Res. 2015, 29, 870–876. [Google Scholar] [CrossRef] [PubMed]
  153. Zhang, X.R. Effect of Forsythiaside A on Immune Regulation in Endotoxemia Mice and Mechanism of Action. Chin. Med. Guide 2016, 22, 57–60. [Google Scholar]
  154. Su, H.C.; Wang, H.Y.; Liu, C.L.; Kong, X.Y.; Lin, N. Effect of Forsythiaside A on Temperature and Expression of TRPA1 in Mice with Yeast Induced Pyrexia. Chin. J. Exp. Tradit. Med. Form. 2016, 22, 134–138. [Google Scholar]
  155. Meng, X.L.; Guo, Y.L.; Su, C.F.; Huang, H.Y.; Gui, X.J.; Li, X.L. Discussion of Inhibitory of Forsythoside A on Efflux Function and Mechanism of P-glycoprotein in Caco-2 Cell Membrane. Chin. J. Exp. Tradit. Med. Form. 2015, 21, 5–8. [Google Scholar]
  156. Lin, Y.H.; Chen, Y.C.; Hu, S.; Chen, H.Y.; Chen, J.L.; Yang, S.H. Identifying core herbal treatments for urticaria using Taiwan’s nationwide prescription database. J. Ethnopharmacol. 2013, 148, 556–562. [Google Scholar] [CrossRef] [PubMed]
  157. Chen, H.Y.; Lin, Y.H.; Chen, Y.C. Identifying Chinese herbal medicine network for treating acne: Implications from a nationwide database. J. Ethnopharmacol. 2016, 179, 1–8. [Google Scholar] [CrossRef] [PubMed]
  158. Wang, G.N.; Pan, R.L.; Liao, Y.H.; Chen, Y.; Tang, J.T.; Chang, Q. An LC-MS/MS method for determination of forsythiaside in rat plasma and application to a pharmacokinetic study. J. Chromatogr. B. 2010, 878, 102–106. [Google Scholar] [CrossRef] [PubMed]
  159. Chu, Y.; Wang, X.Y.; Guo, J.H.; Li, W.; Ma, X.H.; Zhu, Y.H. Pharmacokinetic study of unbound forsythiaside in rat blood and bile by microdialysis coupled with HPLC method. Eur. J. Drug Metab. Pharmacokinet. 2012, 37, 173–177. [Google Scholar] [CrossRef] [PubMed]
  160. Li, Y.X.; Ye, L.H.; Jiang, X.H.; Peng, C. Assessment and modulation of phillyrin absorption by P-gp using Caco-2 cells and MDR1-MDCKII cells. Eur. J. Drug Metab. Pharmacokinet. 2011, 36, 41–47. [Google Scholar] [CrossRef] [PubMed]
  161. Wang, H.R.; Zhang, X.X.; Jia, P.P.; Zhang, Y.F.; Tang, S.W.; Wang, H.T.; Li, S.; Yu, X.L.; Li, Y.F.; Zhang, L.T. Metabolic profile of phillyrin in rats obtained by UPLC-Q-TOF-MS. Biomed. Chromatogr. 2016, 30, 913–922. [Google Scholar] [CrossRef] [PubMed]
  162. Ye, L.H.; Li, Y.X.; Peng, C.; Gong, X.H.; Zheng, X.G. Determination of phillygenin in rat plasma by high-performance liquid chromatography and its application to pharmacokinetic studies. Eur. J. Drug. Metab. Pharmacokinet. 2013, 38, 201–207. [Google Scholar] [CrossRef] [PubMed]
  163. Cheng, Y.W.; Liang, X.L.; Feng, L.Y.; Liu, D.; Qin, M.N.; Liu, S.; Liu, G.F.; Dong, M. Effects of phillyrin and forsythoside A on rat cytochrome P450 activities in vivo and in vitro. Xenobiotica 2017, 47, 297–303. [Google Scholar] [PubMed]
Figure 1. Chemical structures of phenylethanoid glycosides in Forsythiae Fructus.
Figure 1. Chemical structures of phenylethanoid glycosides in Forsythiae Fructus.

Molecules 22 01466 i001CompoundsR
Forsythoside A (1)H
Forsythoside C (Suspensaside, 2)OH
(R)-Suspensaside (3)β-OH
(S)-Suspensaside (4)α-OH
(S)-Suspensaside methyl ether (5)α-OCH3
Suspensaside B (6)OC4H9
(R)-Forsythoside J (7) Molecules 22 01466 i160
(S)-Forsythoside J (8) Molecules 22 01466 i161
Molecules 22 01466 i002CompoundsR
Forsythoside D (9)OH
Forsythoside E (10)H
β-Methoxyforsythoside E (11)OCH3

Molecules 22 01466 i003CompoundsR1R2
Iso-forsythoside A/Forsythoside I/Lianqiaoxinside A (12)OHcaffeoyl
ForsythosideA-4’O-β-d-glucopyranoside (13)(4’O-β-d-glu) caffeoylOH
Forsythenside K (14)coumaroylOH
Poliumoside (15)caffeoylO-β-l-rha

Molecules 22 01466 i004CompoundsR
Acteoside (16)OH
Forsythoside B (17)O-api
Forsythoside G (18)2-O-methyl-api
Forsythoside F (19)O-β-d-xyl
Angoroside A (20)O-arabinose
Molecules 22 01466 i005CompoundsR
Calceolarioside C (21)H
(S)-β-hydroxycalceolarioside C (22)α-OH
(R)-β-hydroxycalceolarioside C (23)β-OH
(S)-β-methoxycalceolarioside C (24)α-OCH3
(R)-β-methoxycalceolarioside C (25)β-OCH3

Molecules 22 01466 i006CompoundsR1R2R3
Calceolarioside A (26)OHOHH
Derhamnosyl suspensaside (27)OHOHOH
β-methoxylacteoside (28)OHO-α-l-rhaOCH3
Caffeoyl calceolarioside C (29)O-β-d-glcO-apiH
Isoforsythiaside (30)O-β-l-rhaOHH

Molecules 22 01466 i007CompoundsR1R2R3
β-Methoxyferruginoside B (31)O-β-d-glcOHOH
β-Methoxylipedoside A (32)OHcoumaroylO-α-l-rha

Molecules 22 01466 i008CompoundsR1R2
Calceolarioside B (33)caffeoylOH
Lianqiaoxinoside C (34)O-β-d-xylcaffeoyl
Plantainoside A (35)OHcaffeoyl

Molecules 22 01466 i009CompoundsR
Forsythoside J (36)O-β-d-xyl
Plantainoside B (37)OH
Forsythoside H (38)O-α-l-rha

Molecules 22 01466 i010CompoundsR1R2R3
Suspensaside A (39)OHcaffeoylO-α-l-rha
Suspensaside A isomer (40)OHcaffeoylcoumaroyl
Demethylsuspensaside A (41)OHcaffeoylO-xyl/O-api
Suspensaside C (42)OHOHO-α-l-rha
Lianqiaoxinoside B (43)caffeoylOHO-α-l-rha

Molecules 22 01466 i011Salidroside R = H (44)
3,4-Dihydroxyphenylethyl-8-O-β-d-glucopyranoside R = OH (45)
Molecules 22 01466 i012Forsythiayanoside C (46)
Molecules 22 01466 i0132-(2,5-Dihydroxyphenyl)-ethyl-O-(6-O-p-hydroxybenzoyl)-d-glucopyranoside R = H (47)
2-(2,5-Dihydroxyphenyl)-ethyl-O-(6-ovanilloyl)-d-glucopyranoside R = OCH3 (48)
Molecules 22 01466 i0142-(3,4-Dihydroxyphenyl)-2-oxo-ethyl-O-l-rhamnopyranosyl-(16)-(4-O-caffeoyl)-d-glucopyranoside. (49)
Molecules 22 01466 i015Brachynoside (50)
Molecules 22 01466 i016Phenethyl alcohol β-d-xylopyranosyl-(1→6)-β-d-glucopyranoside (51)
Figure 2. Chemical structures of lignans in Forsythiae Fructus.
Figure 2. Chemical structures of lignans in Forsythiae Fructus.

Molecules 22 01466 i017CompoundsR1R2R3R4
Arctigenin (52)OCH3OCH3HOH
Arctiin (53)OCH3OCH3HO-glu
Matairesinoside (54)OCH3OHHO-glu
Matairesinol (55)OCH3OHHOH
2′,5′-Dihydroxy-4′′-caffeoyl matairesinol (56)OCH3OHOHcaffeoyl
3′,4′,5′-Trihydroxy-3′′-methoxy-4′′-caffeoyl lignan (57)OHOHOHcaffeoyl
Matairesinol-4′-O-glucoside (58)OCH3O-β-d-glcHOH

Molecules 22 01466 i018CompoundsR1R2R3
Phillygenin (59)OCH3OHH
Phillyrin (forsythin 60)OCH3O-β-d-glcH
Caffeoyl phillygenin (61)OCH3caffeoylH
(+)-Epipinoresinol (62)OHOHH
7′-Epi-8-hydroxypinoresinol (63)OHOHOH
(+) Epipinoresinol-4-β-d-glucoside (64)OHO-β-d-glcH
(+)-8-Hydroxyepipinoresinol-4-O-β-d-glucopyranoside (65)OHO-β-d-glcOH
(+) epipinoresinol-4′-β-d-glucoside (66)O-β-d-glcOHH
forsythialanside E (67)O-β-d-glcOHOH
Molecules 22 01466 i019CompoundsR1R2R3
(+) Pinoresinol (68)OHHOH
(+) Pinoresinol-β-d-glucoside (69)O-β-d-glcHOH
(+) Pinoresinol monomethyl ether-β-d-glucoside (70)O-β-d-glcHOCH3
Pinoresinol diglucoside (71)O-β-d-glcHO-β-d-glc
Caffeoyl pinoresinol (72)caffeoylHOH
(+)-1-Hydroxypinordsinol (73)OHOHOH
(+)-1-Hydroxypinordsinol-4′-O-β-d-glucoside (74)OHOHO-β-d-glc
(+)-1-Hydroxypinordsinol-4′′-O-β-d-glucoside (75)O-β-d-glcOHOH
Molecules 22 01466 i020CompoundsR1R2R3
3′,4′,5′-Trimethoxyl-4′′-hydroxyllignan O-glucoside (76)OCH3HH
Syringaresinol-4-O-β-d-glucoside (77)OHOCH3OCH3

Molecules 22 01466 i021CompoundsR1R2R3
Isolariciresinol (78)HHH
Isolariciresinol-4-O-β-d-glucopyranoside (79)HHO-β-d-glc
Isolariciresinol-9′-O-β-d-glucopyranoside (80)HO-β-d-glcH
Isoolivil (81)OHHH
Molecules 22 01466 i022CompoundsR1R2R3
Cedrusin (82)OHOHOH
Glochidioboside (83)OHOCH3O-glc
Forsythialanside C (84)O-glcOCH3O-rha
Forsythialanside D (85)O-rhaOCH3O-rha
Dihydrodehydrodiconiferyl alcohol-4-O-β-d-glucoside (86)O-glcOCH3OH

Molecules 22 01466 i023Icariside E4 (87)
Molecules 22 01466 i024Forsythialan A R = OH (88)
Forsythialan B R = OMe (89)
Molecules 22 01466 i025rel-(7R,8′R,8S)-Forsythialan C R = β-H (90)
rel-(7R,8′R,8R)-Forsythialan C R = α-H (91)
Molecules 22 01466 i026Forsythialanside A R1 = OMe R2 = O-glc (92)
Forsythialanside B R1 = O-glc R2 = OH (93)
Molecules 22 01466 i027Olivil (94)
Molecules 22 01466 i028Forsythiayanoside B (95)
Molecules 22 01466 i029Forsythiayanoside A (96)
Molecules 22 01466 i0303-Furanone-2-(3-methoxy-4-hydroxyphenyl)-4-veratryl (97)
Molecules 22 01466 i031Lariciresinol R1 = OH R2 = OH (98)
Lariciresinol-4-O-β-d-glucoside R1 = OH R2 = O-β-d-glc (99)
Lariciresinol-4′-O-β-d-glucoside R1 = O-β-d-glc R2 = OH (100)
Molecules 22 01466 i032Benzenebutanoic acid (101)
Figure 3. Chemical structures of natural alcohols with the C6-C2 skeleton in Forsythiae Fructus.
Figure 3. Chemical structures of natural alcohols with the C6-C2 skeleton in Forsythiae Fructus.

Molecules 22 01466 i033CompoundsR1R2R3R4
Isorengyol (102)HOHOHH
Rengyol (103)OHHOHH
Suspenol (104)OHHOHOH
Rengyolester (105)OHH Molecules 22 01466 i153OH
Rengyoside A (106)OHHO-β-d-glcH
Rengyoside C (107)OHH Molecules 22 01466 i154H

Molecules 22 01466 i034Rengynic acid R = OH (108)
Rengynic acid-1′-O-β-d-glucopyranoside R = O-β-d-glc (109)
Molecules 22 01466 i035Rengyolone (halleridone) (110)
Molecules 22 01466 i036Rengyoxide R = OH (111)
Rengyoside B R = O-β-d-glc (112)
Molecules 22 01466 i037Cornoside (113)
Molecules 22 01466 i038Forsythenside A (114)
Molecules 22 01466 i039Forsythenside B (115)
Molecules 22 01466 i040Forsythenside F (116)
Molecules 22 01466 i041Forsythenside H (117)
Molecules 22 01466 i042Forsythenside G (118)
Molecules 22 01466 i043Forsythenside I (119)
Molecules 22 01466 i044Forsythenside J (120)
Figure 4. Chemical structures of iridoids, diterpenoids, terpenoids in Forsythiae Fructus.
Figure 4. Chemical structures of iridoids, diterpenoids, terpenoids in Forsythiae Fructus.

Molecules 22 01466 i045Adoxosidic acid (121)
Molecules 22 01466 i046Adoxosidic acid 10-p-hydroxyphenylacetate (122)
Molecules 22 01466 i0473β-Hydroxylabda-8(17), 13E-dien-15-oic acid (123)
Molecules 22 01466 i0483β-Hydroxyanticopalic acid (124)
Molecules 22 01466 i049Agatholic acid (125)
Molecules 22 01466 i0503-Oxoanticopalic acid (126)

Molecules 22 01466 i051CompoundsR
19-Hydroxylabda-8(17),13(Z)-dien-15-oic acid (127) Molecules 22 01466 i155
19-Hydroxylabda-8(17),13(E)dien-15-oic acid (128) Molecules 22 01466 i156
19-Formyllabda-8(17),13(E)-dien-15-oic acid (129) Molecules 22 01466 i157
19-Formyllabda-8(17),13(Z)-dien-15-oic acid (130) Molecules 22 01466 i158
Labda-8(17),13(Z)-dien-15,18-dioic acid (131) Molecules 22 01466 i159

Molecules 22 01466 i052Labda-8(17),13(Z)-diene-15,19dioic acid (132)
Labda-8(17),13(E)-diene-15,19-dioic acid (133)
Molecules 22 01466 i053Dehydropinifolic acid (134)
Molecules 22 01466 i054Haplopappic acid (135)
Molecules 22 01466 i05518-Hydroxy-7-oxolabda-8(9),13(E)-dien-15-oic acid (136)
Molecules 22 01466 i05619-Dihydroxylabda-7(8),13(E)-dien-15-oic acid (137)
Molecules 22 01466 i057Forsythidin A (138)
Molecules 22 01466 i0583β-Hydroxy-12,13(E)-biformene (139)
3β-Hydroxy-12,13(Z)-biformene (140)
Molecules 22 01466 i05919-Hydroxy-8(17)(E)-13-labdadien-15-oate (141)
Molecules 22 01466 i060Ocotillone (142)
Molecules 22 01466 i061Ocotillol acetate (143)
Molecules 22 01466 i062Garcinielliptone Q (144)
Molecules 22 01466 i0633β-Acetyl-20,25-epoxydammarane-24α-ol R1 = H,R2 = OH (145)
3β-Acetyl-20,25-epoxydammarane-24β-ol R1 = OH,R2 = H (146)
Molecules 22 01466 i064Dammar-24-en-3β-acetoxy-20-ol (147)
Molecules 22 01466 i0653β-Acetoxy-25-methoxydammar-23-en-20β-ol (148)
Molecules 22 01466 i0663β-Acetoxy-20S,24R-dammarane-25-ene-24-hydroperoxy-20-ol (149)
Molecules 22 01466 i067Cabralea lactone 3-acetate (150)
Molecules 22 01466 i068Cabralea lactone 3-acetate 24-methyl ether (151)
Molecules 22 01466 i0693-Acetylisofouquierol (152)

Molecules 22 01466 i070CompoundsR1R2R3R4R5
Oleanolic acid (153)Hβ-OHCOOHHMe
3β-Acetyloleanolic acid (154)Hβ-OAcCOOHHMe
β-Amyrin acetate (155)Hβ-OAcMeHMe
Ursolic acid (156)Hβ-OHCOOHMeH
2α,3α-Hydroxyursolic acid (157)α-OHα-OHCOOHMeH

Molecules 22 01466 i0712α,23-Hydroxyursolic acid (158)
Molecules 22 01466 i0723β-Acetoxy-20α-hydroxyursan-28-oic acid (159)
Molecules 22 01466 i073Betulinic acid R1 = H R2 = OH (160)
3β-Acetylbetulinic acid R1 = H R2 = OAc (161)
2α-Hydroxybetulinic acid R1 = α-OH R2 = OH (162)
Molecules 22 01466 i074Ambrolic acid (163)
Molecules 22 01466 i075Morolic acid (164)
Molecules 22 01466 i0763β-Acetoxyolean-12-en-28-oic acid (165)
Molecules 22 01466 i077Alphitolic acid (166)
Molecules 22 01466 i078Onjisaponin F (167)
Molecules 22 01466 i079Onjisaponin G (168)
Figure 5. Chemical structures of sterols in Forsythiae Fructus.
Figure 5. Chemical structures of sterols in Forsythiae Fructus.

Molecules 22 01466 i082β-Sitosterol R = OH (169)
Daueosterol R = O-β-d-glc (170)
Molecules 22 01466 i083Taraxasterol acetate (171)
Molecules 22 01466 i084Stigmasterol (172)
Molecules 22 01466 i085ψ-Taraxasterol (173)
Molecules 22 01466 i086(6′-O-Palmitoyl)-sitosterol-3-O-β-d-glucoside (174)
Figure 6. Chemical structures of flavonoids in Forsythiae Fructus.
Figure 6. Chemical structures of flavonoids in Forsythiae Fructus.
Molecules 22 01466 g006

CompoundsR1R2R3R4R5
Rutin (175)OHOHO-β-d-glc-O-α-l-rhaOHH
Quercetin (177)OHOHOHOHH
Isorhamnetin (180)OCH3OHOHOHH
Kaempferfol (181)OHHOHOHH
Hyperin (182)OHOHO-β-d-galOHH
Kaempferol-3-O-β-d-glucopyranoside-7-O-α-l-rhamnopyranoside (185)OHHO-β-d-glcO-α-l-rhaH
Kaempferol-3-O-β-d-(2″-O-β-d-glucopyranosyl-6″O-α-l-rhamnopyranosyl)glucopyranoside (186)OHHO-β-d-(2″-O-β-d-glc-6″O-α-l-rha)glcOHH
Wogonin-7-O-glcoside (187)HHHO-β-d-glcOMe
Baicalin (188)HHHO-glcOH

Molecules 22 01466 i087Hesperidin (190)
Molecules 22 01466 i088Forsythoneoside A 7′R (191)
Forsythoneoside B 7′S (192)
Molecules 22 01466 i089Forsythoneoside C M configuration (193)
Forsythoneoside D P configuration (194)
Figure 7. Chemical structures of alkaloids in Forsythiae Fructus.
Figure 7. Chemical structures of alkaloids in Forsythiae Fructus.

Molecules 22 01466 i090Rutaecarpine (246)
Molecules 22 01466 i091Suspensine A (247)
Molecules 22 01466 i092(−)-Egenine R = OH (248)
(−)-7′-O-Methylegenine R = OMe (249)
Molecules 22 01466 i093(−)-Bicuculline (250)
Molecules 22 01466 i094Bis-2-(4-aminophenyl) ethyl-β-d-glucopyranoside (251)
Molecules 22 01466 i095Choline (252)
Figure 8. Chemical structures of other compounds in Forsythiae Fructus.
Figure 8. Chemical structures of other compounds in Forsythiae Fructus.

Molecules 22 01466 i096Palmitic acid (253)
Molecules 22 01466 i097Stearic acid (254)
Molecules 22 01466 i098Succinic acid (255)
Molecules 22 01466 i099Suspenolic acid (256)
Molecules 22 01466 i1002-Furancarboxylic acid (257)
Molecules 22 01466 i101Chlorogenic acid (258)
Molecules 22 01466 i102Anchoic acid (259)
Molecules 22 01466 i1034-Hydroxy-4-isopropylcyclohex-1-enecarboxylic acid (260)
Molecules 22 01466 i104p-Coumaric acid (261)

Molecules 22 01466 i105CompoundsR1R2R3
Protocatechuic acid (262)HOHOH
Vanillic acid (263)HOHOMe
p-Hydroxybenzoic acid (264)HOHH
Benzoic acid (265)HHH
3,4-Dimethoxybenzoic acid (266)HOMeOMe
Syringic acid (267)OMeOHOMe

Molecules 22 01466 i106CompoundsR1R2
Caffeic acid (268)OHOH
trans-Coumaric acid (269)OHH
trans-Ferulic acid (270)OHOMe

Molecules 22 01466 i107Caffeic acid methyl ester (271)
Molecules 22 01466 i108p-Hydroxybenzylacetic acid (272)
Molecules 22 01466 i109Tannic acid (273)
Molecules 22 01466 i110Gallic acid (274)
Molecules 22 01466 i1113-Hydroxybutyric acid (275)
Molecules 22 01466 i112Acetic acid (276)
Molecules 22 01466 i113Pyruvic acid (277)
Molecules 22 01466 i114Malic acid (278)
Molecules 22 01466 i115Fumaric acid (279)
Molecules 22 01466 i116Formic acid (280)
Molecules 22 01466 i117Isoleucine (281)
Molecules 22 01466 i118Leucine (282)
Molecules 22 01466 i119Valine (283)
Molecules 22 01466 i120Threonine (284)
Molecules 22 01466 i121Alanine (285)
Molecules 22 01466 i122Phenylalanine (286)
Molecules 22 01466 i123β-Xylose (287)
Molecules 22 01466 i124β-Glucose (288)
Molecules 22 01466 i125α-Glucose (289)
Molecules 22 01466 i126Raffinose (290)
Molecules 22 01466 i127Sucrose (291)
Molecules 22 01466 i128l-Rhamnose (292)
Molecules 22 01466 i129Lactose (293)
Molecules 22 01466 i130Erythritol (294)
Molecules 22 01466 i131Forsythenside L R1 = H R2 = OH (295)
Sasanquin R1 = OMe R2 = H (296)
Molecules 22 01466 i132Forsythiayanoside D (297)
Molecules 22 01466 i133(6S,9R)-Roseoside (298)
Molecules 22 01466 i134Swertiamacroside (299)
Molecules 22 01466 i1352,3,5,6-Tetrahydro-jacaranone-4-O-β-d-glucopyranoside (300)
Molecules 22 01466 i136Labda-8(17),13E-dien-15,18-dioic acid 15-methyl ester (301)
Molecules 22 01466 i137β-Carotene-5,6-epoxide (302)
Molecules 22 01466 i138Mutatochrome (303)
Molecules 22 01466 i139Neoxanthin (304)
Molecules 22 01466 i1401-Oxo-4-hydroxy-2(3)-en-4ethylcyclohexa-5,8-olide (305)
Molecules 22 01466 i141Esculetin R1 = OH,R2 = OH (306)
6,7-Dimethoxycoumarin R1 = OMe, R2 = OMe (307)
Molecules 22 01466 i142Hydroxytyrosol R = OH (308)
p-Tyrosol R = H (309)
Molecules 22 01466 i1434-Hydroxybenylacetic acid methyl ester (310)
Molecules 22 01466 i1444-Caffeoylrutinose (312)
Molecules 22 01466 i145Protocatechualdehyde (313)
Molecules 22 01466 i146p-Hydroxyphenylethanol (314)
Molecules 22 01466 i147p-Hydroxybenzylalcohol (315)
Molecules 22 01466 i148n-Hentriacontane (316)
Molecules 22 01466 i1522,3-Dihydroxymethyl-4-(3′,4′-dimethoxyphenyl)-γ-butyrolactone (317)
Molecules 22 01466 i150Methyl-α-d-glucopyranoside (318)
Molecules 22 01466 i151Forsythenin R = OMe (319)
4-O-Demethylforsythenin R = OH (320)
Molecules 22 01466 i149Salicifoliol (321)
Table 1. Compounds identified from Forsythiae Fructus.
Table 1. Compounds identified from Forsythiae Fructus.
NO.Compound NameSourceReference
Phenylethanoid Glycosides
1forsythoside A (forsythiaside)UFF, RFF[6,14,15]
2forsythoside C (suspensaside)RFF[6,16]
3(R)-suspensasideUFF[17,18]
4(S)-suspensasideUFF[17,18]
5(S)-suspensaside methyl etherN.M.[18]
6suspensaside BN.M.[16]
7(R)-forsythoside JN.M.[19]
8(S)-forsythoside JN.M.[19]
9forsythoside DN.M.[20]
10forsythoside EUFF[20,21]
11β-methoxyforsythoside EN.M.[22]
12iso-forsythoside A/forsythoside I/lianqiaoxinside AUFF[15,17,21]
13forsythoside A 4′-O-β-d-glucopyranosideN.M.[11]
14forsythenside K (lipedoside A)N.M.[22,23]
15poliumosideN.M.[11]
16acteosideN.M.[22]
17forsythoside BUFF[17,22]
18forsythoside GN.M.[22]
19forsythoside FUFF[21,24]
20angoroside AN.M.[11]
21calceolarioside CUFF[25]
22(S)-β-hydroxycalceolarioside CN.M.[22]
23(R)-β-hydroxycalceolarioside CN.M.[22]
24(S)-β-methoxycalceolarioside CN.M.[22]
25(R)-β-methoxycalceolarioside CN.M.[22]
26calceolarioside AN.M.[26]
27derhamnosyl suspensasideN.M.[22]
28β-methoxyacteosideN.M.[22]
29caffeoyl calceolarioside CN.M.[22]
30isoforsythiasideN.M.[27]
31β-methoxylferruginoside BN.M.[22]
32β-methoxylipedoside AN.M.[22]
33calceolarioside BUFF[21]
34lianqiaoxinoside CUFF[25]
35plantainoside AN.M.[24]
36forsythoside JUFF[21]
37plantainoside BN.M.[24]
38forsythoside HUFF[21,24,28]
39suspensaside AN.M.[16,22]
40suspensaside A isomerN.M.[22]
41demethyl suspensaside AN.M.[22]
42suspensaside CN.M.[14]
43lianqiaoxinoside BUFF[28]
44salidrosideN.M.[29]
453,4-dihydroxyphenylethyl-8-O-β-d-glucopyranosideUFF[17]
46forsythiayanoside CUFF[30]
472-(2,5-dihydroxyphenyl)-ethyl-O-(6-O-p-hydroxybenzoyl)-β-d-glucopyranosideN.M.[11]
482-(2,5-dihydroxyphenyl)-ethyl-O-(6-O-vanilloyl)-β-d-glucopyranosideN.M.[11]
492-(3,4-dihydroxyphenyl)-2-oxo-ethyl-O-α-l-rhamnopyranosyl-(1→6)-(4-O-caffeoyl)-β-d-glucopyranosideN.M.[11]
50brachynosideN.M.[22]
51phenethyl alcohol β-d-xylopyranosyl-(1→6)-β-d-glucopyranosideUFF[21]
Lignans
52arctigeninUFF[17,22]
53arctiinUFF[17,22]
54matairesinosideN.M.[22]
55matairesinolUFF[17,22]
562′,5′-dihydroxy-4′′-caffeoyl matairesinolN.M.[22]
573′,4′,5′-trihydroxy-3′′-methoxyl-4′′-caffeoyl lignanN.M.[22]
58matairesinol-4′-O-glucosideN.M.[31]
59phillygeninUFF, RFF[15,32,33]
60phillyrin (forsythin)UFF, RFF[6,17,33]
61caffeoyl phillygeninN.M.[22]
62(+) epipinoresinolRFF[33]
637′-epi-8-hydroxypinoresinolN.M.[32]
64(+) epipinoresinol-4-O-β-d-glucosideN.M.[34]
65(+)-8-hydroxyepipinoresinol-4-O-β-d-glucopyranosideN.M.[34]
66(+) epipinoresinol-4′-O-β-d-glucosideN.M.[34]
67forsythialanside EN.M.[24]
68pinoresinolN.M.[32]
69(+) pinoresinol-β-d-glucosideN.M.[35]
70(+) pinoresinol monomethyl ether-β-d-glucosideN.M.[35]
71pinoresinol diglucosideN.M.[22]
72caffeoyl pinoresinolN.M.[22]
73(+)-1-hydroxypinordsinol/8-hydroxypinoresinolN.M.[19,32]
74(+)-1-hydroxypinordsinol-4′-O-β-d-glucosideN.M.[19]
75(+)-1-hydroxypinordsinol-4′-O-β-d-glucosideN.M.[19]
763′,4′,5′-trimethoxy-4′′-hydroxyllignan O-glucosideN.M.[22]
77syringaresinol-4-O-β-d-glucosideN.M.[23]
78isolariciresinolUFF, RFF[15,33,36]
79isolariciresinol-4-O-β-d-glucopyranosideRFF[36]
80isolariciresinol-9′-O-β-d-glucopyranosideRFF[36]
81isoolivilRFF[36]
82cedrusinN.M.[32]
83glochidiobosideN.M.[34]
84forsythialanside CN.M.[23]
85forsythialanside DN.M.[23]
86dihydrodehydrodiconiferyl alcohol-4-O-β-d-glucosideN.M.[23]
87icariside E4N.M.[23]
88forsythialan AN.M.[37]
89forsythialan BN.M.[37]
90rel-(7R,8′R,8S)-forsythialan CN.M.[38]
91rel-(7R,8′R,8R)-forsythialan CN.M.[38]
92forsythialanside AN.M.[23]
93forsythialanside BN.M.[23]
94olivilUFF[17,32]
95forsythiayanoside BN.M.[34]
96forsythiayanoside AN.M.[34]
973-furanone-2-(3-methoxy-4-hydroxyphenyl)-4-veratrylN.M.[22]
98lariciresinolN.M.[32]
99lariciresinol-4-O-β-d-glucosideN.M.[24]
100lariciresinol-4′-O-β-d-glucosideN.M.[24]
101benzenebutanoic acidN.M[39]
Aliphatic C6-C2 alcohols
102isorengyolN.M.[40]
103rengyolUFF[6,20,40]
104suspenolN.M.[41]
105rengyolesterN.M.[42]
106rengyoside AN.M.[29]
107rengyoside CN.M.[29]
108rengynic acidN.M.[14,43]
109rengynic acid-1′-O-β-d-glucopyranosideN.M.[44]
110rengyolone (halleridone)N.M.[20,29]
111rengyoxideN.M.[20]
112rengyoside BN.M.[29]
113cornosideRFF[6,23]
114forsythenside AN.M.[23,45]
115forsythenside BN.M.[45]
116forsythenside FN.M.[46]
117forsythenside HN.M.[23]
118forsythenside GN.M.[23]
119forsythenside IN.M.[23]
120forsythenside JN.M.[23]
Iridoids
121adoxosidic acidUFF, RFF[6]
122adoxosidic acid 10-p-hydroxyphenylacetateN.M.[38]
Diterpenoids
1233β-hydroxylabda-8(17), 13(E)-dien-15-oic acidN.M.[47]
1243β-hydroxyanticopalic acidN.M.[48]
125agatholic acidN.M.[48]
1263-oxoanticopalic acidN.M.[38]
12719-hydroxylabda-8(17),13(Z)-dien-15-oic acidN.M.[38]
12819-hydroxylabda-8(17),13(E)dien-15-oic acidN.M.[38]
12919-formyllabda-8(17),13(E)-dien-15-oic acidN.M.[38]
13019-formyllabda-8(17),13(Z)-dien-15-oic acidN.M.[38]
131labda-8(17),13(Z)-dien-15,18-dioic acidN.M.[38]
132labda-8(17),13(Z)-diene-15,19dioic acidN.M.[38]
133labda-8(17),13(E)-diene-15,19-dioic acidN.M.[38]
134dehydropinifolic acidN.M.[38]
135haplopappic acidN.M.[38]
13618-hydroxy-7-oxolabda-8(9),13(E)-dien-15-oic acidN.M.[38]
13717,19-dihydroxylabda-7(8),13(E)-dien-15-oic acidN.M.[38]
138forsythidin AN.M.[38]
1393β-hydroxy-12,13(E)-biformeneN.M.[38]
1403β-hydroxy-12,13(Z)-biformeneN.M.[38]
14119-hydroxy-8(17)(E)-13-labdadien-15-oateN.M.[38]
Triterpenoids
142ocotilloneN.M.[49]
143ocotillol monoacetateN.M.[49]
144garcinielliptone QN.M.[38]
1453β-acetyl-20,25-epoxydammarane-24α-olN.M.[50]
1463β-acetyl-20,25-epoxydammarane-24β-olN.M.[50]
147dammar-24-en-3β-acetoxy-20-olN.M.[38,47,51]
1483β-acetoxy-25methoxydammar-23-en-20β-olN.M.[38]
1493β-acetoxyl-20S,24R-dammarane-25-ene-24-hydroperoxy-20-olN.M.[47]
150cabralea lactone 3-acetateN.M.[47]
151cabralea lactone 3-acetate 24-methyl etherN.M.[38]
1523-acetylisofouquierolN.M.[47]
153oleanolic acidRFF[33,52]
1543β-acetyloleanolic acidN.M.[48]
155β-amyrin acetateN.M.[47]
156ursolic acidRFF[33]
1572α,3α-hydroxyursolic acidN.M.[53]
1582α,23-hydroxyursolic acidRFF[33]
1593β-acetoxy-20α-hydroxyursan-28-oic acidN.M.[48]
160betulinic acidRFF[33,52]
1613β-acetylbetulinic acidN.M.[54]
1622α-hydroxybetulinic acidRFF[33]
163ambrolic acidN.M.[51,55]
164morolic acidN.M.[47]
1653β-acetoxyolean-12-en-28-oic acidN.M.[38]
166alphitolic acidN.M.[38]
167onjisaponin FN.M.[53]
168onjisaponin GN.M.[53]
Sterols
169β-sitosterolN.M.[56]
170daucosterolN.M.[57]
171taraxasterol acetateN.M.[48]
172stigmasterolN.M.[48]
173ψ-taraxasterolN.M.[48]
174(6′-O-palmitoyl)-sitosterol-3-O-β-d-glucosideN.M.[49]
Flavonoids
175rutinUFF, RFF[6,22,58]
176rutin-O-hexosideN.M.[22]
177quercetinUFF, RFF[58]
178quercetin-O-rhamnosyl hexosideN.M.[22]
179trimethoxyquercetin-O-feruloyl rhamnosideN.M.[22]
180isorhamnetinN.M[59]
181kaempferfolN.M.[22]
182hyperinN.M.[18]
183kaempferol dirhamnosideN.M.[22]
184kaempferol-O-rhamnosylhexosideN.M.[22]
185kaempferol-3-O-β-d-glucopyranoside-7-O-α-l-rhamnopyranosideN.M.[11]
186kaempferol-3-O-β-d-(2″-O-β-d-glucopyranosyl-6″O-α-l-rhamno-pyranosyl)glucopyranosideN.M.[11]
187wogonin-7-O-glcosideN.M.[60]
188baicalinUFF, RFF[58]
189hesperidinN.M.[18]
190forsythoneoside AN.M.[11]
191forsythoneoside BN.M.[11]
192forsythoneoside CN.M.[11]
193forsythoneoside DN.M.[11]
Volatiles
194β-pineneN.M.[61]
195myrtenolN.M.[61]
196(+)-α-pineneN.M.[61]
197(−)-trans-pinocarveolN.M.[61]
198sabineneN.M.[61]
199pinocarvoneN.M.[61]
200(−)-terpinen-4-olN.M.[61]
201dipenteneN.M.[61]
202campheneN.M.[61]
203myrceneN.M.[61]
204α-terpineneN.M.[61]
205O-cymeneN.M.[61]
206eucalyptol (1,8-cineole)N.M.[61]
207γ-terpineneN.M.[61]
208campholenic aldehydeN.M.[61]
209(S)-cis-verbenolN.M.[61]
2102,5-cyclooctadien-1-olN.M.[61]
211(1S)-(−)-verbenoneN.M.[61]
212α-pineneN.M.[61]
213β-phellandreneN.M.[62]
214(+)-careneN.M.[62]
215α-terpinoleneN.M.[62]
2161,4-cyclohexadieneN.M.[62]
2174-carvomenthenolN.M.[62]
218(±)-α-terpinelN.M.[62]
219(−)-myrtenalN.M.[62]
2202-methyl-5-(1-methylethenyl)cyclohexanolN.M.[62]
221estragoleN.M.[62]
2221-hexanolN.M.[63]
223(−)-β-pineneN.M.[63]
224(+)-4-careneN.M.[63]
225linaloolN.M.[64]
226trans-carveolN.M.[64]
227p-cymen-8-olN.M.[64]
228trans-nerolidolN.M.[64]
229camphorN.M.[64]
230β-ocimeneN.M.[64]
231germacrene DUFF[65]
232α-cubebeneUFF[65]
233bornyl acetateUFF[65]
234cis-piperitolUFF[65]
235α-pinocarvoneUFF[65]
236α-terpineolUFF[65]
237ocimeneUFF[62,65]
238α-phellandreneUFF[65]
239nutmeg aldehydeRFF[65]
240(-)-alloaromadendrenRFF[65]
241cumene formaldehydeRFF[65]
2423-cyclohexene-1-methanolRFF[65]
2434-methylene-1-cyclohexanoneRFF[65]
244p-cymeneUFF[66]
245limoneneUFF[66]
Alkaloids
246rutaecarpineN.M.[57]
247suspensine AUFF[67]
248(−)-egenineUFF[67]
249(−)-7′-O-methylegenineUFF[67]
250(−)-bicucullineUFF[67]
251bis-2-(4-aminophenyl)ethyl-β-d-glucopyranosideN.M.[68]
252cholineUFF, RFF[6]
Organic acids
253palmitic acidN.M.[56]
254stearic acidN.M.[56]
255succinic acidUFF, RFF[6]
256suspenolic acidN.M.[45]
2572-furancarboxylic acidN.M.[48]
258chlorogenic acidN.M.[18]
259anchoic acidUFF, RFF[58]
2604-hydroxy-4-isopropylcyclohex-1-enecarboxylic acidUFF, RFF[58]
261p-coumaric acidUFF, RFF[58]
262protocatechuic acidseeds[69]
263vanillic acidN.M.[70]
264p-hydroxybenzoic acidN.M.[48]
265benzoic acidN.M.[48]
2663,4-dimethoxybenzoic acidN.M.[48]
267syringic acidN.M.[48]
268caffeic acidN.M.[70]
269trans-coumaric acidN.M.[48]
270trans-ferulic acidN.M.[48]
271caffeic acid methyl esterRFF[36]
272p-hydroxybenylacetic acidN.M.[70]
273tannic acidN.M.[71]
274gallic acidRFF[6]
2753-hydroxybutyric acidUFF[6]
276acetic acidUFF, RFF[6]
277pyruvic acidUFF, RFF[6]
278malic acidUFF, RFF[6]
279fumaric acidUFF[6]
280formic acidUFF[6]
Amino acids
281isoleucineUFF[6]
282leucineUFF[6]
283valineUFF, RFF[6]
284threonineUFF[6]
285alanineUFF[6]
286phenylalanineRFF[6]
Sugar derivatives
287β-xyloseUFF, RFF[6]
288β-glucoseUFF[6]
289α-glucoseUFF, RFF[6]
290raffinoseUFF[6]
291sucroseRFF[6]
292l-rhamnoseRFF[36]
293lactoseN.M.[72]
294erythritolN.M.[60]
295[4]-α-d-GalpA-(1→2]7-[4]-α-d-GalpA-(1→2)-α-l-Rhap-(1→2]2N.M.[73]
Allylbenzene glycosides
296forsythenside LN.M.[23]
297sasanquinN.M.[23]
Other compounds
298forsythiayanoside DUFF[30]
299(6S,9R)-roseosideN.M.[48]
300swertiamacrosideN.M.[74]
3012,3,5,6-tetrahydrojacaranone-4-O-β-d-glucopyranosideN.M.[14]
302labda-8(17),13(E)-dien-15,18-dioic acid 15-methyl esterN.M.[48]
303β-carotene-5,6-epoxideN.M.[72]
304mutatochromeN.M.[72]
305neoxanthinN.M.[72]
3061-oxo-4-hydroxy-2(3)-en-4-ethylcyclohexa-5,8-olideN.M.[38]
307esculetinN.M.[48]
3086,7-dimethoxycoumaN.M.[53]
309hydroxytyrosolN.M.[48]
310p-tyrosolN.M.[48]
3114-hydroxybenylacetic acid methyl esterRFF[36]
3124-caffeoylrutinoseN.M.[20]
313protocatechualdehydeN.M.[48]
314p-hydroxyphenylethanolUFF, RFF[58]
315p-hydroxybenzylalcoholUFF, RFF[58]
316n-hentriacontaneUFF[75]
3172,3-dihydroxymethyl-4-(3′,4′-dimethoxyphenyl)-γ-butyrolactoneN.M.[57]
318methyl-α-d-glucopyranosideN.M.[48]
319forsytheninN.M.[49]
3204-O-demethylforsytheninN.M.[38]
321salicifoliolN.M.[38]
N.M.: Compounds that have not been specifically mentioned from UFF or RFF.
Table 2. Quantitative analysis for the quality control of Forsythiae Fructus.
Table 2. Quantitative analysis for the quality control of Forsythiae Fructus.
AnalytesMethodResultsReference
PhillyrinLC-MSThe contents of phillyrin in Forsythiae Fructus and three medicinal preparations (Xiao′erqingyan granules, Niuhuangshangqing pills, Yinqiao tablets) were 1.30, 0.48, 3.36, 0.35 mg/g, respectively[78]
PhillyrinHPLCThe contents of phillyrin in Forsythiae Fructus from ten habitats were from 0.72 to 3.54 mg/g, indicating the influence of habitat on the quality of Forsythiae Fructus.[79]
Phillyrin
Forsythoside A
HPLCIn four batches of UFF, the contents of phillyrin and forsythoside A were 0.73–2.16% and 0.85–1.56%, respectively. In eleven batches of RFF, the contents of phillyrin and forsythoside A were 0.57–2.50% and 0.33–0.76%, respectively.[80]
Phillyrin,
Forsythoside A
HPLCThe contents of phillyrin and forsythoside A from three batches were 3.08–4.35 mg/g and 15.89–20.76 mg/g, respectively.[81]
Rutin
Forsythin
CE-EDThe contents of rutin and forsythin in Forsythiae Fructus were 2.03 mg/g and 2.95 mg/g, respectively.[82]
Forsythoside A
Rutin
Phillyrin
HPLCIn UFF from different harvesting times, the contents of forsythoside A, rutin and phillyrin were 3.87–8.72%, 0.05–0.36% and 0.10–0.63%, respectively, which reached a peak in early July.[83]
Forsythoside A,
Phillyrin,
Phillygenin
HPLCIn three batches of UFF, the average contents of forsythoside A, phillyrin and phillygenin were 3.3385, 0.2934 and 0.4873 mg/g, respectively. In the RFF, the average contents were 0.3129, 0.2228 and 0.9258 mg/g, respectively.[84]
Rutin
Forsythoside A
Phillyrin
HPLC-PDAThe contents of rutin, forsythoside A and phillyrin in three batches of RFF were linear in the range of 0.1–2.0, 0.12–2.4 and 0.05–1.0 μg/g, respectively.[85]
Forsythoside A
Rutin
Forsythin
HPLC-ESI-MSIn UFF, the contents of forsythoside A, rutin and forsythin were 3.783%, 0.105% and 0.365%, respectively. In RFF, the contents were 0.257%, 0.167% and 0.043%, respectively.[86]
(+)-Pinoresinol-β-d-glucoside,
Forsythoside A,
Phillyrin
Phillygenin
HPLC-PDAIn nineteen batches of UFF, the contents of (+)-pinoresinol-β-d-glucoside, forsythoside A, phillyrin and phillygenin were 3.95–6.14%, 9.15–15.71%, 0.80–1.64% and 0.70–2.10%, respectively. In nineteen batches of RFF, the contents were 3.76–5.55%, 5.91–10.59%, 0.45–1.27% and 1.40–2.00%, respectively. Apart from the harvest times, the plant origins, manufacturing methods and storage conditions also played a role in the variation of the contents of the active components.[87]
Total flavonoids,
Forsythoside A , Rutin, Quercetin
HPLCIn UFF, the contents of total flavonoids, forsythin, forsythoside A, rutin and quercetin were 1.362%, 29.95 ± 0.06 mg/g, 64.0325 ± 0.03 mg/g, 2.6075 ± 0.02 mg/g and almost 0 mg/g, respectively. In RFF, the contents of them were 1.099%, 22.975 ± 0.04 mg/g, 58.3325 ± 0.03 mg/g, 0.57075 ± 0.01 mg/g and 0.0209 ± 0.07 mg/g, respectively.[88]
Cafferic acid, Forsythoside A,
Forsythoside B, Rutin, Hyperin, Forsythin
Arctigenin
RP-HPLCThe contents of cafferic acid, forsythoside A, forsythoside B, rutin, hyperin, forsythin and arctigenin in Forsythiae Fructus from six origins were 3.377–7.457 mg/g, 14.06–88.00 mg/g, 1.325–3.196 mg/g, 0.2682–3.1470 mg/g, 0.4109–0.7008 mg/g, 2.128–5.226 mg/g and 0.7437–3.6720 mg/g, respectively.[89]
Chlorogenic acid, R-suspensaside, S-suspensaside,
S-suspensaside methyl ether, Forsythoside,
(+)-Pinoresinol-β-d-glucoside,
(+)-Epipinoresinol-4′-O-glucoside,
Matairesinol-4′-O-glucoside, rutin,
Hesperidin, Hyperin, Phillyrin,
Phillygenin, (+)-Epipinoresinol
LC-ESI-MSThe fourteen compounds from twelve batches of Forsythiae Fructus from nine regions were quantified and were present at 0.0004–0.0068%, 0.0098–0.0795%, 0.0167–0.1482%, 0.0100–0.4904%, 0.2076–0.8693%, 0.0086–0.2044%, 0.0073–0.1720%, 0.0070–0.0724%, 0.0742–0.2226%, 0.0041–0.0257%, 0.0010–0.0059%, 0.0200–0.4236%, 0.0448–0.1020% and 0.0024–0.1231%, respectively.[18]
R-suspensaside, S-suspensaside methyl ether,
(+)-Pinoresinol-β-d-glucoside, Forsythoside A,
(+)-Epipinoresinol-4′-O-glucoside, Suspensaside A, Rutin, Phillyrin, Pinoresinol,
(+)-Epipinoresinol and Phillygenin
HPLC-DADThe levels of twelve constituents varied from 16.86 to 74.55 mg/g; rutin is the most stable, with only three-fold variation in the detected thirty-three samples. As the main compound, the contents of forsythoside A ranged from 5.15 to 55.78 mg/g.[90]
Forsythoside E, Forsythoside A , Suspensaside A, Rutin, Baicalin, Quercetin, Phillyrin, (+)-Epipinoresinol, (+)-Pinoresinol-4-O-β-d-glucoside (+)-Epipinoresinol-4-O-β-d-glucoside,
Chlorogenic acid, p-Hydroxybenzoic acid, p-Coumaric acid, Anchoic acid
4-Hydroxy-4-isopropylcyclohex-1-enecarboxylic acid,
p-Hydroxyphenyl-ethanol, p-Hydroxybenzylalcohol
HPLC–ESI-MS/MSIn the UFF, the contents of forsythoside A, phillyrin, (+)-epipinoresinol, (+)-epipinoresinol-4-O-β-d-glucoside, (+)-pinoresinol-4-O-β-d-glucoside were 31.1–41.7, 10.8–12.7, 11.1–21.0, 9.1–16.4, 5.2–14.4 mg/g, respectively. In the RFF, the contents of them were 6.7–8.5, 0.8–5.4, 1.6–6.4, 2.2–5.8, 1.2–4.8 mg/g, respectively. Moreover, total contents of flavonoids in the UFF were higher than in the RFF, while those of phenolic acids were on the contrary. Contents of the aliphatic acids and terpenoids were not significantly different between the UFF and the RFF.[58]
α-pinene, Camphene, β-Pinene,
Myrcene, p-Cymene, Limonene
α-Terpineol
GCIn the UFF from sixteen batches, the contents of α-pinene, camphene, β-pinene, myrcene, p-cymene, limonene and α-terpineol were 0.102–0.337%, 0.004–0.018%, 0.342–1.024%, 0.008–0.024%, 0.006–0.032%, 0.003–0.029% and 0.003–0.017%, respectively.[66]
α-Pinene
β-Pinene
GCIn the UFF, the contents of α-pinene and β-pinene were 0.192–0.300% and 0.556–0.934%, while the contents of them were 0.075% and 0.240% in the RFF.[91]
(+)-Pinoresinol-β-d-glucoside,
Matairesinol-4′-O-glucoside,
Hyperin, Phillyrin, Phillygenin
HPLC-ESI-MS/MSThe contents of (+)-pinoresinol-β-d-glucoside, matairesinol-4′-O-glucoside, hyperin, phillyrin and phillygenin in the 75% methanol extract of Forsythiae Fructus were 227.00, 70.80, 2.67, 225.20 and 106.10 mg/mL, respectively.[31]
Table 3. Pharmacological effects of Forsythiae Fructus.
Table 3. Pharmacological effects of Forsythiae Fructus.
ModelsConstituent/ExtractMechanismReference
Anti-inflammatory Activity
LPS-induced liver injury in ratsEthanol extractThe extract inhibited generation of ROS, MDA, TNF-α, IL-1β and IL-6 in serum and liver via activation of Nrf2-mediated antioxidation and inhibition of NF-κB-mediated inflammatory response.[92]
LPS-stimulated RAW 264.7 cellsEthyl acetate fraction of the ethanol extractThe extract at 12.5–200 μg/mL inhibited expression of COX-2, thus decreasing the levels of ROS, NO and PGE2 does-dependently.[93]
LPS-stimulated BV-2 microglial cellsAqueous extract
Forsythin
The extract at 1 μg/mL inhibited the MAPK pathway and down-regulated NO biosynthesis-related genes. Forsythin at 50–200 μg/mL significantly suppressed the production of NO and decreased iNOS and TRL4 protein expression in a dose dependent manner.[94,95]
Soybean β-conglycinin-stimulated weaned pigletsMethanol extractThe methanol extract (100 mg/kg) reduced the levels of anaphylactic antibodies, mast cell degranulation, histamine release, T lymphocyte proliferation and IL-4 synthesis and improved intestinal microbial flora.[96]
Dermatophagoides farinae-induced atopic dermatitis in NC/Nga miceEthanol extract Forsythoside A, Phillyrin, Pinoresinol, PhylligeninThe extract (25, 50, 100, 200 and 400 μg/mL) suppressed expression of chemokines (TARC, MDC and RANTES), adhension molecules (ICAM-1 and VCAM-1) and inflammatory factors (TNF-α and IL-4) in ear tissues. It could also inhibit the production of chemokines in keratinocytes. Further study revealed that forsythoside A, phillyrin, pinoresinol and phylligenin may be the active constituents for the therapy of atopic dermatitis.[97]
Carrageenan-induced ratsEthanol extractThe extract (5 g/kg) alleviated carrageenan-induced paw edema in rats, probably by increasing the production of COX-2 and decreasing the expression of PGE2, PGD2, 6-keto-PGF1α and TXB2.[98]
Xylene-stimulated mice
Acetic acid-stimulated mice
Carrageenan-induced rats
Oleic acid-stimulated rats
VolatilesVolatiles inhibited the ear-swelling induced by xylene at 0.12 and 0.24 mL/kg, withstood the hyperfunction of celiac capillary permeability induced by acetic acid at 0.24 mL/kg, alleviated rats paw edema induced by carrageenan at 0.12 and 0.24 mL/kg, inhibited pleuritis induced by carrageenan at 0.24 mL/kg and decreased acute lung injury induced by oleic acid at 0.12 and 0.24 mL/kg.[99]
Anti-inflammatory Activity
LPS/D-galactosamine-induced acute liver injury miceForsythoside AForsythoside A (15, 30 and 60 mg/kg) decreased the serum levels of ALT, AST and TNF-α, increased expression of Nrf2 and heme oxygenase-1 and inhibited NF-κB activation, thus protecting against LPS/D-galactosamine-induced acute liver injury.[100]
LPS-stimulated RAW264.7 cellsForsythinForsythin (25, 50, 100, 150 and 200 μg/mL) inhibited the production of ROS, IL-6, IL-1β, TNF-α, NO, PGE2, iNOS and COX-2 in a dose dependent manner by suppressing JAK-STAT and p38 MAPK signaling pathway.[101]
LPS-stimulated RAW264.7 cellsForsythoside ATreatment with forsythoside A in LPS-stimulated RAW264.7 cells reduced the secretion of TNF-α, IL-6 and NO via inhibition of HMGB1/TLR4/NF-κB pathaway.[102]
LPS-induced acute lung injury male BALB/c micePhillyrinPhillyrin (20 mg/kg) pretreatment significantly decreased the production of IL-1β, IL-6, TNF-α and the concentration of myeloperoxidase in lung tissues via inhibition of MAPK and NF-κB pathways.[103]
LPS-stimulated RAW264.7 cellsArctiinArctiin (12.5, 25, 50 and 100 μg/mL) inhibited NF-κB pathway, thus reducing the production of IL-1β, IL-6, TNF-α and PGE2 in a dose dependent manner, as well as expression of co-stimulatory molecules (B7-1 and B7-2).[104]
LPS-stimulated BEAS-2B cells90% Forsythoside A extractsForsythoside A extracts (25, 50 and 100 μg/mL) significantly reduced the production of NO in a dose-dependent manner and the level of intracellular ROS in a dose-effect manner.[105]
Bursa of Fabricius of chickensForsythoside AForsythoside A (30 and 60 mg/kg) suppressed the NF-κB-iNOS-NO signaling pathway to reduce the production of IL-6, IL-1β, TNF-α and COX-2.[76]
Allergic dermatitis in NC/Nga miceEthanol extract
Matairesinol
In vitro, the Forsythiae Fructus ethanol extracts at 200 μg/mL inhibited histamine to release from mast cells. Further study revealed that matairesinol suppressed inflammatory cell infiltration, IL-4 and IFN-γ mRNA expression and lowered IgE levels in vivo.[106]
Anti-inflammatory Activity
COPD miceForsythoside AForsythoside A (15, 30 and 60 mg/kg) suppressed the production of IL-1β, IL-6, TNF-α and NO and reversed cigarette smoke induced GSH/GSSG ratio, which were related to activation of Nrf2 dose-dependently and inhibition of NF-κB.[107]
Male C57LB/6 miceForsythinAs a selective inhibitor of PDE4, forsythin significantly decreased the levels of IL-1β, IL-6 and TNF in LPS/H1N1 influenza-induced lung injury and sepsis in vivo. Moreover, authors took it as a lead compound and developed three other PDE4 inhibitors with higher activities.[108]
Male Sprague-Dawley rats RAW 264.7 cellsArctigeninArctigenin (0.1–1.0 mg/ear) significantly decreased myeloperoxidase and eosinophil peroxidase activities in the arachidonic acid (AA) induced edematous tissues homogenate and silica-induced ROS production in the RAW 264.7 cell line at 0.1–10 μM, probably by inhibiting the release or production of AA metabolites and free radicals.[109]
LPS-stimulated BV2 microglia cells nd primary microglia cellsForsythoside AForsythoside A at 2.5, 5 and 10 μg/mL inhibited the production of TNF-α, IL-1β, NO and PGE2 via inhibiting NF-κB and activating Nrf2/HO-1 signaling pathway.[110]
PAF-stimulated rat polymorphonuclear leukocytesSuspensine A, 7′-O-methylegenine, (−)-Egenine, (−)-BicucullineThe four alkaloids at 10 μM inhibited the release of β-glucuronidase from polymorphonuclear leukocytes of rats with the rates of 39.6%, 37.7%, 36.5% and 34.8%, respectively.[67]
Staphylococcus aureus (S. aureus)-stimulated monocyte-macrophageForsythinForsythin at 50 mg/L significantly decreased expression of IL-8, TNF-α, IL-6 and at 100 mg/L also decreased expression of macrophage colony stimulating factor-1 (MCSF-1) dose-dependently.[111]
Antibacterial Activity
Escherichia coli (E. coli)
Staphylococcus aureus (S. aureus)
Essential oilThe essential oil changed the permeability and integrity of the cell membrane, leading to leakage of nucleic acids and proteins with MIC values of 3.13 and 1.56 mg/mL for E. coli and S. aureus, respectively.[112]
Pneumococcus, Escherichia coli (E. coli), S. aureus, Haemophilus influenza, a beta-group Streptococcus, Yersinia enterocxolitica, Klebsiella pneumonia, F‘s dysentery bacillus, Salmonella typhi, Pseudomonas aeruginosaEssential oilThe essential oil showed antibacterial activity against these ten bacteria. Particularly, β-pinene and the oil after chromatography showed a better inhibitory effect on the other bacteria, except Yersinia enterocolitica and Klebsiella pneumonia.[113]
Escherichia coli (E. coli) (BCRC-11634)3β-Acetoxyl-20α-hydroxyursan-28-oic acid
β-Amyrin acetate, Betulinic acid
ψ-Taraxasterol, 3β-Hydroxyanticopalic acid
Agatholic acid, Phillyrin
The seven compounds showed antibacterial effect with MIC values of 4.55, 5.00, 1.20, 1.20, 3.42, 2.62 and 3.94 mg/mL, respectively.[48]
Staphylococcus aureus (S. aureus)Ethanol extractThe extract inhibited secretion of α-hemolysin in the range of 16–128 mg/L dose-dependently.[114]
Escherichia coli (E. coli),
Pseudomonas aeruginosa,
Staphylococcus aureus (S. aureus)
Isoforsythoside A
Forsythoside A
The MIC of isoforsythoside A for E. coli, Pseudomonas aeruginosa and S. aureus were 40.83, 40.83 and 81.66 μg/mL, respectively, and those of forsythoside A were 38.33, 38.33 and 76.67 μg/mL, respectively.[27]
Esherichia coli (E. coli) K88, Staphylococcus aureus (S. aureus)
Salmonella enteric 34R99
Methanol extractThe Forsythiae Fructus methanol extracts protected against E. coli K88, S. aureus and Salmonella enteric 34R99 with minimum concentrations of 25.00, 12.50 and 1.56 mg/mL, respectively.[115]
Helicobacter pyloriBetulinic acid
Oleanolic acid
The Forsythiae Fructus ethanol extracts strongly (82%) inhibited urease activity of Helicobacter pylori. Further study revealed that the active compounds were betulinic acid and oleanolic acid.[52]
Acinetobacter baumanniiAqueous extractThe aqueous decoction of Forsythiae Fructus inhibited the active efflux pump and induced mutations in the nucleotide sequence of the adeb gene at 2.5 and 5 mg/mL.[116]
Antiviral Activity
H1N1-infected MDCK cells80% Ethanol extractThe 80% ethanol extract of Forsythiae Fructus exhibited an inhibitory effect on H1N1 in a dose-dependent manner at the concentration of 1:512 to 1:8192 mg/mL.[8]
H1N1-infected human bronchial epithelial cell line A54995% Ethanol extract
50% Ethanol extract
Aqueous extract
95% Ethanol extract, 50% ethanol extract and aqueous extract exhibited inhibitory effect on RANTES secretion with IC50 values of 42 ± 6, 117 ± 15 and 232 ± 28 μg/mL, respectively. Moreover, 95% ethanol extract displayed dual regulatory effects on MCP-1 production, while 50% ethanol extract and aqueous extract increased MCP-1 production by 1.4–3.3 and 2.6–3.7 times, respectively.[117]
C57BL/6j miceForsythoside AForsythoside A (0.4 μg/mL) inhibited influenza A virus replication by suppressing the expression of TLR7, MyD88, TRAF6, IRAK4 and NF-κB p65 mRNA in vivo.[77]
male BALB/C micePhillyrinPhillyrin at a dose of 20 mg/kg/day protected against influenza A shown by the reduction of lung index, viral titers, IL-6 levels, expression of hemagglutinin protein and the alleviated lung tissue damage.[118]
Influenza A transfected-HeLa cellsPhillyrinPhillyrin significantly decreased the gene expression of IAV nucleoprotein.[119]
PRRSV-infected Marc-145 cellsForsythoside AForsythoside A inhibited porcine reproductive and respiratory syndrome virus (PRRSV) RNA synthesis and promoted secretion of IFN-α. The sterilization rate reached 80% at a concentration of 60 μg/mL.[120]
RSV-infected MDCK cells and Hep-2 cellsCalceolarioside B
Forsythoside A
Calceolarioside B and forsythoside A exhibited EC50 values of 3.43 and 6.72 μM for RSV, respectively.[23]
RSVRengynic acidRengynic acid exhibited an anti-RSV effect with EC50 and MIC values of 9.9 and 41.66 μg/mL, respectively.[43]
IBV-infected primary chicken embryo kidney cellsForsythoside AForsythoside A pretreatment at a dose of 0.64 mM had a direct virucidal effect on IBV, but it had no effect on IBV-infected cells.[121]
IBV-infected HD11 cellsForsythoside AForsythoside A (10 and 20 μM) exhibited an antiviral effect by significantly increasing expression of intracellular receptors (MDA5, LGP2 and NLRC5) and antiviral gene (IRF7, IFN-α, IFN-β) mRNA.[122]
Antioxidant Activity
DPPHIsoforsythoside AIsoforsythoside A exhibited antioxidant activity with an EC50 value of 2.74 μg/mL and Vc exhibited an IC50 of 4.38 μg/mL in the DPPH assay.[27]
DPPH and superoxide anionPolysaccharidesForsythiae Fructus polysaccharides showed significant scavenging capacity on the DPPH and superoxide anion with IC50 values of 0.08 and 2.0 mg/mL, respectively.[123]
DPPH in vitro and diquat-stimulated male Sprague Dawley rats in vivoCH2Cl2 fraction of ethanol extract
Forsythoside A
Forsythialan A
Phillygenin
Phillyrin
The CH2Cl2 fraction of ethanol extract (25, 50 and 100 mg/kg) reduced expression of TNF-α, IL-1β, IL-6, MDA and increased the activities of SOD, GSH-Px, GSH. Forsythoside A, forythialan A, phillygenin and phillyrin may be the main active constituents with IC50 values of 10.43 ± 0.15, 29.85 ± 0.43, 53.64 ± 2.70, 351.14 ± 13.15 μg/mL, respectively.[124]
ABTS radical cationCalceolarioside CCalceolarioside C scavenged the ABTS radical cation with IC50 values of 22.7 μg/mL and the Vc exhibited an IC50 of 7.2 μg/mL.[25]
ABTS radical cationLianqiaoxinoside B
Forsythoside H
Lianqiaoxinoside B and forsythoside H scavenged the ABTS radical cation with IC50 values of 15.6 and 17.7 μg/mL, respectively, while Vc exhibited an IC50 of 6.8 μg/mL.[28]
DPPH, Fe3+ and Fe2+Ethyl acetate extractEthyl acetate extract (1.0 mg/mL) of Forsythiae Fructus exhibited a scavenging rate of 71.39% on the DPPH. It also had a relatively strong ability to reduce Fe3+ and chelate Fe2+.[125]
Peroxynitrite-treated LLC-PK1 cellPhillygenin
8-Hydroxypinoresinol
Phillygenin and 8-hydroxypinoresinol significantly decreased the leakage of lactate dehydrogenase (LDH) at 10 μΜ and even reverse the LDH release induced by 3-morpholinosydnonimine, an ONOO generator, at 50 μM.[126]
High-density lipoproteinPinoresinol, Phillygenin, 8-Hydroxypinoresinol, 7′-Epi-8-Hydroxypinoresinol, Lariciresinol, Isolariciresinol, Olivil, CedrusinThe lignans inhibited the generation of thiobarbituric acid-reactive substances in a dose-dependent manner with IC50 values from 8.5 to 18.7 μM and thermo-labile radical initiator-induced lipid peroxidation with IC50 values from 12.1 to 51.1 μM. Among them, pinoresinol and lariciresinol also exerted an inhibitory effect against Cu2+-induced lipid peroxidation of HDL at a concentration of 3 μM.[32]
D-galactose induced aging micePhillyrinA decrease in weight gain rate, spleen index, SOD, GSH-Px and T-AOC activities in serum and liver tissue and an increase in the content of MDA and MAO-B activities in brain tissue were observed after injection of 15 or 45 mg/kg phillyrin.[127]
Antioxidant Activity
Weaned pigletsEthanol extractDietary supplementation (100 mg/kg) of Forsythiae Fructus ethanol extracts after fourteen days significantly increased glutathione peroxidase activities and serum complement 4 concentration and lowered serum endotoxin and MDA concentration. The oxidative injury disappeared after twenty-eight days.[128]
Corticosterone-treated broilersMethanol extractDietary supplementation (100 mg/kg) of Forsythiae Fructus methanol extract attenuated the decrease of the total antioxidant capacity and SOD activity and increase of serum MDA.[129]
Arbor Acres broilers
under high stocking density
Methanol extractTreatment with Forsythiae Fructus methanol extract (100 mg/kg) increased serum T-AOC and SOD activity and reduced MDA expression. However, no significant differences were found in serum GSH-Px activity.[130]
Neuroprotective Activity
Rotenone-stimulated PC12 cells and male Sprague-Dawley ratsEthanol extractThe ethanol extract (50 and 200 mg/kg) exhibited neuroprotective activity by down-regulating protein expression of p-PI3K, p-Akt, p-IκB, p-P65 and cleaving caspase 8, p-p38 and p-JNK.[131]
SAMP8 mice with composite Alzheimer‘s diseaseForsythoside AForsythoside A (60, 120 and 240 mg/kg) increased the activity of SOD, ChAT, and GSH-PX inordinately and decreased the content of MDA and NO by varying degrees in a dose-dependent manner.[132]
SAMP8 miceForsythoside AOral administration of forsythoside A (60, 120 and 240 mg/kg) decreased the levels of IL-1β, NO, MDA and NE and increased the T-SOD and GSH-Px activities and the production of GLU and Ach.[133]
Scopolamine-induced learning and memory impairment in miceForsythoside AForsythoside A (200 mg/kg) ameliorated scopolamine-induced learning and memory impairment by modulating AchE activity, cAMP expression and p-ERK production and protecting against oxidation.[134]
Gerbils with transient cerebral global ischemiaForsythoside AOral administration of forsythoside A (10 mg/kg) significantly increased the number of viable neurons and decreased degenerating neurons, activated glial cells and the expression of IL-1β and TNF-α, indicating the involvement of anti-inflammatory activities.[135]
25-35 oligomer-stimulated HT22 cellsForsythoside AForsythoside A (25 μg/mL) significantly decreased production of NO to improve neuroinflammation in Aβ25-35 oligomer-stimulated HT22 cells.[136]
Neuroprotective Activity
Glutamate or low-glucose and low-serum or Aβ25-35-stimulated PC12 cellsForsythoside AForsythoside A (0.1, 1 and 5 μmol/L) improved proliferation of PC12 cells and significantly reduced cell death in vitro. Moreover, forsythoside A (0.1 and 1 μmol/L) significantly inhibited cell apoptosis induced by Aβ25-35.[137]
MPP+-stimulated SH-SY5Y neuroblastoma cellsPhillyrinPhillyrin (1, 10 and 100 μmol/L) significantly increased cell viability and reduced leakage of LDH induced by MPP+.[138]
Rotenone-stimulated PC12 cellsForsythoneoside B
Forsythoneoside D
Forsythoneoside B and forsythoneoside D at 0.1 μM inhibited PC12 cell damage induced by rotenone and increased cell viability from 53.9 ± 7.1% to 70.1 ± 4.0% and 67.9 ± 5.2%, respectively.[11]
Anti-tumor Activity
The murine melanoma B16-F10 cell line and C57BL/6 mice bearing melanomaAqueous extractThe aqueous extract inhibited proliferation and angiogenesis of cancer cells, which were closely related to the antioxidant and anti-inflammatory activities via the MAPKs/Nrf2/HO-1 pathway.[7]
HeLa cellsAqueous extractThe aqueous extract (50 μg/mL) promoted activation of the zymogen of caspase 8 to inhibit proliferation of cells in vitro time-dose-dependently, with IC50 values of 93.74, 33.30 and 22.65 μg/mL for 12, 24 and 48 h, respectively.[139]
HeLa cellsEthanol extractIn vitro, the ethanol extract (12.5–100 μg/mL) had an inhibitory effect on the proliferation of Hela cells in a time-dose-dependent manner with IC50 values for the 12, 24 and 48 h groups of 97.68, 39.16 and 25.83 μg/mL, respectively.[140]
SGC7901 cellsAqueous extractIn vitro, the aqueous extract (25–100 μg/mL) inhibited proliferation of SGC7901 cells in a time-dose-dependent manner with IC50 values for the 6, 12 and 24 h of 73.27 ± 3.19, 44.63 ± 2.06 and 35.99 ± 2.43 μg/mL, respectively.[141]
C57BL/6J mice injected with Lewis cellsPhillyrinPhillyrin (5 and 10 g/kg) significantly inhibited the tumor size and tumor tissue density dose-dependently by decreasing the expression of VEGF and increasing the expression of endostatin.[142]
Anti-tumor Activity
A549, Colo205, Hep-3B, HL60, and KB cancer cell lines(+)-8-Hydroxyepipinoresinol-4-O-β-d-glucopyranoside(+)-8-hydroxyepipinoresinol-4-O-β-d-glucopyranoside showed significant cytotoxicity in A549, Colo205, Hep-3B, HL60 and KB cancer cell lines with IC50 values of 9.48, 7.75, 0.59, 4.06 and 38.38 μM, respectively.[34]
MKN-45, MKN-28, SGC-7901, PNAC-1 and HepG-2 cancer cell linesAmbrolic acid
Dammar-24-en-3β-acetoxy-20-ol
Ambrolic acid inhibited SGC-7901 cells by affecting the S period of DNA synthesis and also reduced the levels of pro-caspase 3, 6, 8, 9 and Bcl-2 proteins and increased the levels of Bax protein to induce cell apoptosis, while dammar-24-en-3β-acetoxy-20-ol only had an inhibitory effect on the cancer cells.[51,55]
PC3 cells of prostate cancerDammar-24-en-3β-acetoxy-20-olDammar-24-en-3β-acetoxy-20-ol (6.25–50.0 μg/mL) increased expression of p21, TGF-β and Smad3 and decreased expression of Cyclin D1 and CDC25A to induce cell apoptosis and inhibited the activity of telomerase. Moreover, it affected the radiosensitivity of PC-3 cells of prostate cancer at 25 μg/mL.[143]
Hepatoprotective Activity
CCl4-induced toxicity in ratsPhillygeninPhillygenin at 0.15 and 0.5 mg/kg significantly decreased the levels of ALT, AST, total bilirubin, TNF-α and IL-8 in serum and the content of MDA in liver tissue. Meanwhile, it increased the activities of SOD, GSH-Px and GSH.[10]
Bovine serum albumin-induced hepatic fibrosis in ratsForsythoside AForsythoside A alleviated hepatic fibrosis at 0.1, 0.3 and 1.0 mg/kg by decreasing the hydroxyproline content and the levels of layer fibronectin, hyaluronic acid, IV-collagen and procollagen III.[144]
Human normal liver cell lines LO2ForsythinForsythin reversed nuclear condensation and nuclear fragmentation and decreased expression of apoptosis related proteins (PARP and caspase 3) to prevent alcoholic liver injury does-dependently.[145]
Rats with severe acute pancreatitisAqueous extractThe aqueous extract (1.25, 2.5 and 5 g/kg) significantly reduced the serum levels of amylase, ALT and TNF-α in a dose dependent manner and expression of NF-κB mRNA and Foxp3 mRNA in liver tissue.[146]
Cardiovascular Protective Effect
Streptozotocin-induced diabetic miceEthyl acetate extractOral administration of the extract (50, 100 and 200 mg/kg) after four weeks significantly decreased the levels of blood glucose, triglyceride, creatinine and so on and increased body weight, insulin secretion and glucose tolerance, which were related to inhibition of glucokinase, phosphorenolpyruvate carboxykinase, insulin-1, insulin-2 and duodenal homeobox factor-1, thus exhibiting antidiabetic and antihyperlipidemic activities.[147]
SD rats with atherosclerosisPhillyrinPhillyrin (150 mg/kg) reduced the area of AS plaques and the contents of ICAM-1, VACM-1, IL-1, IL-6 and MDA and increased the contents of NO and SOD, probably by decreaseing expression of sodium hydrogen exchange protein 1 (NHE-1).[12]
Rat aortic ringsForsythoside AForsythoside A inhibited norepinephrine-stimulated vasocontraction by decreasing calcium influx from the extracellular space.[148]
Others
Cisplatin-treated miceAqueous decoctionThe aqueous decoction reduced the contents of serum gastrin and promoted gastrointestinal movement at 3, 6 and 12 g/kg, indicating its anti-vomiting activity.[9]
HepG2 cellsPhillyrinPhillyrin at the concentration of 1, 2.5 and 5 μM induced phosphorylation of LKB1 and activated AMPK, thus reducing expression of SREBP-1c and fatty acid synthase and avoiding accumulation of lipid.[149]
TNF-α-stimulated 3T3-L1 adipocytesPhillyrinPhillyrin (40 μM) suppressed activation of I kappaB kinase and N-terminal kinase to attenuate TNF-α-mediated insulin resistance and lipolytic acceleration.[150]
Obese C57BL/6J micePhillyrinTreatment with phillyrin (15 and 45 mg/kg) significantly decreased body weight, the serum levels of TNF-α and leptin and increased expression of PPAR-β/δ, ANGPTL4 and p-AMPK-α.[151]
Dihydrotestosterone-stimulated miceForsythoside AForsythoside A suppressed apoptosis of hair cells by reducing expression of caspase-9 by 40%, caspase-3 by 53% and increasing the Bcl-2/Bax ratio by 60%. It also retarded the entry into the catagen phase and reduced the expression of TGF-β2 by 75%.[152]
Mice with endotoxemiaForsythoside AForsythoside A (80 mg/kg) enhanced the immune function of mice with endotoxemia, which may be associated with the inhibition of TNF-α and IL-10 secretion and the gene expression of Foxp3.[153]
Yeast-stimulated C57BL/6 miceForsythoside AForsythoside A (4 and 8 mg/kg) significantly decreased the temperature of mice by up-regulating expression of TRPA1 in the paraventricular nuclei (PN), supraoptic nucleus (SO) and dorsal root ganglion (DRG).[154]
Caco-2 cellsForsythoside AForsythoside A inhibited P-gp ATPase activity to influence the efflux of drugs.[155]
Table 4. The investigations about pharmacokinetics of Forsythiae Fructus.
Table 4. The investigations about pharmacokinetics of Forsythiae Fructus.
MarkersMethodsResultsReference
Forsythoside A, Rutin, Phillyrin, Isorhamnetin and QuercetinHPLC-MS/MSThe t1/2 of forsythoside A, rutin, phillyrin, quercetin and isorhamnetin after single oral administration of UFF extract were 1.91 ± 1.76 h, 1.59 ± 0.92 h, 3.52 ± 4.37 h, 2.70 ± 2.70 h and 6.32 ± 4.69 h, respectively, while those were 4.52 ± 4.77 h, 6.54 ± 8.73 h, 14.74 ± 27.34 h, not detected and not detected after single oral administration of RFF extract. The AUC0–24 h of forsythoside A, rutin and phillyrin were significantly different between sigle oral administration of UFF and RFF extract.[59]
(+)-Pinoresinol-β-d-glucoside, Matairesinol-4′-O-glucoside, Hyperin, Phillyrin, PhillygeninHPLC-ESI-MS/MSThe average percentages of (+)-pinoresinol-β-d-glucoside, matairesinol-4′-O-glucoside, hyperin, phillyrin and hillygenin excreted in the bile over the dose administered (12 mL/kg body weight) were 0.002%, 0.234%, 0.116%, 0.288%, and 12.700%, respectively. Hyperin was found in plasma, urine and excrement of rat while the others were detected only in bile, indicating lignans of Forsythiae Fructus were excreted mainly via bile.[31]
Forsythoside ALC-MS/MSForsythoside A was rapidly absorbed into the blood with a Tmax of 20.0 min after oral (100 mg/kg) administration, but the Cmax was only 122.2 ± 45.4 ng/mL, indicating a quite low absolute bioavailability with a value of 0.5%.[158]
Forsythoside AMicrodialysis coupled with HPLCForsythoside A went through hepatobiliary excretion and the bile-to-blood distribution ratio (AUCbile/AUCblood) was 0.32 ± 0.06 after the intravenous administration of 50 mg/kg.[159]
PhillyrinUPLC-Q-TOF-MSA total of thirty-four metabolites of phillyrin were detected in rat bile, urine and feces and M26 was the major one. Phillyrin mainly went through hydrolysis, oxidation and sulfation to transform into the effective forms in vivo.[161]
PhillygeninHPLCThe elimination half-time (t1/2z) of phillygenin after intravenous administration of 1.4, 2.8 and 5.6 mg/kg were 6.02 ± 1.66, 5.62 ± 0.35 and 5.79 ± 0.81 min, respectively and the AUC (0–∞) were 166.29 ± 18.01, 242.40 ± 7.12 and 332.48 ± 23.98 mg/L min, respectively. All these results suggested the pharmacokinetics of phillygenin followed first-order kinetics.[162]
Phillyrin and Forsythoside AUHPLC-MS-MSThe t1/2 of caffeine, tolbutamide, metoprolol and dapsone in rats after intraperitoneal administration were 5.86 ± 0.83, 5.87 ± 0.83, 4.67 ± 0.63 and 1.17 ± 0.15 h, respectively. But when given a pretreatment of phillyrin and forsythoside A, the t1/2 of them changed into 4.63 ± 0.56 and 4.15 ± 0.54, 5.56 ± 0.72 and 4.28 ± 0.74, 3.69 ± 0.54 and 4.17 ± 0.27, 1.05 ± 0.15 and 1.02 ± 0.19 h for phillyrin and forsythoside A, respectively, indicating the inductive effect of phillyrin and forsythoside A on CYP. Further study revealed that phillyrin induced rat CYP1A2 and CYP2D1, while forsythoside A induced CYP1A2 and CYP2C11.[163]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top