|Year : 2022 | Volume
| Issue : 1 | Page : 1-20
Forsythosides as essential components of Forsythia-based traditional chinese medicines used to treat inflammatory diseases and COVID-19
OncoWitan, Scientific Consulting Office, Lille (Wasquehal, 59290), France
|Date of Submission||07-Dec-2020|
|Date of Acceptance||22-Feb-2021|
|Date of Web Publication||16-Sep-2021|
Dr. Christian Bailly
OncoWitan, Lille (Wasquehal), 59290
Source of Support: None, Conflict of Interest: None
The dried fruits of the plant Forsythia suspensa (Forsythia Fructus: Lianqiao in Chinese) are used in many herbal preparations to treat various diseases or the associated symptoms. Forsythia extracts contain phenylethanoid glycosides (PhGs) such as the forsythosides (Fst A-to-P). The leading products, Fst-A,-B and-F (arenarioside), can be found also in >90 other plants inventoried here. The pharmacological properties of Fst are reviewed, with emphasis on their anticancer, antiviral, and antibacterial activities, which essentially derive from their anti-inflammatory and antioxidant effects. Fst-B functions as a potential binder of the repressor protein Kelch-like ECH-association protein 1 (Keap 1), thus promoting the nuclear translocation of the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) implicated in the subsequent activation of the production of antioxidant enzymes and repression of the oxidative stress. The regulation of the Nrf2/Heme oxygenase-1 pathway is the central piece of the multifaceted mechanism of action of Fst-A/B. Their prominent antioxidant and anti-inflammatory effects support the use of these compounds in different inflammation-related diseases and conditions, from sepsis to neuroprotection and many other pathologies discussed here. In addition, these properties contribute to the antiviral action of the compounds. Fst-A/B displays activities against the influenza A virus and different Fst-containing traditional Chinese medicinal (TCMs) have revealed beneficial effects to combat the current COVID-19 pandemic. The mechanisms whereby Fst-A/B could inhibit viral multiplication are discussed. PhGs likely contribute to the anti-COVID-19 activities reported with several TCM such as Shuang-Huang-Lian oral liquid, Lianhua-Qingwen capsules, and others. This review highlights the pharmacological profile of Fst and illustrates health benefits associated with the use of Forsythia Fructus.
Keywords: Chinese medicine; COVID-19; forsythia; forsythoside; mechanism of action; natural products; phenylethanoid glycosides
|How to cite this article:|
Bailly C. Forsythosides as essential components of Forsythia-based traditional chinese medicines used to treat inflammatory diseases and COVID-19. World J Tradit Chin Med 2022;8:1-20
|How to cite this URL:|
Bailly C. Forsythosides as essential components of Forsythia-based traditional chinese medicines used to treat inflammatory diseases and COVID-19. World J Tradit Chin Med [serial online] 2022 [cited 2022 May 18];8:1-20. Available from: https://www.wjtcm.net/text.asp?2022/8/1/1/336830
| Introduction|| |
The forsythosides (Fst) represent a small group of natural products found in several traditional Chinese medicinal (TCM) preparations. The subgroup includes 16 members, named Fst A-to-P, initially isolated from Forsythia species. The compounds are listed in [Table 1] together with their characteristics. The best-known members are Fst-A and forsythoside B (Fst-B) isolated from the plant Forsythia suspensa (Thunberg) Vahl. (weeping forsythia) originating from China. The plant has hollow, pendulous stems about 3 m long and golden-yellow flowers [Figure 1]. Many medicinal preparations include either the plant F. suspensa or the dried fruits of the plant commonly referred to as Forsythia fructus (Lianqiao in Chinese). Both the greenish fruits (Qingqiao) and the yellow fruits (Laoqiao) are used for medical applications.,,, Aqueous extracts of Forsythia Fructus (Lianqiao) are considered as fundamental components in TCM, being among the top ten of the most potent anti-inflammatory herbs
|Figure 1: Illustrations of the plant Forsythia suspensa (Thunberg) Vahl. (flowers and leaves) and its fruits called Forsythia Fructus (known as Lianqiao in Chinese, and Rengyo in Japanese) from which large quantities of forsythoside A can be isolated. The compound is also known as forsythiaside A (3,4-dihydroxy-β-phenethyl-O-α-L-rhamnopyranosyl-(1 → 6)-4-O-caffeoyl-β-d-glucopyranoside)|
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F. suspensa is truly a reservoir of natural products. The plant and the fruits contain diverse flavonoids, alkaloids, and phenylethanoid or phenylpropanoid glycosides., The Fst represent one of the main subgroups of phenylethanoid glycosides (PhGs) found in F. suspensa, but the compounds are also well represented in different species of Phlomis, Callicarpa, Marrubium, Verbascum, and others. Fst compounds could be identified in about 90 plants inventoried in [Table 1]. However, the major medicinal material containing Fst is F. suspensa (and Forsythia Fructus) commonly used to prepare several TCMs. Nineteen TCM preparations made from F. suspensa can be identified [Table 2]. They are used for the treatment of respiratory diseases and infections (such as Siji-kangbingdu mixture, Shufeng Jiedu capsule, Tianreqing injection, and Shuang Huang Lian injection), while others are used to treat liver diseases (such as Dahuang Zhechong pill and Li-Dan-He-Ji granules).,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
|Table 2: Traditional chinese medicine preparations containing forsythosides|
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Interestingly, several recent studies have highlighted the use of Forsythia Fructus-containing TCM to treat the current COVID-19 pandemic. This is the case of Lianhuaqingwen capsule and Shufeng Jiedu capsule, which are both proposed to alleviate the symptoms of the infectious viral disease. Lianhuaqingwen has shown efficacy in COVID-19 patients to reduce the symptoms associated with the coronavirus pneumonia.,,,,,, Fst-A and Fst-I would contribute importantly to the anti-COVID-19 activity. Tianreqing injection is also a medication tested with some success in patients suffering from viral pneumonia,,,, and the preparation contains significant quantities of Fst-A and Fst-E., Similarly, different studies have pointed out the efficacy of Shufeng Jiedu capsules to treat COVID-19,,,, and here again, Fst-A seems to play a role in the antiviral and anti-inflammatory effects of the herbal preparation.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
For these reasons, it is timely to review the pharmacological properties of the Fst and their potential therapeutic uses, but also the limitations associated with the use of these compounds. The present review starts with a brief survey of the molecular diversity of the Fst and then provides a comprehensive analysis of the pharmacological properties of the best known-members in the series, mainly Fst-A and Fst-B (also known as forsythiasides A and B, respectively).
| Molecular Diversity of the Forsythosides|| |
here are 16 Fst, designated Fst A-to-P, but one of them (Fst-L) could not be identified. The structures of the 15 other Fst compounds are presented in [Figure 2]. Fst-A was first isolated in 1981 in Japan, from the fruits (Forsythia fructus called “rengyo” in Japanese) and the leaves of the plant F. suspensa. The compound is composed of a central disaccharide unit (L-rhamnose-(1→6)-D-glucose) substituted with a caffeoyl group at position C-4 on the glucose unit and a 3,4-hydroxyphenylethanol (hydroxytyrosol) unit at position C-1 of the glucose residue [Figure 2]. It is an isomer of verbascoside (also known as acteoside or kusaginin) which bears the rhamnose unit at position C-3. Fst-B was isolated from F. suspensa a few months later by the same group in Japan. The molecule is characterized by the presence of an atypical β-D-apiosyl unit at position C-6 on the central glucose unit. It is a trisaccharide with β-D-apiosyl-(1→6), α-L-rhamnosyl-(1→3)-β-D-glucosyl unit. Fst-B (verbascoside 6'-0-β-D-apiofuranoside) is abundant in the stalk of Forsythiae Fructus but not found in the seeds and pericarp, whereas Fst-A can be found at a relatively high level in each segment. It was rapidly followed with the discovery of Fst-C and Fst-D in 1982, again by the same Japanese research group. They both include a phenylethane-1,2-diol moiety instead of the phenylethanol unit of Fst-A and Fst-B. Fst-C is a hydroxyl derivative of Fst-A, whereas Fst-D lacks the caffeoyl unit, as it is the case for Fst-E [Figure 2]. These four compounds, Fst-A/B/C/D, exhibit a very mild antibacterial activity.,,,
|Figure 2: Chemical structures of the forsythosides and the corresponding discovery dates. forsythoside-A (PubChem CID#5281773, C29H36O15), Fst-B (CID# 23928102, C34H44O19), Fst-C (C29H36O16), Fst-D (C20H30O13), Fst-E (CID# 69634125, C20H30O12), Fst-F (CID# 6442994, C34H44O19), Fst-G (CID# 101231533, C35H46O19), Fst-H (CID# 129449684, C29H35O15), Fst-I (CID# 23958169, C29H35O15), Fst-J (C28H33O15), Fst-K (C30H38O16), Fst-M (C22H26O10), Fst-N (C22H26O10), Fst-O (C24H28O11) and Fst-P (C29H36O14). Note that the structure of forsythoside-D cited in PubMed (CID# 24721571) is incorrect. The structure indicated presents a furofuranyl core corresponding to phyllirin, not forsythoside-D. The structure shown here corresponds to the original structure determined for forsythoside-D in 1982|
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Fst-A and Fst-B are very abundant in the plant kingdom and have been isolated from many plants [Table 1]. F. suspensa produces usually a large quantity of fruits and the plant can be cultivated. Nevertheless, another method to produce Fst-B consists in transforming a root culture of a Fst-producing plant with the bacteria Agrobacterium rhizogenes. The method has been described to produce verbascoside and Fst-B from transformed root culture of Verbascum xanthophoeniceum. It can be applied to produce other PhGs., Callus and cell suspension cultures of F. suspensa, Forsythia viridissima, and Forsythia koreana can be made as well, to produce phenylethanoid derivatives, such as cornoside, vervascoside, and Fst-F (arenarioside).
The three Forsythia species, F. suspensa, F. viridissima, and F. koreana, have been used as herbal medicines in China, Japan, and Korea for centuries and they are known to be rich sources of phenylpropanoid glycosides. Fst-E (decaffeoyl- Fst A) was first isolated in 1984 from the fruits of F. suspensa. Fst-F and-G were isolated 6 years later from the stems of F. viridissima. Fst-F presents a trisaccharide core (α-rhamnosyl-(1 → 3)-glucosyl-(6 → 1)-β-xylosyl) and Fst-G bears an unusual D-2-O-methylapiose unit (α-rhamnosyl-(1 → 3)-glucosyl-(6 → 1)-β-(2-O-methyl) apiosyl). In the literature, Fst-F is often cited as arenarioside [Table 1], initially isolated from the plant Orobanche arenaria. This compound can be found in different Orobanche species. Fst-F is one of the rare PhGs, for which the total organic synthesis of the trisaccharide moiety and a synthetic benzyl protected derivative have been described., Several multisteps total syntheses of different natural PhGs have been reported but not for the Fst.,,,
Fst-H,-I and-J were isolated more recently in 2009, again from the plant F. suspensa. They possess all three a disaccharide core, a caffeoyl group, and a dihydroxyphenylethyl moiety but they differ by the nature of the sugar units and/or the linkage. Fst-H and Fst-I bear the same α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside unit, but the position of the caffeoyl group is different for the two compounds [Figure 2]. In contrast, Fst-J has a β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside unit. It is worth noting here that these compounds Fst-E,-I and-H can be generated in biological milieu by isomerization and/or degradation of Fst-A. Fst-K (7R-suspensaside methyl ether) was isolated in 2016 from an ethanolic extract of F. suspensa. As indicated above, Fst-L could not be found.
The isolation of Fst-M,-N,-O and-P was reported 2017. Starting from 80 kg of the dried fruits of F. suspensa, the authors isolated about 5 mg of each compound. Fst-M,-N and-O possess a single β-D-glucose unit differently substituted. A 4-hydroxyphenylethanol group is common to Fst-M and-N, whereas Fst-O has a 2,5-dihydroxyphenylethanol group connected to the C2-position of the sugar through an ether linkage. On the C6-osition, an ester linkage connects the sugar to 4-hydroxyl-3-methoxylbenzoyl group for Fst-M, whereas Fst-O has a classical feruloyl unit. Fst-P bears a disaccharide unit α-L-rhamnose-(1→6)-β-D-glucose.
Other phenylpropanoid glycosides and lignan glycosides have been isolated from F. suspensa, such as the forsythialensides A-D, forsythenethosides A and B, forsythoneosides, forsythiaside and suspensaside,,,, forsyphensides A-C, susaroysides A-E, suspensanosides A-C, Lianqiaoxinsides A and B,, forsythensides,, and other phenylethanoid and lignan glycosides.,,
| Pharmacological Properties of the Forsythosides|| |
Different types of Forsythia Fructus extracts have revealed anticancer properties. An aqueous extract was shown to reduce markedly the growth of B16-F10 murine melanoma cells both in vitro and in vivo. The effects were attributed to the anti-inflammatory and anti-oxidative activities of the extract, leading to inhibition of tumor cell proliferation and angiogenesis. This extract upregulated the expression of several proteins, notably the antioxidant proteins Nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), the tumor suppressor proteins P53, and phospho-PTEN (phosphatase and tensin homolog deleted on chromosome 1) in the tumor tissue. A parallel study indicated that the antimelanoma effect was linked to a modulation of glycerophospholipid metabolism in cancer cells induced by the Forsythia Fructus extract. The mechanism is likely even more complex because the same extract was also found to activate different anti-inflammatory factors but also to increase the expression of the ubiquitin-regulator protein A20 which inhibits signaling cascades of endotoxin or cytokines in RAW 264.7 murine macrophage cells. Whatever the molecular mechanism, it is interesting to note that water extracts made from the green fruits of F. suspensa displayed much more pronounced anti-melanoma effects in vitro and in vivo than extracts made from the ripe Forsythia fruits. Importantly, the Fst content (Fst-A,-E,-H,-I and-J were detected) was much higher in the green Forsythia extracts compared to the ripe Forsythia extracts., The authors showed that Fst-A,-E and-I (more abundant in the green fruits) were among the cytotoxic components of the aqueous extract and could serve as molecular markers to analyze the quality of extracts and their anticancer potential. However, the anticancer activity of F. Fructus is not solely due to the presence of Fst compounds in the extract; other natural products also contribute to the activity such as betulinic acid and arctigenin.,
A marked anticancer activity has been reported also with extracts of the fruits and leaves of the plant F. koreana, which showed antimetastatic effects by blocking invasion of breast cancer cells. The plant extract inhibited osteoclast formation and osteoclast-mediated bone resorption by reducing the activities of matrix metalloproteinases and cathepsin K. As mentioned above, the three species F. suspensa, F. viridissima, and F. koreana, used as herbal medicines in Asia, possess common genes associated with the biosynthesis of acteoside and Fst-A (33), but the antitumor activity of the plant extracts could derive also in part from the presence of anticancer dammarane-type terpenoids.,
Antiproliferative and anti-inflammatory activities have been observed with nonpolar fractions of F. fructus, suggesting that components other than the Fst can contribute to the global effects of fruit extracts., A marked antitumor activity was observed in vivo in a TE-13 esophageal cancer cell xenograft murine model, using an ethanolic root extract of F. suspensa. In a study comparing the anticancer activity of 130 crude extracts used in Kampo medicine, an extract of Rengyo (Forsythia fruit) was found among the most potent extracts at regulating autophagic cell death in HepG2 hepatocellular carcinoma cells. Fst-A and-B contribute to the anticancer activity, together with other natural products contained in the extract, notably tannic acid which displays a potent antiangiogenic activity through inhibition of the SDF-1/CXCR4 pathway.,
In brief, Forsythia Fructus extracts display anticancer activities and several forsythosides (Fst-A/E/H/I/J) likely contribute to the anticancer activity, most likely through anti-inflammatory and antioxidative effects [Figure 3]. Other natural products included in the extract also contribute the antitumor action.
|Figure 3: Antitumor activity of Forsythia Fructus extracts. Ethanolic extracts made from the fruits of Forsythia species contain numerous natural products, including diverse flavonoids, alkaloids, terpenoids, and phenylethanoid glycosides such as the forsythosides. The extracts inhibit cancer cell proliferation, invasion, and tumor angiogenesis, leading to the observed anticancer effects. The forsythosides contribute to the antitumor action through their antioxidant and anti-inflammatory activities|
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A large number of patents (about 400) cover the extraction, purification, characterization, formulations of Fst natural products from plants and their various medicinal uses. Several patents are focused on the antiviral activities of the compounds [Table 3]. The antiviral activity of Fst-A was first demonstrated using the avian infectious bronchitis virus (IBV) infecting primary chicken embryo kidney cells. Fst-A showed a direct virucidal effect, reducing cell infection by the IBV in vitro, but had no effect on IBV-infected cells. A recent study has confirmed that Fst-A can markedly reduce viral infection in chicken exposed to the avian IBV IBV-M41. The compound was also efficient for the treatment of IBV-M41-infected chicken, through an improvement of CD3+, CD4+, and CD8+ T-lymphocytes in infected chickens and a sustained production of interleukin-2 (IL-2) and interferon-α (IFN-α).
Fst-A has shown activities against different viruses including influenza viruses which infect the respiratory epithelium in human and many vertebrates. However, the bioavailability of Fst-A is very limited, even when the compound is included in traditional medicines such as the TCM antiviral preparation Shuang-Huang-Lian used to treat various bacterial, fungal, and viral infections [Table 2].,, All major PhGs, including compounds such as acteoside and salidroside, show a poor oral bioavailability. However, the bioavailability of Fst-A and its antiviral activity can be enhanced through the use of absorption enhancers, such as water-soluble chitosan, that contributes to limit the influenza virus propagation. Chito-oligosaccharides have been shown to facilitate the intestinal absorption of various PhGs in F. fructus extracts. Fst-B also contributes to the anti-influenza A virus efficacy of Shuang-Huang-Lian recipes. In recent years, the molecular mechanism of action against the influenza virus has been investigated. Fst-A was shown to control influenza A virus (IAV, H1N1) infection by inhibiting the virus replication and downregulating different pro-viral factors such as TLR7 (Toll-like receptor 7), MyD88 (myeloid differentiating factor 88), and nuclear factor kappa-B (NFκB) p65 mRNA. In particular, the down-regulation of the TLR7 signaling pathway induced by Fst-A is key to control IAV infection and the parallel blockade of the TLR4/NFκB axis leads to an essential immunomodulatory action [Figure 4]. Fst-A downregulates the expression of the influenza matrix protein 1 (M1), one of the most abundant protein in influenza virions, and the compound also reduces the inflammatory response caused by influenza A virus (FM1 strain) in mouse lungs by affecting the retinoic acid-inducible gene-I-like receptors signaling pathway. Fst-B also inhibits the TLR4/NFκB axis, contributing to an anti-inflammatory action. The different TCM preparations containing Fst-A and-B thus benefit from the simultaneous attenuation of inflammation and reduction of viral replication in the infected lungs.
|Figure 4: Scheme summarizing the activity of forsythoside-A/B against the Influenza A virus. The compounds inhibit virus-induced inflammatory pathways and the replication of the virus through the indicated signaling route, leading to downregulation of several proteins implicated in virus infection|
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The antiviral activity of Fst-A and-B is not limited to the influenza virus. Fst-A protects peripheral blood mononuclear cells (PBMC) from infection by the bovine viral diarrhea virus (BVDV, a virus at the origin of viral diarrhea and mucosal disease in cattle). The compound inhibits the replication of BVDV, reduces apoptosis of PBMC (through a drug-induced over-secretion of IFN-γ and enhanced secretion of IL-2), and promotes activation of T cells. Moreover, Fst-A promoted proliferation of bovine PBMCs and T cells activation, thereby counteracting the BVDV-induced overproduction of IFN-γ to maintain immune homeostasis.
There is little scientific evidence today that the Fst per se can be active against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) responsible for the current COVID-19 pandemic. However, several TCM preparations containing Fst compounds have revealed beneficial activities against the disease, either to reduce the viral charge or to alleviate the associated respiratory symptoms. Preparation like Shuang-Huang-Lian oral liquid and Tanreqing injection, alone or combined with Western medicine, are claimed to be active against severe pneumonia.,,,, Other TCM preparations have revealed activities against COVID-19, such as those indicated in [Figure 5]. The contribution of the Fst to these effects is unclear at present, but preliminary information suggests that they play a role in the antiviral activity, through their anti-inflammatory action. Notably, the herbal product Lianhuaqingwen (LHQW) capsule can contribute to accelerate the recovery of patients with moderate COVID-19. The treatment helps to reduce fever, fatigue, and coughing in COVID-19 patients and to improve other clinical symptoms such as diarrhea in patients with ordinary or mild COVID-19.,, This phytochemical preparation is known to reduce the proliferation of influenza viruses, through the suppression of NF-B activation and reduction of pro-inflammatory cytokines production (IL-6, IL-8, TNFα, and MCP-1), and it showed the same effect when using SARS-CoV-2-infected Vero E6 cells in vitro. The anti-inflammatory action of Lianhuaqingwen is well established, but the preparation is complex (11 herbal constituents) and more than 60 active compounds have been identified. Among them, 15 effective components have been characterized for their contribution to the anti-inflammatory and antiviral effects, and Fst-A belongs to this group of active compounds (as well as two compounds called “isomers of Fst-A” but not specified). In a recent study, Fst-A,-B and-I were all three identified in Lianhuaqingwen capsules and found to bind to and to inhibit the angiotensin-converting enzyme-2 (ACE2), whereas Fst-E showed little or no effect. Their affinities for the enzyme are modest (KD = 15.8, 61.0, and 18.7 μM for Fst-A,-B and-I, respectively, compared to prunasin and glycyrrhizin, KD = 0.27 and 4.4 μM), but the Fst-compounds could form stable complexes with the enzyme, according to a modeling analysis. This binding is important because the virus SARS-CoV-2 utilizes the ACE2 receptor system for cell entry. This multifunctional transmembrane protein – an essential component of the renin–angiotensin system – is overexpressed in human airway epithelial cells. Drugs which could interfere with the interaction of ACE2 with the SARS-CoV-2 spike protein can be useful to combat COVID-19., Fst-A and its isomer Fst-I could thus play a marked role in the activity of the TCM preparations aforementioned.
|Figure 5: Several forsythoside-containing traditional Chinese medicinal preparations used to combat Influenza (KBD, YQS, SHL, and T) or severe acute respiratory syndrome coronavirus-2 (SHL, T, SFJDC, JQG, QBD, and LHQW) viral infections. The plant and forsythoside-content of these traditional Chinese medicinal is indicated in Table 2|
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Perhaps, another indirect action of Fst against the virus is through the metabolites caffeic acid and hydroxytyrosol which can both inhibit coronavirus in humans.,, On the basis of molecular modeling studies, it has been proposed that caffeic acid binds to the cell-surface heat shock protein A5 (HSPA5) so as to compete for recognition by the viral spike protein [Figure 6]. By this mechanism, caffeic acid could inhibit the cell attachment of the virus. Different caffeic acid derivatives have been proposed as anti-COVID-19 agents., A spray containing hydroxytyrosol combined with α-cyclodextrin (called “Endovir Stop”) is being evaluated in COVID-19 patients, after the recent demonstration of its safety on healthy volunteers. Preliminary clinical data indicated that this spray could improve defenses against SARS-CoV-2. Therefore, the two aglycone constituents of Fst-A/B could also potentially contribute to the antiviral activity. They are also metabolites of the main PhG verbascoside which is viewed as an inhibitor of the SARS-CoV-2 main protease Mpro (also known as 3C-like proteinase, 3CLpro).
|Figure 6: Phenylethanoid glycosides and COVID-19. Most forsythosides are built with a variable glycosidic core substituted with a caffeoyl unit and a hydroxytyrosol unit. The forsythoside natural products and their metabolites are believed to contribute to the antiviral activity. Molecular modeling studies have suggested that forsythoside-B interact with the angiotensin-converting enzyme-2 implicated in the cell entry of the severe acute respiratory syndrome coronavirus-2 virus, whereas caffeic acid and hydroxytyrosol would bind to the cell-surface protein heat shock protein A5 implicated in the interaction with the viral spike protein|
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Antioxidative and anti-inflammatory activities
Recently, the anti-inflammatory activity of Fst-B isolated from the TCM herb Callicarpa kwangtungensis was thoroughly investigated. Fst-B showed the strongest anti-inflammatory activity among six PhGs tested. The compound inhibited the release of TNF-α, IL-6, and nitric oxide in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages [Figure 5]. Fst-B was found to upregulate the expression of HO-1 and quinone oxidoreductase 1 (NQO1), through an inhibition of the interaction between the nuclear transcription factor Nrf2 and its repressor protein Kelch-like ECH-association protein 1 (Keap1). Fst-B also induced the accumulation of Nrf2 in cell nuclei. A potential direct binding of Fst-B to Keap1 was proposed, based on a molecular modeling analysis and a similar physical interaction with Keap1 has been proposed for other structurally related PhGs such as acteoside and echinacoside. Fst-A also activates Nrf2 and reduces endoplasmic reticulum stress. This effect has been evidenced in a model of cerebral ischemic injury induced by middle cerebral artery occlusion in rats. In this case, Fst-A markedly increased the expression levels of Nrf2, superoxide dismutase, and glutathione and reduced malonaldehyde expression, leading to a drug-induced reduction of cell apoptosis. It has been demonstrated also in a model of hydrogen peroxide-induced oxidative stress in PC12 cells.
The regulation of the Nrf2/HO-1 pathway is thus at the origin of the anti-inflammatory action of both Fst-A and Fst-B. This mechanism of action is shared with several other PhGs, such as acteoside, alyssonoside, paraboside B, and others.,,, Fst-B was found to behave as a strong activator of Nrf2 and inducer of HO-1 expression in human keratinocyte cells, providing a long-lasting skin protection. The compound is a potent inhibitor of gene expression and de novo synthesis of all chemokines. It is important to underline that the anti-inflammation action of Fst-B has been well characterized both in vitro but in vivo as well, in a mouse model of acute lung injury. Fst-B was shown to markedly inhibit activation of the TLR4/NFκB signaling pathway in this model, thus reducing the infiltration of inflammatory cell in the inflamed lung. Another good demonstration of the antioxidant activity of Fst-B refers to the capacity of the product to scavenge reactive oxygen species (ROS) liberated by polymorphonuclear neutrophils during inflammatory disorders or when stimulated by chemicals. Other studies have reaffirmed the anti-inflammatory role of Fst-A or-B through an activation of Nrf2 and inhibition of NFκB. This is really the central action of the natural products [Figure 7].
|Figure 7: Antioxidant and anti-inflammatory effects of forsythoside-A,-B. (a) Upon entering macrophages, the compounds have the capacity to inhibit the interaction between the transcription factor Nrf2 and its repressor Keap1, through a selective binding to Keap1. Nrf2 thus released is phosphorylated and can accumulate into cell nuclei to activate transcription of specific genes, through its interaction with antioxidant response elements. The production of several mRNA is enhanced (HO-1, NQO1, and Nrf2) or repressed (COX-2, TNFα, and iNOS) leading to a reduced production of pro-inflammatory cytokines and enzymes which act by reducing the cell oxidative stress and free radicals. (b) The proposed interaction of forsythoside-B with Keap1|
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The anti-inflammatory and antioxidant actions occur in parallel, in a cooperative manner. Fst-A and B are potent antioxidant compounds, showing marked free-radical-scavenging effects., The apiosyl moiety of Fst-B seems to improve the radical scavenging property of the compound because the analog acteoside (vervascoside) lacking the apiosyl unit showed a lower antioxidative capacity compared to Fst-B. In fact, the antioxidant effect and drug-induced regulation of the Nrf2/HO-1 pathway lead to a general cytoprotective effect which can be evidenced at different levels and in different tissues, in particular to protect the cardiovascular and neuronal systems, as evoked hereafter, but also to protect from allergic airway inflammation and asthma. Both Fst-A and Fst-B can reduce the oxidative damages and inflammation induced by CuSO4 in zebrafish larvae, through the modulation of multiple metabolomic pathways.
Interestingly, an aqueous extract of F. suspensa not only exhibited direct anticancer effects, but it contributed also to reduce the unwanted side effects of chemotherapy. The extract was found to reduce oxaliplatin-induced peripheral neuropathy, without affecting the anticancer activity of the platin drug in human cancer cells. The effect was attributed, at least in part, to Fst-A abundantly present in the extract and which has shown neuroprotective effects in vivo. An aqueous extract of F. viridissima has revealed similar neuroprotective effects on oxaliplatin-induced peripheral neuropathy and Fst-A was found to reduce side effects induced by cisplatin in the cochlea of guinea pig. In fact, the drug can reduce neuronal damages and inflammation induced by a variety of stimuli. In another study using organotypic hippocampal slices, Fst-A and an ethanol extract of F. suspensa leaves have shown neuroprotective effects, associated to an upregulation of the endogenous endocannabinoid 2-arachidonoylglycerol and a marked inhibition of cyclooxygenase-2 (COX-2). Moreover, a potential direct interaction between Fst-A and COX-2 enzyme was postulated, based on molecular modeling.
A neuroprotective effect has been evidenced with Fst-B in a model of cerebral ischemia and reperfusion injury. The compound attenuated the blood–brain barrier breakdown and reduced inflammation. Fst-B is a potent agent to reduce neuro-inflammation and to attenuate memory-impairment, suggesting a beneficial action of the molecule (and TCM preparations containing Fst-B) for the treatment of Alzheimer disease. Indeed, Fst-B was found to restore cognitive function in neurodeficient (APP/PS1) mice, through an improvement of amyloid-β (Aβ25–35) peptide deposition and tau protein phosphorylation. It also reduced microglia-mediated neurotoxicity in BV-2 microglial cells and HT22 cells. Similar anti-inflammatory effects in LPS-stimulated BV-2 microglia cells have been reported with Fst-A. The anti-neuroinflammatory action of Fst-B could be useful to limit the progression of the Alzheimer disease. Fst-B inhibits glutamate-induced neurotoxicity. Similarly, Fst-A exhibits protective effects on Aβ-induced apoptosis in PC12 cells by downregulating acetylcholinesterase. The compound can help to improve memory deficit. This property has been demonstrated using a murine model of age-dependent neurodegenerative disorders (senescence-accelerated mouse prone, or SAMP mice). An oral treatment of 8-month-old (SAMP8) mice for 45 days was found to improve the cognitive functions, and the effect was associated with the drug-induced suppression of oxidative stress and decreased production of inflammatory cytokines. The study suggested that Fst-A may be a useful treatment against amnesia. Different structurally related phenylpropanoids, such as tenuifoliside A and arctigenin, have been found to exert similar cognitive enhancing property and to improve memory deficit in mice., It is likely the caffeic acid moiety of Fst-A which is responsible for this effect because this unit (and related units such as p-methoxycinnamic acid, ethyl-p-methoxycinnamate and ferulic acid [4-hydroxy-3-methoxycinnamic acid]), has been shown to improve memory deficit in rats.,, Caffeic acid esters (widely found in propolis extract and plants) are known for their neurogenesis and neuroprotection function., Moreover, ferulic acid derivatives are being designed as multitarget-directed ligands for the treatment of Alzheimer's Disease. Fst-A/B fall into this category and their mechanism of action is complex, as it implicates also a drug-induced upregulation of the levels of the endogenous endocannabinoid 2-arachidonoylglycerol (2-AG), mediated through the cannabinoid receptor 1 (CB1R)-dependent NFκB signaling pathway. This mechanism, as well as the reported binding of Fst-A to acetylcholinesterase, could contribute to reduce the evolution of the Alzheimer disease.,
The capacity of Fst-A and-B to reduce tissue inflammation has been evidenced in different pathological situations and with different experimental models. In particular, Fst-B was found to rescue cardiac function from ischemia-reperfusion injury by limiting inflammation response and antioxidative damages in a rat model. Mechanistically, Fst-B is able to limit the secretion of the potent vasoconstrictor peptide endothelin-1 in endothelial cells treated with chemically oxidized low-density lipoproteins (LDLs). Given the important role of endothelin-1 in atherosclerosis development, the use of phyto-preparations containing Fst-B and-J (and related inhibitors of lipid peroxidation) could be useful to prevent or treat atherosclerosis development.,, Phenylpropanoid glycosides are strong inhibitors of copper-induced LDL oxidation. At this point, it is worth mentioning that a molecular modeling study has suggested that Fst-C, which is not frequently studied, would be able to interact with the enzyme squalene synthase, thereby reducing cholesterol synthesis. However, the proposed lipid-lowering effect of Fst-C has not been validated experimentally; it remains a hypothesis at this stage.
The accumulation of cytotoxic bile acids can lead to liver damages and ultimately to serious liver cirrhosis or liver failure. The TCM prescription Dan-He-Ji (LDHJ), which contains Fst-A, has been developed to treat infantile cholestatic hepatopathy. The phyto-preparation antagonizes calcium-sensing receptor and regulates hepatocyte apoptosis in cholestasis through the mitogen-activated protein kinase pathway. As an active substance of LDHJ, Fst-A contributes to reduce the levels of calcium and ROS and thus the level of apoptosis in cholestatic hepatocytes. A marked hepatoprotective effect has been reported also when using water extract of Forsythia Fructus to protect from liver fibrosis in mice. The plant extract protected against CCl4-induced liver injury by inhibiting hepatic stellate cells activation, reducing hepatic extracellular matrix disposition, and reversing epithelial–mesenchymal transition. The effects can be attributed to different compounds included in the extract, notably the lignan pinoresinol, forsythin, and Fst-A. Fst-A has a direct effect of drug-induced liver injury by inhibiting toxin-induced NFκB activation and serum/hepatic TNFα levels in a mice model of acute liver injury.
Fst-A/B exhibits protective effects against damages to the central nervous system, the heart, the liver, and other organs, such as the kidneys. Indeed, Fst-A was shown to alleviate renal damage in adriamycin-induced nephropathy in rats, and a F. suspensa extract can protect from kidney damages induced by diquat, a commonly used pesticide. As cellular protective agents, Fst-A/B can prevent cellular damages and cell death in many different situations, including in cases of alopecia, reducing apoptosis of hair cells, and retarding their entry into the catagen phase.
Protection from other inflammatory diseases and damages
The anti-inflammatory action of Fst-A and Fst-B can be useful to prevent or reduce other diseases with an inflammatory component such as peritonitis, sepsis, asthma, and others [Figure 8]. Fst-A was found to regulate the production of inflammatory cytokines and chemokine in zymosan-stimulated RAW 264.7 macrophages in vitro. In vivo, the compound decreased the number of neutrophils and reduced the level of TNFα, IL-6, and the monocyte chemoattractant protein-1 (MCP-1, also called CCL-2) in the peritoneal cavity, in a mouse model of zymosan-induced acute peritonitis. Fst-A-induced inhibition of the production of MCP-1 was observed in LPS-stimulated alveolar epithelial MLE-12 cells. In this cell model, Fst-A decreased the adhesion and migration of monocytes to MLE-12 cells, through an upregulation of the microRNA miR-124, and a subsequent inhibition of the expression of MCP-1., However, the mechanism of action of Fst-A is likely multifactorial, implicating several targets. The compound was shown to inhibit the secretion of IL-8 and prostaglandin E2, and calcium influx in the cells expressing the Transient receptor potential vanilloid 1 (TRPV1) channel implicated in the thermoregulation, in a model of yeast-induced pyrexia mice.
|Figure 8: The antioxidant and anti-inflammatory activities of forsythoside-A and forsythoside-B can be useful to combat a variety of diseases and conditions. The two natural products reduce oxidative stress and the inflammatory component of these diseases|
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As mentioned above, the anti-endotoxin effects of Fst-A seem to rely, at least in part, on the capacity of the compound to inhibit the TLR4/MyD88/NFκB signaling pathway. Similarly, Fst-B reduced the production levels of TNFα, IL-6, and HMGB1 in RAW 264.7 macrophages and markedly reduced the lethality in a rat mode of sepsis, induced by cecal ligation and puncture and also in a mouse model of sepsis., The anti-inflammatory action of Fst-A can also be useful for the treatment of bovine mastitis, generally caused by the Gram-positive bacterial pathogen Staphylococcus aureus. Fst-A was found to down-regulate the expressions of TNFα, IL-1 β, and IL-6 and to suppress NFκB and MAPKs activation in S. aureus-stimulated primary bovine mammary epithelial cells.
Interestingly, a recent study has highlighted the activity of an extract of the plant Callicarpa japonica against allergic airway inflammation. The extract contained several phenylpropanoids (in particular verbascoside and Fst-B) and showed a protective activity against ovalbumin-induced airway inflammation, through downregulation of NFκB activation and upregulation of HO-1 (20). Fst-B can be useful to treat allergic inflammation and other skin inflammatory diseases such as prurit and dermatitis. Through its capacity to inhibit the production of chemokines in TNFα/IFNγ-activated human keratinocytes, Fst-A can be considered also for treating allergic skin inflammatory disorders. Again recently, the two compounds verbascoside and Fst-B were found to function as selective inhibitors of the temperature-sensitive and calcium-permeable transient receptor potential vanilloid 3 (TRPV3), which is frequently overactive in chronic pruritus, skin allergy, and other inflammation-related skin diseases., Fst-B dose dependently inhibited human TRPV3 (but not hTRPV1, hTRPV4, and hTRPA1) and reduced cell death of HaCaT keratinocytes expressing a gain-of-function TRPV3 G573S mutant. The compound may bind to TRPV3 and could block the channel, as a putative binding pocket for Fst-B has been identified in the central cavity of mouse TRPV3, based on a molecular modeling analysis. By blocking the channel, the compound could restrict the entry of calcium and calcium overload in cells, responsible for keratinocyte cell death and keratinization, itching, or skin damages. However, the link between this mechanism and the capacity of Fst-B to inhibit the production of pro-inflammatory chemokines at transcriptional and translational levels in keratinocytes remain to be determined.
F. suspensa extracts (FSE) exhibit bacteriostatic activity against Escherichia coli K88, staphylococcus aureus, and salmonella strains. The use of such an extract as a substitute for antibiotic has been proposed, to enhance the antioxidant status and anti-inflammatory function in broiler chicken., FSE is also proposed as a dietary supplementation in sows and newborn piglets. Relatively modest antibacterial effects were initially reported with different Fst compounds, but the bactericidal activities were often relatively weak. However, Fst-B has shown a noticeable activity against different strains of Staphylococcus aureus, notably against the multiple drug-resistant strain S. aureus 1199B (which overexpresses the norA gene encoding a multidrug-resistant efflux pump). The antibacterial effect is more pronounced when using the crude extract of the fruits from F. suspensa, in particular the raw fruits (qingqiao) which contain a higher level of PhGs than the ripe fruits (laoqiao) and display more pronounced antibacterial effects against different bacterial strains. As regard Fst-A, the combination of a bacteriostatic effect and an anti-inflammatory effect can be useful to prevent or treat periprosthetic infection. Fst-A can reduce Staphylococcus aureus and methicillin-resistant S. aureus adhesion and biofilm formation on the surface of titanium alloy (a recurrent problem encountered with orthopedic joint prostheses). Fst-A reduces bacterial adhesion and colony formation on the surface of the titanium disc and attenuates Ti-induced activation of NFκB and cytokines production in macrophages. More globally, Fst-A reduces the inflammatory response stimulated on infection with S. aureus.
| Metabolism of Forsythosides-A|| |
Upon oral administration, the intestinal absorption of the Fst-A mainly occurs by passive diffusion across the different segments of the intestine, notably in the upper part of small intestine, at least in rat.,, The intestinal absorption of Fst-A is limited but the other constituents of Forsythia fructus help to increase the bioavailability of the natural product, as well as the use of a hydrogel delivery system., In rat liver microsomes, Fst-A provides a good substrate for many cytochromes P450 (CYP3A4, CYP2C9, CYP1A2, UGT1A6, UGT1A3, UGT1A1, and UGT1A9) and has an inductive effect on the activities of CYP1A2 and CYP2C11., The compound is a substrate for different transporters such as the efflux pumps P-glycoprotein (P-gp) and the multidrug-resistance-protein, and uptake transporters (OATP), thus explaining the low oral bioavailability of the product.,,, The low intrinsic bioavailability of Fst-A is largely promoted by other natural products found in the different plant extracts which are combined in the TCM preparations. In particular, the combined use of Flos Lonicerae and Forsythia Fructus (two herbs included in different TCM preparations such as Shuang-Huang-Lian tablet, Yin-Qiao-Jie-Du tablet, and Fufang Qin-Lan oral liquid) is beneficial to improve the absorption of Fst-A.,
After an oral administration, Fst-A is largely metabolized. In rats, up to 43 metabolites have been identified in biological samples, mostly in the urine (42 metabolites), plasma (22 metabolites), and feces (42 metabolites). The numerous drug transformations include combination of mono-and di-methylation, mono- and di-glucuronidation, sulfation, and cysteine conjugation. The intestinal metabolites of Fst-A in Human include the two products caffeic acid and hydroxytyrosol formed upon hydrolytic deglycosylation of the natural product, presumably by human intestinal bacteria. In dogs, Fst-A showed a linear pharmacokinetic profile; after intravenous administration of Fst-A, the highest Cmax value reached 54.5 μg/mL, but the drug is also rapidly eliminated, with a T1/2 value >1.5 h in dogs. The toxicology data available for Fst-A and-B are limited. A more precise evaluation of the benefit/risk ratio of Fst-A would be useful.
| Discussion|| |
PhGs are naturally occurring water-soluble compounds, widely distributed in plants. They are endowed with remarkable biological properties.,,, A recent exhaustive survey has identified more than 570 PhGs which display a wide range of pharmacological properties: antibacterial, anticancer, antidiabetic, anti-inflammatory, anti-obesity, antioxidant, antiviral, and neuroprotective properties. The best-known member of the PhGs are arguably acteoside/verbascoside (>1000 references in PubMed Central), echinacoside (250 references), more frequently studied than the Fst (140 references). Nevertheless, the Fst now emerge as a group of natural products with a marked medicinal interest. These compounds are well represented in many traditional Chinese medicine preparations, as reported here. The Fst subgroup includes 16 members (Fst-A-to-P) but one of them (Fst-L) could not be identified, despite an extensive search through the literature, with several search engines. Several of these compounds, in particular the most recent ones, have been isolated and chemically described only. Their structures are known but not their biological properties. On the opposite, Fst-A and-B have been extensively studied over the past 40 years and they clearly emerge as potent cell-protective natural products. They are both potent anti-inflammatory and antioxidant agents, acting mainly through a drug-induced activation of the Nrf2/HO-1 pathway in different cell types, possibly through the sequestration of the Nrf2-suppressor Keap1. This property is shared with other natural products and phenolic compounds qualified as direct or indirect Nrf2 activators, protecting cells from oxidative stress. Upon binding of Fst-B to Keap1, Nrf2 is liberated from the Nrf2-Keap1 complex, translocated into the nucleus, and bound to the antioxidant response element in association with other factors, resulting in the expression of detoxifying enzymes, such as NQO1 and HO-1 [Figure 7]. The mechanism of action of Fst-B is apparently complex and multifactorial, but inflammation is also a multifaceted biological system. Medicinal plants and the natural products that they contain are well suited to reduce inflammation.
Fst-A/B has the capacity to block the expression and/or production of pro-inflammatory cytokines. It is therefore not totally surprising to observe that the two compounds have been proposed as remedies for a large number of inflammatory situations and pathologies [Figure 8]. Inflammation is a general trait associated with many diseases. The molecular pharmacology of inflammation implicates multiple biological targets and mechanisms, depending on the cellular context and the organ considered. For a long time, medicinal plants have been exploited to treat inflammatory symptoms and to reduce associated damages. In this context, the extensive use of the plant F. suspensa (Thunberg) Vahl. is exemplary. The plant and its fruits Forsythia fructus contain numerous anti-inflammatory agents, notably different PhGs such as Fst-A/B which are abundant in the green fruits (laoqiao). Most of the biological and therapeutic effects reported with Fst-A/B derive from their anti-inflammatory and antioxidant effects. This is the foundation of their medicinal activities.
Could Fst-A/B be exploited for the design of new drugs? Probably not the compounds sensu stricto, because they are relatively unstable biologically, with a short half-life in biological media and they show a low bioavailability, at least for Fst-A (pharmacokinetic data are more limited for Fst-B). Designing drugs based on the skeleton of Fst-A would be difficult. Nevertheless, the two compounds can be useful when combined with other products, in the form of plant extracts (confere the antitumor activities reported with different forsythia extracts) and medicinal phyto-preparations. It is interesting to underline the diversity of TCM preparations including F. suspensa or Forsythia fructus. They are used to treat a variety of diseases, mostly some gastrointestinal diseases and lung diseases. Interestingly, several of the Fst-containing TCM exhibit antiviral activities and are being evaluated clinically for the treatment of the current COVID-19 pandemic. As discussed above, the anti-inflammatory and antioxidative activities of compounds such as Fst-A,-B and-I likely contribute positively to the antiviral effects, to reduce the viral charge and the pulmonary symptoms. Different TCM preparations look promising against the symptoms of COVID-19, such as Jinhua Qinggan granules, Qingwen Baidu decoction, Shufeng Jiedu capsules, and a few others [Figure 5]. Among the six TCM preparation containing Fst useful to combat COVID-19, the case of Shuanghuanglian Injection (SHLI) deserves a mention because cases of adverse reactions affecting the skin, mucosa, and/or the digestive system have been observed when using this preparation, with an incidence of about 5%. A pseudo-allergic action of F. suspensa included in the preparation has been noted in different studies., The pseudo-allergic reaction apparently implicates a SHLI-induced reorganization of actin cytoskeleton, an activation of the RhoA/ROCK signaling pathway, and a disruption of the endothelial barrier. A recent study indicated that the effect could be linked to the action of Fst-A and-B (but not Fst-E), which would disrupt the endothelial barrier, inducing an hyperpermeability and thus causing a vascular leakage (with activation the RhoA/ROCK signaling pathway). For this reason, the injectable form of Shuanghuanglian (SHLI) should be used with caution, especially in children. The oral liquid form should be preferred as it is also active against COVID-19 symptoms., The flavonoids baicalin and baicalein are considered as the main bioactive components of the Shuanghuanglian preparation, but the potential beneficial contribution of Fst-A/B cannot be excluded.
Chinese herbal formulae represent an alternative approach to the prevention or treatment of COVID-19. TCMs containing Forsythia Fructus (Lianqiao) are among the most popular and the apparently the most beneficial, at least to alleviate the associated symptoms of the disease. It clearly helps to reduce fever, cough, and fatigue. The contribution of the Fst to these effects is unclear at present, but nevertheless, compounds like Fst-A,-B,-H, and-I stand as potent anti-inflammatory and antioxidant agents that can be useful for other inflammatory situations and diseases.
The author thanks Dr Chang Li (Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China) who kindly helped to identify the structure of Fst-K from a publication in Chinese.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3]