Respiratory syncytial virus (RSV) is a common viral pathogen of the lower respiratory tract, which, in the absence of effective management, causes millions of cases of severe illness per year. Many of these infections develop into fatal pneumonia. In a review of English and Chinese medical literature, recent traditional Chinese medical herb- (TCMH-) based progress in the area of prevention and treatment was identified, and the potential anti-RSV compounds, herbs, and formulas were explored. Traditional Chinese medical herbs have a positive effect on inhibiting viral attachment, inhibiting viral internalization, syncytial formation, alleviation of airway inflammation, and stimulation of interferon secretion and immune system; however, the anti-RSV mechanisms of TCMHs are complicated, which should be further investigated.
Respiratory syncytial virus (RSV) is classified as a nonsegmented, negative-sense, membrane-bound RNA virus of the family Paramyxoviridae, spread by droplets, and causing repeated airway infections [
Due to the nature of the virus and the mode of infection, reinfections are a common event, suggesting that naturally acquired immunity does not provide long-lasting protection. This has made the development of an effective vaccine impossible as yet [
This review aims to explore evidence available on preventative measures against RSV infection, discuss the current status of anti-RSV research on TCMH-derived active compounds, TCMHs, and traditional Chinese medical formulas (TCMFs), and finally highlight the challenges, issues, and future directions of using TCMHs in clinical practice.
Traditional Chinese medical herbs are the most important components of the traditional Chinese medicine (TCM) system, which have been reported to cure infectious diseases, in the form of hot water extracts, for almost 2,000 years. Over 10,000 herbal medicines and 100,000 recipes have been documented in ancient literature [
Nowadays, TCMHs are widely used for the prevention and treatment of viral infectious diseases in China and many other Asian countries. They are associated with advantages such as lower toxicity, economical and multifunctional use in regulating immunological function, and viral destruction [
Prevention is the most important aspect of healthcare, and because of the nature of the respiratory syncytial virus and mode of infection, reinfections are a common event [
The respiratory syncytial virus depends on the host cell to complete its replication cycle, which includes attachment and entry into the host cell, transcription of viral mRNA, viral genome replication, protein synthesis, and the assembly and budding of progeny virus particles [
Following coevolution with the host, many viruses have established sophisticated mechanisms to interact with the host immune system for immune evasion. Among the classes of antiviral agents, immunomodulators are the most abundant in TCMHs [
Moreover, TCMHs have been previously reported to offer efficient protection against RSV and significantly decrease viral load and inflammation [
Resveratrol, a compound synthesized by at least 72 plant species [
In Table
Aqueous extracts of TCMHs in prevention of RSV.
Herbs | Used part | Prevention activity | References |
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Rhizome | Showed its better effect when given before viral infection: viral attachment ↓; viral internalization ↓ | [ |
In HEp-2 cells: IC50 was 212.7 | |||
Secrete IFN- |
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Root | Anti-inflammatory functions: less weight loss; diminishing pulmonary inflammatory response | [ |
Inducing host immune responses toward Th1 type immunity: IgG2a isotype antibodies ↑; IFN- | |||
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Root | In the prevention of RSV infections: improved survival of human lung epithelial cells against RSV infection; inhibited RSV-induced cellular oxidative damage | [ |
Play a role in priming the host immune system: enhanced IFN- | |||
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Rhizome | It is more effective when given before viral inoculation ( |
[ |
In HEp-2 cells: | |||
Stimulate mucosal cells to secrete IFN- |
IL-4: interleukin-4; IFN-
Drug use from natural products has progressed to the isolation of active compounds. Natural products and particularly medicinal plants remain an important source of new drugs, new drug leads, and new chemical entities [
Traditional Chinese medical herbs have been utilized as anti-infectious medicines for thousands of years in China and offer various anti-infectious compounds, particularly for antiviral. An increasing number of TCMH-derived active compounds with antiviral activity are garnering evidence of experimental efficacy. As shown in Green Bae’s research, (−)-(R)-nyasol, (−)-(R)-4′-O-methylnyasol, and broussonin A, three structurally known compounds isolated from the rhizomes of
TCMHs-derived compounds inhibiting RSV.
Herbs | Compounds | Anti-RSV activity | References |
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Fraction III; |
RSV replication ↓ (SI: 13.06; >24.33; MTT: 11.67; >22.32) |
[ |
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Genistein, tectorigenin | Possess potent antiviral activity against RSV (CC50: 450; 500 |
[ |
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RG2-1 [ |
RSV replication ↓ (TC50: 10.66; 5.29 mg/mL; EC50: 420; 262.95 |
[ |
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AP3 [ |
RSV replication ↓; RSV entry ↓ (TC50: 11.45; 10.89 mg/mL; EC50: 0.0986; 0.0801 mg/mL; TI: 116.12; 135.95) [ |
[ |
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Flavonoids | RSV replication ↓ (TC50: 152.9 mg/mL; IC50: 58.6 mg/mL; TI: 2.6); the ribavirin group (TC50: 154.9 mg/mL; IC50: 57.1 mg/mL; TI: 2.7) | [ |
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18 |
RSV replication ↓ (IC50: 4.3–4.5 |
[ |
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Oleuropein | Significant antiviral activities against RSV (TC50: 562.5 |
[ |
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Flavone 6-C-monoglycosides | Potent antiviral activities against RSV (CC50: ranging from 254.5 ± 6.4 to 362.6 ± 15.4 |
[ |
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Quercetin | Possess potent antiviral activity against RSV (IC50: 2.5 |
[ |
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Anagyrine, oxymatrine, sophoranol | Potent antiviral activities against RSV (IC50: 10.4; 10.4; 10.4 |
[ |
TC50 is 50% of toxic concentration; EC50 is the concentration for 50% of maximal effect; IC50 is the concentration of the sample required to inhibit virus-induced CPE 50%; CC50 is the concentration of the 50% cytotoxic effect; selective index (SI) or therapeutic index (TI): CC50/IC50 or TC50/EC50 or TC50/IC50; MTT assay is a colorimetric assay for assessing cell metabolic activity.
Herbs | Compounds | Anti-RSV activity | References |
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Wgonin oroxylin A | Potent antiviral activities against RSV (IC50: 7.4; 14.5 |
[ |
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Uncinoside A; |
Potently inhibit RSV infection (IC50: 6.9; 1.3 |
[ |
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Daphnoretin | RSV replication ↓ (IC50: 5.87 |
[ |
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Genkwanol B; |
Potent antiviral activities against RSV (IC50: 9.6; 6.6; 10.2 |
[ |
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Fractions 10 [ |
Syncytium formation of RSV ↓; potent antiviral activities against RSV (IC50: 3.0–6.0 |
[ |
TC50 is 50% of toxic concentration; EC50 is the concentration for 50% of maximal effect; IC50 is the concentration of the sample required to inhibit virus-induced CPE 50%; CC50 is the concentration of the 50% cytotoxic effect; selective index (SI) or therapeutic index (TI): CC50/IC50 or TC50/EC50 or TC50/IC50; MNCC: the maximal concentration of the sample that did not exert toxic effect detected by microscopic monitoring after 72 h of incubation.
A vast amount of basic research has been conducted on TCMHs. Therefore, the isolation and characterization of pharmacologically active compounds from TCMHs and the testing of their pharmacological activities, in the pursuit of new drug discovery, are now necessary [
Previous studies, as shown in Table
However, even with these unique advantages, screening programs focused on identifying potential anti-RSV agents from TCMHs are using conventional methods. In order to compete with other drug discovery methods, efforts are ongoing to replace these traditional methodologies with modern sample preparation and extraction procedures. Therefore, TCMH research needs to continually improve the speed of screening, isolation, and structure elucidation processes. The most challenging issues are understanding the operative mechanisms to identify TCMH-derived active components, as each kind of TCMH contains multiple active components with multiple targets. Some of these components work directly on the therapeutic targets, whereas others may enhance the bioavailability [
It is known that cell-based assays are often initially carried out for the evaluation of whole extracts that show clinical evidence of antiviral activity. Without larger randomized, double-blind, placebo-controlled multicenter clinical trials, approval of TCMH-derived active compounds will be difficult through international regulatory agencies such as the Food and Drug Administration (FDA) of the United States of America or other equivalent European counterparts.
Above all and in long term, TCMHs still offer a great prospect in the field of pharmaceutical developments. The characteristics of TCMHs offer opportunities for finding active and novel chemical structures against a variety of therapeutic targets.
Traditional Chinese medicine theory is in line with seasons, circumstances, and individuality. For example, in summer, “
In both 2001 and 2002, approximately one-quarter of the bestselling drugs worldwide were natural products or were derived from natural products [
Traditional Chinese medical herbs are the most important components of the TCM system, which have long been used for the multiple combinations of compounds in the form of processed natural products. Experimental findings of TCMHs with the identification of potent antiviral activities against RSV should be made available to the healthcare providers practicing traditional medicine. From a clinical perspective, diseases are complex and variable, combined with complex clinical symptoms. Traditional Chinese medical herbs contain multiple active components with multiple targets, which may be a better choice to achieve multiacting treatment.
Traditional Chinese medicine theories originate from the profound experiences of practitioners with understanding of ancient Chinese medicine, and the methods of application have been passed down through oral history. It is suggested that hot water extracted TCMHs would exhibit direct antiviral activity. In this review, we summarized experiments in vivo or in vitro (Table
Aqueous extracts of TCMHs inhibiting RSV.
Herbs | Used part | Anti-RSV activity | References | ||
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IC50 ( |
CC50 ( |
SI | |||
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Root | 36.8 | 441.3 | 12.0 | [ |
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21.0 | 112.1 | 5.3 | ||
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50.0 | 1000 | 20.0 | ||
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52.1 | 833.3 | 16.0 | ||
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52.1 | >1000.0 | >19.2 | ||
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<44.1 | 352.5 | >8.0 | ||
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<13.0 | >200.0 | >15.4 | ||
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<10.4 | >62.5 | 6.0 | ||
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52.1 | 833.3 | 16.0 | ||
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17.2 | 275.8 | 16.0 | ||
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Root cortex | 26.0 | >833.3 | >32.0 | |
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Rhizome | 46.5 | 185.8 | 4.0 | |
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Aerial parts | 27.6 | 295.0 | 10.7 | |
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13.0 | 208.3 | 16.0 | ||
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49.2 | 196.9 | >4.0 | ||
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31.3 | 350.0 | 11.2 | ||
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Leaf | 37.6 | 255.6 | 6.0 | |
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Flower bud | 50.0 | >1000.0 | >20.0 | |
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Flower | 50.5 | 269.2 | 5.3 | |
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Fruit | 50.0 | 1000.0 | 20.0 | |
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Fruit spike | <10.4 | >62.5 | 6.0 | |
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Whole plant | 37.5 | 800.0 | 21.3 | |
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<13.0 | 416.7 | >32.0 | ||
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50.0 | 1000.0 | 20.0 | ||
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50.0 | >62.5 | >20.0 | ||
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15.6 | 243.8 | 15.5 | [ | |
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15.6 | 500.0 | 31.8 | ||
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512.5 | 32.0 | 16.0 | ||
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Leaf stalk | 12.5 | 500.0 | 40.0 | |
Ribavirin [ |
— | 2.6 | 62.5 | 24.0 | [ |
Ribavirin [ |
— | 3.0 | 62.5 | 20.8 | [ |
IC50 is the concentration of the sample required to inhibit virus-induced CPE 50%; CC50 is the concentration of the 50% cytotoxic effect; selective index (SI) or therapeutic index (TI): CC50/IC50.
Ma et al. recently tested 44 medicinal herbs, used in the TCM system, for treating virus-infectious diseases. The medicinal herbs were tested for antiviral activities against RSV using a cytopathologic effect (CPE) assay. Twenty-seven of the 44 medicinal herbs showed moderate or potent antiviral activities against RSV, with a 50% inhibition concentration (IC50) ranging from 6.3 to 52.1 g/mL and a selectivity index (SI) ranging from 2.0 to 32.1. The control group, ribavirin, had an SI of 24 [
This evidence illustrates that natural products can be a rich source for the discovery of potent anti-RSV agents.
Although traditional natural products have played an important role in drug discovery, in the past few years, many pharmaceutical companies have scaled down or terminated their natural product research [
Despite the recognized therapeutic benefits and the expanding use of medicinal plants worldwide, TCMHs still lack robust evidence from evidence-based medicine (EBM) research, especially the supporting clinical evidence collected under international standards (randomized, placebo-controlled, double-blind, and multicentered clinical studies). As a result, it is a challenge for TCMHs to be accepted by the Western medicine community and mainstream healthcare systems.
Though much debate remains on the feasibility and the validity of applying the EBM criteria to this traditional practice, for the integration of TCM into the Western healthcare system, it is essential to demonstrate its efficacy and safety through high level evidence in accordance with EBM procedures.
Based on TCM theory, a remedy often has a principle of hierarchy, the so-called “monarch,” “minister,” “assistant,” and “guide components” [
A TCM formula contains multiple active herbs with multiple compounds and targets. Some of these components (“monarch” and “minister”) work directly on the therapeutic targets, while others (“assistant” and “guide components”) enhance the bioavailability or counteract drug toxicity of the medicine [
Chinese patent medicine in prevention and inhibition of RSV.
Names | Composition | Mechanisms and results | References | ||
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Plant or mineral | Weight (g) |
Used part | |||
Bu Shen |
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46.15% | Root | Airway inflammation ↓; RSV replication ↓; F protein expression of RSV ↓ ( |
[ |
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30.77% |
Aerial part, |
Regulating the balance between Th1 and Th2/Th17 responses: | ||
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Shuang Huang Lian oral liquid (SHL) |
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25.00% | Rootstalk | RSV replication ↓; the virus titer ↓; airway inflammation ↓; IL- 8 ↓; |
[ |
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25.00% | Flower bud | |||
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50.00% | Fruit | |||
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Sheng Ma Ge Gen Tang (SMGGT) |
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33.33% | Radix | The crude extract of SMGGT was more effective when given before viral infection ( |
[ |
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22.22% | Radix | |||
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22.22% | Rhizoma | The SMGGT group: CC50: 3000 | ||
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11.11% | Radix | |||
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11.11% | Root-like stem | Epithelial cells secrete IFN- | ||
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Xia Sang Ju Granule (XSJG) |
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66.23% | Fruit spike | RSV replication ↓; the virus titer ↓; |
[ |
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23.18% | Flower | |||
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10.60% | Leaf |
Th1 cell: T helper 1 cell; Th2 cell: T helper 2 cell; Th17-cell: T helper 17 cell; GATA3: transcription factors GATA binding protein 3; STAT6: signal transducer and activator of transcription 6; ROR
Names | Composition | Mechanisms and results | References | ||
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Plant or mineral | Weight (g) | Used part | |||
Jin Xin oral liquid |
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3 | Stem | Lung inflammation ↓; RSV replication ↓; |
[ |
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10 | Seed | |||
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10 | Velamen | During early stage infection (on days 2 and 4 after infection), the TLR3-IRF3-IFN- | ||
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10 | Rootstalk | |||
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10 | Root | |||
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10 | Seed | During the later stage of infection (7 d after infection), the TLR3-IRF3-IFN- | ||
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10 | Root | |||
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15 | — | |||
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Qing Fei oral liquid |
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4 | Stem | A multicentered single-blind, random controlled clinical study of 166 children in Nanjing in China showed that the curative and the effective rate of the QOL group: 80.00%; 19.38%; |
[ |
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10 | Seed | |||
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10 | Velamen | |||
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6 | Bombycidae | |||
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10 | Root | |||
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6 | Seed | Airway inflammation ↓; |
[ | |
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12 | Root | |||
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24 | — | RSV replication ↓; |
[ | |
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6 | Rootstalk | |||
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12 | Rootstalk |
TLR3: toll-like receptors 3; IRF3: interferon regulatory factor 3; IFN-
TCM formulas in prevention and inhibition of RSV.
Names | Composition | Mechanisms and results | References | ||
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Plant or mineral | Weight (g) | Used part | |||
Modified Ding Chuan Tang (MDD) |
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12 | Root | MDD exhibited significant antiviral and anti-inflammatory effects: lung viral loads ↓; |
[ |
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9 | Root | |||
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10 | Flower | |||
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4 | Stem | |||
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Ge Gen Tang (GGT) |
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3.0 | Twig | GGT was more effective given before than after viral inoculation ( |
[ |
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4.5 | Stem | |||
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3.0 | Radix | |||
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3.0 | Radix | |||
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6.0 | Radix | |||
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4.5 | Root-like stem | |||
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4.0 | Fruit | |||
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Jia Wei Yu Ping Feng Tang (JYT) |
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27.7 | Root | Viral attachment ↓; RSV internalization ↓; lung lesions and complication ↓; |
[ |
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16.7 | Rhizome | |||
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16.7 | Root | |||
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16.7 | Flower bud | |||
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11.1 | Rhizome | |||
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11.1 | Fruit |
IC50 is the concentration of the sample required to inhibit virus-induced CPE 50%; CC50 is the concentration of the 50% cytotoxic effect; selective index (SI) or therapeutic index (TI): CC50/IC50; NF-
Names | Composition | Mechanisms and results | References | ||
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Plant or mineral | Weight (g) | Used part | |||
Liu He Tang (LHT) |
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2.0 | Whole plant | LHT was more effective when given before viral inoculation ( |
[ |
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1.5 | seed | |||
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2.0 | Root-like stem | |||
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2.0 | Fruit | |||
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2.0 | Seed | |||
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1.5 | Radix | |||
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2.0 | Bark | |||
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1.5 | Root | |||
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1.5 | Root and stem | |||
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2.5 | Sclerotium | |||
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1.5 | Seed | |||
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1.5 | Root-like stem | |||
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1.5 | Fruit | |||
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Xiao Qing Long Tang (XQLT) |
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9.0 | Stem | Hot water extract of XQLT dose-dependently inhibited HRSV-induced plaque formation when given before viral inoculation ( |
[ |
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6.0 | Twig | |||
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9.0 | Root | |||
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6.0 | Root | |||
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3.0 | Rhizome | |||
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9.0 | Tuber | |||
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3.0 | Whole plant | |||
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3.0 | Fruit |
IC50 is the concentration of the sample required to inhibit virus-induced CPE 50%; CC50 is the concentration of the 50% cytotoxic effect; selective index (SI) or therapeutic index (TI): CC50/IC50; IFN-
Traditional Chinese Medicine Formulas have been used as remedies against infectious diseases for thousands of years due to their significant anti-inflammatory, antimicrobial, and antiviral activities, with little or no adverse effects [
Based on the improvements in experiments in vivo or in vitro, a number of Chinese patent medicines are currently undergoing FDA clinical trials in the hope of fulfilling EBM research criteria. This includes Danshen dripping pill (
Traditional Chinese Medicine Formulas rely on written traditional Chinese medicine and an educational system of TCM scholars. According to Shanghan Lun (Treatise on Cold Pathogenic Diseases), written by Zhang Zhongjing, TCMFs should be administered three times. A dosage three times a day is recommended to avoid an overdose and to ensure the better absorption of drugs. This is to ensure a balanced blood drug concentration, according to modern medicine [
In TCM theory, the quality of the decoction is the key to cure diseases successfully; hence detailed requirements of the decocting methods should be illustrated. The methods of decocting medicinal herbs were passed down through the form of hot water extracts [
Compared to Western medicines, advantages of TCMFs include individual treatment based on “multicomponents, multichannels, and multitargets” application and syndrome differentiation. The characteristics of TCMFs are to balance the body and improve clinical symptoms of a patient. Considering these unique characteristics, development of TCMFs, in Tables
With the development of science and technology and the increasing need of modern clinical practice, the disadvantages of oral TCM preparations have gradually been realized. These include single administration, old formulation, large dosage, slow effect, and outdated preparation and transport methods.
The development of Chinese patent medicines has aided the classification; however, in treating acute and severe diseases, TCM formulas are criticized for their slow effect and large dosage. This prevents TCM from being able to solve urgent medical diagnoses. Moreover, dosage needs to be improved: for a convenient use of the drug and the improvement of the therapeutic effect, the dosage needs to be improved while upholding the active effect. More experiments and clinical trials are needed in the field of TCMFs.
The spread of RSV is initiated through viral attachment and internalization. The severity of the RSV-infectious disease is positively correlated with the viral load [
Traditional Chinese medical herbs can prevent the respiratory viral infection induced by RSV, by inhibiting viral attachment and penetration and reducing the increased susceptibility of the cell to the invasion of RSV. From details in Table
Traditional Chinese medical herbs can counteract RSV infection not only through the direct inhibition of viral attachment, internalization, or replication, but also by the enhancement of immunity (Table
The mechanisms of TCMHs-based prevention and treatment of RSV.
Prevention | Treatment |
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Viral attachment ↓ [ |
RSV entry ↓ [ |
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IFN- |
RSV replication ↓ [ |
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IFN- |
Syncytium formation of RSV ↓ [ |
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The survival of human lung epithelial cells ↑ [ |
Lung inflammation ↓ [ |
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Activate the immune system [ |
F protein expression of RSV ↓ [ |
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Blocked proinflammatory gene expression [ |
Viral loads in serum and lung tissue ↓ [ |
Antiviral cytokines play an important role in the immune system process of preventing and inhibiting RSV infection. Traditional Chinese medical herbs can stimulate antiviral cytokines such as IFN-
Despite the evident successes of drug discovery from medicinal plants, future endeavors face many challenges. Efforts are needed to continuously improve the quality and quantity of TCMH-derived compounds, herbs, and formulas that enter the drug development phase, in an effort to compete with other drug discovery efforts [
Prevention is the most important aspect of healthcare; however due to the nature of the RSV and its mode of infection, a safe and effective RSV vaccine has remained elusive. Traditional Chinese medical herbs can enhance immunity to prevent RSV infection, and, furthermore, TCMHs can form part of anti-RSV medications by inhibiting viral attachment, viral penetration, and reducing the increased susceptibility of the cell to the invasion of RSV. This review details evidence that TCMH can be effective as preventative or treatment medications for RSV, the advantages of lower cost, better patient outcomes, and fewer adverse reactions. From the research that has been conducted in this review, we can see great potential value of conducting trials using TCMH. However, further research, especially focused on the toxicity issues, is required to develop the level of evidence to support TCMH to be applied to practice.
The authors declare that there is no conflict of interests regarding the publication of this paper.
All the authors wrote the first draft of the paper together. All the authors contributed to the review of all papers and constructed the final report.
This study was supported by National Natural Science Foundation of China (no. 81373688), the Postgraduate Research and Innovation Project of Colleges and Universities of Jiangsu Province (Grant no. SJLX_0432), and The project of Youth Foundation of Jiangsu Province (Grant no. BK 20151004).