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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 7  |  Issue : 2  |  Page : 167-183

Progress of traditional chinese medicine treating COVID-19


1 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
2 School of Pharmacy, Tongji Medical College, Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
3 Department of Urology and Pharmacology, University of California, Irvine, Orange, CA 92868, USA
4 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016; School of Pharmacy, Tongji Medical College, Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Date of Submission31-May-2020
Date of Acceptance03-Jul-2020
Date of Web Publication09-Apr-2021

Correspondence Address:
Prof. Hua Li
Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030
China
Prof. Li-Xia Chen
Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_68_20

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  Abstract 


The new coronavirus pneumonia (coronavirus disease 2019 [COVID-19]), caused by the new coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), mainly manifests by fever, dry cough, and fatigue. The emergence of SARS-CoV-2 poses a huge threat to people's lives. Unfortunately, so far, there are no effective treatment drugs and vaccines. Traditional Chinese medicine (TCM) has played an important role and achieved good results for treating this epidemic. More than 85% of patients with SARS-CoV-2 infection in China have received TCM treatment. In this article, we describe the progress of TCM for the COVID-19 therapy.

Keywords: Chinese patent medicines, coronavirus disease 2019, decoctions, traditional Chinese medicine


How to cite this article:
Li MX, Yang YY, Liu Y, Zheng MZ, Li J, Chen LX, Li H. Progress of traditional chinese medicine treating COVID-19. World J Tradit Chin Med 2021;7:167-83

How to cite this URL:
Li MX, Yang YY, Liu Y, Zheng MZ, Li J, Chen LX, Li H. Progress of traditional chinese medicine treating COVID-19. World J Tradit Chin Med [serial online] 2021 [cited 2021 Sep 24];7:167-83. Available from: https://www.wjtcm.net/text.asp?2021/7/2/167/316617




  Introduction Top


Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Its main clinical manifestations are fever, cough, headache, fatigue, and dyspnea. Although the spread of the epidemic in China has been effectively controlled, it is still being accelerated in other parts of the world, involving >200 countries and regions. As of May 9, the global total of confirmed cases was >3.93 million, with >270,000 deaths. SARS-CoV-2 is an enveloped single-stranded RNA virus, belonging to β-coronavirus.[1] The genome sequence homology of SARS-CoV-2 and SARS-CoV is 79.5%,[2],[3] while that of SARS-CoV-2 and MERS-CoV is only 50%.[4] In addition, SARS-CoV-2 binds host cells to the same receptor as SARS-CoV, namely angiotensin-converting enzyme 2 (ACE2).[2]

At present, there are no special drugs and vaccines for COVID-19 treatment. The popularity of COVID-19 has shown a huge impact on people's lives and social-economic development. Based on the experience of treating SARS or MERS, and the current clinical guidelines, the treatment of COVID-19 patients in China adopts natural medicine and traditional Chinese medicine (TCM) treatment.[5],[6],[7] In the fight against the COVID-19 epidemic, TCMs have reported to play an important role and achieve good results, highlighting their characteristics and advantages. TCM has accumulated rich experience through fighting against epidemics (named “Yi” diseases in TCM) for thousands of years, which recommends treatment plans usually based on the disease condition, local climate characteristics, and different physical conditions. By searching the websites of the Chinese Clinical Trial Registry to collect Chinese medicine therapy for COVID-19, we found that as of May 9, a total of 648 clinical trials have been registered, 90 of which are studies on TCM [Table 1]. Moreover, some articles on TCM treatment of COVID-19 have been published recently.[8],[9],[10],[11] Herein, based on the current research reports, we elaborate on the progress and future prospects of TCM in the treatment of COVID-19.
Table 1: 90 traditional Chinese medicines in clinical trials

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  Chinese Patent Medicines Top


Since the outbreak of COVID-19, many TCMs have been promptly and comprehensively involved in the entire process of diagnosis and treatment. Integrated Chinese and Western medicine treatment has effectively reduced the incidence of mild-to-severe and critically ill patients and improves the cure rate. The diagnosis and treatment plan (Trial Version 3) for new coronavirus infectious disease first describe the relevant contents of the TCM treatment plan in detail. Until now, the Newest Trial Version 7 has been issued, and some Chinese patent medicines [Table 2] have been recommended for cases of medical observation period and severe and critical cases of the clinical treatment period (confirmed cases) in the Chinese medicine treatment section. According to the diagnosis and treatment plan for new coronavirus infectious disease published in various places in China, we also summarized the involved Chinese patent medicines herein [Table 3].
Table 2: Chinese patent medicine recommended by “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7)”

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Table 3: Chinese patent medicines involved in the diagnosis and treatment plan for COVID-19 issued by local governments of China

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Lianhua Qingwen capsule has been included in the recommended medication of COVID-19 diagnosis and treatment plan in many countries and localities.[12] Clinical studies have shown that Lianhua Qingwen has a significant effect on relieving the symptoms of fever, cough, sputum, and shortness of breath in COVID-19 patients. COVID-19 mainly manifests as fever, fatigue, and dry cough. Lianhua Qingwen, composed of 13 herbs, is derived from two TCM prescriptions: Maxing Shigan decoction and Yinqiaosan. Maxing Shigan decoction which was originally described in “Shang Han Lun,” can inhibit the entry of virus, which has been designated for the treatment of bronchitis, pneumonia, and early stage of measles.[13] Yinqiaosan is mainly used to treat “warm disease” characterized by fever, thirst, and headache. Lianhua Qingwen capsule has been widely used as an antiviral agent in clinical practice, especially for various respiratory viral infections. An experiment evaluating the efficacy and safety of Lianhua Qingwen capsule for the treatment of H1N1 influenza virus infection showed that Lianhua Qingwen capsule obviously relieved fever, cough, sore throat, and fatigue compared with oseltamivir.[14],[15] Another study showed that Lianhua Qingwen capsule exerts anti-influenza activity by inhibiting virus reproduction and affecting immune function.[16] Lianhua Qingwen capsule was reported to have a broad-spectrum effects on a range of influenza viruses and specifically regulate the immune response to viral infections.[16] In addition, the anti-influenza activity of Lianhua Qingwen in infected mice may depend on the regulation of cytokines, especially those associated with cytokine storms.[16] Pathological studies have shown that the pathological features of COVID-19 are very similar to SARS and MERS.[17],[18],[19] Previous studies have confirmed that Lianhua Qingwen can significantly inhibit SARS-CoV in vitro and also has a certain inhibitory effect on MERS-CoV. In short, Lianhua Qingwen could have a solid theoretical foundation for the treatment of COVID-19.

A study pointed out that the Lianhua Qingwen combination can significantly relieve the main symptoms and slow down the progress of COVID-19.[20] Recently, Runfeng et al. studied the antiviral activity of Lianhua Qingwen on SARS-CoV-2 and its potential role in regulating the host immune response.[21] The results showed that Lianhua Qingwen significantly inhibited the replication of SARS-COV-2, affected the virus morphology, and significantly reduced the production of pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-6, chemokine (C-C motif) ligand 2 CCL-2/monocyte chemoattractant protein [MCP-1], and CXCL-10/IP-10), exerting anti-inflammatory activity.[21] Their research confirmed that Lianhua Qingwen possesses antiviral and anti-inflammatory activity against SARS-CoV-2 infection, further supporting the clinical application of Lianhua Qingwen in combination with existing therapies for COVID-19.[21] Lianhua Qingwen can reduce inflammatory cytokines in patients with chronic obstructive pulmonary disease (COPD).[22] Furthermore, it also inhibits the virus-induced activation of NF-κB and reduces the expression levels of IL-6, IL-8, TNF-α, IP-10, and MCP-1.[16] Lianhua Qingwen has a potential inhibitory effect on the arachidonic acid pathway, which may be an important target for the treatment of COVID-19. Therefore, Lianhua Qingwen can suppress inflammatory storms, reduce lung damage induced by SARS-CoV-2 infection, and improve lung function.

In summary, Lianhua Qingwen not only exhibits antiviral effect but also inhibits inflammatory response and regulates the function of immune system, demonstrating that Lianhua Qingwen can be used to treat COVID-19 due to its advantages of overall regulation and multi-target therapy.

Xuebijing injection plays a protective role against lung injury caused by paraquat by downregulating the expression of p38 MAPK in rats.[23] It also showed anti-inflammatory effect on lung injury caused by dichlorvos poisoning and downregulated the expression of TLR4 and NF-κB.[24] Xuebijing can antagonize endotoxin and inhibit the excessive release of inflammatory mediators, such as interferon (IFN) and IL, thereby inhibiting inflammatory reactions and enhancing immunity. At present, Xuebijing injection has become the recommended medication for COVID-19, which promotes the elimination of inflammatory factors, and is mainly used for the early- and mid-term treatment of severe and critically ill patients. It can improve the cure rate and discharge rate and reduce the chance of conversion from severe to critically ill.

Jinhua Qinggan granules have anti-influenza effects[25] and are safe and effective in treating influenza patients with wind–heat affecting Fei syndrome.[26] Clinical studies have shown that Jinhua Qinggan granules can significantly reduce the levels of IFN gamma (IFN-γ) and C-reactive protein cytokines in the serum of influenza patients. Jinhua Qinggan granules exhibited a potential inhibitory effect on the arachidonic acid pathway, which may inhibit pneumonia caused by SARS-CoV-2 by relieving cytokine storms.[27] Clinical studies have shown that Jinhua Qinggan granules have a definite effect on the therapy of COVID-19 light and normal patients, as well as can shorten the time of fever, increase the normalization rate of lymphocytes and white blood cells, and improve related immunological indicators.

Shenfu injection can alleviate endotoxin-induced acute lung injury (ALI) in rats by inhibiting the TNF-α-NF-κB pathway.[28] It can also reduce the levels of IL-6, IL-8, and TNF-α and increase the expression of IL-4 and IL-10.[29] Shenfu injection can regulate the level of cytokines, enhance the body's immune function, and reduce immune dysfunction after recovery.[29] Besides anti-inflammatory, anti-oxidant, anti-shock, and immunomodulatory effects, Shenfu injection can also be used for viral pneumonia, viral myocarditis, etc. In the treatment of severe pneumonia in the elderly COVID-19 patients, Shenfu injection effectively eliminates inflammatory mediators.[30] COVID-19 critically ill patients are often found multiple organ failure and the disease progresses quickly, and Shenfu injection can play a good role in rescuing critically ill patients.

Xingnaojing injection is used for cleaning heat toxicity, improving brain function, and promoting blood flow.[31] Many studies have shown that Xingnaojing injection possesses good therapeutic effects on consciousness diseases, including stroke and various coma.[32],[33],[34] Compared with traditional drug treatment, Xingnaojing injection exhibits obvious recovery advantages by improving neurological deficits and hemorheology and reducing the level of TNF-α in serum.[33],[35],[36] The anti-inflammation, antioxidation, and immune regulation of Xingnaojing injection[37] makes it currently be recommended as the therapy for severe and critically ill patients with COVID-19.

The predecessor of Jinye Baidu granule is a special anti-infective preparation developed by Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, which was invented in 1970, and has 50 years of research and clinical application history until now. It is mainly made up of the classic anti-infection TCM formulas of Lonicera japonica, Clerodendrum cyrtophyllum Turcz., Taraxacum mongolicum, and Houttuynia cordata Thunb. It possesses antivirus, antipyretic, anti-inflammatory, antibacterial, endotoxin suppression, and immunity enhancement functions. Jinye Baidu granule has been used for the treatment of viral pneumonia, acute upper respiratory tract infection, influenza, and other viruses, as well as bacterial infectious diseases. During the 2003 SARS epidemic, Jinye Baidu granule was used in the prevention and treatment of SARS-CoV infection and has achieved good therapeutic results. Therefore, it is praised as “TONGJI COFFEE” by foreign friends. In this epidemic, Jinye Baidu granule once again played an important preventive and therapeutic role against SARS-CoV-2 infection. Jinye Baidu granule is listed as one of the prevention and treatment drugs of COVID-19.


  Chinese Medicine Decoctions Top


We summarize the TCM decoctions involved in the trial of diagnosis and treatment program for COVID-19 issued by the National Health Commission [Table 4] and local governments [Table 5]. According to the Chinese patent medicines mentioned above, we have made a detailed overview on the composition and predicted active ingredients and action mechanism of the frequently used Chinese patent medicines and decoctions in clinic [Table 6].
Table 4: The traditional Chinese medicine decoction involved in “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Versions 1-7)”

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Table 5: Chinese herbal medicine decoctions for treating COVID-19 in various places of China

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Table 6: Composition, predicted active ingredients, and action mechanism of the frequently used Chinese patent medicines and decoctions

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Qingfei Paidu decoction was recommended for COVID-19 treatment in the new coronavirus pneumonia diagnosis and plan (Trial Version 6). Qingfei Paidu decoction is an optimized combination of classic prescriptions for treating exogenous fever caused by cold evils in “Treatise on Febrile and Miscellaneous Diseases” by Zhang Zhongjing in the Han Dynasty. For this prescription, >300 chemical components and >200 blood components have been identified, and >790 potential targets have been initially predicted, confirming its therapeutic effect through acting on multi-components and multi-targets. Network pharmacology results showed that Qingfei Paidu decoction produced a multi-directional intervention on the occurrence and development of COVID-19.[38] It may interfere with COVID-19 through multiple components targeting at a variety of signaling pathways.[39] After long-term clinical observation in COVID-19 therapy, Qingfei Paidu decoction can block the development of light and ordinary types to heavy and critical types and effectively rescue heavy and critical patients.

Huashi Baidufang and Xuanfei Baidufang are effective prescriptions based on clinical observations of the academician teams of Huang Luqi and Zhang Boli in the treatment frontline of Wuhan, respectively. They showed good effects in blocking the development of disease and relieving symptoms, especially in shortening the course of the disease.

Shashen Maidong decoction can improve the immune function of rats with radiation pneumonitis by increasing the concentration of IFN-γ and decreasing the concentration of IL-4. It regulates the body's immune function and restores the stability of the internal environment possibly by increasing the relative ratio of IFN-γ/IL-4 to regulate Th1/Th2 immune imbalance.[40] In the treatment of COVID-19, Shashen Maidong decoction is the recommended medication for patients in recovery stage.


  Single Traditional Chinese Medicine and its Active Ingredients Top


Based on the recently announced diagnosis and treatment plan on COVID-19, we summarize the recommended TCMs and ingredients in the plan and screen out the commonly used medicinal materials to describe in detail [Table 7]. We hope to provide a reference for combating the epidemic and help the development of TCM. Moreover, the active ingredients commonly used in the treatment of COVID and their mechanisms of action are listed in [Table 8]. Since the screening of active ingredients is very important for the development of TCM, many methods and technologies have been applied for the screening of active ingredients, such as the screening based on bioassay-guided fractionation, the screening based on serum pharmacochemistry and serum pharmacology, the screening based on metabonomics, the screening based on molecular recognition technology, and the screening based on computer virtual technology. The potential active components against SARS-CoV-2 mentioned in this paper are screened by molecular docking method, and their binding patterns and affinity were predicted.
Table 7: Frequency of single Chinese medicine used at present

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Table 8: The potential active components and mechanism of the representative COVID-19 treatment

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Antipyretic and anti-inflammation

Bupleurum chinense

Bupleurum chinense has a long history of application in China. Studies have reported that the chemical constituents of B. chinense mainly include triterpene saponins, volatile oils, flavonoids, lignins, and phenylpropanol derivatives.[41] The crude extracts and pure compounds obtained from B. chinense show various biological activities, such as anti-inflammatory, anti-viral, anticancer, antipyretic, antimicrobial, hepatoprotective, immunomodulatory, and neuroprotective effects.[42] Saikosaponin A shows anti-inflammatory role by inhibiting the NF-κB and NLRP3 signaling pathways and protective effect on ALI induced by LPS.[43] Saikosaponin A can inhibit H1N1 virus replication, downregulate NF-κB expression, and reduce caspase-3–dependent viral ribonucleoprotein nuclear export, showing strong anti-influenza virus activity.[44] Saikosaponin C inhibits the synthesis of hepatitis B virus (HBV) pgRNA by targeting HNF1α and HNF4α.[45] An in vitro experiment showed that Saikosaponins can inhibit human coronavirus 229E.[46] Saikosaponin C also exhibits inhibitory activity against HBV.[47] Saikosaponin b2 can effectively inhibit the entry of HCV.[48] B. chinense volatile oil also exhibits obvious antipyretic and anti-inflammatory effects. Therefore, B. chinense and its constituents may be potential therapeutic drugs for COVID-19.

Scutellaria baicalensis Georgi.

Flavonoids and their glycosides are the main active ingredients of Scutellaria baicalensis Georgi. Baicalin exerts antipyretic and anti-inflammatory effects by inhibiting the N-methyl-D-aspartate receptor-dependent hydroxyl radical pathway in the hypothalamus and reducing TNF-α.[49] Baicalin can also increase the expression of caspase-3 in the pancreas of severe acute pancreatitis rats and inhibit the expression of TNF-α mRNA and P-selectin protein.[50] Baicalein inhibits cyclooxygenase-2 (COX-2) gene expression by inhibiting C/EBP-beta DNA binding activity, thereby playing a role in inhibiting inflammation.[51] Baicalin shows anti-inflammatory, antioxidant, and antiadipogenic effects in atherosclerosis in a dose-dependent manner by inhibiting the NF-κB and p38 MAPK signaling pathways.[52] Dinda et al. described in detail the antioxidant and anti-inflammatory effects of baicalin and baicalein and the molecular mechanisms of chemoprophylaxis and chemotherapy in the treatment of inflammation-related diseases.[53] Moreover, baicalin shows low toxicity and high efficacy against Chikungunya virus (CHIKV), suggesting its potential as an antiviral agent for CHIKV infection.[54] For human immunodeficiency virus type 1 (HIV-1),[55],[56] H1N1 virus,[57] coxsackievirus B3,[58] human T-cell leukemia virus type I,[59] chronic HBV,[60] enterovirus 71 (EV71),[61] Duck hepatitis A virus type 1,[62] respiratory syncytial virus,[63] Newcastle disease virus,[64] dengue virus (DENV),[65] and Zika virus (ZIKV),[66] baicalein exhibits relatively good inhibitory effect on all of these viruses. Recently, researchers found that the ethanolic extract of S. baicalensis Georgi. can inhibit the activity of SARS-CoV-2 3CLpro in vitro.[67] Besides, in Vero cells, it also inhibited the replication of SARS-CoV-2 with an EC50 of 0.74 μg/mL.[67] Furthermore, they also found that baicalein intensively inhibited the activity of SARS-CoV-2 3CLpro activity with an IC50 of 0.39 μM.[67] In another study, baicalin and baicalein were determined to the first class of noncovalent and nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro, which showed strong antiviral activity in cell-based systems.[68] It is worth noting that the binding pattern of baicalein and SARS-CoV-2 3CLpro determined by X-ray protein crystallography is significantly different from those of known inhibitors.[68] Baicalein is secured to the core of the substrate-binding pocket by interacting with two catalytic residues (the critical S1/S2 subsite and the oxyanion loop), thereby preventing the peptide substrate from approaching the active site.[68] These studies highlight the great potential of S. baicalensis Georgi. and baicalein as anticoronavirus drugs. Baicalin is shown to have a high binding affinity for Papain-like proteinase (PLpro) protein, indicating its potential utility in treating SARS-CoV-2 infection.[69]

Ephedra sinica Stapf.

Ephedra sinica Stapf. has been used for the treatment of asthma, antipyretics, and rheumatoid arthritis and mainly contains six ephedrine alkaloids as its pharmacologically active ingredients: (-)-ephedrine, (+)-pseudoephedrine, (-)-N-methylephedrine, (+) -N-methyl pseudoephedrine, (-)-norephedrine, and (+)-norpseudoephedrine.[70] E. sinica extract can downregulate the phosphorylation of Raf/MEK1/2/ERK1/2, thereby inhibiting the expression of COX-2 and matrix metalloproteinase-1 (MMP-1) induced by ultraviolet B.[71] COX-2 and MMP-1 are the representative signs of skin inflammation and photoaging, respectively.[71] Ephedra A and B from E. sinica roots can inhibit the activation of NF-κB in RAW 264.7 macrophages, thereby inhibiting LPS-induced inflammatory mediators.[72] E. sinica Stapf. has an inhibitory effect on the growth of influenza A/PR/8 virus in the MDCK cells.[73] E. sinica Stapf. is one of the core drugs of Chinese medicine-mediated Mycoplasma pneumoniae pneumonia treatment.[74] The type A proanthocyanidins in E. sinica stems have antibacterial activity.[75] Ephedra polysaccharides offer a potential treatment for COPD by modulating inflammatory cytokines and TGF-β1/Smad2 pathway to reduce airway and lung inflammation.[76]

Citri Reticulatae Pericarpium/Citri Grandis Exocarpium

Citri Reticulatae Pericarpium and Citri Grandis Exocarpium are one of the main medicinal materials recommended by the Chinese medicine section of the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7).” Their peels are rich in flavonoids, such as hesperidin and hesperetin. Study has shown that hesperidin targets the binding interface between S protein and ACE2.[69] Hesperidin may disrupt the interaction between ACE2 and RBD.[69] Hesperetin, as the main in vivo metabolite of hesperidin, can inhibit SARS-CoV 3CLpro cleavage activity in a dose-dependent manner in a cell-based assay, with an IC50 of 8.3 μM.[77] Molecular docking studies also showed that hesperidin possessed very high binding affinity with 3CLpro,[78],[79] S protein RBD, and ACE2.[78] Furthermore, hesperidin can firmly bind to SARS-CoV-2 Mpro.[80],[81] These studies have explained to a certain extent the mechanism by which Citri Reticulatae Pericarpium and Citri Grandis Exocarpium display a potent efficiency in the prevention and treatment of COVID-19.

Camellia sinensis (L.) O. Ktze.

Camellia sinensis (L.) O. Ktze. has been used in China for thousands of years. For a long time, it is not only a daily drink for people but also as a classic prescription in TCMs for clearing heat and detoxifying. (-)-Epigallocatechin gallate (EGCG), belonging to catechins, is the main component of C. sinensis (L.) O. Ktze. EGCG has antioxidation, antivirus, anticancer, and antiradiation damage activities. EGCG is currently reported to have an inhibitory effect on human papillomavirus,[82] herpes simplex virus (HSV),[83],[84],[85],[86] adenovirus,[87] HBV,[88] HCV,[89],[90],[91] ZIKV,[92],[93],[94],[95] HIV,[96],[97],[98] Ebola virus,[99] influenza virus,[100],[101],[102],[103] SARS-CoV,[104] etc., Through computer screening, Wu et al. found for the first time that EGCG showed a strong interaction with SARS-CoV-2 PLpro.[69] Moreover, EGCG and ACE2 also have a good affinity.[69] Later, they discovered that EGCG and furin have a strong interaction.[105] EGCG and epigallocatechin (EGC) were found to have good enzyme inhibitory activity against SARS-CoV 3CLpro, and molecular docking showed that EGC can produce hydrogen-binding interactions with multiple amino acid residues in the active pocket of 3CLpro.[104] Researchers recently found that EGCG can bind to the SARS-CoV-2 spike protein, preventing the Spike protein from binding to the ACE2 receptor, thereby preventing the virus from entering the host cells.[106] In addition, EGCG has the effect of promoting the dissociation of the spike protein that has bound to ACE2.[106] It has been used as a clinical adjuvant therapy in patients with SARS-CoV-2 infection in Kunming Third Hospital.[106] Moreover, two studies have also found that EGCG has a good binding affinity with 3CLpro and PLpro.[107],[108] These results indicate that EGCG may prevent viral protein maturation and RNA replication by targeting one or more key enzymes of SARS-CoV-2, thereby displaying antivirus effect. In addition, it may also act on human ACE2 or furin to prevent SARS-CoV-2 from entering the host cells. The above findings have laid a theoretical foundation for the in-depth study of EGCG as a potential COVID-19 therapeutic drug.

Lonicera japonica

Lonicera japonica is one of the components in Jinye Baidu granule, Lianhua Qingwen capsule, and Jinhua Qinggan granule. Researchers discovered an atypical miRNA in L. japonica: MIR2911, which has broad-spectrum targeting anti-influenza virus activity. The results show that MIR2911 can target the mRNA of influenza viruses (H1N1, H5N1, and H7N9), thereby inhibiting virus replication.[109] Luteolin, a flavonoid, is a major constituent of L. japonica, with a variety of pharmacological activities. Luteolin is mainly used for the treatment of cough, expectoration, and infectious diseases. Many studies have shown that it can inhibit influenza A virus, HIV, human herpes virus, and Japanese encephalitis virus.[110],[111],[112],[113] Luteolin was also reported to inhibit the replication of DENV by inhibiting furin.[114] Study has found that luteolin has a good affinity with NSP15 (mfScore = −57.11, Score = −33.55),[69] suggesting that luteolin is a potential drug candidate against SARS-CoV-2. Moreover, some studies have pointed out that the binding ability of luteolin to ACE2 is higher than that of lopinavir, ritonavir, and ribavirin, and its binding ability to Mpro is similar to the above three antiviral drugs.[21] Luteolin was also speculated to inhibit SARS-CoV-2 replication by inhibiting furin,[114] a new target for the treatment of SARS-CoV-2.[105] Luteolin could cross the blood–brain barrier,[113] suggesting that it may also have a therapeutic effect on the central nervous system infections caused by SARS-CoV-2. L. japonica also contains other antiviral active ingredients, such as chlorogenic acid and kaempferol-3-O-rutinoside, the latter of which has a good affinity with PLpro and may be a potential anti-SARS-CoV-2 drug candidate.[69]

Immunoregulation

Astragalus mongholicus Bunge

Astragalus mongholicus Bunge is a TCM with immunomodulating effect. There is evidence that Astragalus mongholicus Bunge can change the response of LPS-stimulated macrophages and has an immunomodulatory effect, reducing the production of TNF-α, IL-6, IL-10, and IL-12 in a dose-dependent manner.[115] Astragalus mongholicus Bunge extract can increase macrophage migration and release of immune response medium through heparanase (HPA), thereby activating the immune response of macrophages.[116] The most important active ingredients of Astragalus mongholicus Bunge in regulating immune function have been reported to include Astragalus polysaccharides (APS), astragalosides, and Astragalus flavones. APS showed strong immunomodulatory activity by stimulating macrophages and could be used as an immunotherapy adjuvant.[117] (1) APS strongly inhibits the activation of NF-κB and downregulates the phosphorylation of ERK and JNK in LPS-stimulated macrophages, an important signaling pathway involved in the production of TNF-α and IL-1β, indicating that APS can inhibit the activation of NF-κB and phosphorylation of ERK and JNK, and dabish the production of TNF-α and IL-1β.[118] APS can also reduce the replication of H9N2 avian influenza virus (H9N2 AIV) and promote early humoral immunity in young chickens.[119] APS inhibits porcine circovirus type 2 replication by inhibiting oxidative stress and blocking the NF-κB pathway.[120] Through the analysis of the currently released diagnosis and treatment plan, it is found that Astragalus mongholicus Bunge is one of the frequently used TCMs. In this fight against COVID-19, Astragalus mongholicus Bunge shows a potent effect on enhancing immunity and respiratory resistance.

Glycyrrhiza uralensis Fisch.

Glycyrrhiza uralensis Fisch. and its main active ingredients including glycyrrhizin, glycyrrhizic acid, glycyrrhetinic acid, and glycyrrhizin polysaccharide show potent immunomodulatory effects. Glycyrrhizin shows multiple immunomodulatory activities and interferes with the immune response by targeting dendritic cells (DCs). Studies have shown that glycyrrhizin can upregulate the expression of CD80, CD86, and MHCII on the surface of DCs and increase the production of IL-12.[121] In addition, glycyrrhizin also enhanced the proliferation of allogeneic T-cells, increased the expression of IFN-γ and IL-10, reduced the production of IL-4, and thereby regulated the Th1-type immune response.[121] Glycyrrhizin is also a promoter of late signal transduction of IL-2 production by T-lymphocytes.[122] IL-12 plays an important role in the development of Th1 cell-mediated immune response, and glycyrrhizin can enhance the production of IL-12 in peritoneal macrophages.[123] Glycyrrhizin can also enhance the production of IL-10 by liver DCs in hepatitis mice.[124] Other studies have also shown that glycyrrhizin can enhance the activity of NK cells/NKT cells.[125] The antiviral activity of glycyrrhizin has also been confirmed.[126] Glycyrrhizin and its modified compounds exhibit inhibitory activity against HIV-1 and HSV-1.[127] A study evaluated the antiviral potential of 6-azauridine, ribavirin, mycophenolic acid, pyrazolin, and glycyrrhizin against two clinical isolates coronaviruses (FFM-1 and FFM-2) in SARS patients.[128] The results showed that among all compounds, glycyrrhizin possessed obvious inhibition on SARS-associated viruses.[128] Furthermore, one study indicates that glycyrrhizin could bind to ACE2.[129] Luo et al. discussed the potential of glycyrrhizin in the treatment of COVID-19 from the perspective of pharmacological effects, including downregulation of pro-inflammatory cytokines, binding to ACE2, inhibition of thrombin, inhibition of intracellular reactive oxygen species accumulation, and suppression of excessive production of airway exudate.[130] Recently, Zhu et al. found that in Vero E6 cells, liquiritin significantly inhibited the replication of SARS-CoV-2 with an EC50 of 2.39 μM.[131] They pointed out that liquiritin could mimic type I interferon, thereby exerting antiviral functions.[131]


  Conclusion Top


Since the outbreak of COVID-19, scientists have made their efforts to do a lot of research and have gained great progress in the research of new drugs and vaccines. Small molecule drugs such as remdesivir and chloroquine have entered clinical research. However, the law of new drug development determines that the discovery of new anti-SARS-CoV-2 drugs needs more patients. In the fight against COVID-19, TCM has played an important role and shown many advantages in intervening sudden infectious diseases such as viral pneumonia. Lianhua Qingwen capsule shows good efficacy in treating light and ordinary patients and obvious curative effect in relieving fever, cough, and fatigue. Xuebijing injection can promote the elimination of inflammatory factors and is mainly used for the early and mid-term treatment of severe and critically ill patients. Qingfei Paidu decoction plays an important role in preventing the development of patients from light and normal type to severe and critical type. At the same time, it also shows obvious effects on the rescue process of heavy and critical patients. In the diagnosis and treatment plan, B. chinense, S. baicalensis Georgi., Astragalus mongholicus Bunge, etc., also have a high frequency of use and important clinical value. TCM can not only be used to prevent and block the course of disease but also restore the body's resistance and promote rehabilitation. Then, TCM contains a variety of active ingredients, which has multi-target effects and is not easy to develop drug resistance. More importantly, many kinds of TCMs also have powerful anti-inflammatory and immune regulatory effects in their traditional use. Therefore, it is an important strategy to making full use of the advantages of TCM and combine with Western medicine for disease therapy. In the treatment of COVID-19 at critical phases, integrating TCM and Western medicine makes it easier and faster to control the disease, suppress cytokine storms, and reduce the mortality of critical patients. Therefore, it is necessary to give full play to TCM in the treatment of pneumonia caused by new coronavirus, strengthen the integration of TCM and Western medicine, and carry out scientific and standardized prevention and treatment by using TCM.

Although TCM has achieved good clinical results, some issues still deserve attention. The most important point is that the composition of TCM is relatively complex, and its efficacy and mechanism of action also need to be further clarified by clinical trials and in-depth pharmacological research. With the development of computer-aided drug discovery, scientists can screen effective small molecules from TCM based on the protein structures of disease targets, so as to provide clear evidence for the study on efficacy of prescriptions and the optimization of prescriptions in the clinic. In short, the multi-component and multi-target characteristics of TCM make it have great advantages and high clinical value in the treatment of COVID-19.

Acknowledgments

Nil.

Financial support and sponsorship

This work was financially supported by National Mega-project for Innovative Drugs (grant number 2019ZX09721001-004-007), National Natural Science Foundation of China (NSFC) (NOs. 81773594, U1803122, U1703111, 81473254, and 81773637), the Fundamental Research Fund for the Central Universities (HUST COVID-19 Rapid Response Call, No. 2020kfyXGYJ037, China), and Liaoning Revitalization Talents Program (NO. XLYC1807182).

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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