記住我
REVIEW ARTICLE
Year : 2022 | Volume
: 8
| Issue : 3 | Page : 279-313
Traditional Chinese medicines against COVID-19: A global overview
Chang-Liang Yao1, Wen-Long Wei1, Jian-Qing Zhang1, Qi-Rui Bi1, Jia-Yuan Li1, Ikhlas Khan2, Rudolf Bauer3, De-An Guo1
1 Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory Research Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
2 National Center for Natural Products Research, School of Pharmacy, University of Mississippi, MS, USA
3 Department of Pharmacognosy, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria
Correspondence Address:
Prof. De-An Guo
Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory Research Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Haike Road 501, Shanghai, 201203
China
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2311-8571.353502
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, continues to be a global concern. Traditional Chinese medicines (TCMs) are an important element of the fight against COVID-19 in China. The combined application of TCMs and conventional medicines in the treatment of COVID-19 has achieved beneficial results, including the resolution of symptoms, prevention of disease progression, and reduced mortality. In this review, we summarize and discuss the current applications of TCMs with respect to COVID-19, as well as update the preclinical and clinical research, including chemical analysis, molecular mechanisms, quality control, drug development, and studies of clinical efficacy. The expectation is that a better understanding of the roles of TCMs against COVID-19 will improve the response to COVID-19, both in China and globally.
Keywords: Coronavirus disease 2019, clinical efficacy, molecular mechanism, traditional Chinese medicine
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a disease of global concern since the initial outbreak in the late December 2019. According to the World Health Organization (WHO) (https://www.who.int/data), by May 10, 2022, the number of confirmed cases and deaths had reached 515,478,861 and 6, 255, 835, respectively, among which 1,377,646 confirmed cases and 15,469 confirmed deaths occurred in China. Relative to the total (global) number of cases and number of deaths, China has experienced a relatively low rate of cases (0.27%) and confirmed deaths (0.25%), which stands in contrast with the fact that China accounts for approximately 19.44% of the world population. In addition to a relatively strict epidemic prevention policy, the high degree of TCM utilization in combating COVID-19 was an important element in reducing the spread and mortality of the disease in China; more than 90% of confirmed cases were treated with TCMs.
More than 2 years after the initial outbreak, COVID-19 continues to be a highly infectious disease of global concern. Apart from preventative measures (e.g. vaccinations), great efforts have been made to find effective treatments of different modalities, including small molecules, monoclonal antibodies (mAbs), and alternative medicine. Paxlovid, a combination of nirmatrelvir and ritonavir, is an example of successful small molecule therapy. It is an oral antiviral drug authorized for the treatment of mild-to-moderate COVID-19 by disrupting the replication of SARS-CoV-2.[1] However, the drug must be taken within 5 days of the onset of symptoms, and the treatment cost of around $530 a course (in the United States) is relatively high. In addition, paxlovid is not recommended for patients with severe renal impairment or liver disease. These factors restrict its use worldwide. A number of anti-SARS-CoV-2 mAbs targeting the spike protein have been developed and approved for marketing, including bebtelovimab, sotrovimab, and antibody cocktails, such as bamlanivimab plus etesevimab, casirivimab plus imdevimab, and tixagevimab/cilgavimab.[2] However, mAbs are not recommended for patients with severe COVID-19. Alternative medicines,[3],[4] such as Chinese, Ayurvedic, and Unani medicines, have also been explored for the treatment of COVID-19, and these approaches have the advantage of lower cost and high degree of patient compliance. TCM is well developed and recognized as part of the Chinese health system, and its systematic theory is derived from clinical experience.
In China, TCMs have long been used for the treatment of infectious diseases, such as SARS.[5] Likewise, it is not surprising that TCMs have been widely used in China to combat COVID-19; in fact, TCMs are recorded in the guidelines for the diagnosis and treatment of COVID-19, issued by the National Health Commission (NHC) of China. The combined application of TCMs and western medicines (WMs) in the treatment of COVID-19 has achieved beneficial responses with respect to resolution of symptoms,[6] prevention of disease progression,[7] and reduced mortality.[8] Some reviews have emphasized the integration of TCMs and WMs, the important prescriptions and medicines,[9] and the efficacies and underlying mechanisms.[10] In several studies, researchers have investigated the chemical components, molecular mechanisms, and clinical efficacy of TCMs. However, there are few comprehensive reviews of this type of research,[9],[10],[11] and the latest progress was not included. Therefore, we aim with this review to summarize the beneficial use of TCMs against COVID-19 from different perspectives, including chemical analysis, molecular mechanisms, quality control, drug development, and clinical efficacy. We searched the online databases such as Web of Sciences (https://www.webofscience.com/), PubMed (https://pubmed.ncbi.nlm.nih.gov/), and CNKI (https://www.cnki.net/) using the keywords including “COVID-19,” “SARS-CoV-2,” “traditional Chinese medicine,” “herbal medicines.” It is anticipated that this review will promote better understanding of the roles of TCMs in combating COVID-19.
Traditional Chinese Medicines Adopted for Coronavirus Disease 2019 TreatmentOverview and classification of traditional Chinese medicines against coronavirus disease 2019
The clinical use of TCM is mainly in the form of Chinese patent medicines (CPMs) and Chinese medicinal prescriptions (CMPs). CPMs, available in various dosage forms, are processed from Chinese medicinal materials, according to certain treatment principles. The description of prescriptions includes the names, dosage, and use of a group of herbs that are used for the treatment of disease. CPMs are typically derived from CMPs. There is documented evidence in China that CPMs and CMPs have significant advantages in terms of viral clearance and alleviation of clinical symptoms. In particular, the latest edition of the NHC guidelines for COVID-19 recommends “three medicines and three prescriptions,” including Qingfei Paidu (QFPD) decoction, Xuanfei Baidu (XFBD) decoction, Huashi Baidu (HSBD) decoction, Lianhua Qingwen (LHQW) capsules, Jinhua Qinggan (JHQG) granules, and Xuebijing (XBJ) injection. Details of the CMPs that have been used to control the COVID-19 pandemic are listed in [Table 1]. According to statistical analysis, there are approximately 60 prescriptions to be used to fight against the different stages of COVID-19. As shown in [Figure 1], compared with the herbs indicated in the NHC guidelines for COVID-19, the most frequently used herbs are Glycyrrhizae radix et rhizoma (Gancao), Gypsum fibrosum (Shigao), Scutellariae radix (Huangqin), Forsythiae fructus (Lianqiao), Ephedrae herba (Mahuang), Armeniacae semen amarum (Kuxingren), Pogostemonis herba (Guanghuoxiang), and Citri reticulatae pericarpium (Chenpi). Statistically, most of these herbs belong to the groups of TCMs categorized as heat-clearing, dampness-resolving, and cold-dispelling, and such medicines are widely used for curing colds; for example, Scutellariae radix (Huangqin), Forsythiae fructus (Lianqiao), Lonicerae japonicae flos (Jinyinhua), Pogostemonis herba (Guanghuoxiang), Citri reticulatae pericarpium (Chenpi), and Ephedrae herba (Mahuang) [Table 2]. Flavonoids and alkaloids are the main active constituents of these herbs, which have been shown in published studies to have anti-COVID-19 virus activity [Table 3]. All of these factors contributed to the high frequency of use of these herbs.
Figure 1: The frequency of commonly used herbs in formulae for prevention of coronavirus disease 2019 during the pandemic (a) and in the guideline of coronavirus disease 2019 (b). The numbers are the times of the herbs used according to the statistic results listed in [Table 1]
Table 1: Chinese medicinal prescriptions have been used for controlling the pandemic of coronavirus disease 2019
Table 2: Chinese medicinal herbs used for preventing the pandemic of coronavirus disease 2019
Table 3: Summary of the phytochemical agents from Chinese herbal medicines that have shown to exert activity against coronavirus disease 2019According to previous studies, more than 20 herbs possessing antiviral and anti-inflammatory activities have the potential to be used in the treatment of COVID-19. As shown in [Table 2], most of these herbs exerted antiviral activity by inhibiting SARS-CoV-2 Mpro, 3C-like protease (3CLpro), and angiotensin-converting enzyme 2 (ACE-2) targets, and others exhibit anti-inflammatory activity. Based on the properties of TCMs, these herbs can be divided into heat-clearing, qi-regulating, purging, tonify-deficiency, and nourishing medicines. Heat-clearing medicines with antiviral activities account for the highest proportion; some examples are Scutellariae radix (Huangqin), Forsythiae fructus (Lianqiao), and Lonicerae japonicae flos (Jinyinhua).
Scutellariae radix (Huangqin) is an herbal medicine that has been frequently used for the prevention of COVID-19 during the pandemic. It is present in various important CMPs, such as JHQG granules and QFPD decoctions. It is a heat-clearing drug that has been demonstrated to have good anti-SARS-CoV-2 activity by inhibiting 3CLpro in in vitro experiments.[73],[75] The flavonoids baicalein, baicalin, and scutellarein, all of which are important constituents of Huangqin, have shown promise in the treatment of COVID-19 [Table 2]. However, the efficacy of Huangqin needs to be confirmed through in vivo studies.
The results of in vitro and molecular docking studies indicate more than 40 herbal compounds [Figure 2] that show activity against COVID-19, with the main targets of SARS-CoV-2 being Mpro, 3CLpro, and ACE-2 [Table 3]. A high proportion of these compounds are flavonoids and alkaloids; some terpenes and saponins were also identified. It is well known that these two components are commonly found in medicinal herbs, such as Scutellariae radix (Huangqin), Lonicerae japonicae flos (Jinyinhua), Forsythiae fructus (Lianqiao), and Ephedrae herba (Mahuang), which are frequently used to both prevent and treat COVID-19 infections. This partly explains why TCMs play a pivotal role in the COVID-19 pandemic.
Figure 2: 47 compounds with from herbs with antivirus activity against coronavirus disease 2019Application of traditional Chinese medicines against coronavirus disease 2019
General use of Chinese patent medicines and prescriptions against coronavirus disease 2019 in China
Since the outbreak of COVID-19, China's health authorities have pushed forward the full and in-depth intervention of TCM for the treatment of COVID-19 infection.[127],[128],[129],[130] TCMs alone or in combination with WMs were officially incorporated as a strategy for COVID-19 prevention, control, and treatment in China.
Based on the transmission characteristics and case characteristics of Delta, Omicron, and other mutant strains, nine successive versions of the NHC guidelines have been issued. In these guidelines, 21 CPMs and CMPs, such as “three medicines and three prescriptions” along with Huoxiang Zhengqi capsules, Reduning injection, Tanreqing injection, and Xingnaojing injection, have been officially approved to treat patients with different clinical manifestations of COVID-19.[131]
Based on the NHC guidelines, 24 provinces, municipalities, and autonomous regions of China issued their own regional COVID-19 protocols according to regional and population characteristics. Approximately 149 CPMs and CMPs, including 146 Chinese medicines, were prescribed by TCM practitioners, indicating the universal application of TCMs for COVID-19 prevention in China.[132],[133],[134],[135] As an example, there are significant climatic differences between northern and southern China, and the regional protocol against COVID-19 has been adapted to local climatic conditions. In eight areas of northern China, Ophiopogonis radix (Maidong), Scrophulariae radix (Xuanshen), and other TCMs for nourishing yin and moistening dryness were mostly used; in contrast, Atractylodis macrocephalae rhizoma (Baizhu), Agastache Herba (Huoxiang), and other aromatic dehumidification TCMs were mostly used in five areas of southern China as an adaptation to local climatic conditions. In addition, different prescriptions were adopted according to individual variability to reflect the principle of suiting measures. For example, in elderly patients without underlying disease, invigorating Qi and strengthening the spleen, as well as nourishing Yin and moistening the lung is regarded as the main method; Codonopsis radix (Dangshen), Poria (Fuling), Scutellariae radix (Huangqin), Lilii bulbus (Baihe), and Atractylodis macrocephalae rhizoma (Baizhu) are used. For pregnant women, Atractylodis macrocephalae rhizoma (Baizhu), Scutellariae radix (Huangqin), Lonicerae japonicae flos (Jinyinhua), and Ophiopogonis radix (Maidong) were used to nourish yin and clear away heat, regulate the breath, and calm the fetus. The prevention of COVID-19 using TCM should focus on comprehensive prevention and flexible use of various measures to achieve the best prevention effect.[136]
Use of traditional Chinese medicines in early intervention in coronavirus disease 2019 patients
TCMs play an essential role in early intervention in COVID-19 infections; in the majority of COVID-19 patients treated with TCMs, symptoms improve. As of March 23, 2020, there were 74,187 confirmed COVID-19 cases treated with TCMs, accounting for 91.5% of the total, of which 61,449 were in Hubei, China, accounting for 90.6% of the local cases. An effective rate above 90% was observed for TCM.[137]
In combating the 2022 outbreak of COVID-19 in Shanghai, TCMs have been widely utilized, except in case of special groups, such as pregnant women, infants, and particular patient populations. In the early April 2022, TCM prevention and intervention were carried out for nearly all citizens of Shanghai, China, with a total of 25 million Chinese herbal tea substitutes, TCM decoctions, and a variety of CPMs distributed to families and companies, mainly to those close contacts and subclose contacts, asymptomatic carriers, and mild- and moderate-type patients.[138] The intervention of TCMs against COVID-19 in Shanghai played a significant role in prevention and treatment.
Integration of traditional Chinese medicines and western medicines against coronavirus disease 2019
Previous reports have shown that integrated TCMs with WMs (ITW) resulted in better treatment outcomes compared with the WMs treatment alone. In a recent review article,[139] 16 studies were analyzed, encompassing 1645 valid confirmed COVID-19 patients, including 895 patients in the experimental group with ITW treatment and 750 patients in the control group with WM treatment. ITW has been shown to be effective in the transformation process of the moderate-to-severe type and has displayed beneficial actions in the treatment of severe diseases.[140],[141] Published guidelines on the treatment of severe COVID-19 with ITW are a useful resource for public health practitioners, medical staff, and scientists.[142]
During the COVID-19 prevention and control program in Shanghai, an ITW treatment strategy for severe and critically ill older patients was performed, especially for those suffering from underlying diseases. In view of the pathogenesis of the Omicron variant strain, combined with the characteristics of the elderly, an expert consensus on TCM treatment of elderly patients with novel coronavirus has been formulated; case studies were regularly performed and statistics on TCM treatment collected on a daily basis.[143] The results indicated that ITW is of great significance in lowering mortality rates and improving quality of life for individuals in these vulnerable groups.
Applications of traditional Chinese medicines against coronavirus disease 2019 overseas
Not only have TCMs been shown to have real clinical value in the fight against COVID-19 within China, but they have also contributed to COVID-19 prevention and treatment overseas. According to statistical data, China has introduced TCM diagnosis and treatment plans to more than 150 countries and regions and TCM products to more than 10 countries in need; as well, TCM experts have been sent to 29 countries to help contain the spread of COVID-19.[42] China has provided technical solutions through remote video exchanges and has shared medical treatment experiences with Japan, Korea, Italy, the United States, Iran, and Singapore. The Malaysian TCM Working Group provided free TCM services to COVID-19 patients under the rehabilitation period. JHQG granules and LHQW capsules were delivered to Iraq and Italy, respectively, to support their response to COVID-19.[144]
Recently, the WHO published an expert review of TCM for COVID-19, which clearly affirmed the safety and beneficial effects of TCMs in the treatment of COVID-19 and encouraged WHO member states to consider the Chinese model of ITW to curb the spread of COVID-19. This reflects the increasing recognition of the value of TCM in combatting COVID-19 epidemics worldwide and marks a further step in the internationalization of TCM.[145]
New traditional Chinese medicine drugs against coronavirus disease 2019
“Three medicines and three prescriptions”
As part of the national response to the COVID-19 pandemic, numerous CPMs and CMPs were screened for efficacy in clinical applications.[9],[30],[146] “Three medicines and three prescriptions,” including QFPD decoction, XFBD decoction, HSBD decoction, LHQW capsules, JHQG granules, and XBJ injections, were proven effective and authorized for marketing by the National Medical Products Administration of China.[147] The LHQW capsule was actively promoted for foreign registration and received marketing authorization in Mongolia, Uzbekistan, Kenya, and Ukraine. It has been approved for marketing in more than 20 countries and regions, including Brazil, Indonesia, Kuwait, and Cambodia. In Uzbekistan, it is included in the white list of antiepidemic drugs issued by the Ministry of Health. In Thailand and Cambodia, LHQW has been listed as an approved treatment in designated COVID-19 hospitals for the treatment of local patients. In July 2021, LHQW was selected by the Ministry of Health of Cambodia as a home treatment protocol for patients with mild symptoms.[148],[149]
The general use of “three medicines and three prescriptions” demonstrates that TCM might have great value in the prevention and treatment of COVID-19. The use of TCMs in country-wide responses to the COVID-19 pandemic is illustrative of the transformation of TCM theory into practice.
Research and development of new traditional Chinese medicine drugs
The COVID-19 pandemic has also spurred the research and development of new TCM drugs. Based on the global COVID-19 drug research and development data statistics published by NextPharma (https://nextpharma.com/), Shenfu injection, Jinye Baidu granules, and Kangbingdu (tablet, dropping pill, oral liquid, and capsules) are in phase III clinical trials as candidate treatments of COVID-19. In addition, Xiyanping injection, Reduning injection, Shenqi Fuzheng injection, Tanreqing (capsules, injection), Xiaoer Huake Zhitan granules, and compound Danshen dropping pills are in phase II clinical trials. The multicomponent, multitarget, and multipathway treatment characteristics of TCM have great advantages in combatting COVID-19. However, more rigorous clinical trial designs and solid research on pharmacodynamic substances are essential for the internationalization of TCMs. There is still a long way to go for anti-COVID-19 TCM drugs research and development.
Preclinical Studies of Traditional Chinese Medicine Drugs Against Coronavirus Disease 2019Pharmacological research
TCM formulas (including LHQW granules, JHQG granules, and QFPD decoctions) widely used for improving the symptoms of COVID-19 patients in clinical practice have been summarized and reviewed for their efficacy and mechanisms to confront COVID-19.
Antiviral effect
According to previous reports, JHQG granules referenced the classical Maxingshigan decoction, and Yinqiaosan is composed of 12 herbal medicines and is mainly used to improve lung symptoms in COVID-19 patients. JHQG granules exhibited therapeutic effects in COVID-19 patients; the clinical symptoms of COVID-19 were alleviated and the progression of the disease from the mild-to-severe stage was slowed. JHQG granules possess antiviral activities and can inhibit the SARS-CoV-2 life cycle. Among the 12 herbs in JHQG granules, Scutellariae radix (Huangqin), Anemarrhenae rhizoma (Zhimu), and Taraxaci herba (Niubangzi) could restrain SARS-CoV-2 transcription and replication and revealed excellent antiviral effects in COVID-19 patients.[150] Qinlan oral liquid, a heat-clearing and detoxifying TCM, has a therapeutic effect on lung injury in rats infected with the novel coronavirus, inhibiting virus replication and significantly decreasing inflammation in lung tissue.[151] Phillyrin isolated from Forsythiae fructus (Lianqiao), which is present in JHQG granules and LHQW granules, inhibited virus proliferation in vitro and reduced the expression of proinflammatory cytokines (such as interleukin [IL]-1β, tumor necrosis factor [TNF]-α, and monocyte chemoattractant protein [MCP]-1) induced by HCoV-229E and SARS-CoV-2 through the NF-κB signaling pathway.[152] In addition, the studies showed that Qingjin Jianghuo decoction, Shufeng Jiedu (SFJD) capsules, Reyanning mixture, and Toujie Quwen granules all exhibited inhibitory activities against SARS-CoV-2 in vivo.[47],[50],[153]
ACE-2, a membrane protein, binds to SARS-CoV-2 and carries it into the cytoplasm. The spike protein of SARS-CoV-2 participates in the infection process by mediating the fusion of the virus with the host membrane protein.[154],[155],[156] SARS-CoV-2 is encased in the endosome, and the virus RNA is exposed in the endosome acidic system. The exposed RNA then enters the nucleus, where replication and reverse transcription take place. The new SARS-CoV-2 virions that were replicated in the nucleus are then released and infect other healthy cells. The LHQW granule consists of 11 herbal drugs, and its dominant chemical constituents are flavonoids, phenylpropanoids, anthraquinones, and triterpenoids. Studies have shown that LHQW granules can reduce the plaque formation of SARS-CoV-2 in plaque reduction assays and can reduce the number of virions in infected cells, as well as the number of surface virions.[157] LHQW granules may block the binding of SARS-CoV-2 to ACE-2 to inhibit viral invasion into the cytoplasm. Another study showed that ingredients of LHQW granules, such as Lonicerae japonicae flos (Jinyinhua) and Forsythiae fructus (Lianqiao), could inhibit the combination of novel coronavirus and ACE-2 on the cell surface.[158] Meanwhile, emodin isolated from Rhei radix et rhizoma (Dahuang) in the LHQW granules could effectively hinder the interaction of SARS coronavirus spike protein and ACE-2.[83] The monomers (neochlorogenic acid, forsythoside A, forsythoside I, etc.) in the LHQW granules showed significant inhibitory effects against ACE-2.[117] Researchers have reported that luteolin (isolated from Lonicerae japonicae flos) and baicalein (isolated from Scutellariae radix) may be the main active constituents that inhibit the interaction of the virus and ACE-2, reduce inflammation, and regulate immunity in COVID-19 patients through the signaling pathways of nuclear factor (NF)-κB, IL-17, hypoxia inducible factor-1, and arachidonic acid.[159] The QFPD decoction was shown to exert protective effects against body injury caused by COVID-19 through antiviral and anti-inflammatory activities. The ingredients in QFPD decoction (Ephedrae herba [Mahuang], Bupleuri radix [Chaihu], and Scutellariae radix [Huangqin]) have the effects of preventing cytokine storm and blocking the binding of the virus with the ACE 2 receptor.[160],[161],[162] In addition, XFBD, HSBD, and the common herbs Glycyrrhizae radix et rhizoma (Gancao) and Scutellariae radix (Huangqin) in formulations for the treatment of COVID-19 showed potential anti-SARS-CoV-2 activity by inhibiting the ACE-2 receptor.[161],[162],[163]
3CLpro is an essential enzyme for the replication of coronaviruses, which could be used as an antiviral drug target for blocking infection.[164] For example, studies revealed that Rhei radix et rhizoma (Dahuang) and Houttuyniae herba (Yuxingcao) in the LHQW granules could block the transcription and replication of SARS-CoV-2 via inhibiting 3CLpro, which may explain the effectiveness of LHQW granules in treating COVID-19.[150] According to the network pharmacology and docking scores of forsythoside E, hyperin, and rutin in the LHQW granules, these chemical constituents can act on 3CLpro targets, more effectively than does lopinavir antiretroviral medicine.[157] Shuanghuanglian oral liquid also inhibited the 3CLpro of SARS-CoV-2 in a dose-dependent manner. The chemical constituents (baicalin and baicalein) were screened as nonpeptidomimetic inhibitors of the 3CLpro target of SARS-CoV-2, indicating that Shuanghuanglian oral liquid possesses potent antiviral activity against COVID-19 in a cell-based system.[41] In addition, studies have demonstrated that JHQG, XBJ, HSBD, and XFBD inhibit SARS-CoV 3CLpro.[161],[165]
Spro, a viral spike protein, regulates membrane fusion and receptor binding.[166],[167] The results of network pharmacology and molecular docking studies indicate that the chemical constituents (kaempferol, luteolin, and quercetin) in HSBD have excellent affinity for spike proteins. Molecular docking of XBJ showed that the bioactive components could dock with the Spro receptor.[168] Viral Plpro is an indispensable part of SARS-CoV-2 replication and can be used as a potential target for antiviral drugs. Investigators have shown that the active constituents in the QFPD decoction exhibit excellent docking with papain-like protease protein.[160],[169],[170] RNA-dependent RNA polymerase (RdRp) plays an important role in coronavirus replication and transcription.[171] Toujie Quwen granules could reduce symptoms in COVID-19 patients during the early stages. The Chinese medicine–compound–target network was established to reveal the mechanism of action of Toujie Quwen granules against COVID-19; the results indicated that the top compounds with the highest scores interact with the 3CL enzyme and RdRp. Toujie Quwen granules might possess efficacy against COVID-19 by inhibiting viral infection and regulating related targets and pathways of immunity and inflammation.[172] Nonstructural protein 14 (nsp14) was shown to play an essential role in virus replication.[173] In the QFPD decoction, two chemical constituents (leucocyanidol and cyclo (L-Tyr-L-Phe)), interacted with nsp14.[160]
Regulation of cytokines/chemokines
In organisms infected with microorganisms, the production of a variety of cytokines is greatly increased, resulting in acute respiratory distress syndrome (ARDS). When the human body is infected with SARS-CoV-2, T cells are activated, which quickly proliferate and secrete IL-16 and granulocyte-macrophage colony stimulating factor. IL-16 combines with glycoprotein CD4 on the T cell surface, which stimulates the production of cytokines.
The cytokine storm syndrome occurs in patients with severe COVID-19, due to the high inflammatory response triggered by the virus.[174] IL-6, an essential cytokine, possesses a variety of physiological functions, such as the regulation of immune cell proliferation and differentiation.[175] IL-1β, an essential proinflammatory cytokine, is closely associated with the origin and development of ARDS.[176] TNF is a significant inflammatory factor that drives cytokine production, cell survival, or death.[177] Chemokine (C–C motif) ligand 2 (CCL2) is a crucial chemokine that regulates monocyte/macrophage migration and infiltration of monocyte/macrophage.[178] Patients with severe COVID-19 showed ascending levels of proinflammatory cytokines and manifested as ARDS. Hence, the intervention of relevant cytokine or cytokine signaling could be beneficial for the prognosis recovery of COVID-19.[179]
Studies have demonstrated that the cytokine storm phenomenon occurs in patients with severe COVID-19;[180] consequently, the inhibition of cytokine storm by TCM prescriptions could improve COVID-19 symptoms. For example, LHQW granules can significantly reduce the levels of TNF-α, CCL2 and IL-6 in infected cells in vitro,[157] indicating that LHQW granules have the potential to suppress cytokine storms induced by SARS-CoV-2 in humans. Moreover, the ingredients of LHQW granules (such as Rhei radix et rhizoma [Dahuang]) suppressed the immoderate release of inflammatory mediators (such as IL-1β and IL-2), resulting in less injury to the lungs.[181],[182],[183] In addition, LHQW granules have been shown to inhibit the increase of proinflammatory cytokine levels (IL-6, IP-10, MCP-1, TNF-α) in a dose-dependent manner.[157]
In a randomized trial, XBJ significantly reduced IL-6, IL-8, TNF-α, and C-reactive protein (CRP) levels compared with controls over a 14-day treatment cycle; in addition, the levels of TNF-α, interferon-gamma inducible protein 10kDa (IP-10), and macrophage inflammatory protein-1β (CCL4) decreased in 11 patients with severe COVID-19 who were given XBJ for 7–8 days.[184] XBJ clearly relieved multiple symptoms of severe patients compared with controls and had no obvious side effects. These results suggest that XBJ likely inhibits the proinflammatory cytokine storm (IL-6, IL-8, and TNF-α) and reduces the mortality rate of severely COVID-19 patients.[185]
Immunoregulation
Immunity plays an important role in the prevention of external infections and maintenance of internal homeostasis. TCM can improve immunity and prevent disease progression in patients with COVID-19. COVID-19 patients were treated with coordinating TCM (Toujie Quwen granule) or WM (abidole and ambroxol hydrochloride) in a randomized controlled trial (RCT). After treatment, the lymphocyte count was increased in the TCM group and the level of CRP was lower than that in the WM group. The levels of CD8+ and CD4+ were elevated in the TCM group and decreased in the WM group. These results suggested that TCM could control the expression levels of T cells and recover immunological functions.[186] The therapeutic effects of XBJ in patients with severe COVID-19 were evaluated. The XBJ group showed obvious improvements in respiratory function, CD4+ T cell levels, and immunity compared with the conventional group after treatment, suggesting that XBJ has a potential role in improving lung function and immunity.[187] Studies have reported that JHQG granules and their active components (such as luteolin and myricetin) have obvious therapeutic effects by inhibiting the production of IL-6 in COVID-19 patients[188] and could significantly decrease IL-6 levels and increase IFN-γ levels in the plasma of treated individuals. These results indicated that JHQG granules were immunocompetent against COVID-19 infection.[189]
Improving the gastrointestinal function
Reyanning was used to treat mice infected with COVID-19, resulting in improved gastrointestinal function and immunity as well as a reduction in the inflammatory factors; given that these results are from an in vivo study, they can serve as a reference for clinical research.[190]
Network pharmacology
Network pharmacology and molecular docking were used to reveal the mechanism of action of LHQW granules on anti-SARS-CoV-2. The active components (naringenin, β-carotene, etc.) in the LHQW granule were shown to inhibit Akt1 kinase, reduce tissue damage, and aid in eliminating SARS-CoV-2 infection.[191] Another study revealed that 160 active components in the LHQW granule possessed therapeutic actions on SARS-CoV-2 by acting on 57 different targets, including MAP kinase (MAPK) 1, toll-like receptor (TLR)-signaling pathway, IL-6, and TNF-α; these results demonstrate how LHQW granules can act on multiple targets to cure COVID-19 infection.[192] In addition, the chemical constituents (quercetin, luteolin, wogonin, and kaempferol) in LHQW granules had high affinity with nine targets in COVID-19, namely IL-6, IL-1β, IL-10, TNF-α, CXCL8, MAPK1, MAPK8, VEGFA, and CASP3. Among them, four components were strongly associated with the viral 3CLpro receptor.[53]
The QFPD decoction has been widely used to cure COVID-19 patients.[191] The mechanism of QFPD decoction in the treatment of COVID-19 has been explored through network pharmacology.[193] The QFPD decoction can act on ribosomal proteins, which are crucial for viral replication and inhibit viral mRNA translation. QFPD decoction mainly regulated MAPK1, MAPK3, MAPK8, MAPK14, IL-6, RELA, and STAT1 targets, inhibited inflammatory response, improved immune function, and relieved lung injury through TNF and NF-κB signaling pathways. Moreover, Qingfei oral solution docked with three targets (RdRp, 3CLpro, and PLpr) for the treatment of viral pneumonia with fever and cough symptoms.[194]
Several researchers have also reported the mechanism of action of the QFPD formula on SARS-CoV-2, based on network pharmacology combined with computer-aided drug design programs. In total, 148 relevant targets of SARS-CoV-2 were screened, and 302 active components in the QFPD decoction targeted the ACE-2 and 3CLpro receptors. The bioactive constituents with high scores (such as quercetin, baicalein, and β-sitosterol.) and five key targets (MAPK14, NOS2, PPARG, prostaglandin-endoperoxide synthase 2 [PTGS1], and PTGS2) were identified. The molecular docking results demonstrated that quercetin possessed excellent combining capacity with the PTGS2 target. The gene ontology (GO) and KEGG pathway analysis revealed that luteolin, baicalein, naringin, quercetin, and kaempferol exhibited anti-inflammatory and anti-SARS-CoV-2 activities.[195] Investigators in another study discovered 186 active components in QFPD decoction which acted on 200 specific targets and 51 common targets for SARS-CoV-2. The GO and enriched KEGG pathway results showed that IL-17, NF-κB, TNF, and Th17 were involved in immune regulation, anti-inflammation, and neuroprotection.[169]
The results of a network pharmacology study revealed that XFBD can inhibit the onset of cytokine storm, improve excessive immune activation, and regulate the levels of IL-6 and chemokine CXC ligand-8, Th1, Th2, and Th17 in COVID-19 patients.[196] The targets of these active constituents were mostly related to lung injury and viral infection pathways; the application of XFBD prevented progression from moderate to severe/critical stages of disease. A molecular docking study revealed that XFBD inhibited SARS-CoV-2 3CLpro, and the active constituents (quercetin, kaempferol, rhein) blocked the binding of ACE-2 to SARS-CoV-2. Furthermore, XFBD regulated the level of cytokines (IL-6, IL-1β), chemokines (CCL2), MAPKs (MAPK1, MAPK3), and nitric oxide synthase 2, which aided the recovery of COVID-19 patients.[161] A reverse finding target technique was established and applied to screen chemical constituents in XFBD that have anti-SARS-CoV-2 and anti-inflammatory effects; the active constituents (rutin, pachypodol, axillarin, etc.) were then isolated.[197]
A total of 45 active components of XBJ could be docked with the spike protein, 3CLpro, and ACE-2 receptor on SARS-CoV-2. The active components (apigenin, luteolin, and quercetin) may improve the regulation of TNF-α, IL-6, and MAPK1. Hydroxysafflor yellow B, rutin, and salvianolic acid B may have antiviral, anti-inflammatory, and immune regulatory activities in patients infected with COVID-19 via binding to SARS-CoV-2 proteins. These abundant active components and their various viral targets and pathways illustrate the multitarget and synergistic effects of XBJ in the treatment of COVID-19.[168] In another study, the active components of XBJ, namely kaempferol, chlorogenic acid, luteolin, paeoniflorin, rosmarinic acid, gallic acid, quercetin, and tanshinone, target various sites of SARS-CoV-2.[198] The bioactive constituents (baicalein, kaempferol, and luteolin) and crucial targets (estrogen receptor 1 [ESR1], DPP4, and CALM1) were screened by molecular docking. The potential mechanisms of XBJ in patients with COVID-19 require further investigation based on the results of network pharmacology. According to network pharmacology research, active compound–target–signal pathways were explored to reveal the potential therapeutic mechanisms of HSBD in severe COVID-19 cases. The 11 chemical constituents in HSBD were considered to be the main active constituents (aloe-emodin, baicalein, catechin, etc.), which target 45 different genes (with respect to TNF-α, IL-1β, IL-6, etc.) in SARS-CoV-2-infected patients. Among them, luteolin, β-sitosterol, naringenin, aloe-emodin, and quercetin have been shown to inhibit SARS-CoV 3CLpro, and kaempferol also has an inhibitory effect on the SARS-CoV 3a protein.[197] ACE-2, ADRA1A, ESR1, and HDAC1 may be the key targets of active components in HSBD. The important signaling pathways (such as NF-κB, arachidonic acid metabolism, and AMP-activated protein kinase) in COVID-19 patients after treatment were identified through enriched KEGG analysis,[199] indicating that HSBD might have therapeutic effects in severe COVID-19 cases via multiple sites and signaling pathways (such as NF-κB, AGE-RAGE, TNF-α, and RIG-I-like receptor).[168] In a network pharmacology study, it was reported that 138 active components are contained in HSBD, including baicalein, which has excellent affinity for the 3CLpro receptor of SARS-CoV-2, and licorice phenol, which has affinity for the ACE-2 receptor in COVID-19.[200] It has also been shown that baicalein and quercetin have strong affinity for the ACE-2 receptor, which indicates that HSBD exerts a therapeutic effect via inhibiting ACE-2.[163] Furthermore, kaempferol, luteolin, and quercetin have been shown to have strong affinity for SARS-CoV-2 3CLpro, spike protein, and the host ACE-2 receptor.[168] The combination of clinical research and network pharmacology has demonstrated that HSBD has a good curative effect in the treatment of severe COVID-19 patients.[163]
In the treatment of COVID-19, dayuanyin mediates diverse signaling pathways, including binding ACE-2, acting on PTGS2, heat shock protein 90 alpha family class a member 1, and ESR1.[201] Qingfei Dayuan granules, a CPM based on dayuanyin, possessed excellent combining capacity with receptors.[202] In addition, Huoxiang Zhengqi Oral Liquid, Huanglian Jiedu decoction,[203] Qingwen Baidu Liquor,[204] and Xue's Wuye Lugen decoction tea drink[205] might also have a beneficial therapeutic action on COVID-19 patients, based on network pharmacology analyses.
Safety evaluation
Partial TCM herbs that have adverse or toxic effects, such as Ephedrae herba (Mahuang) and Asari radix et rhizoma (Xixin), should be used cautiously. Mahuang poses a risk of hepatic, renal, and cardiologic toxicity due to its ephedrine content, and Xixin may induce renal and carcinogenic toxicity because of its trace of aristolochic acid or derivatives.[206] Clinicians have reported adverse effects – such as diarrhea, nausea, vomiting, and liver damage – from TCM treatment of COVID-19. In clinical practice, practitioners can reduce or avoid the incidence of these adverse reactions through relevant processing, reasonable compatibility, and appropriate dosage, based on their clinical experience. Notwithstanding these potential risks, a number of CPMs (such as XBJ injection, LHQW capsule, and SFJD capsule) and CMPs (such as Qingwen Baidu Recipe, Pneumonia No. 1 formula, and Qingfei Touxie Fuzheng recipe) have been reported to have no adverse reactions. The safety of CPMs and CMPs has been described in a recent review.[207]
Quality control
Systematic exploration of the chemical basis of TCMs provides a basis for probing the therapeutic basis and establishing quality standards. Generally, compared with a much broader variety of herbal prescriptions, only a few investigations have focused on chemical profiling or component characterization of preparations used in COVID-19. Ten articles published by Chinese scientists characterized the chemical components of LHQW capsules,[117] QFPD granules/decoction,[149],[208],[209] Yupingfeng powder,[210] XFBD granules,[211] HSBD prescription,[212] Qimai Feiluoping decoction,[213] SFJD capsule,[214] and a single herb, Forsythiae Fructus,[215] with 132, 108/405/498, 61, 51, 217, 56, 46, and 278 chemicals, respectively [Table 4]. Their therapeutic bases were further explored or validated via network pharmacology, molecular docking, anti-ACE-2 activity screening, serum pharmacochemistry, and other cell model in vitro experiments in single or combination modes. The chemical constituents of QFPD prescriptions, which have been proven to be effective in clinical practice, have been reported in some detail.[149],[208],[209] Liu et al. developed a ultra-high performance liquid chromatography-Q Orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) method to tentatively characterize 405 components, including 40 alkaloids, 162 flavonoids, 44 organic acids, 71 triterpene saponins, and 88 other compounds in a QFPD prescription. In addition, the absorbed components and metabolites in mouse serum and tissues were also characterized, including 195 chemical components (104 prototypes and 91 metabolites) in mouse serum and 165, 177, 112, 120, 44, and 53 components in the lung, liver, heart, kidney, brain, and spleen of QFPD-treated mice, respectively.[149] Shen et al. established a triplex off-line liquid chromatography (LC) × LC system by combining a reversed-phase (RP) LC × hydrophilic interaction LC system and two RPLC × RPLC systems, which could provide good orthogonality and greatly improve peak capacity. The method was favorable for both polar and weakly polar components, and 498 compounds were ultimately identified in QFPD decoction.[209] Systematic characterizations of other CPMs that were approved before 2020, such as XBJ injection and Tanreqing injection, were not included in this section.
Table 4: Chemical analysis of traditional Chinese medicine against coronavirus disease 2019Hundreds of guidelines and expert consensus statements concerning diagnosis, therapy, and clinical trials has been developed and published since the outbreak of COVID-19.[216] However, there are few official guidelines focusing on the quality control and evaluation of TCMs, especially CPMs or prescriptions, although they have played a major role in the emergency response to COVID-19. Shi et al.[217] reviewed the current quality standards of 47 herbal medicines used most frequently from 141 representative Chinese formulas in fighting COVID-19, which showed the requirements for quality control, maker compounds, and safety indicators to be different in mainstream pharmacopoeias. With respect to CPMs, the “Q-maker” concept (Zhang et al.[218]) was recommended in quality standards and quality control system to ensure the production of “high-quality drugs” in the secondary development of CPM SFJD capsules. In addition, the LHQW capsule, a frequently used drug in combatting COVID-19, underwent relatively adequate quality control in qualitative and quantitative analysis of major constituents, therapeutic effect evaluation in H1N1, and quality marker discovery.[219],[220],[221],[222] In the case of other CPMs (eight injections and four oral preparations) listed in the COVID-19 guidelines, their quality standards can be found in the Chinese Pharmacopoeia (2020)
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