key: cord-0714325-y6g1m2k6
authors: DAI, Yu-Jie; WAN, Shi-Yao; GONG, Shuai-Shuai; LIU, Jin-Cheng; LI, Fang; KOU, Jun-Ping
title: Recent advances of traditional Chinese medicine on the prevention and treatment of COVID-19
date: 2020-12-31
journal: Chinese Journal of Natural Medicines
DOI: 10.1016/s1875-5364(20)60031-0
sha: 5c243eafffe114560b0eef78b413a236c9c547ca
doc_id: 714325
cord_uid: y6g1m2k6

Coronavirus disease-2019 (COVID-19) is a new highly infectious disease caused by a novel coronavirus. Recently, the number of new cases infected pneumonia in the world continues to increase, which has aroused great concern from the international community. At present, there are no small-molecule specific anti-viral drugs for the treatment. The high mortality rate seriously threatens human health. Traditional Chinese medicine (TCM) is a unique health resource in China. The combination of TCM and Western medicine has played a positive and important role in combating COVID-19 in China. In this review, through literature mining and analysis, it was found that TCM has the potential to prevent and treat the COVID-19. Then, the network pharmacological studies demonstrated that TCM played roles of anti-virus, anti-inflammation and immunoregulation in the management of COVID-19 via multiple components acting on multiple targets and multiple pathways. Finally, clinical researches also confirmed the beneficial effects of TCM on the treatment of patients. This review may provide meaningful and useful information on further drug development of COVID-19 and other viral infectious diseases.

Since December 2019, a novel coronavirus (named "severe acute respiratory syndrome coronavirus 2 ", SARS-CoV-2) has erupted around the world. On March 12, 2020, the World Health Organization has officially declared coronavirus disease 2019 (COVID-19) as a global pandemic. According to the epidemic real-time data statistics, as of July 12, a total of 85 522 people have been diagnosed in China, with 4 648 deaths, and 12 756 366 people have been diagnosed abroad, with 562 975 deaths. The study found that the process of infection caused by SARS-CoV-2 is closely related to angiotensin-converting enzyme 2 (ACE2). The spike protein (S protein) of SARS-CoV-2 enters human cells through binding ACE2 receptor and then drives the virus to reproduce and attack new cells [1, 2] . The clinical symptoms of COVID-19 patients mainly include fever, cough, fatigue, myalgia, diarrhea and complications of multiple organ damage [3, 4] . Currently, specific small-molecule anti-viral drugs have not been available for the treatment. The COVID-19 is still a serious threat to human health, and effective prevention and treatment are crucial in this situation.

COVID-19 has been considered to belong to the category of "epidemic disease" in traditional Chinese medicine. The cause is that the human body feels the external toxin and pathogen. The pathogenesis is mainly "wet, heat, poison, stasis, deficiency " and the lesions are mainly in the spleen, lungs and stomach [5, 6] . Chinese herbalists have accumulated valuable experience and played an essential role in the fight against the disease for thousands of years [7] . The General Office of the National Health and Health Commission of China and the Office of the State Administration of Traditional Chinese medicine (TCM) issued "Diagnosis and Treatment of Pneumonia Caused by Novel Coronavirus Infection ", which reflects the characteristics and advantages of TCM in the prevention and treatment of pneumonia [8, 9] . Early intervention of TCM has effectively alleviated the development of the disease. The combination of TCM and Western medicine reduced adverse events and other complications induced by glucocorticoid, anti-biotic and anti-viral treatments [10] .

At present, the published reviews on the research progress of TCM in the prevention and treatment of COVID-19 mainly focus on the following aspects: summarize the under-standing of the etiology, pathogenesis and syndrome characteristics of COVID-19 by the theory of TCM [11] , review the clinical application [12, 13] or explore the rules of TCM [14] and new natural compounds with anti-SARS-CoV-2 activity [15] . Whereas, our present review mainly focuses on the usage of TCM prescriptions, its extracts and active ingredients through literature mining analysis, experimental research and clinical application analysis. What's more, we summarized the names, compositions, specific action pathways and characteristics of TCM which have potential anti-SARS-CoV-2 activity in the form of tables and pictures. This study might provide some support or new clues for the prevention and treatment of COVID-19 and other viral infectious diseases.

It is found that TCM has anti-virus, anti-inflammation, immunoregulation functions through literature mining and analysis. Hence, they are considered to have the potential to treat COVID-19. The Office of the State Administration of TCM has selected Qingfei Paidu Decoction (QFPD) as a general prescription for the prevention and treatment of COVID-19. This prescription is based on Mahuang Decoction (MHD), Xiaochaihu Tang (XCHT), Wuling Powder (WLP), Shegan Mahuang Decoction (SGMHD) and Ju-Zhi-Jiang Decoction (JZJD), and is suitable for patients with mild symptoms, critical and convalescent patients. QFPD could play a rapid antiviral effect and shorten the treatment time of patients through the TCM theoretical analysis combined with the initial clinical observations [16] . It was believed that Huashibaidu prescription (HSBD) could regulate the qi of the lung through the literature analysis. Hence, it was recommended for the treatment of severe pneumonia through multiple targets [17] . Symptoms of qi deficiency often appear in convalescent patients. Shengmai San (SMS) is a classic prescription that can be applied to the diseases of qi and yin-deficiency and also has pharmacological effects such as antifibrosis. What's more, it could accelerate the recovery time of patients and prevent the occurrence of sequelae [18] . At the same time, literature demonstrated that the Yiqi Fumai Lyophilized Injection (YQFM) could treat COVID-19 with cardiovascular disease [19] . Additionally, Xuebijing injection (XBJ) contains Chinese herbal extracts of Carthamus tinctorial, Radix Paeoniae Rubra, Ligusticum chuanxiong Hort, and Salvia. According to the current clinical basis of XBJ, it has in-depth research value in the treatment of severe pneumonia patients [20] . In the trial version seven, Huoxiang Zhengqi Powder (HXZQ), Jinhua Qinggan Granules (JHQG), Lianhua Qingwen Capsules (LHQW), Shufeng Jiedu Capsules (SFJD), Reduning Injection (RDN) and other Chinese patent medicines were also mentioned. HXZQ is a frequently-used damp-clearing prescription and has efficacy of reliving superficies, dispersing dampness, and harmonizing stomach. Combined with HXZQ, it not only has anti-bacterial and anti-vir-al effects but also could regulate gastrointestinal function and the body's immunity. It is considered that it has the potential to treat COVID-19 with the digestive tract as the first symptom [21] . At the same time, it is found that HXSQ, JHQW, LHQW and SFJD have a potential role to improve the symptoms of fever, fatigue and gastrointestinal discomfort in COVID-19 patients during medical observation period discovered by searching and analyzing Chinese and English databases [22] . Another report showed that the volatile oil of TCM has the functions of anti-tussive, expectorant, anti-viral and immune regulation. Chinese herbal medicines such as Agastache rugosa, tangerine peel, Atractylodis Rhizoma and Atractylodes macrocephala may be potentially beneficial for the treatment of COVID-19 [23] . Besides, compound glycyrrhizin has anti-viral, anti-inflammatory and hormone-like effects. Literature analysis found that it could reduce the incidence of a late hormone withdrawal syndrome in patients with COVID-19 [24] . Through the analysis of the above literature, the potential feasibility of the TCM prescriptions for the treatment of COVID-19 was elucidated. More experimental and clinical research are still needed to prove the safety and effectiveness of single Chinese herbs and natural active ingredients.

Amounts of network pharmacological studies have suggested that the possible mechanisms of TCM for the treatment of COVID-19 include anti-virus, anti-inflammation, immunoregulation, and others through multiple components acting on multiple targets and multiply pathways. The relevant studies were summarized as follows.

Existing researches showed that SARS-CoV-2 3CL hydrolase (Mpro) is vital for the replication of SARS-CoV-2 and plays an indispensable role in the proteolytic processing of viral polyproteins (essential proteins for viral replication and function) [25] . Therefore, TCM with the capacity to target Mpro or ACE2 holds the promise to prevent the infection of SARS-CoV-2. Through network pharmacology and molecular docking methods, Mpro and ACE2 were used as targets to determine the binding energy, and it was found that HXZQ [26] , JHQG [27] , LHQW [28] , XBJ [29] , Tanreqing Injection (TRQ) [30] had a good binding force and exerted a therapeutic role by inhibiting virus entry and replication. Other literature indicated that the phosphatidylinositol-3 kinase (PI3K)/total protein kinase B (AKT) pathway could regulate various types of angiogenesis and cell proliferation, which was related to the replication, assembly and pathogenicity of SARS-CoV-2 [31] . Network pharmacological analysis indicated that HXZQ [32] , QingfeiPaidu Decoction (QFPD) [33] and XBJ [29, 34] could also play a therapeutic role by regulating PI3K-Akt to inhibit virus invasion and replication.

Moreover, some natural products such as baicalin, hes-peridin, glycyrrhizin and nicotinamide could play an antiviral effect of COVID-19 through the ACE2 receptor [35] .

The "cytokine storm " is one of the main pathogenic mechanisms of COVID-19 [36] . It means that the body will produce and release a variety of inflammatory factors after being infected, such as Tumor Necrosis Factor-α (TNF-α), Interleukin-1(IL-1), Interleukin-6 (IL-6), Interleukin-12 (IL-12) and Interferon-α (IFN-α), Interferon-β (IFN-β). The release of "inflammatory" cytokines will induce new cytokine production and release which will in turn cause cell and organ damage. Therefore, improving the body's cytokine storm and oxidative stress status presumably could reduce the severity and mortality rate. HXZQ [37] , JHQG [38, 39] , Shengjiang powder (SJS) [40] , HSBD [41] , QFPD [42, 43] , Maxing Shigan Decoction (MXSG) [44] , XCHD [45] , XBJ [46] , RDN [47] , Xiyanping Injection(XYP) [35] , a TCM composition [48] containing Agastache rugosa, Chrysanthemi Indici Flos, Moslae Herba, and Artemisia annua could act on TNF, MAPK, NF-κB such signaling pathways to suppress the elevated cytokine levels. Additionally, vitamin C, curcumin and glycyrrhizin exerted a potential protective effect on SARS-CoV-2 infection by preventing cytokine storms [49] . It is worth noting that the arachidonic acid (AA) metabolic pathway can mediate the production of multiple inflammatory factors [50] , such as monocyte chemoattractant protein-1 (MCP-1), TNF, IL and IFN etc. Therefore, it is considered to be closely related to the occurrence and development of inflammation. Cluster model analysis revealed that HXZQ, JHQG, LHQW, QFPD, XBJ, RDN and TRQ have potential inhibitory effects on AA pathway to treat pneumonia caused by SARS-CoV-2 through alleviating "cytokine storm" [51] .

Virus-infected cells release signals to recruit and activate immune cells. These immune cells secrete a variety of cytokines and chemokines to recruit more immune cells to the lesion site. However, this can lead to excessive immune responses and damage the body. TCM could alleviate excessive immune responses to restore normal physiological functions of the body. Based on the network pharmacology, LHQW was reported to have 55 common targets with SARS-CoV-2 [52] , which were enriched in immunity (mainly the innate immune pathway induced by type I interferon) and inflammation (TNF, IL-17, Toll-like receptors) [28] . The significant pathways of TRQ included Th17 cell differentiation pathway, MAPK, EGFR and TNF signaling pathway, which could alleviate excessive immune response, inhibit activated cytokines and eliminate inflammation [30] . A TCM prescription containing Tripterygium Wilfordii could regulate immunity against viruses [53] .

To date, other potential targets and pathways of Chinese herbal medicine prescriptions were predicted through network pharmacological analysis. For example, the increase of creatine kinase (CK) and lactate dehydrogenase (LDH) is related to lung cell damage and systemic symptoms [3] , thus, HXZQ [54] may treat COVID-19 by reducing CK and LDH levels to improve oxygenation index and systemic symptoms. The potential signal pathways of Shufeng Jiedu Capsule (SFJD) for preventing and treating COVID-19 were IL-17, HIF-1 and Toll-like receptors, and the targets were IL-10, IL-6, prostaglandin-endoperoxide synthase (PTGS), Glycogen synthase-3 (GSK3B), transcription activator-1 (STAT-1) [55, 56] . HSBD showed 49 potential targets for COVID-19 including IL-6, TNF, MAPK1, MAPK8 and IL-1β [57] . Shengmai injection (SMI) treated COVID-19 through caspase (CASP), PTGS, NOS and other signaling pathways [58] , and YQFM played a role in the early therapy of COVID-19 by inhibiting microvessel exudation, invigorating qi, astringing and solidifying [59] , it was also helpful for acute and severe cardiopulmonary patients [19] .

There is a myriad of literature on network pharmacology analysis of single Chinese herbs and natural products. For example, Agastache rugosa showed 16 active ingredients and 10 related targets, which were acted on Toll, MAPK and other signaling pathways [60] . Seven effective compounds, fortynine corresponding targets and thirty-one pathways were screened from Rhubarb and illustrated that it could treat COVID-19 through multi-component and multi-target [61] . Moreover, Quercetin and (-)-Epigallocatechin gallate and other 12 TCM monomers showed similar affinity to IL-6, ACE2 and SARS-CoV-2 as recommended medicines, and thus played a vital role in the treatment of COVID-19 [62] .

Additionally, there are still many TCM prescriptions in the experimental research stage. For example, A centralizing and lung-saving medicine composition might reverse the progression of COVID-19 and reduce the deterioration rate [63] . There are some TCM sachets [64] , nebulizers [65] , fumigation preparations [66] and aromatherapy [67] with disinfection function under research which could help stop the spread of the epidemic.

A randomized clinical trial on LHQW of 284 COVID-19 patients is useful to confirm the beneficial effect of TCM. In the trial, 142 patients were given LHQW for 14 consecutive days (4 capsules, three times a day), the results manifested that the recovery rate (91.5% vs 82.4%), the improvement rate (83.8% vs 64.1%) and the clinical cure rate (78.9% vs 66.2%) of the treatment group were higher than the control group, with no serious adverse reactions [68] . This trial showed that LHQW could be considered to ameliorate clinical symptoms of COVID-19. Furthermore, 22 065 subjects were given HXZQ and Jinhao Jiere Granules (JHJR) for preventive administration for 5 consecutive days with the protection rate of the intervention group was 91.8%, which indicated that they provided effective protection for the community [69] . Then, 123 COVID-19 patients were additionally given JHQG for 5 consecutive days [70] , and the disappearance rate of fever symptoms in the treatment group was about 85.0%, which was 27.0% higher than that in the control group, and the Hamilton anxiety score decreased significantly in the treatment group (6.37) than in the control group (4.88), indicating that JHQG could effectively relieve the symptoms and anxiety of patients. A retrospective analysis of 68 patients found that the effective rate (91.2%) of the treatment group combined with the SFJD for 7 days was dramatically higher than that of the control group (70.6%, P < 0.05), and no adverse events occurred [71] . The analysis revealed that the combined use of SFJD was effective and safe.

On the other hand, 214 confirmed cases in four pilot provinces were treated with QFPD (3 days as a course of treatment), which showed a total effective rate of more than 90% [72] . Among these, 98 patients were treated for 9 days and the total effective rate was 92.09%, of which the recovery rate was 41.13%, the significant efficiency was 26.92%, and the effective rate was 24.04% [73] . These trials provided strong evidence for the clinical application of QFPD. Furthermore, 80 patients were given MXSG for 5−7 days, the effective rate was 95% [74] ; Forty patients were given MXSG combined with conventional treatment for 7 days, and the disappearance rates of the main clinical symptoms (fever, fatigue, cough) were 96.8% (30/31), 100.0% (28/28) and 81.8% (18/22) respectively [75] . It showed that the combined use of MXSG could effectively improve the symptoms of patients. And 44 patients were given XBJ treatment for 7 consecutive days, which indicated that the overall effectiveness of the intervention group (68.2%) was slightly higher than that of the control group (50.0%), and no serious adverse reactions occurred [76] . The clinical trials showed that XBJ also had a certain therapeutic effect. Nevertheless, there are dozens of TCM are conducting clinical trials at present, certain specific Chinese medicines are also incorporated (Table 3 ).

TCM has accumulated thousands of years' experience in the treatment of pandemic and endemic diseases. Literature analysis has indicated the potential feasibility of QFJD, HS-BD, XBJ and other Chinese herbal preparations to treat COV-ID-19. Although its safety and effectiveness need to be clarified, it can provide a theoretical basis for subsequent experiments and clinical research. At present, most of the TCM preparations have been explored their potential mechanisms and targets by network pharmacology and molecular docking. The results showed that some TCM preparations could inhibit virus entry and replication in vivo by binding to Mpro and ACE2 targets, such as HXZQ, JHQG, LHQW, XBJ, TRQ and XYP. Also, they could play an anti-inflammatory role by acting on TNF, MAPK, Toll, NF-κB, IL-17, HIF-1 and other signaling pathways, which embodied the unique characteristics and advantages in the improvement of multiple organ damage. HSBD might act on the RIG-1/IRF/IFN-β, NF-κB/TNF-1L signaling pathways to reduce the release of inflammatory factors to alleviate lung injury. LHQW possibly modulated AGE/RAG1/ROS, PI3K/AKT and other signaling pathways to reduce kidney damage caused by inflammation. QFPD, MXSG potentially reduced the heart and brain damage linked with Caspase-3/Bcl-2, TNF-R1/MAPK and other signaling pathways. Compared with Western medicine treatment, TCM has its unique treatment concepts and principles. For example, QFPD is a common and core prescription in the prevention and treatment of COVID-19, and patients can be treated based on syndrome differentiation individually following the TCM theory [77] . Also, HXZQ could not only act on the main pathogenesis of " wet poison ", but also restore the qi mechanism to improve patients' symptoms [37] . LHQW is a representative Chinese drug for treating viral infection-related diseases and has a broad clinical application basis [78] . XBJ showed no immunosuppressive effects in the treatment of clinical severe and critical COVID-19 patients. What's more, the incidence of adverse reactions was low and the clinical effect was remarkable [47] . These findings have shown that compounds and preparations of TCM have their unique characteristics and potential advantages in treating COVID-19 ( Fig. 1) and also provided a clinical basis for the follow-up TCM treatment plan and new drug development. Among them, the TCM composition and the action pathways for the prevention and treatment of the COVID-19 are shown in Table 1 .

Moreover, literature mining and big data analysis showed that some natural products including quercetin, puerarin, porphyrin, quercetin-7-O-β-D-glucoside and patchouli alcohol in Patchouli have a better combination with Mpro, which could reduce virus replication. Seven effective compounds such as β-sitosterol and aloe-emodin in Rhubarb purportedly had the anti-viral, anti-inflammatory, anti-oxidative stress, anti-apoptosis and regulation of body immunity effects through multiple pathways and multiple targets. Meanwhile, the active ingredients of TCM such as glycyrrhizin and baicalin could inhibit the virus activity. For the experimental study of single Chinese herbs or extracts, Rhubarb, Scutellaria baicalensis Geor, Coptidis Rhizoma, Flos Lonicerae, Folium isatidis and other antipyretics or antidotes have a certain therapeutic effect, which could provide a reference for the new combination of TCM. For example, there are some TCM sachets and sprays which have applied for patents to help reduce the prevalence and mortality. The effective components and action pathways of single TCM and natural active components for anti-SARS-CoV-2 are shown in Table 2 .

The above summary suggests that TCM and its preparations showed the unique superiority of a full course of treatment and a full range of treatments. Early prevention and early treatment could reduce the mortality rate, improve symptoms, decrease the occurrence of complications and recurrence, which showed broad application prospects. The network pharmacological analysis indicates that the possible [9]

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To investigate the intervention ef

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