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Traditional Chinese medicine in COVID-19

COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread across the globe, posing an enormous threat to public health and safety. Traditional Chinese medicine (TCM), in combination with Western medicine (WM), has made important and lasting contributions in the battle against COVID-19. In this review, updated clinical effects and potential mechanisms of TCM, presented in newly recognized three distinct phases of the disease, are summarized and discussed. By integrating the available clinical and preclinical evidence, the efficacies and underlying mechanisms of TCM on COVID-19, including the highly recommended three Chinese patent medicines and three Chinese medicine formulas, are described in a panorama. We hope that this comprehensive review not only provides a reference for health care professionals and the public to recognize the significant contributions of TCM for COVID-19, but also serves as an evidence-based in-depth summary and analysis to facilitate understanding the true scientific value of TCM.


Introduction
The outbreak and spread of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has inflicted immense losses on human lives and properties all over the world. Globally, as of August 7, 2021, there have been more than two hundred million confirmed COVID-19 cases, including more than four million of deaths (WHO, https:// covid19.who.int/). SARS-CoV-2 is an enveloped, single-stranded, positive-sense, b-coronavirus RNA virus that belongs to the subfamily Coronavirinae, family Coronavirdiae, order Nidovirales. It shares about 79.6% identity of genome sequence with SARS-CoV and 96% similarity with bat coronavirus at the whole-genome level 1,2 . SARS-CoV-2 is transmitted from person to person via respiratory droplets, high concentration of aerosols, and occasionally feces or urine. Currently, no approved specific anti-viral drug is recommended to defeat COVID-19, which may lead to acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and even death.
It is well documented that traditional Chinese medicine (TCM) has accumulated abundant clinical experience and effective prescriptions to control and treat infectious diseases in about 500 epidemics occurred in China over more than 3000 years in the past 3 . The combined therapy of TCM and Western medicine (WM) had significantly reduced mortality, shortened duration of fever, decreased chest radiograph abnormalities, and relieved secondary fungal infections among patients receiving glucocorticoids in combating severe acute respiratory syndrome (SARS) 4 . Owning to the positive role of TCM in treating previous coronavirus pneumonias such as SARS, middle east respiratory syndrome (MERS), and other epidemic diseases 4e9 , the National Health Commission of China recommended to use TCM as one of the strategies for COVID-19 remedy. This epidemic was deemed as the category of "pestilence" with the pathological characteristics of "dampness, heat, toxin, deficiency, and stasis" under TCM theory 10e12 . Over the past year, TCM achieved remarkable efficacy in treating patients at all stages infected with SARS-CoV-2 in China. Typical clinical characteristics contain clinical manifestations, laboratory findings, and chest imaging features, as well as the pathogenesis of SARS-CoV-2 infection and therapeutic targets including SARS-CoV-2 invasion and replication, immune response, and cytokine storm, ARDS and MODS were outlined in published papers. In this review, the therapeutic efficacities and pharmacological mechanisms of TCM for this epidemic disease were systematically documented and discussed, aiming at displaying an in-depth understanding of TCM against COVID-19.

Understanding COVID-19 in TCM theory
In the theory of TCM, COVID-19 is deemed as the category of "dampness-toxin pestilence" 10 . The distinct disease stages of TCM treatment can be divided into mild, moderate, severe, and critical. The main patterns in mild stage are cold-damp constraint and damp-heat accumulation in the lung, where dispersing lung and removing pathogenic factors, and resolve turbidity with aroma are needed; The main patterns in moderate stage are damp-toxin constraint in the lung and cold-damp obstructing the lung, where eliminating heat and dampness, detoxification, and invigorate spleen are needed; The main patterns in severe stage are epidemic toxin blocking the lung, blazing of both qi and yin, where tonifying qi and yin, ventilating lung qi, co-treatment of lung and intestines are needed. The main patterns in critical stage are internal blockage and external desertion, where tonifying qi and preventing exhaustion, cool blood and nourishing yin, and restore consciousness are needed 13e15 . Syndrome differentiation is one of the most important principles for TCM to treat COVID-19.

The recommended TCMs for distinct stages of COVID-19 treatment
According to the officially issued 7th and 8th trial version of Diagnosis and Treatment Protocol for COVID-19 in China and other references 14,16e23 , there are more than 18 recommended TCMs to prevent and treat COVID-19, covering from medical observation period (suspected cases) to clinical treatment period (confirmed cases) including distinct disease stages of mild, moderate, severe, and critical, as shown in Fig. 1. Among them, the highly recommended three Chinese patent medicines (CPMs) are Jinhua Qinggan granules, Lianhua Qingwen capsule (granules), and Xuebijing injection, and three Chinese medicine formulas are Qingfei Paidu decoction, Huashi Baidu formula, and Xuanfei Baidu formula, with proven efficacies in treating COVID-19 24,25 . Jinhua Qinggan granules clear heat and detoxifying, and diffuse the lung. It is composed of 12 herbal medicines originating from Maxingshigan-Yinqiaosan formula, which could shorten time to fever resolution in patients with H1N1 influenza virus infection occurred in 2009 26 . Lianhua Qingwen capsule (granules), containing 13 herbal medicines and with a clinical indication for clearing heat, diffusing the lung, and detoxifying, was an innovative CPM for the treatment of SARS in 2003 27,28 . Xuebijing injection, a five-herbal injection medicine and with a clinical indication for dissolving stasis and detoxifying, was derived from a modified Xuefu Zhuyu decoction and was developed and marketed during SARS. The Chinese medicine formula Qingfei Paidu decoction consists of 21 herbal medicines from five classic formulas of Treatise on Febrile Diseases. It clears the lung and calm panting, and is the first recommended universal treatment formula for all stages from mild to critical of COVID-19 25,29 . Huashi Baidu formula is composed of 14 medicinal herbs. It serves to clearing heat and detoxifying, removing dampness, mainly suitable for the treatment of mild, moderate, and severe COVID-19 patients 30,31 . Xuanfei Baidu formula is derived from classic formulas including Maxing Shigan decoction and Maxing Yigan decoction, and is composed of 13 medicinal herbs. It detoxifies and removes blood stasis, diffuses the lung, removes dampness, clears heat, and is mainly applicable to treat mild and moderate COVID-19 patients 32 . Beyond the above mentioned medicines and formulas, Chinese herbal injections, including Xiyanping injection, Reduning injection, Tanreqing injection, Shenfu injection, Shengmai injection, and Shenmai injection, were more suitable as supplemental treatments for severe or critical COVID-19 cases with their advantages of fast absorption, high bioavailability, and clearer ingredients in contrast to orally administrated TCMs 33e35 .

Clinical evidence of TCM for COVID-19
A total of 40 representative clinical trials, including 11 randomized controlled trials (RCTs), 16 retrospective cohort studies (RCSs), 5 multi-center clinical observations, and 8 others were completed and summarized 27,28,30e32,36e70 . According to the available clinical data, integrated TCM and WM exhibited several clinical advantages in COVID-19 treatment, including the outcomes of 1) clinical manifestations, 2) lung features, and 3) laboratory findings as shown in Table 1 27,28,30e32,36e70 . Furthermore, based on Table 1, the clinical evidence of TCM for typical characteristics of COVID-19 were analyzed and summarized in  Table 2 59 reduced the level of C-reactive protein (CRP). Shufeng Jiedu capsule decrease the level of interleukin-6 (IL-6) 54 .
For severe or critical stages: 1) Xuebijing injection 43 and Qingfei Paidu decoction 45 improved the conditions of patients and reduced multiple organ dysfunction. 2) Xuebijing injection 43 , Qingfei Paidu decoction 45 , and Huashi Baidu formula 30 improved chest CT imaging or promoted lung lesions absorption; Chansu injection 61 ameliorated the respiratory function and shorten the respiratory support step-down time. 3) Both Xuebijing injection 43 and Chansu injection 61 improved the oxygenation index of PaO 2 / FiO 2 ; Xuebijing injection 43 and Qingfei Paidu decoction 45 decreased the level of CRP, and increased WBC or lymphocyte count; In addition, Xuebijing injection reduced the level of inflammatory mediators of TNF-a, IP-10, MIP-1b, and RANTES 42 ; Qingfei Paidu decoction decreased biochemical parameters of CK and LDH, and the level of blood urea nitrogen 45 ; Maxing Shigan decoction increased CD4 þ T and CD8 þ T count 59 ; Huashi Baidu formula 30 decreased CRP, erythrocyte sedimentation rate (ESR), serum ferritin, and myoglobin level; Yidu-toxicity blocking lung decoction reduced the levels of IL-6 and TNF-a 62 .
For all stages: 1) Qingfei Paidu decoction 46 and Qingfei Dayuan granules 63 ameliorated extensive adverse symptoms such as fever, cough, fatigue, chest tightness, and headache; Xuanfei Huazhuo decoction relieved the symptoms of cough, fever, sputum, diarrhea, fatigue, and loss of appetite 65 . 2) Qingfei Paidu decoction 45 65 reduced the level of CRP and ESR, and the biochemical parameters of AST and ALT. What's more, Qingfei Paidu decoction decreased the level of a thrombotic marker Ddimer 46 .
A plentiful of clinical studies and analyses proved that integrated Chinese and Western medicine therapy are much better than pure use of WM for COVID-19 71e80 . A recent systematic Figure 1 The recommended Chinese patent medicines or Chinese medicine formulas for distinct stages of COVID-19 treatment.  review and meta-analysis of RCTs involving 2275 patients revealed that integration of TCM and WM group was more effective than WM treatment alone in the indicators of clinical cure rate, conversion rate from mild to critical, length of hospital stay, total score of clinical symptoms, symptoms of fever, cough and fatigue, TCM syndrome, negative conversion rate of viral nucleic acid, inflammatory biomarkers of CRP and lung CT without significant difference in adverse effects 81,82 . Another similar meta-analysis of RCTs including 1259 COVID-19 patients showed consistent results that TCM with WM treatment could improve the amounts of severe and critical conversion, length of hospital stay, time of antipyretic, and resolution rate of fever, fatigue, and tachypnea 83 .
In summary of clinical evidence, TCM is beneficial for treating COVID-19 in 1) relieving the typical symptoms of fever, cough, fatigue, dry throat, sore throat, sputum production, shortness of breath, myalgia, and diarrhea; shortening the duration of positive viral nucleic acid, reducing the time to symptom recovery and the progression to severe disease, and protecting against multi-organ injury; 2) improving the lung features including lung inflammatory absorption, CT imaging, lung injury, lung function, and oxygenation index; 3) regulating laboratory index including inflammatory and immune response related the count of WBC, lymphocyte, CD4 þ T and CD8 þ T, and the level of CRP, IL-6, TNF-a, and ESR, single or multi-organ injury related the level of procalcitonin, CK, LDH, ALT, and AST, and thrombosis related D-dimer level. Taking full advantage of integration of TCM and WM is one of the important reasons for the rapid containment of this epidemic in China. Additional high-quality RCTs are needed to demonstrate the effectiveness and adverse events of TCM in the treatment of COVID-19.

Potential mechanisms of TCM for SARS-CoV-2 invasion and replication
Although the direct evidence is still lacking, increasing reports suggested that TCM resource holds great promises for agents against SARS-CoV-2 invasion and replication. Numerous efforts had been made to identify the antiviral effects of CPMs and herbals, as shown in Table 3. Lianhua Qingwen capsule with a half maximal inhibitory concentration (IC 50 ) of 411.2 mg/mL 89 , Liu Shen capsule 107 with an IC 50 of 0.6 mg/mL, and Shuanghuanglian preparation 109 with an IC 50 of 0.93e1.2 mL/mL were confirmed to inhibit SARS-CoV-2 replication in Vero E6 cells. In addition, Pudilan Xiaoyan oral liquid not only inhibited SARS-CoV-2-stimulated Vero E6 cells in vitro, but also showed the potential efficacy on SARS-CoV-2-infected human   50 values ranged from 1 to 10 g/mL 117 . It was not difficult to find that although several TCMs like Liu Shen capsule and Dahuang showed a good performance in suppressing viral replication or activity, more studies are still necessary to be implemented to reveal more receivable anti-viral CPMs and herbal extracts especially the recommended CPMs in vitro and in vivo.
Noticeably, a considerable number of ingredients derived from TCMs were found to have anti-viral invasion and anti-viral replication activities by targeting diverse molecules, as seen in Table 4. The interaction between spike protein and ACE2, primed by serine protease transmembrane protease serine 2 (TMPRSS2), is the key step for SARS-CoV-2 host invasion. Emodin from Yaoyong Dahuang was able to inhibit S protein and ACE2 interaction with an IC 50 of 200 mmol/L 117 , while hesperidin from Citrus aurantium (Suancheng) was predicted to target the binding between spike RBD and ACE2 with high affinity 124 . Besides, geniposide from Gardenia jasminoides (Zhizi) was found through virtual screening of 2140 compounds with pharmacophoric features, which could target the active site residues of TMPRSS2 with a binding energy score of À14.69, and is even greater than that of the standard inhibitor of camostat mesylate 126 . Seven isolated tanshinones derived from Salvia miltiorrhiza (Danshen) including tanshinone IIA, tanshinone IIB, methyl tanshinonate, crytotanshinone, tanshinone I, dihydrotanshinone I, and rosmariquinone showed marked inhibitory activities to both proteases of 3CLpro and PLpro 149 . Particularly, dihydrotanshinone I exerted powerful effects with IC 50 values of 14.4 mmol/L regarding 3CLpro and 4.9 mmol/L regarding PLpro 149 . Furthermore, crytotanshinone exhibited the most potent nanomolar level inhibitory activity toward PLpro with an IC 50 of 0.8 mmol/L 149 . Baicalin and baicalein, the major bioactive ingredients of Shuanghuanglian preparation, were characterized as the first noncovalent and nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro, also possessed good anti-SARS-CoV-2 activity in Vero E6 cell-based system 109 . What's more, celastrol 143,144 , tingenone 143 , xanthoangelol E 150 , and hesperetin 151 targeting 3CLpro, while hirsutenone 155 , methyl tanshinoate, tanshinone I 149 , xanthoangelol E 150 , isobavachalcone, 4 0 -O-methylbavachalcone, psoralidin 157 , and tomentin A-E 158 targeting PLpro, may have relatively strong anti-viral replication efficacy with IC 50 below or near 10 mmol/L. Notably, the well-known anti-malarial 165 , anti-tumor 166 , and immune modulation 167 compound artemisinin from Artemisia apiacea (Qinghao), and its derivatives including arteannuin B, artesunate, dihydroartemisinin, arteether, and lumefantrine presented favorable anti-SARS-CoV-2 effects. Among these artemisinin derivatives, arteannuin B showed the highest anti-viral potential with an IC 50 of 10.28 mmol/L, while lumefantrine exerted therapeutic promise owing to its high plasma and lung concentrations after multiple dosing. The deeper pharmacological mechanism analysis revealed that these two compounds acted at the post-entry step of SARS-CoV-2 infection 137 . Significantly, lycorine from Lycoris radiata (Shisuan) had a powerful inhibitory effect on virus activity with an IC 50 of 15.7 nmol/L and may serve as a candidate for the development of new anti-SARS-CoV-2 drug in the treatment of COVID-19 164 . In addition, a Vero E6 cellbased large-scale anti-SARS-CoV-2 activity of 1058 natural compounds were screened, and 17 newly discovered compounds showed strong anti-virus propagation effects with the IC 50 values ranging from 0.011 to 11.03 mmol/L. Among them, bufalin from toad venom (Chansu) exerted the antiviral effect with an IC 50 of 18 nmol/L by targeting the ion transport function of Na þ /K þ -ATPase 139 . Theaflavin was predicted to exert anti-viral replication by inhibiting RdRp activity 130 . The binding affinities with the critical proteins of a portion of ingredients presented above were also predicted by in silico screening and molecular docking 124,168 . Whether these TCM ingredients could be used to combat COVID-19 need further in vitro and in vivo validation. Pharmacokinetic profiles including absorption, distribution, metabolism, and excretion (ADME) on the promising leads should be further studied.

Potential mechanisms of TCM for immune and inflammatory regulation
Antiviral monotherapy for patients hospitalized with COVID-19 is quite not enough, especially for severely and critically ill patients 169 . Except for the broad-spectrum antiviral activity, TCM process   89 and Liu Shen capsule 107 reduced pro-inflammatory cytokines production such as TNF-a, IL-6, MCP-1, and IP-10 in SARS-CoV-2 infected Huh-7 cells. In addition, Lianhua Qingwen capsule was analyzed to repair lung injury by modulating inflammatory process and cytokine storm 90 . Maxing Shigan decoction is the basic prescription of "three medicines and three formulas" apart from Xuebijing injection, was revealed to regulate immunity and reduce cytokine storm, as well as protect alveolarecapillary barrier of lung and relieve pulmonary edema by utilizing integrated network pharmacological approaches 101 . As same as Maxing Shigan decoction, Qingfei Paidu decoction showed multiple immune regulation, anti-inflammation, and lung injuryerepair activities with its main ingredients of baicalin, glycyrrhizin, hesperidin, and hyperoside by targeting proteins including TNF-a, IL-6, IL-10, and CCL2 93e96 . Furthermore, several ingredients such as baicalin and glycyrrhizin of Qingfei Paidu decoction could inhibit platelet aggregation 96 . Dayuanyin is the basic formula of Qingfei Dayuan granules that might process an antiinflammatory and immunoregulatory effects via acting on IL-6, IL-1b, and MCP-1, with its ingredients containing kaempferol, isoflavone, and formononetin 63,104 . Glycyrrhizin is an anti-viral agent and clinically used anti-inflammatory ingredient from Glycyrrhiza uralensis (Gancao) was determined to elevate immunity and suppress inflammatory stress through T cell receptor and VEGF signaling pathways 141,159,173 . Matrine was not only predicted to suppress host cell apoptosis and inflammation by targeting the TNF-a, IL-6, and CASP3 in the TNF signaling, but also validated to reduce lung tissue damage and lung index by decreasing the production of IL-6, IL-10, TNF-a, and IFN-g, increasing the percentage of CD4 þ T cells, CD8 þ T cells, and B cells in peripheral blood, and lessening viral load in lung tissue in a mouse model combining human coronavirus pneumonia with cold-dampness pestilence attacking the lung 112,113 .
Although systems pharmacology is a convenient and effective tool to propose the mechanism of action of TCM at a holistic level, all the results above need to be further validated. IL-6 was considered as one of the most important molecules in cytokine storm 174e182 . Administration with Dayuanyin reduced the level of IL-6 in mild, moderate, and even severe clinical stages of COVID-19 104 . Besides, Shufeng Jiedu capsule 54 , Yidu-toxicity blocking lung decoction 62 , Qingfei Touxie Fuzheng recipe 67 , and diammonium glycyrrhizinate 70 were confirmed to decrease the level of IL-6 in COVID-19 patients, as seen in Table 1. Interestingly, except for the strong anti-SARS-CoV-2 activity 137 , artemisinin and its derivatives regulated multiple immune cells including macrophage, monocyte, dendritic cell, and T cell to inhibit pro-inflammatory cytokine release and cytokine storm outbreak to protect tissues from injury 183 (Table 3).

Potential mechanisms of TCM for ARDS and MODS treatment
In contrast with WM therapy, TCM is adept at treating complications of COVID-19 such as ARDS and MODS which are likely caused by the concurrence of viral toxicity, endothelial damage, cytokine storm, excessive immune, and microthrombus holistically (Table 3). Xuebijing injection was certified to treat severe pneumonia, sepsis, coagulopathy, SIRS, and MODS, owing to its various effects on cytokine reduction, immunoregulation, microcirculation improvement, anti-coagulation, pro-angiogenesis, and neutralization of released bacterial cytotoxins 42,184e189 . Xuebijing injection   was able to improve the oxygenation index of PaO 2 /FiO 2 and reduce the level of pro-inflammatory cytokines of TNF-a, IP-10, MIP-1b, and RANTES in the treatment of COVID-19 42, 43 . It was also reported that Xuebijing injection could downregulate the expression of IL-6, IL-1, TLR4, MAPK, and NF-kB, maintain the balance of Tregs and Th17 cells in acute lung injury 190e193 . Besides, Xuebijing injection processed the potential to alleviate liver damage, acute lung injury-induced left ventricular ischemia/reperfusion, sepsis-induced acute kidney injury, and sepsis-induced myocardial injury via inhibiting inflammation, apoptosis, and endothelial injury 194e199 . Systems pharmacological analysis revealed that Qingfei Paidu decoction could protect multi-organ including nervous system, sensory system, digestive system, and circulatory system by regulating key enzymes, G protein-coupled receptors, ion channels, and transporters 96 .
In the background of great demands for acute lung injury and ARDS therapy of COVID-19, more than one hundred of natural products from TCM with their potential benefits and underlying mechanisms of anti-inflammation, antioxidant stress, antiapoptosis, and anti-pulmonary fibrosis were summarized and categorized. According to their chemical structures, these were divided into flavonoids (e.g., luteolin, baicalein), alkaloids (e.g., berberine, matrine), terpenoids (e.g., pogostone, andrographolide), polyphenols (e.g., honokiol, curcumin), quinonoids (e.g., emodin, shikonin), and other compounds (e.g., osthole, imperatorin) 200 . In addition, a systematic review and meta-analysis of 19 eligible RCTs including Tanreqing injection, Shengmai injection, Shenfu injection, Danshen injection, Reduning injection, and Xuebijing injection demonstrated that Chinese medicine injections were adjuvant therapy with great potential benefits for the treatment of ALI/ ARDS 33 . For example, based on the effects of inhibiting inflammatory cytokines of IL-6, IL-8, IL-1b, and TNF-a, regulating immune, and elevating the oxygenation index of PaO 2 , Tanreqing injection was proved to improve lung injury, pulmonary infection, airway inflammation, and airway mucus hypersecretion 201e204 . Reduning injection was demonstrated to prevent pulmonary neutrophil infiltration, lung injury and severe pneumonia which may attribute to downregulating IL-1b, IL-18, TNF-a, NF-kB, and pyrin domain containing 3 levels, lowering myeloperoxidase activities, and reducing reactive oxygen species production 205e207 . Xiyanping injection, a famous Chinese medicinal preparation of andrographolide sulfonate, was reputed as one of the most effective alternatives to antibiotics, which has been widely used to ameliorate lung damage, bronchitis and community acquired pneumonia probably through inhibiting NF-kB and MAPK-mediated inflammatory responses 208,209 . Besides, Xiyanping injection and Reduning injection were used to treat diarrhea in children. Xiyanping injection could ameliorate colitis by inhibiting Th1/Th17 response in mice 210 .
Cardiovascular disease is a high frequent comorbidity and complication of COVID-19. Three Chinese injection medicines including Shenfu injection, Shengmai injection, and Shenmai injection, have both pulmonary and cardiac protective effects. For instance, Shenfu injection is effective in the treatment of heart failure, myocardial hypertrophy, cardiac arrest, myocardial ischemia-reperfusion injury, myocardial fibrosis, and acute viral myocarditis, partly through suppressing apoptosis and inflammation, improving microcirculation, reducing mitochondrial damage and coagulation-fibrinolysis disorders 211e221 . Moreover, Shenfu injection has a protective effect on gastrointestinal tract and intestinal mucosa 222,223 . Xingnaojing injection and Angong Niuhuang pill are different preparations share similar ingredients for stroke treatment in clinic. Both of them ameliorate cerebral  ischemia/reperfusion injury, cerebral infarction, cerebral edema, blood-brain barrier disruption, and acute cerebral hemorrhage because of their benefits in brain microvascular endothelial cells, hippocampal and cortical neurons protection, and their antiinflammation and anti-apoptosis effects 224e231 .
3.4. Potential mechanisms of the representative and commonly used herbs in the treatment of COVID-19 Analyses of the main compositions of the "three medicines and three formulas" and other related literatures identified G. uralensis  233 . It is worth noting that the anti-COVID-19 effects and mechanisms of TCM may be exerted via the gutelung axis and mediated by gut microbiota 234e236 . For example, short-term intervention of Qingfei Paidu decoction dose-dependently regulates the host metabolism and gut microbiome in rats, indicating that altering gut microbiota composition may be part of the anti-COVID-19 mechanisms of Qingfei Paidu decoction 237 . It is of particularly significance to consider that the solubility and bioavailability of certain TCM ingredients, such as resveratrol, quercetin, baicalin, curcurmin, emodin, and tanshinone IIA, are limited, leading to poor absorption into the bloodstream after oral administration. These ingredients may exert their therapeutic effects though interplaying with gut microbiota 238 . For instance, resveratrol could also alleviate intestinal inflammation and oxidative damage by modulating the composition of gut microbiota in addition to the direct antiviral effect 239 . What's more, to improve the bioavailability, a nanomicellar form of curcumin was used to decrease IL-6 and IL-1b expression and secretion in patients with COVID-19 240 .
In summary of preclinical evidence, the anti-COVID-19 effects and mechanisms of TCM include but not limited to 1) inhibiting SARS-CoV-2 invasion and replication by targeting the key proteins of spike, ACE2, TMPRSS2, 3CLpro, PLpro, RdRp, and spikeeACE2 interaction; 2) regulating immune and inflammatory response by targeting inflammatory cytokines such as IL-1, TNF-a, and IL-8, and chemokines like CCL5, CCL2, and IP-10, which are secreted by monocytes, macrophages, dendritic cells, CD4 þ T cells, and CD8 þ T cells; 3) protecting against ARDS and MODS by suppressing the crosstalk of viral toxicity, endothelial damage, cytokine storm, excessive immune, and microthrombus by targeting IL-6, CRP, D-dimer, and procalcitonin.
Finally, by integrating the clinical evidence and potential mechanisms of TCM for COVID-19, a panorama is drawn in Fig. 3, hoping that the effect and mechanism of TCM for COVID-19 could be viewed and understood within a single framework.

Conclusions and perspectives
Although a great quantity of review articles have been published on the topic of TCM in COVID-19 13,14,19,23,25,35,71,87,168,171,241e277 , our work offers something unique. 1) To our knowledge, this is the first review of TCM on COVID-19 that integrates evidence-based scientific findings from bedside to bench with the most comprehensive and updated literatures. 2) The pathogenesis and potential mechanisms of TCM remedy in three phases corresponding to distinct stages for COVID-19 are first systematically described and presented within a single panorama by integrating available clinical and fundamental evidence.
A valuable lesson learned from China's COVID-19 battle is that perseverance in combination of TCM and WM is the right and sensible choice 71,249 . Looking ahead, several critical issues need to be addressed as we prepare to face similar or even more serious global health threats in the future. Firstly, as the pandemic continues to evolve, the pathogenesis of COVID-19 is not fully elucidated. It is reasonable to postulate that the crosstalk of viral toxicity, endothelial damage, cytokine storm, excessive immune, and microthrombus are essential contributors for severely or critically ill patients with COVID-19, which need to be validated further. Secondly, due to a lack of in-depth understanding, there are still some skepticisms on the validity of treating COVID-19 with TCM 278e280 . More RCTs with high accuracy, clinical safety, rigorous design, and large sample, as well as in-depth mechanistic explorations with compatibility principal should be conducted to provide more reliable evidence for TCM in COVID-19 intervention, especially for the highly recommended three CPMs and three Chinese medicine formulas. Thirdly, the rehabilitative effects of TCM ought to be continuous concerned and long-term medical observed for the COVID-19 patients in recovery phase, especially for the aged. A recent paper published in The Lancet on 6-month consequences of 1733 COVID-19 patients revealed that those with severe disease discharged from hospital showed common syndromes of fatigue or muscle weakness, sleep difficulties, and anxiety or depression 281,282 . Meanwhile, a comparison of 425 non-treatment with 143 TCM-treated COVID-19 patients post discharge showed that TCM was beneficial for decreasing IL-6 and procalcitonin, and increasing red blood cell, hemoglobin, and platelet count 283 .
Overall, the purpose of this review is to scientifically and systematically evaluate the roles of TCM in combating COVID-19. The efficacies and potential mechanisms of TCM remedy in three phases of distinct stages of COVID-19 are discussed and presented comprehensively within a single panorama by integrating available clinical and preclinical evidence. Finally, although the availability of anti-COVID-19 vaccines and a global vaccination program have brought great hope for the ultimate control of the disease, threat of viral variants and new epidemics still exist. Therefore, it is of scientific value to historically and objectively summarize the contribution of TCM during the pandemic, which could be deployed in the future to combat against COVID-19 and other infectious diseases around the world.

Acknowledgments
This study was supported by grants from National Science and Technology Emergency Project (Integrated Traditional Chinese  and Western Medicine to Control COVID-19, 2020yfc0841600

Conflicts of interest
The authors declare no conflicts of interest.