Research Progress on Main Symptoms of Novel Coronavirus Pneumonia Improved by Traditional Chinese Medicine
- 1School of Pharmacy, State Key Laboratory of Characteristic Chinese Drug Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- 2Central Laboratory, Teaching Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
Novel coronavirus (COVID-19) pneumonia has become a major threat to worldwide public health, having rapidly spread to more than 180 countries and infecting over 1.6 billion people. Fever, cough, and fatigue are the most common initial symptoms of COVID-19, while some patients experience diarrhea rather than fever in the early stage. Many herbal medicine and Chinese patent medicine can significantly improve these symptoms, cure the patients experiencing a mild 22form of the illness, reduce the rate of transition from mild to severe disease, and reduce mortality. Therefore, this paper summarizes the physiopathological mechanisms of fever, cough, fatigue and diarrhea, and introduces Chinese herbal medicines (Ephedrae Herba, Gypsum Fibrosum, Glycyrrhizae Radix et Rhizoma, Asteris Radix et Rhizoma, Ginseng Radix et Rhizoma, Codonopsis Radix, Atractylodis Rhizoma, etc.) and Chinese patent medicines (Shuang-huang-lian, Ma-xing-gan-shi-tang, etc.) with their corresponding therapeutic effects. Emphasis was placed on their material basis, mechanism of action, and clinical research. Most of these medicines possess the pharmacological activities of anti-inflammatory, antioxidant, antiviral, and immunity-enhancement, and may be promising medicines for the treatment or adjuvant treatment of COVID-19 patients.
Novel coronavirus (Corona Virus disease 2019, COVID-19) pneumonia has become a massive threat to global public health. It is highly infectious, with a relatively high mortality rate, causing a sharp increase in the number of infections in a short period. Of even greater concern, is that some people infected with COVID-19 do not have obvious symptoms in the initial stage, and become potential super-communicators. More than 80,000 COVID-19 cases have been confirmed in China so far. Surprisingly, by the end of April, 2020, novel infections were almost zero, the country was recovering, and the epidemic in China was nearing completion. However, the virus is still causing panic around the world. The Director-General of the World Health Organization (WHO) declared that COVID-19 can be characterized as a pandemic on March 11, 2020 (World Health Organization, 2020). The epidemic is spreading rapidly in Italy, the United States, Spain, Germany, Iran, France, South Korea, Japan, and other countries. More than 1.6 billion confirmed cases and 650,000 cumulative deaths have been reported worldwide as of July 28, 2020. Although most of these countries have a well-developed medical and health service system, they are caught in the dilemma of shortage and exhaustion of public medical resources. At the same time, they are facing a sharp increase in the number of patients, which will lead to a series of serious consequences, such as a severe shortage of timely medical treatment, a high incidence of transition from mild to severe disease, an increasing mortality of the severely-affected patients, and a large-scale infection of medical staff. Therefore, it is of great value and significance to share the treatment experience of China in anti-epidemic to all countries in the world, so that more infected people can get treatment, and a greater public health crisis can be avoided.
At present, the transmission characteristics and clinical symptoms of COVID-19 have been relatively fully recognized. It is infectious and can be transmitted through respiratory droplets, digestive tracts, and contact; and the population is generally susceptible (Guan and Xian, 2020; Medical Administration Bureau, 2020). The incubation period is about 7 days on average and up to 14 days. Fever, dry cough, and fatigue are the main clinical manifestations. Half of the patients developed dyspnea after 8 days. Severe patients rapidly progressed to acute respiratory distress syndrome (ARDS), septic shock, metabolic acidosis, and coagulation dysfunction that are difficult to correct (Huang et al., 2020). However, there is still a lack of effective means of treatment. The research and development cycle of new drugs and vaccines is too long, so it is the first choice to seek effective treatment strategies in the existing treatment methods.
The COVID-19 belongs to the scope of “Wen Yi” in traditional Chinese medicine (TCM). And TCM has unique cognition and rich experience in diagnosis and treatment of “Wen Yi”. The integration of traditional Chinese and western medical treatments played a unique role in the prevention and treatment of SARS in 2003 (Zhang et al., 2004). It may be one of the reasons that the mortality rate in Mainland China (7%, 349/5327) was lower than that in Hong Kong, (17%, 299/1755), Taiwan (11%, 37/346), or even in the world (9.6%, 774/8096) (Wu et al., 2008). Dr. J. Kenneth Baillie, a member of the WHO panel on clinical management for COVID-19, suggested that corticosteroid treatment should be avoided, and argued that steroids have little benefit to patients, with harm outweighing the benefit. He proposed that clinicians may give priority to symptomatic and supportive treatment (Russell et al., 2020), which is highly consistent with the concept of syndrome differentiation and treatment in TCM. According to the clinical observation of 34 cases carried out by Professor Zhang Boli and others in the Wuhan Jiangxia makeshift hospital, the disappearance rate of other concomitant symptoms, the clinical cure rate, and the incidence of common type patient to severe type in the integrated group were respectively 85.3%, 91.2%, and 5.9%. Compared with conventional western medical therapy, treatment with TCM was significantly better than those in the western medicine group (38.9%, 61.1%, and 33.3%). It was found that the treatment of COVID-19 using an integration of TCM and western medicine may significantly relieve the clinical symptoms, shorten the course of the disease, and improve the clinical cure rate, which is superior to the results using western medicine alone (Xia et al., 2020). Moreover, the participation of TCM in all provinces of China is as high as 90%, which has demonstrated that TCM has made an important contribution to the prevention and control of this epidemic.
Therefore, this review aimed to summarize various Chinese herbal medicines (Table 1, Figure 1) and Chinese patent medicines that have properties which would be beneficial in treating symptoms associated with coronavirus infection (fever, cough, fatigue and diarrhea). Additionally, evidence quality evaluation criteria were established to select references suitable for this study, as shown in Table 2. Based on the existing literature, we sought drugs with scientific evidence that improve the clinical manifestations of patients with COVID-19, which may provide supplementary and alternative treatments to underdeveloped or medically under-resourced areas. More importantly, we hope to explore the potential drugs for COVID-19 and provide novel ways and ideas for the prevention and treatment of COVID-19.
Figure 1 Therapeutic effect of Chinese Herbal Medicine on the main symptoms (fever, cough, fatigue and diarrhea) of COVID-19 in the early stage.
The Mechanism of Fever
Fever is known as a characteristic defensive host mechanism, consisting of an increase in body temperature, occurring in response to various types of infectious or non-infectious stimuli(Aryal et al., 2019). Based on guidelines for the management of febrile illnesses provided by authorities such as the WHO and the Society of Critical Care Medicine and the Infectious Disease Society of America, among others, equivalent rectal temperature of ≥ 38°C or axillary temperatures of ≥ 37.5°C are indicative of fever in both adults and children (Ogoina, 2011). Fever is not only a disease, but also an important clinical manifestation of many diseases (Dewitt et al., 2017). One of the important clinical manifestations of COVID-19 is fever. From January 1 to January 28, 2020, 136 (98.6%) of 138 consecutive confirmed COVID-19 patients in the Central South Hospital of Wuhan University in China had clinical manifestations of fever. Early fever generally lasts for 5 to 7 days, during which the virus is strong, but the patient’s vital energy is not declining, approaching the turning point. Early control can directly lead to the recovery. Therefore, understanding the mechanism of fever is crucial for the diagnosis, treatment, and prognosis of COVID-19 patients.
Material Basis of Fever
Fever is usually caused by the interaction of immune cells with exogenous pyrogen and endogenous pyrogenic cytokines. The peripheral fever signal is transmitted to the central temperature regulating center through humoral and neural pathways, thus producing fever (Zeisberger, 1999). Exogenous pyrogen refers to microorganisms and their metabolites from outside, and also the most common fever activators, mainly including bacteria, viruses, fungi, parasites, mycobacteria, etc. (Laupland, 2009). The currently recognized major pyrogenic cytokines are interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) (Prajitha et al., 2018).
IL-1 represents a family of two agonists (IL-1α and IL-1β) (Conti et al., 2004). Numerous studies have demonstrated the capacity of peripherally administered IL-1α and IL-1β to evoke fever in a variety of species (Kluger, 1991; Dinarello, 1996). The current explanation for this is that IL-1 induces intermediates, prostaglandin E2 (PGE2), and cyclooxygenase 2 (COX-2), which are considered necessary downstream events which mediate peripheral IL-1-induced fever (Li et al., 2001; Ching et al., 2007). Receptors for IL-6 exist in two forms, a soluble receptor, sIL-6R, and a membrane bound receptor, IL-6R (Vallières and Rivest, 1997). Injection of IL-6 into lateral ventricle can upregulate COX-2 (Cao et al., 2001), increase the level of PGE2 in CSF, and produce fever (Dinarello et al., 1991). Recent research further confirms this view that the pyrogenic effect of IL-6 is exerted by its binding to IL-6 receptors on brain endothelial cells, and that the ligand binding in turn leads to induced expression of the prostaglandin synthesizing enzyme COX-2 via intracellular signaling involving the STAT3 pathway (Eskilsson et al., 2014). Intravenous administration of recombinant human TNF (rh TNF) into rabbits can cause fever, and also reveals that the pyrogenic potential of rh TNF is correlated with increased production of PGE2 (Nakamura et al., 1988). TNF-α is the first member of the LPS-induced cytokine cascade to appear following the injection of this exogenous pyrogen (Roth et al., 1998). Again, the mechanism is related to glutathione. It has been shown that the regulation of TNF-α biosynthesis induced by LPS is redox sensitive and requires the participation of the glutathione mediated signaling pathway. In the presence of glutathione, it can activate the activity of PGE synthase-1 (mPGES-1) to produce PGE2 (Wrotek et al., 2015).
The Humoral Transmission Pathway of Fever Signal
As mentioned above, the production of PGE2, a common connection has been found in the three kinds of important pyrogenic cytokines. Therefore, PGE2 is considered as the final medium of fever (Roth and Blatteis, 2014). It has been shown that PGE2 from peripheral or central all cause fever (Romanovsky et al., 1999; Blatteis et al., 2000). The pyrogenic cytokines released in the blood by exogenous pyrogen stimulation may play a role outside the brain by binding and activating the cytokine receptor on the capillaries located in the periventricular organs, thus leading to the release of PGE2 (Blatteis, 2006). In addition, in this pathway, the fever signal can also be carried by the PAMPS. The circulating PAMPs represented by LPS release PGE2 through arachidonic acid pathway by binding and activating TLR-4 on the capillaries of the organs around the central chamber of the BBB, and then activate the thermal neurons in the front of the hypothalamus, causing fever (Steiner et al., 2006; Turrin and Rivest, 2004). The synthesis of PGE2 is related to the activation of NF-κB or STAT3 in brain endothelial cells (Nadjar et al., 2005; Rummel et al., 2006).
The Neural Transmission Pathway of Fever Signal
The characteristics of febrile reactions are early rapid reaction and late delayed reaction. The activation of the neural pathway is believed to be another mechanism by which fever is rapidly initiated (Roth and De Souza, 2001). It has been shown that the activation of complement component 5A (C5a) immediately triggered the release of PGE2 from Kupffer cells (KC) after LPS injection (Perlik et al., 2005). PGE2 stimulates homologous receptors on the afferent vagus of the liver and binds to EP3 receptors in the OVLT/POA region, resulting in fever (Oka, 2004). PGE2 can also enhance the release of neurotransmitters, especially cAMP released by hypothalamic cells that can change the temperature setting (Dinarello, 2004). Therefore, we believe that PGE2, a rapid fever signal, plays a triggering role in the initial stage of fever through the neural pathway, while the fever signal in the humoral pathway plays a more important role in maintaining fever (Figure 2).
Fever is caused by the interaction of immune cells with exogenous pyrogen and endogenous pyrogenic cytokines. The most widely studied pyrogenic cytokines include 1L-1, IL-6, TNF-α, IFNs, and CNTF. After the virus and other pathogens infect the body, they can activate NF-κB to cause the release of TNF-α, IL-1, IFNs, chemokine, etc., which can mediate the aggregation and infiltration of a large number of immune cells into the lung tissue, activate the signal transduction pathway in the cells, start the cascade reaction of waterfall inflammation, release the amount of cytokines, and continuously activate more inflammatory cells to form a vicious cycle. It eventually leads to a cytokine storm. Chen et al. (2020) analyzed 99 confirmed cases of COVID-19, and proposed that the virus spreads through respiratory mucosa to infect other cells, induce a cytokine storm in vivo, and produce a series of immune responses. Therefore, it is essential for in the treatment of COVID-19 to inhibit excessive immune cell activation and cytokine production. TCM and its preparations can achieve an antipyretic effect by inhibiting 1L-1, IL-6, TNF-α, and other pyrogenic cytokines, and also can indirectly achieve the effect of initial treatment of COVID-19 by inhibiting the cytokine storm.
Single Chinese Herbal Medicine
Gypsum Fibrosum is a variety of fibrous crystalline aggregate of hydrous calcium sulfate. Although its main component is hydrous calcium sulfate, it also contains inorganic elements such as sodium, magnesium and iron. Wang et al. (2009) studied the antipyretic activity of Gypsum Fibrosum by intraperitoneal injection of LPS in rats. The body temperature of rats with fever decreased significantly after the intragastric administration of Gypsum Fibrosum extract (0.8 g/ml), indicating that it exerts an antipyretic effect; furthermore, it was speculated that its active components may be the inorganic elements. Calcium is the main ion component of Gypsum Fibrosum. Following the action of gastric acid, part of the gypsum decoction can be transformed into soluble calcium, which can then be absorbed into the bloodstream through the intestines, increasing the calcium ion concentration in the blood, so as to regulate the temperature center and relieve the fever. Zhou et al. (2012) injected a 15% yeast suspension subcutaneously into rat backs, resulting in fever. The rats were infused with gypsum suspension for 7 days (10 g/kg). The results showed that gypsum could play an antipyretic role by reducing the synthesis of PGE2. Gypsum Fibrosum is usually used with Anemarrhena Rhizoma in clinic as antipyretic. One of the most classical prescriptions is Baihu Decoction. When they are used together, it can enhance the dissolution rate of calcium ion and the antipyretic effect of Gypsum Fibrosum (Jia et al., 2013).
Bupleuri Radix is the dry root of Bupleurum chinense DC and Bupleurum scorzonerifolium Willd. Phytochemical studies reveal that this plant contains essential oils, triterpenoid saponins, polyacetylenes, flavonoids, lignans, fatty acids, and sterols (Yang et al., 2017). In the fight against SARS, it once appeared on the treatment list and attracted scientific attention (Zhao et al., 2007). Bupleuri Radix has good antipyretic effect and has been widely used in clinic. The main components of essential oil and saikosaponin play the role of antipyretic. Chen et al. (2010) injected ET into the normal rabbit to induce fever. The essential oil was extracted from Bupleuri Radix as raw material to prepare the gel, which was sprayed into the nasal cavity of the febrile rabbits. Once 0.2 ml was given, the temperature dropped 0.5°C after 5 h, and the temperature decreased by 0.8°C after 24 h. The results showed that the essential oil of Bupleuri Radix had an antipyretic effect which could play an antipyretic role by reducing the concentration of cAMP in the cerebrospinal fluid of febrile rabbits. Jin et al. (2014) found the antipyretic effect of essential oil and saikosaponin of Bupleuri Radix. The results demonstrated that the antipyretic effect of the treatment group was significant as compared with the control group. Some studies have shown that saikosaponin can significantly reduce the expression of TNF-α, IL-1β, IL-6, and other cytokines. It can also inhibit the NF-κB signaling pathway by inhibiting the phosphorylation of extracellular signal regulated kinase (downstream of TNF-α) (Kim et al., 2015). In conclusion, Bupleuri Radix may play an antipyretic role by reducing cAMP concentration and inhibiting the expression of TNF-α, IL-1β, IL-6, and the NF-κB inflammatory signaling pathway. However, Bupleuri Radix could lead to hepatotoxicity in high doses and with long-term use (Yang et al., 2017).
The commonly used Chinese herbal medicines as antipyretics are listed in Table 3 in addition to the above.
Chinese Patent Medicine
Shuang-huang-lian series preparations are made from Lonicera Japonica Flos (Jin-yin-hua), Scutellariae Radix (Huang-qin), and Forsythiae Fructus (Lian-qiao). The existing clinical randomized controlled trials demonstrate that Shuang-huang-lian preparations exhibit a certain antipyretic effect. Although it contains a large number of active ingredients, only chlorogenic acid, baicalin, and forsythin have been officially included in the quality control standard (Gao et al., 2014). Baicalin is a type of flavonoid extracted from Scutellariae Radix, which has an obvious antipyretic effect. In vivo studies demonstrated that the antipyretic effect of baicalin was related to a decrease in TNF-α, IL-1 β, IL-6, and other cytokines in serum, hypothalamus, and CSF (Li and Ge, 2010).In addition, baicalin inhibited the LPS-modulated upregulation of TLR4 mRNA and protein expression and TNF-α and IL-1β mRNA expression in rats, and downregulated NF-κB activation with simultaneous decreases in TNF-α and IL-1β protein expression (Ye et al., 2015). Forsythoside A (FTA), a monomer of phenethyl alcohol glycosides extracted from Forsythiae Fructus. A previous study suggested that FT-A significantly downregulated TRPV1 expression in the hypothalamus and DRG of yeast-induced pyrexia mice. TRPV1 is a non-selective cation channel gated by noxious heat, playing major roles in thermoregulation. FT-A alleviated fever of yeast-induced pyrexia mice via suppression of TRPV1 expression and activation, inhibition of MAPKs, activation of the hypothalamus and DRG, and subsequently decreased secretion of pyretic cytokine as PGE2 and IL-8 (Liu et al., 2017).In addition, FT-A can significantly enhance the phagocytic function of macrophages in LPS-stimulated ra-w264.7 cells and reduce the secretion of TNF-α (Guan et al., 2013). FT-A can also inhibit TNF-α and NF-κB by blocking the LPS/TLR4 signaling pathway (Zeng et al., 2017). It is suggested that FT-A can also inhibit the LPS/TLR4 signaling pathway and reduce TNF-α secretion in order to achieve an antipyretic effect. In a randomized controlled trial to systematically evaluate Shuang-huang-lian injection in the treatment of acute upper respiratory tract infection, it was found that Shuan-ghuang-lian can significantly reduce the fever caused by acute upper respiratory tract infection (Zhang et al., 2013).In addition, Shuang-huang-lian is widely used in the clinical treatment of infectious diseases such as pneumonia, influenza, acute tonsillitis and acute pharyngitis (Song et al., 2000; Chen et al., 2002).
The commonly used Chinese patent medicine as antipyretics are shown in Table 4.
The Pathophysiological Mechanism of Cough
Cough is a common respiratory disease and one of the early symptoms of bronchitis, pneumonia, asthma, and pertussis (Swarnkar et al., 2013). It is a natural protective mechanism, which helps to clear the secretion of the respiratory tract and prevent harmful particles from entering the respiratory system (Song et al., 2015). From another perspective, cough is one of the ways to enhance the transmission of the virus to the next victim, so inhibiting cough can help reduce the transmission between people (Morice et al., 2015). Cough is usually divided into three types: acute cough (lasting for less than three weeks), subacute cough (lasting for three to eight weeks), and chronic cough (persistent greater than eight weeks) (Kim et al., 2016). Acute cough is commonly associated with viral upper respiratory infection (O’Connell, 1998). Acute infection and inflammation (such as bronchitis or pneumonia) may cause dry cough in some cases (Urso and Michaels, 2016). The cough caused by the COVID-19 lasts for less than 3 weeks, and most of them do not produce sputum, which is actually an acute dry cough.
In general, cough is characterized by changes in the normal respiratory pattern caused by reflex, which is mediated by stimulation of extrapulmonary vagal afferent nerves and the brainstem (Mahashur, 2015). The pathophysiological mechanism of a cough may be related to the following two aspects: sensitizing cough receptors by increasing inflammatory mediators, such as bradykinin, tachykinin or prostaglandin, these sensitive cough receptors will cause an increase in the cough reflex; inducing or enhancing cough sensitivity by contraction of bronchial smooth muscle. The molecular mechanism involved in the former may be regulated by a series of G-protein coupled receptors (GPCRs). The activation of GPCRs has both inhibitory effects (e.g. β2-adrenoceptor and cannabinoid receptors), and excitatory effects (e.g. EP3 and bradykinin B2 receptors) on sensory nerves and the cough reflex (Maher et al., 2011). Prostaglandin E2 and bradykinin can activate airway sensory nerve through EP3 and B2 receptors, and mediate its action through TRPV1 and TRPA1 receptors. The activation of β2-adrenergic and cannabinoid CB2 receptors can inhibit sensory nerves and cough. The main receptors associated with cough reflex are shown in Table 5.
Postinfectious cough may occur in the following three ways: 1) The viral infection causes dripping of nasal secretions or produces inflammatory mediators, which lead to an inflammatory reaction of the bronchial mucosa. The inflammatory mediators act on the sensory nerve endings of the airway, increasing the sensitivity of the cough receptors. 2) The virus increases the activity of neuraminidase, destroys the cholinergic M receptor, reduces the affinity with the M receptor, and finally leads to the hyperfunction of cholinergic nerve, which increases the airway responsiveness. 3) By upregulating the expression of neuropeptides, the virus induces neurogenic inflammation, which affects the excitability of afferent nerves and indirectly stimulates cough receptors (McGarvey et al., 2014; Schnoeller et al., 2014). Therefore, the treatment of a cough after infection requires controlling airway inflammation, and reducing airway hyperresponsiveness and cough sensitivity.
Cough is not only one of the main symptoms of COVID-19, but also one of the main routes of transmission of SARS-CoV-2. The virus causes upper respiratory tract infections and pulmonary inflammation, which results in coughing. Many Chinese herbal medicines like Glycyrrhizae Radix et Rhizoma, Asteris Radix et Rhizoma, Farfarae Flos not only have excellent antitussive effect, but also have anti-inflammatory activity. They may reduce airway or pulmonary inflammation by mediating inflammation-related pathways such as NF-κB and reducing airway inflammatory factors. There is a strong association in hyperinflammatory responses in patients with severe COVID-19 infection, so the intervention of these the TCM substance in the early stage of COVID-19 may prevent the disease from mild to severe. TCM possesses the potential effect of synergistic treatment of COVID-19 through multi-components, multi-targets, and multi-ways, which is also in line with the concept of holistic treatment of TCM.
The treatment of a cough includes: blocking the level of corresponding receptor of the cough reflex; covering the irritated mucosa in the mouth and throat with mucilaginous herbs, and protecting cells from local stimulation of the mouth or throat, so as to relieve the cough reflex (Fink et al., 2018); controlling airway inflammation and reducing airway hyperresponsiveness (Figure 3).
Single Chinese Herbal Medicine
Glycyrrhizae Radix et Rhizoma
Glycyrrhizae Radix et Rhizoma, the dried root and rhizome of the legume glycorrhiza urensis Fisch., glycorrhiza inflata Bat., glycorrhiza glabra L., is one of the oldest and most popular herbs in the world, exhibiting anti-inflammatory, antiviral, antibacterial, antioxidant, and anticancer activities, immunomodulatory pharmacological activity. It is commonly used in the treatment of cough and lung disease, bronchitis, and gastric ulcer (Pastorino et al., 2018). It contains mainly flavonoids, triterpenoid saponins and glycosides (Hosseinzadeh and Nassiri-Asl, 2015). Among them, the active components with an antitussive effect may be liquiritin apioside, liquiritin, liquiritigenin, 18β-glycyrrhetinic acid and its derivatives, and polysaccharides (Anderson and Smith, 1961; Kamei et al., 2005; Kuang et al., 2018). It has been reported that 50% methanol extract (100 mg/kg) and 70% ethanol extract (800 mg/kg) of Glycyrrhizae Radix et Rhizoma have significant inhibitory effects on the cough reflex in a capsaicin-induced guinea pig cough model and sulfur dioxide gas-induced mouse cough model respectively (Kamei et al., 2003; Jahan and Siddiqui, 2012). In addition, the antitussive effect of the water-extracted polysaccharide fraction (arabinose (52%), galactose (22%), rhamnose (6%) and fucose (2%)) in the citric acid-induced cough model of guinea pigs was even stronger (81%) than that of codeine (62%) at a dose of 50 mg/kg (Saha et al., 2011; Nosalova et al., 2013). Mucus and bioadhesion may be two of the reasons behind its pharmacodynamic effect. The water-extracted polymer fraction of Glycyrrhizae Radix et Rhizoma exhibits bioadhesion to the epithelial mucosa, forming the polysaccharide layer in airway mucus, protecting cells from local oral or pharyngeal stimulation, indirectly affecting the sensitivity of cough receptors and inhibiting cough. Polysaccharides also have the ability to replenish water to epithelial cells, reducing dry cough and supporting phlegm, and increasing mucus secretion through vagal reflex (Nosalova et al., 2013). In addition, it was shown that the cough suppressant effect of liquiritin apioside may depend on the peripheral (regulation of the ATP sensitivity K+ channel) and the central mechanism (regulation of the 5-HT system), a possible additional pathway for the cough suppressant effect of Glycyrrhizae Radix et Rhizoma, which may be another way for Glycyrrhizae Radix et Rhizoma to play an antitussive role (Kamei et al., 2003).
Asteris Radix et Rhizoma
Asteris Radix et Rhizoma consists of the dried roots and rhizomes of Aster tataricus L. f. In the clinical application of TCM, it has been proved to be an effective medicine for the treatment of phlegm cough disease, which has a history of thousands of years. Aster extract exhibits anti-inflammatory, anti-oxidation, anti-tumor and other biological activities. Asteris Radix et Rhizoma is rich in chemical components, including terpenes, flavonoids, sterols, cyclopeptides, etc. (Xu et al., 2013). Among them, the main active components of antitussive effect may be asterone, episorbitol, caffeoylquinic acids, astersaponins, aster peptides (Yu et al., 2015), luteolin, and quercetin (Yang et al., 2016). The antitussive effect of Asteris Radix et Rhizoma has been reported many times. Ren et al. observed the antitussive effect of different polar segments of Asteris Radix et Rhizoma through ammonia liquor-induced mice cough model, and the results showed that petroleum ether group, final mother liquor group and 75% ethanol group (5 g/kg) could prolong the latent period of mice cough, inhibit the frequency of cough within 2 min, and n-butanol group had significant antitussive effect, which indicated that aster Asteris Radix et Rhizoma had antitussive effect (Ren et al., 2015). Recently, it was found that in an ammonia-induced mouse cough model, the cough frequency of mice treated with 50% ethanol fraction (40 and 80 mg/kg) eluted from 70% ethanol extract was significantly reduced by 42.9% and 56.5% (both (p <0.001), cough latency increased by 50.5%, 70.9% (both p <0.01). Through further analysis, it is speculated that eliminating or reducing tracheal inflammation (a major source of cough and sputum) through the TLR4-mediated NF-κB pathway may be the mechanism behind its antitussive effect (Yu et al., 2015).
Farfarae Flos, flower bud of Tussilago farfara L., is widely used in the treatment of cough, tuberculosis and other diseases (Zhao et al., 2014). Farfarae Flos possesses a variety of pharmacological activities, such as anti-inflammatory, antioxidant, anticancer, neuroprotective activities (Lee et al., 2014; Lee et al., 2018). Extensive phytochemical studies have shown that Farfarae Flos contains a large number of components, including volatile oils, phenolic acids, sterols, alkaloids, terpenes, etc. Besides, alkaloids, flavonoids, terpenes and saponins are considered to exert antitussive effects (Han et al., 2016). A series of studies have found that the monomeric components with antitussive bioactivity may be 4,5-O-dicaffeoylquinic acid, caffeic acid, chlorogenic acid, 3,5-O-dicaffeoylquinic acid, 3,4-O-dicaffeoylquinic acid, rutin, kampferol analogues, 2,2-dimethyl-6-acetylchromanone, tussilagone, Bauer-7-ene-3β,16α-diol, β-sitosterol, and sitosterone (Li et al., 2012; Wu et al., 2016; Li et al., 2018a; Yang et al., 2020). The antitussive effect of Farfarae Flos has been reported in an animal cough model induced by ammonia. Its aqueous extract at the dose of 2.8 g/kg significantly prolonged the latent period of expectoration and reduced the cough frequency in mice (Li et al., 2012). Further study found that the antitussive effect of Farfarae Flos may be related to four pathways, including the alterations of valine, leucine and isoleucine biosynthesis, pyruvate metabolism, glycerolipid metabolism, phenylalnine, tyrosine and tryptophan biosynthesis, and the imbalance of these pathways is related to a variety of neurological and inflammatory diseases (asthma, emphysema, chronic obstructive pulmonary disease (COPD)) (Li et al., 2018a). In addition, caffeoylquinic acid in Farfarae Flos may inhibit the release of PGE2 in raw 264.7 cells and mediate the cough response by inhibiting leukocytosis or decreasing LPS induced up regulation of COX-2 protein and mRNA levels (Wu et al., 2016). What is more, a network pharmacology study has found that the active components of Farfarae Flos involve 18 targets such as interleukin-2 (IL-2), COX-2, human ribonuclease A3 (RNase3), and biological processes and metabolic pathways related to signal transduction, inflammation and energy metabolism (Li et al., 2018b). These researches have provided a scientific basis for further elaboration of the mechanism of cough and phlegm elimination of Farfarae Flos. Farfarae Flos is safe and effective in the traditional dose range, but the potential toxicity due to the emergence of pyrrolidine alkaloids also needs to be paid attention (Liu et al., 2020).
The commonly used Chinese herbal medicines for cough are listed in Table 6 in addition to the above.
Chinese Patent Medicine
Ma-xing-gan-shi-tang (MXGST) is composed of four Chinese herbal medicines, Ephedrae Herba, Armeniacae Semen Amarum, Glycyrrhizae Radix et Rhizoma, and Gypsum Fibrosum. It is a commonly used antitussive prescription in China. It has been made into a variety of prescription preparations, including Maxingzhike tablets, Maxingganshi soft capsules, Maxingganshi concentrated granules, Maxingzhike syrup, Maxingganshi mixture, etc. Ephedrine, amygdalin, ephedrine, glycyrrhizic acid, and amygdalin are considered as the main active components (Wang et al., 2016). A series of clinical studies have shown that MXGST is widely used in the treatment of cough, asthma, pneumonia, COPD, and other diseases (Chen et al., 2013; Wang et al., 2014; Lin S. K. et al., 2016; Liao et al., 2017). In an animal experimental study, Lin et al. adopted citric acid-induced cough in guinea pigs cough model to study the pharmacological effect of MXGST water extract in clinical application, and evaluated its subacute toxicity, and found that MXGST water extract (0.4, 1.0 g/kg) has a significant dose-dependent antitussive effect on guinea pigs, which is a safe and effective traditional Chinese medicine prescription (Lin Y. C. et al., 2016). In addition, this study also proved that MXGST water extract has an antipyretic effect on LPS-induced fever rats, which suggests that MXGST may be a promising drug for the treatment of COVID-19. Further studies have found that the antitussive mechanism of MXGST is related to the partial relaxation of bronchial smooth muscle by blocking the acetylcholinergic receptor and histaminergic receptor (Lin Y. C. et al., 2016). Another study showed that MXGST may stimulate the β2-adrenoceptor of bronchial smooth muscle and has an anti-inflammatory effect that inhibits neutrophils from entering the airway (Kao et al., 2001). In terms of composition, the antitussive mechanism of MXGST may be related to the sympathetic α- and β-adrenoceptors activated by ephedrine alkaloids and amygdalin inhibit the central cough center (Miyagoshi et al., 1986).
The commonly used Chinese patent medicines with antitussive effects are shown in Table 7.
Pathological Process and Possible Pathogenesis
Pathological fatigue refers to fatigue caused by a certain disease, and it is also a symptom of the onset of the disease (Matura et al., 2018). It will cause a sub-healthy state of the decline of the function of body, which should be paid great attention (Wang et al., 2018). This kind of fatigue is common in chronic fatigue syndrome (CFS). Some scholars have proposed several hypotheses about the causes and mechanisms of CFS, such as viral infection, immune dysfunction (Yang et al., 2010), and neuroendocrine system disorders (Norheim et al., 2011; Cho et al., 2013). Among them, virus infection is an important factor causing CFS.
A large number of clinical observations have found that the clinical symptoms of CFS are very similar to the symptoms of viral infections, such as fever, sore throat, and muscle swelling when some CFS patients develop symptoms (Collin et al., 2018). At present, there is no firm evidence that CFS is necessarily related to viral infections. The theoretical basis for CFS caused by viral infections is not sufficient, and experts and scholars have not reached a consensus. However, experts agree on this point that virus infection will further cause an imbalance in the immune system of the body, resulting in damage to the central nervous system and muscle structure (Nair and Diamond, 2015).
Pathological Fatigue and Immune Function
Brenu et al. (2010) used flow cytometry and found that compared with normal healthy people, granulocyte respiration broke out in patients with CFS, and natural killer (NK) cell expression of CD56 decreased significantly. Nakamura et al. (Nakamura et al., 2010) found that the anti-inflammatory factor interleukin 10 (IL-10) in patients with CFS is higher than that in normal people and the levels of immunoglobulins IgA, IgG, and IgM are disordered. This suggests that immune dysfunction may be one of the mechanisms of CFS. In addition, FIL-1 is a pro-inflammatory cytokine that contains two receptor agonists that induce the expression of other pro-inflammatory factors: IL-1α and IL-1β (Lampa et al., 2012). Cyclooxygenase-2 (Coxoxy-2) inhibitors and inducible nitric oxide synthase (iNOS) inhibitors are targets for the treatment of pain, depression, and fatigue (Von Ah et al., 2008). IL-1 causes expressions of COX-2 and iNOS (Maes, 2009). Therefore, elevated IL-1 levels may be related to fatigue (Miaskowski et al., 2012). At the same time, it was found that in human and animal models affected by CFS, levels of IL-1, IL-6, and TNF-α were also increased (Reyes-Gibby et al., 2013). These pro-inflammatory cytokines can signal the central nervous system and produce behavioral symptoms such as fatigue.
IL-2 is a multifunctional small molecule protein with high activation. It is an immunoregulatory lymphokine produced by activated CD4+ T cells and a small amount of CD8+ T cells. It can enhance the activity of NK cells and CD + T cells, thereby inducing IL-1B (Almeida et al., 2002). The production of receptors produces λ-INF, which maintains the growth of T cells in vitro and activates a variety of immune cells. The level of IL-2 reflects the functional status of T cells, and its ability to produce is an important indicator of the immune function of the body’s cells (Hilgers and Frank, 1994). Therefore, a decrease in the level of IL-2 may produce a fatigue state.
Pathological Fatigue and Neuroendocrine System Disorders
The occurrence of CFS is also closely related to changes in the neuroendocrine system (You et al., 2011). The clinical manifestations of fatigue, depression, bone, and muscle pain in patients with CFS are similar to those in patients with decreased adrenal function (Klimas and Koneru, 2007). The hypothalamus-pituitary-adrenal (HPA) axis contains neurons that synthesize corticotropin releases hormones (CRH) (Tak et al., 2011). CRH regulates adrenocorticotropic hormone (ACTH) through the pituitary. ACTH stimulates the synthesis of corticosteroids such as cortisol or corticosterone through the adrenal cortex. HPA axis disorders often occur in CFS. Inflammatory mediators cause excessive release of corticosterone, which can cause chronic pain, immunosuppression and chronic fatigue. According to Zhao’s research (Zhao, 2010), chronic compound stimulation can lead to a decrease in 5-HT levels in the hippocampus and occipital cortex, disrupt the balance of the hypothalamus-pituitary-adrenal axis, and disrupt the internal environment and cause CFS (Katafuchi, 2006). In addition, cortisol is one of the main effective hormones of the adrenal system acting on peripheral tissues. It was found that cortisol levels in CFS patients were significantly elevated, and the pathogenesis of CFS was related to abnormal HPA negative feedback regulation or excessive activation (Luo et al., 2019). CFS patients have a low level of serum cortisol during steady state, and often experience physical or emotional stress prior to the onset of the disease, which in turn activates the hypothalamic-pituitary-adrenal axis system, leading to increased release of cortisol and adrenocorticotropic hormone. It affects the immune, nervous and other systems, and then produce fatigue symptoms. Therefore, reducing the release of glucocorticoids such as cortisol by adjusting the HPA axis may alleviate the development of pathological fatigue.
Pathological Fatigue and Oxidative Stress
The body will produce a large amount of oxygen free radicals during metabolism, which can attack polyunsaturated fatty acids in biofilms, trigger lipid peroxidation reactions, and thus form lipid peroxides, such as malondialdehyde (MDA), resulting in damage to cells and tissues. The level of superoxide dismutase (SOD) activity indirectly reflects the body’s ability to scavenge oxygen free radicals, while the level of MDA indirectly reflects the severity of the body’s cells attacked by free radicals (Hui et al., 2014). MDA is a lipid peroxide formed by free radical attack on polyunsaturated fatty acids in the biofilm to trigger lipid peroxidation. The increase of free radicals will lead to damage to the integrity of the biofilm, increase permeability of the biofilm, release extracellular of enzymes, make electrolyte imbalance, decrease enzyme activity and cell function, resulting in fatigue (Chen and Yan, 2005). At the same time, the body also has antioxidant systems including: SOD, glutathione (GSH), CAT, etc. At present, studies have shown that the mental fatigue of CFS is related to the large amount of oxygen free radicals generated in the brain and the antioxidant system is inhibited (Logan and Wong, 2001). Therefore, it is of great significance to seek ways to improve the antioxidant capacity of the body for the treatment of CFS.
It is known that the early pathogenesis of diseases such as COVID-19, SARS, and MERS are immunodeficiency and excessive oxidative stress. These two factors are the common pathological basis for death. For example, peripheral blood flow cytometry was performed on the lung tissue of COVID-19 dead patients. The results showed that CD4+ and CD8+ T cells were significantly reduced, T cells were overactivated, and CCR4+, CCR6+, Th17 in CD4+ T cells increased, and CD8+T cells are rich in cytotoxic particles, which activate the immune system and induce a large number of immune cells to infiltrate into the lung tissue. Other studies have shown that viral infections can directly lead to increased ROS production in alveolar epithelial cells, GSH, SOD, and glutathione peroxidase (GSH-Px) activity is reduced, causing severe oxidative stress in cells, which further aggravating acute lung injury.
These two factors happen to be the same as the causes of fatigue. We hope that the drugs can also treat coronavirus while relieving fatigue symptoms. Therefore, based on the basic pathophysiological mechanism of COVID-19, this section focuses on summarizing the anti-inflammatory and antioxidant intervention strategies of Chinese herbal medicines to specifically block or reverse its pathological development process. This is of great significance for improving the clinical cure rate and reducing the case fatality rate.
Single Chinese Herbal Medicine
Astragali Radix is the dried root of the legume Mongolian Astragalus membranaceus (Fisch.) Bge.var.mongholicus (Bge.) Hsiao or Apodium Astragalus membranaceus (Fisch.) Bge. Its main ingredients are saponin, flavonoids, polysaccharides, and amino acids (Zhang H. et al., 2014). Huang et al. (2017) administered 40 male pathologically-fatigued BALB/c mice with astragalus polysaccharides (APS) via intragastric administration every morning at 8:00 am for 28 days. The required APS was dissolved in 2.0 mL of normal saline. Chronic fatigue can significantly reduce mRNA levels of mitochondrial fusion-related proteins Mfn-1, Mfn-2, and Opa-1 in mice, while mRNA levels of mitochondrial division-related protein Drp-1 significantly increase, indicating that chronic fatigue can make mice mitochondrial fusion-split imbalance in skeletal muscle, eventually causing mitochondrial dysfunction. APS can improve mitochondrial autophagy in skeletal muscle cells by reducing the level of oxidative stress in tissues. In addition, APS can stimulate the origin of mitochondria, maintain the mitochondrial fusion-split balance, improve mitochondrial dysfunction, and ultimately improve cell energy metabolism, thereby increasing the ability of mice to resist chronic fatigue.
Ginseng Radix et Rhizoma
Ginseng Radix et Rhizoma consists of the dried roots and rhizomes of the genus Panax ginseng C.A.Mey. The main components of ginseng are saponins, polysaccharides, proteins, volatile oils, amino acids, and flavonoids (Lee et al., 2002). Song (2014) Treated 30 male SD rats after successful CFS modeling with ginsenoside aqueous solution 60 mg/kg/d for 6 consecutive weeks. The results showed that compared with the model group, the SOD and GSH activities in the ginsenoside group were significantly increased, and the MDA content was significantly reduced, with a very significant difference (p <0.01). This shows that the increase of free radicals will lead to the damage of the integrity of the biofilm, the increase of the permeability of the biofilm, the release of enzymes inside and outside the cell, leading to abnormal conditions inside and outside the cell, electrolyte imbalance, and decline in cell function, which will cause fatigue. Therefore, ginsenoside Rg1 is thought to reduce the production of the peroxidation product MDA, increase the activity of antioxidant enzymes, improve the antioxidant capacity of nerve cells, reduce the generation of free radicals, and thus increase the ability to resist CFS (Soares et al., 2007).
The commonly used Chinese herbal medicines for fatigue are listed in Table 8 in addition to the above.
Chinese Patent Medicine
Angelica Decoction for Replenishing Blood, is composed of Astragali Radix and Angelicae Sinensis Radix in a 5:1 ratio. The primary chemical components of Astragalus are saponins, flavonoids, and polysaccharides; the main chemical components of angelica are volatile oils, organic acids, and polysaccharides. Liu et al. modeled 56 SD male rats (180–220 g) by tying an iron block weighing approximately 10% of the rat’s own weight to its tail, and then placing it into a transparent water tank with a depth of 30 cm, at a constant temperature of 25 degrees Celsius. The rats were forced to swim exhaustively. When the rats’ swimming movements were uncoordinated or their heads sank into the water surface within 10 s, they could not return to the water surface, and the 15.00 g/kg drug was administered to the stomach for 29 consecutive days after modeling successfully. The results showed that compared with the blank group, the Angelica Decoction for Replenishing Blood could significantly reduce the levels of TNF-α and IL-6 in the serum (p < 0.01). This demonstrates that CFS can produce inflammation in the body, and Angelica Decoction for Replenishing Blood can effectively alleviate this situation. At the same time, the activity of SOD in the serum of angelica buxue decoction group increased significantly (p <0.01), suggesting that a large number of free radicals in CFS rats may lead to oxidative stress. Angelica buxue decoction can effectively remove free radicals in the body and alleviate the oxidative stress reaction of the body. Threonine is an essential amino acid. When it is lacking, the synthesis of immunoglobulins and the production of T-lymphocytes and B-lymphocytes will be affected, thereby upsetting the body’s immune functioning. Serine is involved in the production of immune hemoglobin and antibodies, and plays an important role in the maintenance of the immune system. Metabolomics results show that Angelica Decoction for Replenishing Blood can improve the thymic degenerative changes by increasing the levels of threonine and serine, promote the differentiation and maturation of white blood cells, and block the NF-кB, JNK, and p38MAPK signaling pathways to regulate the immune system and improve chronic fatigue syndrome (Liu et al., 2011).
The commonly used Chinese patent medicines for fatigue are shown in Table 9.
The Mechanism of Diarrhea
Diarrhea, a common digestive disease, is caused by a variety of pathogens and other factors. Diarrhea results from the abnormal absorption or transport of water and electrolytes in the intestine. Any substance, whether infectious biological factor, noninfectious humoral factor, or some drugs, which blocks the active absorption or activation of active secretion of the intestine, will cause diarrhea. Diarrhea is also caused by the increase of osmotic gradient or hydrostatic pressure in intestinal tissue. Infection with bacteria, viruses, or parasites is the main cause of diarrhea, which is also known as infectious diarrhea or gastroenteritis (Thapar and Sanderson, 2004; Schlossberg, 2015). The occurrence and spread of infectious diarrhea are considered to be the results of poor sanitation. Other causes of diarrhea include hyperthyroidism, lactose intolerance, inflammatory bowel disease, drug effects, and irritable bowel syndrome.
Clinically, quite a few patients infected with COVID-19 experienced diarrhea in the early stage or in the course of the disease, which is mostly self-limiting and varies in severity. In the course of treatment, it was also found that diarrhea caused by COVID-19 mainly occurred after antiviral treatment. Infectious virus particles were isolated from feces of some patients, which increased the possibility of feces-oral transmission. The main causes of diarrhea were considered to be gastrointestinal mucosal injury or gastrointestinal dysfunction caused by COVID-19 and adverse reactions caused by the use of antiviral drugs. The mechanism may be related to the rapid and massive production of various cytokines such as TNF-, IL-6, IL-1, and IL-8 in body fluids when patients were infected with COVID-19.
TCM has thousands of years of valuable experience in the treatment of diarrhea. Many antidiarrheal TCM substances, such as Pogostemon Herba, Atractylodis Rhizoma, and Citri Reticulatae Pericarpium, may prevent and treat diarrhea by TNF, IL-6, VIP, and NF-κB. Some of them can also enhance the anti-virus ability of the body by enhancing the immunity, and protect various organs at the same time. Patients with mild conditions can recover quickly by strengthening their own immunity and eliminating the virus by the immune mechanism.
Single Chinese Herbal Medicine
Pogostemon Herba is a dry aboveground part of the Pogostemon cablin (Blanco) Benth. The chemical constituents of Pogostemon Herba can be divided into two categories: volatile components (patchouli oil) and non-volatile components, including monoterpenes, and sesquiterpenes, flavonoids, organic acids, and alkaloids. A large number of studies showed that the main components of patchouli oil include patchouli alcohol and patchouli ketone. Chen et al. (1998) found that the water extraction and oil-free extraction can inhibit the gastrointestinal propulsion of the normal mice and treat diarrhea in mice caused by Sennae Folium, suggesting that two extractions can inhibit diarrhea by inhibiting the excessive peristalsis of the small intestine. Therefore, the effective component of Pogostemon Herba to improve intestinal function may be water-soluble. Wu et al. (2020) established a rat model of intestinal mucositis via intraperitoneal injection of 5-fluorouracil, and intragastrically administrated Patchouli alcohol (PA) (10, 20, and 40 mg/kg) to evaluate the effect of PA on intestinal mucositis. The results showed that PA could effectively improve diarrhea in intestinal mucositis rats, preliminary confirming PA efficacy. Further experiments revealed that PA not only decreased the levels of TNF-α, IL-1β, IL-6, and MPO but also increased the level of IL-10 significantly. In addition, the expression of mucosal barrier proteins and the microbiota community were also improved after PA treatment in diseased rats. Hence, PA may prevent the development and progression of intestinal mucositis by improving inflammation, protecting the mucosal barrier, and regulating intestinal microbiota.
Citri Reticulatae Pericarpium
Citri Reticulatae Pericarpium, commonly referred to as “Chen-pi” in Chinese, is an orange-colored Citrus reticulata Blanco fruit peel. Up to now, approximately 140 chemical components have been isolated and identified from Citri Reticulatae Pericarpium, including alkaloids, flavonoids, and essential oils. And among them, flavonoids were considered to be the primary bioactive constituents of herbal medicine, mainly including hesperidin and nobiletin. The Citri Reticulatae Pericarpium decoction can alleviate diarrhea of rats caused by Sennae Folium. Guan (Guan et al., 2002) found that the Citri Reticulatae Pericarpium decoction (6.25%, 12.5%, 25%, 50%, 75%, 100%) can significantly inhibit the spontaneous activity of the isolated duodenum of rabbits, reduce the contractility and tension, and show a dose-response relationship. It has an antagonistic effect on the enhancement of ileal contraction induced by acetylcholine, BaCl2, and 5-HT. Moreover, it may further relax the isolated rabbit intestines which first used atropine, epinephrine and dopamine, but the tension decreased. It is suggested that the inhibitory effect of hesperidin on intestinal motility may not be the main component of Citri Reticulatae Pericarpium. The inhibitory effect of Citri Reticulatae Pericarpium is mediated by the cholinergic receptor, 5-HT receptor, or directly on smooth muscle.
Atractylodis Rhizoma is derived from the dried roots of Atractylodes lancea (Thunb.) DC. and Atractylodes chinensis (DC.) Koidz. The main components in its essential oil are atractylol (a mixture of β-cineole and atractylol), atractylone, atractylon, etc. Ancient Chinese doctors thought that Atractylodis Rhizoma could be used for dampness blocking, abdominal distention, diarrhea and so on. Modern research has found that Atractylodis Rhizoma has anti-diarrhea and anti-inflammatory effects. Wang et al. (2002) found that β-cineole can significantly improve the physical signs and inhibit the gastrointestinal movement of spleen deficient mice. β-eucalyptol has an obvious antagonistic effect on the acceleration of gastrointestinal motility induced by neostigmine loaded mice, and also on the gastrointestinal motility induced by Rhei Radix et Rhizoma. Research has shown that (Chen et al., 2018) the N-butanol portion of Atractylodis Rhizoma can significantly improve the level of serum anti-inflammatory factor IL-10 and AQP3 of colon mucosa, reduce the level of TNF-α and diarrhea index, relieve the inflammation of the digestive tract, promote the absorption of water by the colon, and play a role in strengthening the intestine and stopping diarrhea. The results showed that the antidiarrheal effect of Atractylodis Rhizoma was enhanced after frying coke and the N-butanol extract was one of the effective parts of Atractylodis Rhizoma. Shi (Shi et al., 2020) found that the ethanol extract of deep-fried Atractylodis Rhizoma can significantly reduce the level of intestinal inflammatory cytokines, increase the expression of AQP3 and AQP8, and restore the abnormal water metabolism. In addition, it can regulate intestinal flora and improve intestinal structure. The commonly used Chinese herbal antidiarrheal medicines are listed in Table 10 in addition to the above.
Chinese Traditional Patent Medicine
Huoxiang Zhengqi Oral Liquid is composed of Atractylodis Rhizoma, Citri Reticulatae Pericarpium, Magnoliae officinalis Cortex, Angelicae dahuricae Radix, Poria, Arecae Pericarpium, Pinelliae Rhizoma, licorice extract, patchouli oil, and perilla leaf oil. The active ingredients of Huoxiang Zhengqi Oral Liquid mainly include liquiritin, narirutin, hesperidin, ammonium glycyrrhetate, honokiol, magnolol, thymol, guanosine, adenosine, imperatorin, isoimperatorin. Different Huoxiang-Zhengqi preparations have certain anti-diarrhea effects. Taking Huoxiang Zhengqi Oral Liquid as an example, long-term clinical experience shows that it has a significant effect on improving gastrointestinal symptoms. It was found that Huoxiang Zhengqi Oral Liquid could significantly improve the symptoms of diarrhea in spleen deficient rats with dampness syndrome (Xue et al., 2011). Its mechanism might be related to the increased of the expression of ZO-1 in the ileal mucosa, the regulation of CD4 and CD8 T cells in Peyer’s patch, and the inhibition of TNF-α level in intestinal homogenate (He et al., 2007).
The commonly used Chinese traditional patent medicines of antidiarrheal are shown in Table 11.
Conclusion and Perspectives
The anti-epidemic experience of China shows that it is of great value in the clinical treatment for COVID-19 to intervene early, improve clinical symptoms of patients, block the transition of mild cases to severe cases, shorten the course of the disease and promoting self-recovery, which can minimize the incidence and mortality of severe illness, and make full use of tight and limited medical resources. At present, the focus is on the research of antiviral drugs and vaccines, but there are few reports on treating early mild symptoms. Fever, cough, and fatigue are the most common symptoms of COVID-19, while some special patients experience diarrhea rather than fever in the early stage. Therefore, this paper summarizes the physiological and pathological processes of fever, cough, fatigue, and diarrhea, and explores the material basis, action mechanism and clinical research of Chinese herbal medicines and Chinese patent medicines with corresponding therapeutic effects, in order to provide reference for the efficient use of existing drugs. TCM has the unique properties of multi-components and multi-targets. The majority of these mentioned drugs may not only exert the effects of antipyretic, antitussive, anti-fatigue, and antidiarrheal, but also have the properties of anti-inflammation, antioxidation and immunity enhancement; and some of them are antiviral.
Such rich pharmacological activities are of great benefit in the initial treatment of COVID-19. On the one hand, these medicines may have the ability to relieve symptoms, reduce the rate of infection and prevent the transition from mild to severe in the early stages of infected patients. On the other hand, it is possible to cut down the dosage or use of hormones, decrease the dosage of first-line antiviral drugs or shorten their usage time, so as to minimize the potential damage to the liver by these drugs, and reduce the mortality of critically ill patients through the treatment of integrated traditional Chinese medicine and western medicine. However, these medicines also have shortcomings, mainly manifested in the lack of in-depth research on the material basis and mechanism of action, as well as the imperfection of clinical trials. Therefore, it is urgent to design more stringent controlled clinical trials in order to provide more scientific and reliable evidence for fighting COVID-19 all over the world.
D-KZ and LH put forward the idea. C-HL, L-LM, H-ML, and WL gather the materials, and wrote the paper. R-CX, Z-MC, and J-ZL contributed to the revisions. All authors contributed to the article and approved the submitted version.
We are grateful to the support of National Nature Science Fund (81773918) and Innovative Research Team Project of Chinese Medicine Discipline in Chengdu University of Traditional Chinese Medicine (CXTD2018006).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Almeida, A. R. M., Legrand, N., Papiernik, M., Freitas, A. A. (2002). Homeostasis of Peripheral CD4+ T Cells: IL-2Rα and IL-2 Shape a Population of Regulatory Cells That Controls CD4+ T Cell Numbers. J. Immunol. 169 (9), 4850–4860. doi: 10.4049/jimmunol.169.9.4850
Aryal, S., Adhikari, B., Panthi, K., Aryal, P., Mallik, S. K., Bhusal, R. P., et al. (2019). Antipyretic, Antinociceptive, and Anti-Inflammatory Activities from Pogostemon benghalensis Leaf Extract in Experimental Wister Rats. Medicines (Basel). 6 (4), 96. doi: 10.3390/medicines6040096
Brenu, E. W., Staines, D. R., Baskurt, O. K., Ashton, K. J., Ramos, S. B., Christy, R. M., et al. (2010). Immune and hemorheological changes in Chronic Fatigue Syndrome. J. Transl. Med. 8 (1), 1–10. doi: 10.1186/1479-5876-8-1
Cao, C., Matsumura, K., Shirakawa, N., Maeda, M., Jikihara, I., Kobayashi, S., et al. (2001). Pyrogenic cytokines injected into the rat cerebral ventricle induce cyclooxygenase-2 in brain endothelial cells and also upregulate their receptors. Eur. J. Neurosci. 13 (9), 1781–1790. doi: 10.1046/j.0953-816x.2001.01551.x
Chen, A. G., Yan, J. (2005). Effects of moderate load exercise training on behavior and oxygen free radicals in psychologically stressed rats. Chi. J. Behav. Medl. Sci. 14 (7), 582–583. doi: 10.3760/cma.j.issn.1674-6554.2005.07.003
Chen, X., He, B., Li, X., Li, H., Luo, J. J. (1998). Comparison of effects of three extracts of herba pogostemonis on the intestinal function. Pharmacol. Clinics Chin. Mater. Med. 14 (2), 31–33. doi: CNKI:SUN:ZYCA.0.1998-09-014
Chen, X., Howard, O. Z., Yang, X., Wang, L., Oppenheim, J. J., Krakauer, T. J. (2002). Effects of Shuanghuanglian and Qingkailing, two multi-components of traditional Chinese medicinal preparations, on human leukocyte function. Life Sci. 70 (24), 2897–2913. doi: 10.1016/S0024-3205(02)01541-2
Chen, E., Chen, J., Cao, S. L., Zhang, Q. Z., Jiang, X. G. (2010). Preparation of nasal temperature-sensitive in situ gel of Radix Bupleuri and evaluation of the febrile response mechanism. Drug Dev. Ind. Pharm. 36 (4), 490–496. doi: 10.3109/03639040903264371
Chen, H. Y., Lin, Y. H., Thien, P. F., Chang, S. C., Chen, Y. C., Lo, S. S., et al. (2013). Identifying core herbal treatments for children with asthma: implication from a chinese herbal medicine database in taiwan. Evid. Based Complement. Alternat. Med. 2013, 125943. doi: 10.1155/2013/125943
Chen, X. S., Chen, H. X., Sun, X. J., Liu, Y. J., Pan, S. S. (2018). Pharmacodynamics of n-butyl alcohol parts extracted fromAtractylodis lancea before and after the deep-fired in model rats with spenasthenic diarrhea. Chin. J. Hosp. Pharm. 38 (03), 246–249. doi: 10.13286/j.cnki.chinhosppharmacyj.2018.03.08
Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., et al. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet (Lond. Engl.) 395 (10223), 507–513. doi: 10.1016/s0140-6736(20)30211-7
Cheng, N., Zhu, J., Ding, P. (2017). Clinical Effects and Safety of Zhi Sou San for Cough: A Meta-Analysis of Randomized Trials. Evid. Based Complement. Alternat. Med. 2017, 1–11. doi: 10.1155/2017/9436352
Chi, A., Kang, Y., Zhang, Y., Wang, Z., Min, R., Song, J. (2017). Urinary metabolomics study of Epimedium polysaccharide for the treatment of chronic fatigue rats. J. Shaanxi Normal Univ.(Nat. Sci. Edition). 45 (2), 116–124. doi: 10.15983/j.cnki.jsnu.2017.02.224
Ching, S., Zhang, H., Belevych, N., He, L., Lai, W., Pu, X., et al. (2007). Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration. J. Neurosci. 27 (39), 10476–10486. doi: 10.1523/JNEUROSCI.3357-07.2007
Cho, H. J., Kivimäki, M., Bower, J. E., Irwin, M. R. (2013). Association of C-reactive protein and interleukin-6 with new-onset fatigue in the Whitehall II prospective cohort study. Psychol. Med. 43 (8), 1773–1783. doi: 10.1017/S0033291712002437
Collin, S. M., Heron, J., Nikolaus, S., Knoop, H., Crawley, E. (2018). Chronic fatigue syndrome (CFS/ME) symptom-based phenotypes and 1-year treatment outcomes in two clinical cohorts of adult patients in the UK and The Netherlands. J. Psychosom. Res. 104 (1), 29–34. doi: 10.1016/j.jpsychores.2017.11.007
Dinarello, C. A., Cannon, J. G., Mancilla, J., Bishai, I., Lees, J., Coceani, F. (1991). Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells. Brain Res. 562 (2), 199–206. doi: 10.1016/0006-8993(91)90622-3
Ding, P., Wang, Q., Yao, J., Zhou, X. M., Zhu, J. (2016). Curative Effects of Suhuang Zhike Capsule on Postinfectious Cough: A Meta-Analysis of Randomized Trials. Evid. Based Complement. Alternat. Med. 2016, 8325162. doi: 10.1155/2016/8325162
Eskilsson, A., Mirrasekhian, E., Dufour, S., Schwaninger, M., Engblom, D., Blomqvist, A. (2014). Immune-induced fever is mediated by IL-6 receptors on brain endothelial cells coupled to STAT3-dependent induction of brain endothelial prostaglandin synthesis. J. Neurosci. 34 (48), 15957–15961. doi: 10.1523/JNEUROSCI.3520-14.2014
Fink, C., Schmidt, M., Kraft, K. (2018). Marshmallow Root Extract for the Treatment of Irritative Cough: Two Surveys on Users’ View on Effectiveness and Tolerability. Complement. Med. Res. 25 (5), 299–305. doi: 10.1159/000489560
Gao, X., Guo, M., Peng, L., Zhao, B., Su, J., Liu, H., et al. (2013). UPLC Q-TOF/MS-Based Metabolic Profiling of Urine Reveals the Novel Antipyretic Mechanisms of Qingkailing Injection in a Rat Model of Yeast-Induced Pyrexia. Evid. Based Complement. Alternat. Med. 2013, 864747. doi: 10.1155/2013/864747
Gao, X., Guo, M., Li, Q., Peng, L., Liu, H., Zhang, L., et al. (2014). Plasma metabolomic profiling to reveal antipyretic mechanism of Shuang-huang-lian injection on yeast-induced pyrexia rats. PLoS One 9 (6), e100017. doi: 10.1371/journal.pone.0100017
Guan, F. L., Wang, R. J., Wang, J. H. (2002). Effect of Chenpi and Hesperidin on Contractile Activity of Intestinal Muscle Strips in vitro. Lishizhen Med. Mater. Med. Res. 2002 (02), 65–67. doi: 10.3969/j.issn.1008-0805.2002.02.001
Guan, J., Shen, H., Zhang, Y., Cui, D. (2013). Effects of forsythoside on lipopolysaccharide (LPS)-stimulated RAW264. 7 macrophages. Afr. J. Pharm. Pharmaco. 7 (26), 1847–1853. doi: 10.5897/ajpp2013.3584
Han, Y. L., Wu, W.-W., He, R. L., Wang, B. (2016). Antitussive and Expectorant Activity of Different Chemical Constituents from the Crude Tussilago farfara Flower. Lishizhen Med. Mater. Med. Res. 27 (06), 1347–1349. doi: 10.3969/j.issn.1008-0805.2016.06.024
He, Y., Luo, X., Qian, X., Wu, C. (2007). Effects of Huoxiang Zhengqi liquid on enteric mucosal immune responses in mice with Bacillus dysenteriae and Salmonella typhimurium induced diarrhea. World J. Gastroenterol. 32 (22), 2397–2400. doi: 10.3321/j.issn:1001-5302.2007.22.017
Hilgers, A., Frank, J. (1994). Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes. Wien Med. Wochenschr. 144 (16), 399–406. doi: 10.1300/J092v02n0103
Hu, Y. X., Chen, H. F., Song, Y. P., Tan, S. S., Luo, X. Q., Yang, W. L. (2017). Study on the Mechanism of Aurantii Fructus Immaturus and Its Main Active Ingredients in Promoting Gastrointestinal Motility of Model Rats with Spleen Deficiency. China Pharm. 28 (13), 1747–1750. doi: 10.6039/j.issn.1001-0408.2017.13.06
Huang, Y. F., Zhu, D. J., Lu, L. U. (2017). Effects of Astragalus polysaccharide on skeletal muscle mitochondria in mice with chronic fatigue. Guangdong Med. J. 38 (12), 1789–1794. doi: 10.13820/j.cnki.gdyx.20170607.001
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395 (10223), 497–506. doi: 10.1016/s0140-6736(20)30183-5
Jahan, Y., Siddiqui, H. (2012). Study of antitussive potential of Glycyrrhiza glabra and Adhatoda vasica using a cough model induced by sulphur dioxide gas in mice. Inter. Jof. Pharma. Sci. Res. 3 (6), 1668.
Jiang, K., Song, Q., Wang, L., Xie, T., Wu, X., Wang, P., et al. (2014). Antitussive, expectorant and anti-inflammatory activities of different extracts from Exocarpium Citri grandis. J. Ethnopharmacol. 156, 97–101. doi: 10.1016/j.jep.2014.08.030
Jin, G., Li, B., Wang, S. (2014). Research on the Mechanism, the Effects and Material Foundation of ChaiHu in Relieving Fever. Western J. Tradit. Chin. Medi. 2 (2), 8–13. doi: 10.3969/j.issn.1004-6852.2014.02.008
Kamei, J., Nakamura, R., Ichiki, H., Kubo, M. (2003). Antitussive principles of Glycyrrhizae radix, a main component of the Kampo preparations Bakumondo-to (Mai-men-dong-tang). Eur. J. Pharmaco. 469 (1-3), 159–163. doi: 10.1016/s0014-2999(03)01728-x
Kamei, J., Saitoh, A., Asano, T., Nakamura, R., Ichiki, H., Iiduka, A. (2005). Pharmacokinetic and pharmacodynamic profiles of the antitussive principles of Glycyrrhizae radix (licorice), a main component of the Kampo preparation Bakumondo-to (Mai-men-dong-tang). Eur. J. Pharmacol. 507 (1-3), 163–168. doi: 10.1016/j.ejphar.2004.11.042
Kao, S. T., Yeh, T. J., Hsieh, C. C., Shiau, H. B., Yeh, F. T., Lin, J. G. (2001). The effects of Ma-Xing-Gan-Shi-Tang on respiratory resistance and airway leukocyte infiltration in asthmatic guinea pigs. Immunopharm. Immunot. 23 (3), 445–458. doi: 10.1081/iph-100107343
Kim, S. O., Park, J. Y., Jeon, S. Y., Yang, C. H., Kim, M. R. (2015). Saikosaponin a, an active compound of Radix Bupleuri, attenuates inflammation in hypertrophied 3T3-L1 adipocytes via ERK/NF-κB signaling pathways. Int. J. Mol. Med. 35 (4), 1126–1132. doi: 10.3892/ijmm.2015.2093
Kim, K. I., Shin, S., Lee, N., Lee, B. J., Lee, J., Lee, H. (2016). A traditional herbal medication, Maekmoondong-tang, for cough: A systematic review and meta-analysis. J. Ethnopharmacol. 178, 144–154. doi: 10.1016/j.jep.2015.12.005
Lampa, J., Westman, M., Kadetoff, D., Agreus, A. N., Mattre, E. L., Andersson, M., et al. (2012). ). Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice. Proc. Natl. Acad. Sci. U. S. A. 109 (31), 12728–12733. doi: 10.1073/pnas.1118748109
Lee, J. H., Kim, S. R., Bae, C. S., Kim, D., Hong, H. N., Nah, S. Y. (2002). Protective effect of ginsenosides, active ingredients of Panax ginseng, on kainic acid-induced neurotoxicity in rat hippocampus. Neurosci. Lett. 325 (2), 0–133. doi: 10.1016/s0304-3940(02)00256-2
Lee, H. J., Cho, H. S., Jun, S. Y., Lee, J. J., Yoon, J. Y., Lee, J. H., et al. (2014). Tussilago farfara L. augments TRAIL-induced apoptosis through MKK7/JNK activation by inhibition of MKK7TIPRL in human hepatocellular carcinoma cells. Oncol. Rep. 32 (3), 1117–1123. doi: 10.3892/or.2014.3279
Lee, J., Song, K., Huh, E., Oh, M. S., Kim, Y. S. (2018). Neuroprotection against 6-OHDA toxicity in PC12 cells and mice through the Nrf2 pathway by a sesquiterpenoid from Tussilago farfara. Redox Bio. 18, 6–15. doi: 10.1016/j.redox.2018.05.015
Li, Y. M., Liu, W. H. (2019). Study on the Mechanism of Coicis Semen Decoction on Gastrointestinal Motility and Hormone Level in Rats with Spleen Deficiency Syndrome. Acta Chin. Med. 34 (1), 90–93. doi: 10.16368/j.issn.1674-8999.2019.01.021
Li, Z. Y., Zhi, H. J., Xue, S. Y., Sun, H. F., Zhang, F. S., Jia, J. P., et al. (2012). Metabolomic profiling of the flower bud and rachis of Tussilago farfara with antitussive and expectorant effects on mice. J. Ethnopharmacol. 140 (1), 83–90. doi: 10.1016/j.jep.2011.12.027
Li, J., Zhang, Z. Z., Lei, Z. H., Qin, X. M., Li, Z. Y. (2018a). NMR based metabolomic comparison of the antitussive and expectorant effect of Farfarae Flos collected at different stages. J. Pharm. BioMed. Anal. 150, 377–385. doi: 10.1016/j.jpba.2017.12.028
Li, J., Gao, L., Gao, Y. (2018b). Exploration in targets action of antitussive and expectorant bioactive components from Farfarae Flos based on network pharmacology. Chin. Tradit. Herbal Drugs 049 (001), 179–187. doi: 10.7501/j.issn.0253-2670.2018.01.025
Liao, Y. N., Hu, W. L., Chen, H. J., Hung, Y. C. (2017). The Use of Chinese Herbal Medicine in the Treatment of Chronic Obstructive Pulmonary Disease (COPD). Am. J. Chin. Med. 45 (2), 225–238. doi: 10.1142/s0192415x17500148
Liew, W. K., Loh, W., Chiang, W. C., Goh, A., Chay, O. M., Iancovici Kidon, M. J. (2015). Pilot study of the use of Yin Qiao San in children with conventional antipyretic hypersensitivity. Asia Pacific Allergy 5 (4), 222–229. doi: 10.5415/apallergy.2015.5.4.222
Lin, L. G., Li, K. M., Tang, C. P., Ke, C. Q., Rudd, J. A., Lin, G. (2008). Antitussive stemoninine alkaloids from the roots of Stemona tuberosa. J. Nat. Prod. 71 (6), 1107–1110. doi: 10.1021/np070651+
Lin, S. K., Tsai, Y. T., Lo, P. C., Lai, J. N. (2016). Traditional Chinese medicine therapy decreases the pneumonia risk in patients with dementia. Med. (Baltimore). 95 (37), e4917. doi: 10.1097/md.0000000000004917
Lin, Y. C., Chang, C. W., Wu, C. R. (2016). Antitussive, anti-pyretic and toxicological evaluation of Ma-Xing-Gan-Shi-Tang in rodents. BMC Complement. Altern. Med. 16 (1), 456. doi: 10.1186/s12906-016-1440-2
Liu, Y., Zhang, H. G., Li, X. H. (2011). A Chinese Herbal Decoction, Danggui Buxue Tang, Improves Chronic Fatigue Syndrome Induced by Food Restriction and Forced Swimming in Rats. Phytoth. Res. 25 (12), 1825–1832. doi: 10.1002/ptr.3499
Liu, Y., Xiang, L. H., Sun, G., Wang, X. H., Zhao, H. Y., Wang, Z., et al. (2012). Effects of Wu Ling San on expression of AQP4 and AQP4mRNA in colon mucosa of rat model of diarrhea. Chin. J. Basic Med. Tradit. Chin. Medi. 18 (05), 547–549. doi: 10.3969/j.issn.1006-3250.2005.03.014
Liu, R., Huang, Q., Shan, J., Duan, J. A., Zhu, Z., Liu, P., et al. (2016). Metabolomics of theAntipyretic Effects of Bubali Cornu (Water Buffalo Horn) in Rats. PLoS One 11 (7), e0158478. doi: 10.1371/journal.pone.0158478
Liu, C., Su, H., Wan, H., Qin, Q., Wu, X., Kong, X., et al. (2017). Forsythoside A exerts antipyreticeffect on yeast-induced pyrexia mice via inhibiting transient receptor potential vanilloid function. Int. J. Biol. Sci. 13 (1), 65. doi: 10.7150/ijbs.18045
Liu, J. X., Wang, Y. L., Li, Y., Zou, D. X., Wang, D. F., Ma, X. R., et al. (2019). Experimental study on the effect of Sishen Wan on intestinal flora in rats with diarrhea-type irritable bowel syndrome. Acta Pharm. Sin. 54 (04), 670–677. doi: 10.16438/j.0513-4870.2018-0920
Liu, C., Wu, H., Wang, L., Luo, H., Lu, Y., Zhang, Q., et al. (2020). Farfarae Flos: A review of botany, traditional uses, phytochemistry, pharmacology, and toxicology. J. Ethnopharmacol. 260, 113038. doi: 10.1016/j.jep.2020.113038
Luo, Y. L., Zhang, C. C., Li, P. B., Nie, Y. C., Wu, H., Shen, J.-G., et al. (2012). Naringin attenuates enhanced cough, airway hyperresponsiveness and airway inflammation in a guinea pig model of chronic bronchitis induced by cigarette smoke. Int. Immunopharmacol. 13 (3), 301–307. doi: 10.1016/j.intimp.2012.04.019
Luo, C., Xu, X., Wei, X., Feng, W., Huang, H., Liu, H., et al. (2019). Natural medicines for the treatment of fatigue: Bioactive components, pharmacology, and mechanisms. Pharmacol. Res. 148, 104409. doi: 10.1016/j.phrs.2019.104409
Maes, M. (2009). Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr. Opin. Psychiatry 22 (1), 75–83. doi: 10.1097/YCO.0b013e32831a4728
Matura, L. A., Malone, S., Jaime-Lara, R., Riegel, B. (2018). A Systematic Review of Biological Mechanisms of Fatigue in Chronic Illness. Biol. Res. Nurs. 20 (4), 410–421. doi: 10.1177/1099800418764326
McGarvey, L. P., Butler, C. A., Stokesberry, S., Polley, L., McQuaid, S., Abdullah, H., et al. (2014). Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma. J. Allergy Clin. Immunol. 133 (3), 704–12.e4. doi: 10.1016/j.jaci.2013.09.016
Medical Administration Bureau (2020). Diagnosis and treatment of novel coronavirus pneumonia (Trial version 7). Available at: http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989/files/ce3e6945832a438eaae415350a8ce964.pdf (Accessed July 28, 2020).
Miaskowski, C., Cooper, B. A., Dhruva, A. (2012). Evidence of associations between cytokine genes and subjective reports of sleep disturbance in oncology patients and their family caregivers. PLoS One 7 (7), e40560. doi: 10.1371/journal.pone.0040560
Miyagoshi, M., Amagaya, S., Ogihara, Y. (1986). Antitussive effects of L-ephedrine, amygdalin, and makyokansekito (Chinese traditional medicine) using a cough model induced by sulfur dioxide gas in mice. Planta Med. 4), 275–278. doi: 10.1055/s-2007-969151
Morice, A. H., Kantar, A., Dicpinigaitis, P. V., Birring, S. S., McGarvey, L. P., Chung, K. F. (2015). Treating acute cough: wet versus dry - have we got the paradigm wrong? ERJ Open Res. 1 (2), 00055–2015. doi: 10.1183/23120541.00055-2015
Nadjar, A., Tridon, V., May, M. J., Ghosh, S., Dantzer, R., Amédée, T., et al. (2005). NFκB activates in vivo the synthesis of inducible Cox-2 in the brain. J. Cereb. Blood Flow Metab. 25 (8), 1047–1059. doi: 10.1038/sj.jcbfm.9600106
Nair, S., Diamond, M. (2015). Innate immune interactions within the central nervous system modulate pathogenesis of viral infections. Curr. Opin. Immunol. 36 (1), 47–53. doi: 10.1016/j.coi.2015.06.011
Nakamura, H., Seto, Y., Motoyoshi, S., Kadokawa, T., Sunahara, N. (1988). Recombinant human tumor necrosis factor causes long-lasting and prostaglandin-mediated fever, with little tolerance, in rabbits. J. Pharmacol. Exp. Ther. 245 (1), 336–341. doi: 10.1016/0160-5402(88)90038-1
Nakamura, T., Schwander, S. K., Donnelly, R., Ortega, F., Togo, F., Broderick, G., et al. (2010). Cytokines across the Night in Chronic Fatigue Syndrome with and without Fibromyalgia. Clin. Vaccine Immunol. 17 (4), 582–587. doi: 10.1128/cvi.00379-09
Ni, Y. D., Wang, J. H., Wang, R. J. (2003). Effect of the Semen Arecae on animal gastrointestinal activity. Pharmacol. Clinics Chin. Mater. Medica 19 (5), 27–30. doi: 10.3969/j.issn.1001-859X.2003.05.017
Ouyang, X. L., Li, J., Wang, J. H., Liu, W. H., Yang, G. L. (2018). Clinical Study of Guipi Decoction in Treating Chronic Fatigue Syndrome of Deficiency of Heart and Spleen. Inf. Tradit. Chin. Medi. 35 (2), 87–90. doi: 10.19656/j.cnki.1002-2406.180060
Pastorino, G., Cornara, L., Soares, S., Rodrigues, F., Oliveira, M. (2018). Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review. Phytother. Res. 32 (12), 2323–2339. doi: 10.1002/ptr.6178
Perlik, V., Li, Z., Goorha, S., Ballou, L. R., Blatteis, C. M. (2005). LPS-activated complement, not LPS per se, triggers the early release of PGE2 by Kupffer cells. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289 (2), R332–R339. doi: 10.1152/ajpregu.00567.2004
Prajitha, N., Athira, S. S., Mohanan, P. V. (2018). Pyrogens, a polypeptide produces fever by metabolic changes in hypothalamus: Mechanisms and detections. Immunol. Lett. 204, 38–46. doi: 10.1016/j.imlet.2018.10.006
Qian, W., Shan, J., Shen, C., Yang, R., Xie, T., Di, L. (2019). Brain Metabolomics Reveal the Antipyretic Effects of Jinxin Oral Liquid in Young Rats by Using Gas Chromatography-Mass Spectrometry. Metabolites 9 (1), 6. doi: 10.3390/metabo9010006
Ren, L. H., Xin, R. H., Peng, W. J., Wang, G. B., Luo, Y. J., Luo, C. Y., et al. (2015). Comparison on efficacy of different polarity section extract from Aster tataricus. J. South. Agric. 46 (04), 675–679. doi: 10.3969/j.issn.2095-1191.2015.4.675
Reyes-Gibby, C. C., Wang, J., Spitz, M., Wu, X., Yennurajalingam, S., Shete, S. (2013). Genetic Variations in Interleukin-8 and Interleukin-10 Are Associated With Pain, Depressed Mood, and Fatigue in Lung Cancer Patients. J. Pain Symptom Manage. 46 (2), 161–172. doi: 10.1016/j.jpainsymman.2012.07.019
Romanovsky, A. A., Ivanov, A. I., Karman, E. K. (1999). Blood-borne, albumin-bound prostaglandin E2 may be involved in fever. Am. J. Physiol. 276 (6), R1840–R1844. doi: 10.1152/ajpregu.1999.276.6.R1840
Roth, J., De Souza, G. E. (2001). Fever induction pathways: evidence from responses to systemic or local cytokine formation. Braz. J. Med. Biol. Res. 34 (3), 301–314. doi: 10.1590/s0100-879x2001000300003
Roth, J., Martin, D., Störr, B., Zeisberger, E. (1998). Neutralization of pyrogen-induced tumour necrosis factor by its type 1 soluble receptor in guinea-pigs: effects on fever and interleukin-6 release. J. Physiol. 509 (1), 267–275. doi: 10.1111/j.1469-7793.1998.267bo.x
Rummel, C., Sachot, C., Poole, S., Luheshi, G. N. (2006). Circulating interleukin-6 induces fever through a STAT3-linked activation of COX-2 in the brain. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291 (5), R1316–R1326. doi: 10.1152/ajpregu.00301.2006
Russell, C. D., Millar, J. E., Baillie, J. K. (2020). Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 395 (10223), 473–475. doi: 10.1016/s0140-6736(20)30317-2
Saha, S., Nosal’ova, G., Ghosh, D., Fleskova, D., Capek, P., Ray, B. (2011). Structural features and in vivo antitussive activity of the water extracted polymer from Glycyrrhiza glabra. Int. J. Biol. Macromol. 48 (4), 634–638. doi: 10.1016/j.ijbiomac.2011.02.003
Schnoeller, C., Roux, X., Sawant, D., Raze, D., Olszewska, W., Locht, C., et al. (2014). Attenuated Bordetella pertussis vaccine protects against respiratory syncytial virus disease via an IL-17-dependent mechanism. Am. J. Respir. Crit. Care Med. 189 (2), 194–202. doi: 10.1164/rccm.201307-1227OC
Shi, K., Qu, L., Lin, X., Xie, Y., Tu, J., Liu, X., et al. (2020). Deep-Fried Atractylodis Rhizoma Protects against Spleen Deficiency-Induced Diarrhea through Regulating Intestinal Inflammatory Response and Gut Microbiota. Chin. J. Exp. Tradit. Med. Form. 21 (1), 124. doi: 10.3390/ijms21010124
Soares, D. D., Coimbra, C. C., Marubayashi, U. (2007). Tryptophan-induced central fatigue in exercising rats is related to serotonin content in preoptic area. Neurosci. Lett. 415 (3), 274–278. doi: 10.1016/j.neulet.2007.01.035
Song, Z. J., Johansen, H. K., Moser, C., Faber, V., Kharazmi, A., Rygaard, J., et al. (2000). Effects of Radix Angelicae sinensis and shuanghuanglian on a rat model of chronic Pseudomonas aeruginosa pneumonia. Chin. Med. Sci. J. 15 (2), 83–88.
Song, K. J., Shin, Y. J., Lee, K. R., Lee, E. J., Suh, Y. S., Kim, K. S. (2015). Expectorant and antitussive effect of Hedera helix and Rhizoma coptidis extracts mixture. Yonsei Med. J. 56 (3), 819–824. doi: 10.3349/ymj.2015.56.3.819
Song, Y. (2014). Effect of ginsenoside Rg1 on the activity of antioxidant enzyme system in rats with chronic fatigue syndrome. Shaanxi J. Tradit. Chin. Medi. 35 (1), 101–103. doi: 10.3969/j.issn.1000-7369.2014.01.057
Steiner, A. A., Chakravarty, S., Rudaya, A. Y., Herkenham, M., Romanovsky, A. A. (2006). Bacteriallipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells. Blood 107 (10), 4000–4002. doi: 10.1182/blood-2005-11-4743
Sui, F., Lin, N., Guo, J. Y., Zhang, C. B., Du, X. L., Zhao, B. S., et al. (2010). Cinnamaldehyde up-regulates the mRNA expression level of TRPV1 receptor potential ion channel protein and its function in primary rat DRG neurons in vitro. J. Asian Nat. Prod. Res. 12 (1), 76–87. doi: 10.1080/10286020903451732
Swarnkar, V., Abeyratne, U. R., Chang, A. B., Amrulloh, Y. A., Setyati, A., Triasih, R. (2013). Automatic identification of wet and dry cough in pediatric patients with respiratory diseases. Ann. BioMed. Eng. 41 (5), 1016–1028. doi: 10.1007/s10439-013-0741-6
Tak, L. M., Cleare, A. J., Ormel, J., Manoharan, A., Kok, I. C., Wessely, S., et al. (2011). Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. Biol. Psychol. 87 (2), 0–194. doi: 10.1016/j.biopsycho.2011.02.002
Tao, J., Hou, Y., Ma, X., Liu, D., Tong, Y., Zhou, H. (2016). An integrated global chemomics and system biology approach to analyze the mechanisms of the traditional Chinese medicinal preparation Eriobotrya japonica - Fritillaria usuriensis dropping pills for pulmonary diseases. BMC Complement. Altern. Med. 16 (4). doi: 10.1186/s12906-015-0983-y
Tsai, C. C., Lin, M. T., Wang, J. J., Liao, J. F., Huang, W. T. (2006). The antipyretic effects of baicalin in lipopolysaccharide-evoked fever in rabbits. Neuropharmacology 51 (4), 709–717. doi: 10.1016/j.neuropharm.2006.05.010
Turrin, N. P., Rivest, S. (2004). Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems. Exp. Biol. Med. (Maywood). 229 (10), 996–1006. doi: 10.1177/153537020422901003
Vallières, L., Rivest, S. (1997). Regulation of the genes encoding interleukin-6, its receptor, and gp130 in the rat brain in response to the immune activator lipopolysaccharide and the proinflammatory cytokine interleukin-1β. J. Neurochem. 69 (4), 1668–1683. doi: 10.1046/j.147110224159.1997.69041668.x
Von Ah, D. M., Kang, D. H., Carpenter, J. S. (2008). Predictors of cancer-related fatigue in women with breast cancer before, during, and after adjuvant therapy. Cancer Nurs. 31 (2), 134–144. doi: 10.1097/01.NCC.0000305704.84164.54
Wang, J. H., Xue, B. Y., Liang, A. H., Wang, L., Fu, M. H., Ye, Z. G., et al. (2002). Effects of beta-eudesmol, an active constituent from Rhizoma Atractylodis on small intestine movement in rats. Chin. Pharm. J. 37 (4), 266–268. doi: 10.3321/j.issn:1001-2494.2002.04.009
Wang, D., Zhu, J., Wang, S., Wang, X., Ou, Y., Wei, D., et al. (2011). Antitussive, expectorant and anti-inflammatory alkaloids from Bulbus Fritillariae Cirrhosae. Fitoterapia 82 (8), 1290–1294. doi: 10.1016/j.fitote.2011.09.006
Wang, D., Wang, S., Chen, X., Xu, X., Zhu, J., Nie, L., et al. (2012). Antitussive, expectorant and anti-inflammatory activities of four alkaloids isolated from Bulbus of Fritillaria wabuensis. J. Ethnopharmacol. 139 (1), 189–193. doi: 10.1016/j.jep.2011.10.036
Wang, H. M., Lin, S. K., Yeh, C. H., Lai, J. N. (2014). Prescription pattern of Chinese herbal products for adult-onset asthma in Taiwan: a population-based study. Annals of allergy, asthma & immunology : official publication of the American College of Allergy. Asthma Immunol. 112 (5), 465–470. doi: 10.1016/j.anai.2014.02.012
Wang, C., Wang, Y. M., Guo, F., Zhang, K. R., Chi, A. P., Sports, S. O., et al. (2015). Immune function of Ziziphus Jujube polysaccharides on Chronic Fatigue Syndrome Rats. J. Northwest Univ. 45 (1), 73–78. doi: 10.16152/j.cnki.xdxbzr.2015-01-016
Wang, J. W., Chiang, M. H., Lu, C. M., Tsai, T. H. (2016). Determination the active compounds of herbal preparation by UHPLC-MS/MS and its application on the preclinical pharmacokinetics of pure ephedrine, single herbal extract of Ephedra, and a multiple herbal preparation in rats. J. Chromatogr. B Analyt. Technol. BioMed. Life Sci. 1026, 152–161. doi: 10.1016/j.jchromb.2015.12.027
Wang, X., Qu, Y., Zhang, Y., Li, S. P., Sun, Y. Y., Chen, Z. P., et al. (2018). Antifatigue Potential Activity of Sarcodon imbricatus in Acute Excise-Treated and Chronic Fatigue Syndrome in Mice via Regulation of Nrf2-Mediated Oxidative Stress. Oxid. Med. Cell Longev. 2018, 9140896. doi: 10.1155/2018/9140896
World Health Orgnization (2020). Novel Coronavirus(2019-nCoV). Available at: https://www.who.int/zh/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—11-march-2020 (Accessed July 28, 2020).
Wu, Q. Z., Zhao, D. X., Xiang, J., Zhang, M., Zhang, C. F., Xu, X. H. (2016). Antitussive, expectorant, and anti-inflammatory activities of four caffeoylquinic acids isolated from Tussilago farfara. Pharm. Biol. 54 (7), 1117–1124. doi: 10.3109/13880209.2015.1075048
Wu, J., Gan, Y., Li, M., Chem, L., Liang, J., Zhuo, J., et al. (2020). EPatchouli alcohol attenuates 5-fluorouracil-induced intestinal mucositis via TLR2/MyD88/NF-kB pathway and regulation of microbiota. Biomed. Pharmacother. 124, 109883–1758. doi: 10.1016/j.biopha.2020.109883
Xia, Q. L., Wang, T., Lu, S. M., Pan, S. Y. (2013). Research Progress in Analysis,Extraction,Purification and Pharmacological Effects of Amygdalin. Food Sci. 52 (9), 1346–1353. doi: 10.7506/spkx1002-6630-201321079
Xia, W. G., An, C. Q., Zheng, C. J., Zhang, J. X., Huang, M., Wang, Y. (2020). Clinical Observation on 34 Patients with Novel Coronavirus Pneumonia (COVID-19) Treated with Integrated Traditional Chinese and Western Medicine. J. Tradit. Chin. Med. 61 (05), 375–382. doi: 10.13288/j.11-2166/r.2020.05.002
Xie, J., Fei, Z. B., Chen, Y. L., Ma, L. (2017). Anti-diarrhea Effect of Aqueous Extract of Magnolia officinalis Leaves. J. Anhui Agric. Sci. 45 (19), 107–109. doi: 10.3969/j.issn.0517-6611.2017.19.036
Xu, N. Y., Gu, Z. L., Xie, M. L. (2004). Determination of the Content of Flavonoids in the Active Fraction of Modified Zhisousan. Acta Acad. Med. Suzhou.2004 24 (6), 841–669. doi: 10.1016/S0898-6568(03)00096-2
Xu, Y. T., Shaw, P. C., Jiang, R. W., Hon, P. M., Chan, Y. M., But, P. P. (2010). Antitussive and central respiratory depressant effects of Stemona tuberosa. J. Ethnopharmacol. 128 (3), 679–684. doi: 10.1016/j.jep.2010.02.018
Xu, H. M., Yi, H., Zhou, W. B., He, W. J., Zeng, G. Z., Xu, W. Y., et al. (2013). Tataricins A and B, two novel cyclotetrapeptides from Aster tataricus, and their absolute configuration assignment. Tetrahedron Lett. 54 (11), 1380–1383. doi: 10.1016/j.tetlet.2012.12.111
Xu, Y., Ming, T. W., Gaun, T. K. W., Wang, S., Ye, B. A. (2019). comparative assessment of acute oral toxicity and traditional pharmacological activities between extracts of Fritillaria cirrhosae Bulbus and Fritillaria pallidiflora Bulbus. J. Ethnopharmacol. 238, 111853. doi: 10.1016/j.jep.2019.111853
Xue, X. Q., Huang, X. K., Huang, N.,. G., Liu, E. H., Ren, L. Y. (2011). Effects of Huoxiang Zhengqi Liquid on Expression of ZO-1 in Ileum Mucosa of Rats with Dampness Retention Syndrome. Chin. J. Exp. Tradit. Med. Formulae 2011 (16), 69. doi: 10.3969/j.issn.1005-9903.2011.16.064
Yang, X. Z., Zhu, J. Y., Tang, C. P., Ke, C. Q., Lin, G., Cheng, T. Y., et al. (2009). Alkaloids from roots of Stemona sessilifolia and their antitussive activities. Planta Med. 75 (2), 174–177. doi: 10.1055/s-0028-1088345
Yang, X., Lv, Y., Tian, L., Zhao, Y. (2010). Composition and systemic immune activity of the polysaccharides from an herbal tea (Lycopus lucidus Turcz). J. Agric. Food Chem. 58 (10), 6075–6080. doi: 10.1021/jf101061y
Yang, H., Shi, H., Zhang, Q., Liu, Y., Wan, C., Zhang, L. (2016). Simultaneous Determination of Five Components in Aster tataricus by Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry. J. Chromatogr. Sci. 54 (4), 500–506. doi: 10.1093/chromsci/bmv171
Yang, F. D., Dong, X. X., Yin, X. B., Wang, W. P., You, L., Ni, J. (2017). Radix Bupleuri: a review of traditional uses, botany, phytochemistry, pharmacology, and toxicology. BioMed. Res. Int. 2017, 7597596–7597612. doi: 10.1155/2017/7597596
Yang, L., Jiang, H., Wang, S., Hou, A., Man, W., Zhang, J., et al. (2020). Discovering the Major Antitussive, Expectorant, and Anti-Inflammatory Bioactive Constituents in Tussilago Farfara L. Based on the Spectrum-Effect Relationship Combined with Chemometrics. Molecules 25 (3), 620. doi: 10.3390/molecules25030620
Ye, L., Tao, Y., Wang, Y., Feng, T., Li, H. (2015). The effects of baicalin on the TLR2/4 signaling pathway in the peripheral blood mononuclear cells of a lipopolysaccharide-induced rat fever model. Int. Immunopharmacol. 25 (1), 106–111. doi: 10.1016/j.intimp.2014.12.028
You, L. Y., Zhao, M. M., Regenstein, J. M., Ren, J. Y. (2011). In vitro antioxidant activity and in vivo anti-fatigue effect of loach (Misgurnus anguillicaudatus) peptides prepared by papain digestion. Food Chem. 124 (1), 188–194. doi: 10.1016/j.foodchem.2010.06.007
Yu, P., Cheng, S., Xiang, J., Yu, B., Zhang, M., Zhang, C., et al. (2015). Expectorant, antitussive, anti-inflammatory activities and compositional analysis of Aster tataricus. J. Ethnopharmacol. 164, 328–333. doi: 10.1016/j.jep.2015.02.036
Zeng, X. Y., Yuan, W., Zhou, L., Wang, S. X., Xie, Y., Fu, Y. J. (2017). Forsythoside A exerts an anti endotoxin effect by blocking the LPS/TLR4 signaling pathway and inhibiting Tregs in vitro. Int. J. Mol. Med. 40 (1), 243–250. doi: 10.3892/ijmm.2017.2990
Zhang, M. M., Liu, X. M., He, L. (2004). Effect of integrated traditional Chinese and Western medicine on SARS: a review of clinical evidence. World J. Gastroenterol. 10 (23), 3500. doi: 10.3748/wjg.v10.i23.3500
Zhang, J. Y., He, P., Li, Y. K. (2010). Experimental Study on Effect of Bitter Apricot Seed,Platycodon Root,and Their Compatibility for Relieving Cough and Expelling Phlegm. Chin. J. Exp. Tradit. Med. Formulae 16 (18), 173–175. doi: 10.3969/j.issn.1005-9903.2010.18.052
Zhang, H., Chen, Q., Zhou, W. W., Gao, S., Lin, H. G., Ye, S. F., et al. (2013). Chinese medicine injection shuanghuanglian for treatment of acute upper respiratory tract infection: a systematic review of randomized controlled trials. Evid. Based Complement. Alternat. Med. 2013, 987326–987335. doi: 10.1155/2013/987326
Zhang, H., Min, D., Fu, M., Tian, J., An, X. (2014). Effects of astragalus and its active ingredients on ischemia reperfusion injury in isolated guinea-pig heart. Zhonghua xin xue guan bing za zhi. 42 (9), 759–764. doi: 10.3760/oma.j.issn.0253-3758.2014.09.011
Zhang, T., Xie, Z., Wang, M., Jie, L., Meng, Y., Zhai, Z., et al. (2014). Experimental Research of the Effect of Modified Sini Power Granules on Weight,Activity and Interleukin-2 of Chronic Fatigue Syndrome Model Mice. China J. Chin. Med. 29 (2), 223–225. doi: 10.16368/j.issn.1674-8999.2014.02.040
Zhang, Z., Lu, F., Liu, H., Zhao, H., Liu, Y., Fu, S., et al. (2017). An integrated strategy by using target tissue metabolomics biomarkers as pharmacodynamic surrogate indices to screen antipyretic components of Qingkaikling injection. Sci. Rep. 7 (1), 6310. doi: 10.1038/s41598-017-05812-0
Zhao, J., Dong, Z., Zhu, Y., Chen, G. B., Liu, C. (2009). Anti-inflammation,analgesic and anti-diarrhea effect of volatile oil from A.longiligulare.T.L.Wu. Chin. Tradit. Patent Medi. 31 (07), 1010–1014. doi: 10.3969/j.issn.1001-1528.2009.07.009
Zhao, J., Evangelopoulos, D., Bhakta, S., Gray, A. I., Seidel, V. (2014). Antitubercular activity of Arctium lappa and Tussilago farfara extracts and constituents. J. Ethnopharmacol. 155 (1), 796–800. doi: 10.1016/j.jep.2014.06.034
Zhen, G., Jing, W., Jing, J., Xu, D., Zheng, L., Li, F. (2018). Effects of Modified Zhisou Powder on Airway Mucus Production in Chronic Obstructive Pulmonary Disease Model Rats with Cold-Dryness Syndrome. Evid. Based Complement. Alternat. Med. 2018, 7297141. doi: 10.1155/2018/7297141
Zhong, S., Nie, Y. C., Gan, Z. Y., Liu, X. D., Fang, Z. F., Zhong, B. N., et al. (2015). Effects of Schisandra chinensis extracts on cough and pulmonary inflammation in a cough hypersensitivity guinea pig model induced by cigarette smoke exposure. J. Ethnopharmacol. 165, 73–82. doi: 10.1016/j.jep.2015.02.009
Zhong, S., Liu, X. D., Nie, Y. C., Gan, Z. Y., Yang, L. Q., Huang, C. Q., et al. (2016). Antitussive activity of the Schisandra chinensis fruit polysaccharide (SCFP-1) in guinea pigs models. J. Ethnopharmacol. 194, 378–385. doi: 10.1016/j.jep.2016.08.008
Zhou, X., Leung, P. H., Li, N., Ye, Y., Zhang, L., Zuo, Z., et al. (2009). Oral absorption and antitussive activity of tuberostemonine alkaloids from the roots of Stemona tuberosa. Planta Med. 75 (6), 575–580. doi: 10.1055/s-0029-1185363
Keywords: COVID-19, traditional Chinese medicine, fever, cough, fatigue, diarrhea
Citation: Luo C-h, Ma L-l, Liu H-m, Liao W, Xu R-c, Ci Z-m, Lin J-z, Han L and Zhang D-k (2020) Research Progress on Main Symptoms of Novel Coronavirus Pneumonia Improved by Traditional Chinese Medicine. Front. Pharmacol. 11:556885. doi: 10.3389/fphar.2020.556885
Received: 29 April 2020; Accepted: 25 August 2020;
Published: 11 September 2020.
Edited by:Hung-Rong Yen, China Medical University, Taiwan
Reviewed by:Yuelin Song, Beijing University of Chinese Medicine, China
Subhash Chandra Mandal, Government of West Bengal, India
Priyia Pusparajah, Monash University Malaysia, Malaysia
Copyright © 2020 Luo, Ma, Liu, Liao, Xu, Ci, Lin, Han and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
†These authors have contributed equally to this work