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Herb Exocarpium Citri grandis in the prevention and treatment of COVID-19

Abstract Huajuhong (Exocarpium Citri grandis, ECG) is a traditional Chinese herbal medicine and has been used for the treatment of respiratory diseases for hundreds of years. Recently, ECG has been listed in a traditional Chinese medicine formula in the Guidelines for the Diagnosis and Treatment of Coronavirus Disease 2019 (sixth edition) in China. To date, the effect and mechanism of ECG against respiratory diseases have not been systematically reviewed. In this paper, the researchers summarized the effects of ECG and its pharmacologically active compound naringin in functioning as an antitussive and expectorant, improving lung function, alleviating acute lung injury, attenuating pulmonary fibrosis, and enhancing antiviral immune response, so as to provide a reference for its clinical application in the prevention and treatment of multiple respiratory diseases, including coronavirus disease 2019.

Keywords Huajuhong; Exocarpium Citri grandis; Naringin; coronavirus disease 2019; Clinical application

Background The coronavirus disease (COVID-19), which broke out in Wuhan at the end of 2019, is rapidly becoming a huge challenge for global public health systems due to its strong infectivity and no specific drug treatment [1, 2]. To date, most COVID-19-infected patients manifest clinical symptoms, such as fever, dry cough, fatigue, and dyspnea. Some severe cases have developed various fatal complications, including acute respiratory distress syndrome, septic shock, metabolic acidosis, and coagulation dysfunction [3, 4]. Clinical imaging shows that multiple small patchy shadows and interstitial changes appear in lung tissue (especially evident in the lung periphery zone) in the early stages of COVID-19 infection. Subsequently, multiple ground-glass infiltration, as well as infiltration shadows and parenchymal lesions, can be observed in the lung tissue in severe cases [5, 6]. The latest autopsy results show that the small airways and alveoli of the dead patients contain a large amount of viscous secretions, which may lead to pulmonary embolism and, eventually, death [7]. The damage of COVID-19 to the human body is multifaceted, especially to the respiratory system, which may lead to serious symptoms, such as pulmonary hypofunction and acute lung injury [8]. Recently, the clinical treatment and prevention of COVID-19 involves administering antiviral and anti-inflammatory drugs, improving lung function, promoting sputum excretion, and alleviating acute lung injury. Traditional Chinese medicine (TCM) has played an important role in the prevention and treatment of COVID-19 [9]. Huajuhong is the dried epicarp of Exocarpium Citri grandis (ECG), which originated from Huazhou town in the Guangdong province of South China [10]. It was first documented in an ancient TCM book, Bencao Gangmu Shiyi (Supplement to Compendium of Materia Medica), which was written in 1765 C.E. Moreover, ECG has been used as folk herbal medicine in the treatment of respiratory diseases for hundreds of years [11, 12]. ECG was included in the Chinese Pharmacopoeia since 1977 and was a primary ingredient in many famous TCM prescriptions [13]. The flavonoids contained in ECG, especially naringin, have been proven to be the primary active components [14, 15]. The researchers’ preliminary studies have revealed that ECG possessed excellent antitussive, expectorant, anti-asthmatic [14], and anti-inflammatory effects [16]. Its antitussive effects are not associated with the central nervous system; that is, it’s does not depend on the C fibers in the trachea but are rather related to the discharge of rapid adaptation receptors (RARs) [17]. Furthermore, toxicological studies suggested that ECG has no obvious toxic and side effects on the nervous system, cardiovascular system, and respiratory system of experimental animals [18]. A systematic chemical profiling analysis revealed that naringin is the primary flavonoid in ECG [10, 19]. Naringin (naringenin-7-O-rhamnoglucoside) is a flavanone glycoside that is widely distributed in plant-based food [20]. Evidence from numerous studies supports that naringin possesses pharmacological benefits for the treatment of multiple illnesses [21–23]. Besides, naringin and its metabolite naringenin are systematically evaluated for their therapeutic effects on respiratory diseases [24, 25]. Both are found to be effective in relieving cough, phlegm, and pulmonary inflammation [26–28]. Moreover, the efficacy of naringin against Severe Acute Respiratory Syndromeis also documented (Chinese patent: ZL03126908.7) [29]. Recently, ECG has been listed in a TCM formula in Diagnosis and Treatment Protocol for COVID-19 (Trial Version 6) issued by the National Health Commission of the People’s Republic of China [30]. However, the efficacy and mechanism of ECG against respiratory diseases have not been systematically reviewed yet. In this paper, the authors summarized the efficacy of ECG in functioning as an antitussive and expectorant, improving lung function, alleviating acute lung injury, attenuating pulmonary fibrosis, and enhancing antiviral immune response, to show its potential application in the prevention and treatment of multiple respiratory diseases, including COVID-19.

Application prospect of ECG against COVID-19 Antitussive efficacy ECG was found to exert significant antitussive effects on pathological cough caused by smoking and ovalbumin-induced cough-variant asthma in guinea pigs [31, 32]. Gao et al. investigated the antitussive mechanism of naringin in a guinea pig cough model [26]. Naringin was found to be a peripheral antitussive. Further studies suggested that the mechanism of action of naringin did not associate with either the sensory neuropeptide system or the modulation of ATP-sensitive K+ channels. It is considered to exhibit its peripheral antitussive effects through RARs, which were the main afferent nerve fibers to stimulate cough [33]. Shi et al. evaluated the relaxant effect of naringin on rat tracheal smooth muscle by measuring the muscular tension in rat tracheal rings using a mechanical recording system [34]. Naringin was observed to relax tracheal smooth muscle by opening large conductance Ca2+-activated K+ channels, which mediate plasma membrane hyperpolarization and reduces Ca2+ influx. The obtained results revealed the therapeutic potential of naringin against cough-variant asthma. Expectorant efficacy Naringin has a regulating effect on mucus and serous components in sputum [35, 36]. On the one hand, naringin can significantly inhibit the synthesis and secretion of rat airway mucin 5AC induced by lipopolysaccharides (LPS) and the proliferation of airway epithelial goblet cells, while significantly inhibiting the high secretion of mucin induced by epidermal growth factor [35]. On the other hand, the expression and function of cystic fibrosis transmembrane conductance regulator in the basal parietal membrane promotes the secretion of Cl− to the airway cavity. This then activates aquaporin (AQP) through osmotic pressure to promote the secretion of serous fluids in the airway, while upregulating the expression of AQP1 and AQP5, which are inhibited by LPS and particulate matter (PM) 2.5 [36]. Improving lung function Naringin was proven to improve lung function and regulate pulmonary secretion [24]. Shi et al. revealed that naringin improved lung function in mice with lung injury caused by cigarette smoke and PM 2.5 [37]. Naringin can increase dynamic lung compliance, decrease static lung compliance, reduce lung resistance, increase peak expiratory flow rate, increase FEV20/FVC, and improve total lung air volume. These results suggest that naringin not only improves the elasticity of respiratory muscles and affect elastic resistance, but also increases the size of the respiratory tract and reduce airway resistance. Alleviating acute lung injury Naringin possesses a significant inhibitory effect on LPS-induced acute lung inflammation [38–40]. In addition, naringin also significantly inhibits cigarette smoke-induced symptoms of chronic obstructive pulmonary disease, such as chronic airway inflammation, high secretion of mucus, cough hyperresponsiveness, and airway hyperresponsiveness [28, 31]. On the one hand, naringin can significantly inhibit the level of pro-inflammatory factor interleukin 8 in alveolar lavage fluid, reduce neutrophil infiltration, inhibit the decrease of anti-inflammatory factor interleukin 10, and promote the expression of lipoxin A4 receptor. On the other hand, by regulating the release of nitric oxide and metabolism of pro-oxidant homocysteine, naringin can reduce lung inflammation and damage to lung tissue, as well as promote inflammation resolution [41]. Attenuating pulmonary fibrosis Pulmonary fibrosis is a severe diffuse pulmonary inflammatory disease caused by a variety of factors. Its pathogenesis includes damage to alveolar epithelial cells, aggregation and activation of inflammatory cells, apoptosis, fibroblast proliferation, and collagen production [42]. Chen et al. evaluated the protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice. The results showed that naringin reduced the levels of tumor necrosis factor-α, transforming growth factor-β1, matrix metalloproteinase-9, tissue inhibitors of metalloproteinases-1, hydroxyproline, and malonaldehyde; while it also significantly increased the activities of several antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and heme oxygenase) [43]. Enhancing antiviral immune response In a preliminary study, the researchers evaluated the potential of naringin in the supportive treatment of severe acute respiratory syndrome (Chinese patent: ZL03126908.7) [29]. Recently, Cheng et al. investigated the effects of several flavonoids on immunoregulation and its use in potential targeting ACE2 (angiotensin-converting enzyme 2), which is a receptor of the coronavirus [44]. Naringin was found to inhibit the expression of the proinflammatory cytokines induced by LPS in raw macrophage cell lines, showing its effects for preventing a cytokine storm. Further molecular docking revealed that naringin had stronger binding affinity to ACE2, suggesting its potential in preventing coronavirus infection. Moreover, some metabolites derived from naringin are also found to possess antiviral activities. For example, 3-(4′-hydroxyphenyl) propionic acid (HPPA) is the primary metabolite of naringin that is catabolized by gut microbiota [45–47]. HPPA is absorbed by the intestinal tract into the blood circulatory system and then reach the lungs and trachea [48]. Recently, HPPA was found to enhance the type I interferon signal, enhance the immune response of macrophages, and regulate the function of antigen-presenting cells and T cells, thereby opening up and enhancing the entire body [49]. The antiviral immune response can enhance type I interferon signaling to prevent influenza infection before it occurs [50], given that naringin is eventually degraded into HPPA [51]. Hence, naringin intake can probably enhance antiviral immune response.

Conclusions In summary, ECG is a pharmacologically active folk herb which can be used for the treatment of respiratory diseases (Figure 1). It contains flavonoids that have been assigned as the primary active components, especially naringin. To be specific, its therapeutic effects in respiratory diseases are described above: (1) naringin is a peripheral antitussive and exerts its efficiency through RARs; (2) naringin has a regulating effect on both mucus and serous components in sputum; (3) naringin can improve lung function and regulate pulmonary secretion; (4) naringin can alleviate acute lung injury by inhibiting the secretion of pulmonary inflammatory factors and promote inflammation resolution; (5) naringin possesses therapeutic effects in attenuating pulmonary fibrosis; (6) naringin can enhance the antiviral immune response through its catabolite HPPA. These results suggest that naringin has a great potential for application in alleviating the respiratory symptoms caused by COVID-19.

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