Therapeutic Effects and Molecular Mechanisms of Bioactive Compounds Against Respiratory Diseases: Traditional Chinese Medicine Theory and High-Frequency Use

Respiratory diseases, especially the pandemic of respiratory infectious diseases and refractory chronic lung diseases, remain a key clinical issue and research hot spot due to their high prevalence rates and poor prognosis. In this review, we aimed to summarize the recent advances in the therapeutic effects and molecular mechanisms of key common bioactive compounds from Chinese herbal medicine. Based on the theories of traditional Chinese medicine related to lung diseases, we searched several electronic databases to determine the high-frequency Chinese medicines in clinical application. The active compounds and metabolites from the selected medicines were identified using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) by analyzing oral bioavailability and drug similarity index. Then, the pharmacological effects and molecular mechanisms of the selected bioactive compounds in the viral and bacterial infections, inflammation, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, asthma, and lung cancer were summarized. We found that 31 bioactive compounds from the selected 10 common Chinese herbs, such as epigallocatechin-3-gallate (EGCG), kaempferol, isorhamnetin, quercetin, and β-sitosterol, can mainly regulate NF-κB, Nrf2/HO-1, NLRP3, TGF-β/Smad, MAPK, and PI3K/Akt/mTOR pathways to inhibit infection, inflammation, extracellular matrix deposition, and tumor growth in a series of lung-related diseases. This review provides novel perspectives on the preclinical study and clinical application of Chinese herbal medicines and their bioactive compounds against respiratory diseases.


INTRODUCTION
Respiratory diseases include respiratory infectious diseases, asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary disease (ILD), and lung cancer. These diseases are characterized by the injuries of bronchial and alveolar tissue to cause respiratory dysfunction and even respiratory failure. Respiratory infectious diseases mainly caused by viruses or bacteria and often contagious, remain a major global public health problem. For example, since the outbreak of coronavirus disease  at the end of 2019, there have been nearly 180 million confirmed cases, including 3.9 million deaths by June 25, 2021(Mortality et al., 2019Berlin et al., 2020). Pneumonia is another common respiratory infection, it can lead to hospitalization and death in all age group, and the annual costs exceed $10 billion in the United States and Europe (Global, 2018;Stets et al., 2019). Chronic respiratory diseases such as COPD, ILD, pulmonary fibrosis (PF), and lung cancer, seriously affect human health, these diseases were associated with more than 4 million deaths (7% of all deaths) worldwide in 2017 (Global, 2018). They are induced by long-term exposure to airborne pollutants, tobacco, or kitchen smoke, and their mortality by 18.0% in the last 30 years (Li et al., 2020a). COPD has become the fourth leading cause of death worldwide (Ferkol and Schraufnagel, 2014). Moreover, the quality of life in patients with ILD and IPF is severely affected due to progressive scarring of the lung parenchyma and impairment of pulmonary function (Wollin et al., 2019;Spagnolo et al., 2021). In addition, lung cancer has poor survival and high mortality, and it is the most common cause of cancer-related death worldwide (Siegel et al., 2021). The concern due to the global burden of respiratory diseases, such as the ongoing global pandemic of COVID-19, COPD, and lung cancer, has stimulated research on the treatment and prevention of respiratory diseases. Therefore, the therapeutic effects and molecular mechanisms of potential intervention strategies have become a hot spot for multidisciplinary research.
Traditional Chinese medicine (TCM) has a history of more than 3,000 years and has been used for the prevention and treatment of many respiratory diseases. The ancient medicine books named "Shennong Ben Cao Jing" and "Shanghan Lun" clearly recorded the theories of traditional Chinese medicine, such as reducing phlegm and relieving cough and asthma, and many prescriptions for the prevention and treatment of lungrelated diseases. Based on thousands of years of clinical application and the modernization of TCM research, hundreds of Chinese medicines have been shown to be effective in the current clinical applications for treating respiratory infections, asthma, chronic lung diseases, and lung cancer; these effects are based on the therapeutic and improved effects for acute respiratory symptoms and lung dysfunction (Ren et al., 2020;Zhang et al., 2021). Importantly, bioactive compounds or their metabolites from these medicines with high-frequency use, such as saponins, flavonoids, alkaloids, and phenolic acids, are critical for the prevention and treatment of respiratory diseases (Shahidi and Yeo, 2018;Ory et al., 2019;Russo et al., 2020). Currently, the roles of different medicines are summarized in most review, not for potential active components of these medicines for fighting the diseases of respiratory systems. It is necessary to summarize the recent findings regarding the therapeutic effects and molecular mechanisms of bioactive compounds from commonly used Chinese medicines for preventing and treating a series of lung-related diseases. In this review, we first searched English or Chinese electronic databases for clinical studies of TCM against respiratory diseases to identify the Chinese medicines with high-frequency use in the clinical setting. The active components and their metabolites from the selected medicines were identified using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) by analyzing oral bioavailability and drug similarity index. Then, the published studies for advanced research of those bioactive compounds after screening in multiple disorders of respiratory system were collected. Finally, we summarized the pharmacological effects and molecular mechanisms of the selected bioactive compounds in the viral and bacterial infections, inflammation, acute lung injury (ALI), COPD, PF, and lung cancer. This review provides new insights into the clinical use of medicinal herbs for the prevention and treatment of respiratory diseases.
system. After sorting, we identified 165 bioactive compounds from these 10 herbs, such as epigallocatechin-3-gallate (EGCG), kaempferol, apigenin, ellagic acid and resveratrol for further analysis. Then, we searched the databases (PubMed, EMBASE, or Web of Science) using the keywords for one of the ingredients from the TCMSP and a type of disease, such as respiratory infection, COVID-19, inflammation, ALI, PF, COPD, asthma, or lung cancer to obtain articles published from January 2000 to May 2021.
Articles that included both components and disease terms, excluding review articles were identified as reference lists (4,519 articles). Titles and abstracts of all the records were screened to exclude irrelevant studies (duplicates: n 3,276; publication before 2000: n 171, non-English: n 20). We further excluded the irrelevant records for the subject (n 416), target herbs (n 216), Chinese medicinal formulae/mixture compounds (n 60), targeting drug delivery system (n 25), or computational study without experimental validation (n 60). Moreover, 74 reports for component analysis were added to obtain 349 full-text articles for eligibility assessment. Finally, 129 articles for the therapeutic effects and molecular mechanisms of 31 bioactive compounds from the selected 10 herbs were enrolled in the final analysis, after excluding similar studies or those not relevant to our topic of this review (n 234). The detailed flow chart of the published articles collection is shown in Figure 1.

Viral and Bacterial Infections
Bacterial and viral infections account for up to 70% of all pathogenic diseases in humans (Smith et al., 2014). Influenza is one of the most prevalent respiratory diseases, and accounts for nearly 5-15% of people all respiratory infections. Although most patients recover, about 0.5 million people die of influenza each year (Petrova and Russell, 2018). The outbreak of COVID-19 has become a global health emergency on a pandemic scale, which has given rise to various studies and developments of antiviral drugs and vaccines. Coronaviruses identify the angiotensin-converting enzyme 2 (ACE2) as the main entry point into the respiratory epithelial cells of the host (Zhou et al., 2020a). Potential targets, including retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5/mitochondrial antiviral signaling/TNF receptor-associated factor 3/interferon regulatory factor 3 (IRF3)/IRF7, and Toll-like receptors (TLRs)/TIR-domain-containing adapter-inducing interferonβ/nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (MAPK)/activating protein-1 (AP-1) pathways as intercellular sensors have been detected to study translation and budding process of SARS-CoV-1 and MERS viruses infection with SARS-CoV-1 using in vitro and in vivo models (Stertz et al., 2007), which may cause cellular death, hyperinflammation, and cytokine storm during viral infections (Azkur et al., 2020).
Neochlorogenic acid from Tussilago farfara L. and Lianhuaqingwen granules inhibit the ACE2 enzyme activity (Chen et al., 2021a). Hesperidin and hyperoside from Eriobotrya japonica (Thunb.) Lindl. show antiviral and antiinflammatory effects against H1N1 virus (Ding et al., 2018;Ling et al., 2020). In H9N2 virus-induced pneumonia, kaempferol inhibits TLR4/Myeloid differentiation factor 88 (MyD88)/NF-κB signaling pathways to reduce the production of inflammatory factors and enhance antioxidant ability (Zhang et al., 2017a). β-sitosterol from eight herbs, such as Morus alba L., and Datura metel L., inhibits RIG-I and signal transducer and activator of transcription 1 (STAT1) signaling pathway to improve interferon sensitization (Zhou et al., 2020b). As for bacterial infections, it has been reported that benzaldehyde has a good inhibitory effect on a variety of bacteria (Lee et al., 2014a). SARS-CoV-2 spike receptor-binding domain, ACE2, and inflammatory response are essential targets of these bioactive compounds, which may be related to Toll-like receptor and MAPK signaling pathways. Overall, the antiviral and antibacterial effects of these active compounds mentioned above are shown in Table 1.

Inflammation and ALI
ALI is common in pulmonary infection, lung contusion, pulmonary embolism, and near-drowning, it can lead to acute respiratory distress syndrome (ARDS) (Suresh et al., 2000). The mortality of ARDS ranges from 35 to 46%, which is higher than mortality of breast cancer or HIV infection . Patients recovered from ARDS may experience physical, neuropsychiatric, and neurocognitive morbidity that persistently impair their quality of life (Fan et al., 2014).

Chronic Obstructive Pulmonary Disease
The pathogenesis of COPD is related to chronic inflammation, oxidative stress, cellular senescence, corticosteroid resistance, cell apoptosis, and changes in pulmonary histology and functions. The proinflammatory cytokines and chemokines (TNF-α, IL-1, IL-6, and IL-8), the signaling pathways (NF-κB and MAPK pathways), and various stress-related molecules (SOD, MDA, GSH) participate in the different pathological stages of COPD . IL-8 recruits neutrophils and secretes several neutrophil elastases and metalloproteases, e.g., MMP-9, which results in alveolar destruction. GM-CSF and IL-6 contribute to the increase in airway smooth muscle mass and proliferation, leading to bronchial obstruction (Knobloch et al., 2018;Jamal Jameel et al., 2021). Human airway smooth muscle cells (HASMCs) contributing to the secretion of cytokines and chemokines are related to non-type 2 airway inflammation and remodeling processes in COPD (Knobloch et al., 2013;Knobloch et al., 2016;Knobloch et al., 2019). Exposure to gases from cigarette smoking and inhaled particles such as PM2.5 are two archetypical inducing factors of COPD, which means that cigarette smoke and PM2.5 are commonly used for establishing in vivo and in vitro models of COPD (Rabe and Watz, 2017). Many studies have shown that multiple herbs, such as Tussilago farfara L., Eriobotrya japonica (Thunb.) Lindl., and Morus alba L. can inhibit the progression of COPD. Tussilagone and EGCG from the herbs mentioned above enhance the antiproliferative activity through the inhibition of the NF-κB pathway (Choi et al., 2018;Lakshmi et al., 2020). Amygdalin ameliorates the process of epithelial-mesenchymal transition (EMT) through the TGF-β/Smad pathway in cigarette smokeexposed BEAS-2B cell line and mice model . Ursolic acid attenuates emphysema and enhances airway remodeling via unfolded protein response (UPR) signaling pathways (Lin et al., 2019;Li et al., 2020b). Liquiritin can reduce pulmonary inflammation by targeting the TGF-β pathway (Guan et al., 2012). Resveratrol inhibits the autophagic process and decreases IL-1β production by inactivation of NLRP3 inflammasome (Ding et al., 2019) or regulation of p53 destabilization (Navarro et al., 2017). Alveolar macrophages are important immune and inflammatory regulatory cells in the lung tissue (Gerlach et al., 2015). Resveratrol reduces the expression of MMP-9, GM-CSF and inflammatory mediators including IL-6, IL-8, and MCP-1 in alveolar macrophages under the stimulation of different harmful substances (Culpitt et al., 2003;Knobloch et al., 2011). Other reports have shown that resveratrol inhibits cytokines and chemokines (CCL-2, IL-6, IL-8) and ameliorates bronchial obstruction-related secretory proteins (GM-CSF and VEGF) in HASMCs from smokers and COPD patients. Similar to the findings against inflammation and ALI, SIRT1 and p38 MAPK are regarded as therapeutic targets of resveratrol in lipoteichoic acid Frontiers in Pharmacology | www.frontiersin.org August 2021 | Volume 12 | Article 734450 5 (LTA)-or TNF-α-stimulated HASMC models (Knobloch et al., 2010;Knobloch et al., 2014). The abovementioned therapeutic effects and mechanisms of resveratrol have also been demonstrated in animal models Wang et al., 2017a). Together, these findings suggest that six main compounds can regulate NF-κB, UPR, TGF-β, MAPK and SIRT1 pathways to inhibit COPD in different cell and animal models ( Table 3).

Pulmonary Fibrosis
It is now clear that many elements of the innate and adaptive immune response participate in the differentiation and activation of fibroblasts. The pathogenesis of PF is related to adaptive and innate immune activation, inflammation, epithelial/endothelial damage, EMT and cell apoptosis. Specifically, the activation of TGF-β or NF-κB pathway is the primary factor driving the progression of PF (Kitani et al., 2003;Wynn and Ramalingam, 2012). Some natural products, such as β-sitosterol, quercetin, ferulic acid, hesperidin, and EGb761 from various herbs, inhibit PF by downregulating TGF-β. β-sitosterol and ferulic acid suppress EMT and reduce extracellular matrix (ECM) through the TGF-β/Smad-dependent signaling pathways (Park et al., 2019;Ali et al., 2021). Quercetin suppresses Akt/mammalian target of rapamycin (mTOR) pathway in TGF-β-mediated responses and reduces fibrotic factors, such as collagen I, collagen III, and IL-6 (Xiao et al., 2020b). Another study has reported that quercetin enhances the expression of caveolin1 (CAV1), the cell membrane lipid raft and a protective factor for PF, to inhibit ligand-induced apoptosis in fibroblasts (Hohmann et al., 2019). For other bioactive compounds, hesperidin and EGb761 improve the progression of PF by mediating the proinflammatory cytokines and apoptosis-related proteins via the crosstalk of NF-κB and TGF-β pathways Pan et al., 2020).

Lung Cancer
Lung cancer is the malignant tumor with the highest mortality rate. It causes 1.6 million deaths every year, but treatment can effectively prolong survival and quality of life (Siegel et al., 2021). TCM treatment can effectively improve the quality of life and survival time of patients with advanced lung cancer with or without conventional therapy Jiang et al., 2016b;Xu et al., 2011). Active components of TCM participate in the treatment of lung cancer through the regulation of multiple pathways ( Table 6). Ursolic acid and β-sitosterol show a good lung cancer-inhibiting effect via the TGF-β/Smad pathway (Ruan et al., 2019;Sundarraj et al., 2012;Wang et al., 2017b). Caffeic acid and sanguinarine enhance the antiproliferative effect of paclitaxel in lung cancer A549 and H1299 cells (Lin et al., 2012). Sanguinarine can target NF-κB pathway-mediated autophagy and mitophagy to block lung cancer progression (Yu et al., 2020b). Meanwhile, the p53 protein is a transcription factor that inhibits cell proliferation or survival, acting as a key tumor suppressor protein (Skoulidis and Heymach, 2019). Loss or mutant of p53 induces lung cancer with shortened latency and increases rapid progression and poor prognosis (Donehower et al., 2019). Natural products such as hyperoside, resveratrol, liquiritin, and formononetin have a good effect on improving the antitumor function of p53 and inducing the apoptosis of tumor cells. Hyperoside increases Caspase-9/Caspase-3 activation to induce apoptosis in in vitro and in vivo models of A549 and H1975 cells Lü, 2016). Resveratrol decreases antiapoptotic factors, Bcl-2 and Bcl-xl and the levels of MMP2, and MMP9 by upregulating the p53/HO-1 pathways against lung cancer (Liu et al., 2010;Rasheduzzaman et al., 2018;Li et al., 2019). Liquiritin decreases the expression levels of PCNA, p-PTEN, caspase family, and PARP (Zhou and Ho, 2014). Formononetin promotes Mcl-1 ubiquitination and degradation via Fbw7 to enhance the EGFR-TKI sensitivity Yu et al., 2020c). The PI3K/Akt signaling pathway is an important dysregulated pathway in tumorigenesis, which controls lung cancer growth, metabolism, motility, and other key cellular processes (Janku et al., 2018). Isorhamnetin and apigenin inhibit EMT and decrease invasion by inhibiting Akt activation (Chang et al., 2018b;Luo et al., 2019). Moracin N induces autophagy mTOR signaling pathway . Furthermore, isorhamnetin as a potential application in adjuvant radiotherapy inhibits the activation of NF-κB and increases the expression of IL-13 (Du et al., 2020). Resveratrol and ellagic acid promote lung cancer cell apoptosis via the PI3K/Akt signaling pathway (Liu et al., 2018b;Li et al., 2019). Amygdalin downregulates the phosphorylation of Akt to inhibit invasion and migration of H1299 and PA cells (Qian et al., 2015). Inactivation of STAT3 is a target for increasing cisplatin sensitivity in lung cancer treatment, galangin, and laricitrin are STAT3 inhibitors in adjuvant chemotherapy (Chang et al., 2016a;Chang et al., 2016b;Yu et al., 2018). Oleanolic acid enhances mitophagy through the PINK1/Parkin axis in A549 cells (Castrejón-Jiménez et al., 2019). Rosmarinic acid could reverse the cisplatin resistance by inhibiting the expression of P-gp, MDR1, and MAPK pathways and plays a key role in the treatment of non-small cell lung cancer (NSCLC) (Liao et al., 2020). EGCG from Eriobotrya japonica (Thunb.) Lindl. and Ginkgo biloba L. can suppress the levels of Axl and Tyro three to reduce the resistance to platinum (Kim and Lee, 2014). Ginkgolide B and glabridin from Ginkgo biloba L. have inhibitory effects on autophagy and angiogenesis, mediated by Beclin-1 or FAK/Src complex, respectively (Tsai et al., 2011;Wang et al., 2020c). In H1975 cell model, ursolic acid inhibits the Wnt/β-catenin pathway to suppress proliferation and induce apoptosis . As a cisplatin sensitizing agent, ginkgetin enhances the ferroptosismediated disruption of the Nrf2/HO-1 axis (Lou et al., 2021). Kaempferol downregulates Nrf2 and upregulates miR-340 to induce apoptosis and autophagy (Han et al., 2018;Fouzder et al., 2021). As for quercetin, it can target aurora B or miR-16-5p/WEE1 pathways to inhibit lung cancer progression and enhance the radiosensitivity of NSCLC cells (Xingyu et al., 2016;Wang et al., 2020d). Hesperidin exhibits antiproliferative and apoptosis induction effects by regulating the miR-132/ZEB2 signaling pathway (Birsu Cincin et al., 2015;Tan et al., 2020). Luteolin inhibits cell proliferation and induces apoptosis via miR-34a-5p targeting MDM4 and RhoA (Jiang et al., 2018;Masraksa et al., 2020). Taken together, these results demonstrate that these bioactive compounds have anticancer effects by targeting multiple pathways, including NF-κB, p53, TGF-β, or miRNAs ( Table 6). Collectively, the network of bioactive compounds, targets, signal pathways, and different pulmonary diseases is visualized in Figure 2. These bioactive compounds, such as isorhamnetin, formononetin, resveratrol, and galangin are active substances of types of saponins, flavonoids, and alkaloids, which can regulate different key targets (NF-κB, PI3K/Akt, Nrf-2, NLRP3) to regulate cytokine production, oxidative stress or chemotherapy sensitivity against a series of lung-related diseases.

DISCUSSION
According to the theories of TCM and commonly used Chinese medicines in the clinical application against respiratory diseases, this review summarizes the pharmacological effects and molecular mechanisms of 31 active compounds of 10 Chinese herbal medicines in six main lung-related diseases, including pulmonary infection, ALI, PF, COPD, asthma, and lung cancer.   pathways, reducing the release of cytokines and chemokines, and suppressing inflammation by pathological reaction, oxidative stress, and ROS production. Eriobotrya japonica (Thunb.) Lindl. and its compounds (EGCG, isorhamnetin, hesperidin, hyperoside, kaempferol, β-sitosterol) may be considered an effective Chinese herbal medicine for the treatment of viral infections. Flavonoids, including apigenin, galangin, isorhamnetin, rutin, moracin M, amygdalin, hesperidin, quercetin, formononetin, luteolin, and liquiritin, exhibit good bioactivity against ALI. As for inflammation, bioactive compounds from Aster tataricus L.f. and Eriobotrya japonica (Thunb.) Lindl. have potential anti-inflammatory activity, suggesting that apigenin, quercetin, luteolin, and isorhamnetin are effective anti-inflammatory compounds. In the studies of COPD, bioactive compounds have mainly attenuated cigarette smoke-induced emphysema, airway remodeling, and inflammation through the NF-κB, MAPK, and TGF-β/Smad pathways, and resveratrol is one of the important and effective bioactive substances against COPD. Multiple components, including β-sitosterol, ferulic acid, quercetin, hesperidin, EGb761, and resveratrol, are directly or indirectly related to TGF-β/Smad, which is a crucial target for PF. These components can effectively suppress biological process of EMT and ECM. In asthma, rosmarinic acid, tussilagone, formononetin, and galangin targeting the MAPK and NF-κB pathways to reduce OVA-specific IgE, and ameliorate airway hyperplasia and hypertrophy. Importantly, these active components such as organic acids and flavonoids can inhibit the proliferation and migration of lung cancer and increase its sensitivity to radiotherapy and chemotherapy. Hyperoside, resveratrol, glabridin, luteolin, and kaempferol are considered potential candidates for the treatment of lung cancer based on a large number of studies. Collectively, ECCG, kaempferol, isorhamnetin, quercetin, and β-sitosterol are important bioactive compounds for prevention and treatment of ALI, PF, and lung cancer. Taken together, multiple bioactive compounds from the 10 different herbs have potential therapeutic effects against respiratory diseases by regulating various molecular pathways (Figures 2, 3). However, in the studies of different bioactive compounds on respiratory diseases, three important aspects should be considered. Firstly, only key and common active ingredients in each herb are summarized, which might not be fully representative of the herb. More active components should be further identified to explore their pharmacological effects against respiratory diseases. Secondly, multiple compounds In a herb can target similar or different signaling pathways to play the potential roles in those diseases. The network of various targets of different components might be used to explain the combined effect of the formula. Thirdly, different signaling pathways or pathological procedures in infection, inflammation, COPD, or lung cancer are potential targets for these active ingredients. However, the potential targets and the binding role of these active compounds still remain unclear. It should be a future direction for most researchers to confirm specific targets of those potential drug candidates using multiple modern techniques. Finally, the quantitative analysis for the biological activity, toxicity and selectivity of 31 bioactive compounds should be performed in a kind of respiratory diseases to predict the FIGURE 2 | Network of bioactive compounds, targets, pathways, and six main respiratory diseases.
Frontiers in Pharmacology | www.frontiersin.org August 2021 | Volume 12 | Article 734450 promising candidates for drug development using systematic review and meta-analysis. Overall, this review provides novel perspectives on the preclinical study and clinical application of herbal medicines and their bioactive compounds against respiratory diseases.

CONCLUSION
In summary, 10 Chinese herbal medicines were selected based on the theories of TCM and high-frequency use of Chinese medicines in clinical application. The pharmacological effects and molecular mechanisms of 31 bioactive compounds from these 10 Chinese herbs in infection, ALI, PF, COPD, asthma, and lung cancer were summarized. The bioactive compounds, such as epigallocatechin-3-gallate, kaempferol, isorhamnetin, quercetin, and β-sitosterol, can mainly regulate the NF-κB, Nrf2/HO-1, NLRP3, TGF-β/Smad, MAPK, and PI3K/Akt/mTOR pathways to inhibit infection, inflammation, extracellular matrix deposition, and tumor growth in a series of lung-related diseases. This review provides novel perspectives on the preclinical study and clinical application of Chinese herbal medicines and their bioactive compounds against respiratory diseases.

AUTHOR CONTRIBUTIONS
JW and QW collected, analyzed, and reviewed the literatures and wrote the draft manuscript; JW, QW, LD, SS, and YL added/ checked references and assembled figures/tables; LS, TW, and DZ supervised the manuscript; ZW and XL designed and revised the whole manuscript. All authors have read and agreed to the published version of the manuscript.

ACKNOWLEDGMENTS
We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript. Frontiers in Pharmacology | www.frontiersin.org August 2021 | Volume 12 | Article 734450