key: cord-0734431-07vql51z
authors: Yang, Liyan; Wang, Zhonglei
title: Natural Products, Alone or in Combination with FDA-Approved Drugs, to Treat COVID-19 and Lung Cancer
date: 2021-06-18
journal: Biomedicines
DOI: 10.3390/biomedicines9060689
sha: 38d73821b14860c7e444733389d19d261096c3f8
doc_id: 734431
cord_uid: 07vql51z

As a public health emergency of international concern, the highly contagious coronavirus disease 2019 (COVID-19) pandemic has been identified as a severe threat to the lives of billions of individuals. Lung cancer, a malignant tumor with the highest mortality rate, has brought significant challenges to both human health and economic development. Natural products may play a pivotal role in treating lung diseases. We reviewed published studies relating to natural products, used alone or in combination with US Food and Drug Administration-approved drugs, active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lung cancer from 1 January 2020 to 31 May 2021. A wide range of natural products can be considered promising anti-COVID-19 or anti-lung cancer agents have gained widespread attention, including natural products as monotherapy for the treatment of SARS-CoV-2 (ginkgolic acid, shiraiachrome A, resveratrol, and baicalein) or lung cancer (daurisoline, graveospene A, deguelin, and erianin) or in combination with FDA-approved anti-SARS-CoV-2 agents (cepharanthine plus nelfinavir, linoleic acid plus remdesivir) and anti-lung cancer agents (curcumin and cisplatin, celastrol and gefitinib). Natural products have demonstrated potential value and with the assistance of nanotechnology, combination drug therapies, and the codrug strategy, this “natural remedy” could serve as a starting point for further drug development in treating these lung diseases.

As a traditional source for modern pharmaceutical discovery and potential drug leads, natural products have played an integral role in treating patients due to their unique structural, chemical, and biological diversity [1] [2] [3] . The current race to identify efficacious drugs, natural products with promising therapeutic effects has attracted significant attention, especially for the prevention and treatment of lung diseases, such as pulmonary fibrosis [4] , asthma [5] , acute lung injury [6] , chronic obstructive pulmonary disease [7] , defective pulmonary innate immunity [8] , coronavirus disease 2019 (COVID-19) [9] , and lung cancer [10] . Among the myriad of known lung maladies, COVID-19 and lung cancer are currently the most important public health concerns and burdens worldwide [11, 12] .

The highly contagious COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread quickly across all continents [13, 14] . Presently, this global pandemic has posed a significant threat to the lives of billions of individuals through human-to-human transmission [15, 16] . In this scenario, the rapid discovery of efficacious agents against the fast-spreading COVID-19 pandemic is currently Transmembrane protease serine 2 (TMPRSS2), a critical factor enabling SARS-CoV-2 infection, can interact with ACE2 [30] . It has been reported that platycodin D, a triterpenoid saponin isolated from Platycodon grandiflorum, prevents TMPRSS2-driven infection in vitro by impairing membrane fusion [31] . Platycodin D has IC50 values of 0.69 μM and 0.72 μM for SARS-CoV-2 pseudovirus (pSARS-CoV-2) overexpression of ACE2 (ACE2 + ) and ACE2/TMPRSS2 + , respectively, and IC50 values of 1.19 μM and 4.76 μM for SARS-CoV-2 in TMPRSS2-negative Vero cells and TMPRSS2-positive Calu-3 cells, respectively [31] . Resveratrol, a remarkable phytoalexin, may effectively inhibit the replication of SARS-CoV-2 S protein in Vero E6 cells at an EC50 of 4.48 μM [32] , and has an excellent safety tracking record, with no cytotoxicity even up to a concentration of 150 µ M [33] .

The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is another promising target that regulates the replication of the viral genome [34] . Corilagin, a non-nucleoside inhibitor, is a gallotannin isolated from the medicinal plant Phmllanthi Fructus [35] . Corilagin has been reported to inhibit SARS-CoV-2 infection with an EC50 value of 0.13 μM in a concentration-dependent manner by preventing the conformational change of RdRp and inhibits SARS-CoV-2 replication [36] . Furthermore, corilagin, as identified via molecular dynamics simulation-guided studies, could also be used as an endogenous M pro candidate, with an 88% anti-SARS-CoV-2 M pro activity at concentrations of 20 μM in vitro [37] .

Bafilomycin B2, which can be isolated from Streptomyces sp. HTL16, indicates enhanced inhibitory potency against SARS-CoV-2 at IC50 values of 5.11 nM (in the full-time approach) and 8.32 nM (in the pretreatment-of-virus approach) in Vero E6 cells, respectively [38] . While bafilomycin B2 has demonstrated potential effectiveness in inhibiting the The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is another promising target that regulates the replication of the viral genome [34] . Corilagin, a non-nucleoside inhibitor, is a gallotannin isolated from the medicinal plant Phmllanthi Fructus [35] . Corilagin has been reported to inhibit SARS-CoV-2 infection with an EC 50 value of 0.13 µM in a concentration-dependent manner by preventing the conformational change of RdRp and inhibits SARS-CoV-2 replication [36] . Furthermore, corilagin, as identified via molecular dynamics simulation-guided studies, could also be used as an endogenous M pro candidate, with an 88% anti-SARS-CoV-2 M pro activity at concentrations of 20 µM in vitro [37] .

Bafilomycin B 2 , which can be isolated from Streptomyces sp. HTL16, indicates enhanced inhibitory potency against SARS-CoV-2 at IC 50 values of 5.11 nM (in the full-time approach) and 8.32 nM (in the pretreatment-of-virus approach) in Vero E6 cells, respectively [38] . While bafilomycin B 2 has demonstrated potential effectiveness in inhibiting the viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient.

The above evidence supports the potential value of the above natural products as therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natural products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Table 1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020. Table 1 . Other natural products with anti-SARS-CoV-2 activities in vitro.

Name Structure EC 50 or IC 50 

1 Acetoside viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient. The above evidence supports the potential value of the above natural products a therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natura products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Table  1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020. [47] 0.043 Vero E6 cells [39] 2

Anacardic acid viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient. The above evidence supports the potential value of the above natural products a therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natura products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Table  1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020. 2.07 USA-WA1/2020 [26] 3 Andrographolide viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient. The above evidence supports the potential value of the above natural products a therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natura products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Table  1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020. [47] 0.034 Calu-3 cells [40, 41] 4 Apigenin-7-O-glucoside viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient. The above evidence supports the potential value of the above natural products as therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natura products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Table  1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020. [47] 0.074 Vero E6 cells [39] 5 Artemisinin viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient. The above evidence supports the potential value of the above natural products a therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natura products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Tabl 1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020. [41, 42] 6 Azithromycin viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient. The above evidence supports the potential value of the above natural products a therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natura products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Table  1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020. 7 Baicalin viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient. The above evidence supports the potential value of the above natural products a therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natura products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Table  1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020. 8 Cannabidiol viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient. The above evidence supports the potential value of the above natural products a therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting mor validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natura products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Tabl 1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoVagents since 2020. Catechin-3-O-gallate viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient. The above evidence supports the potential value of the above natural products a therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natura products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Tabl 1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020. HEK293T human embryonic kidney cells [62] 8.44 HEK293T human embryonic kidney cells [62] Traditional Chinese medicines have attracted considerable attention due to their ability to effectively inhibit SARS-CoV-2 [63] [64] [65] . For example, the Qingfei Paidu decoction (QFPD) has shown an ability to treat COVID-19 patients at all stages with excellent clinical efficacy (cure rate >90%) [66, 67] . Shuanghuanglian oral liquid or injection (SHL), another well-known traditional Chinese medicine, dose-dependently inhibits SARS-CoV-2 M pro replication [68] . In addition to the above-mentioned QFPD and SHL, several other traditional Chinese medicines (such as Kegan Liyan oral liquid and Toujie Quwen granule) listed in Table 2 contain Scutellaria baicalensis Georgi (Chinese name: Huangqin), whose major component is baicalein, exerts a marked anti-SARS-CoV-2 effect (IC 50 of 0.94 µM, and SI > 212) [69] . Furthermore, it is crucial to investigate how herbal medicine affects SARS-CoV-2 infection by studying its active ingredients. To elucidate the underlying molecular mechanisms, a crystal structure of SARS-CoV-2 M pro complexed with baicalein was constructed at a resolution of 2.2 Å (the Protein Data Bank (PDB) ID: 6M2N) [68] . Analysis of the core of the substrate-binding pocket revealed multiple interactions (such as hydrogen bonding with Leu141/Gly143 and Ser144/His163, π-π interactions with Cys145 and His4, and hydrophobic interactions with Met49 and His41), which effectively blocked SARS-CoV-2 replication via noncovalent incorporation [68] . The relevant studies [70] [71] [72] provided direct data for a better understanding of the molecular mechanisms of Chinese herbal medicine by studying its active ingredients. Traditional Chinese medicines have attracted considerable attention due to their ability to effectively inhibit SARS-CoV-2 [63] [64] [65] . For example, the Qingfei Paidu decoction (QFPD) has shown an ability to treat COVID-19 patients at all stages with excellent clinical efficacy (cure rate >90%) [66, 67] . Shuanghuanglian oral liquid or injection (SHL), another well-known traditional Chinese medicine, dose-dependently inhibits SARS-CoV-2 M pro replication [68] . In addition to the above-mentioned QFPD and SHL, several other traditional Chinese medicines (such as Kegan Liyan oral liquid and Toujie Quwen granule) listed in Table 2 contain Scutellaria baicalensis Georgi (Chinese name: Huangqin), whose major component is baicalein, exerts a marked anti-SARS-CoV-2 effect (IC50 of 0.94 μM, and SI > 212) [69] . Furthermore, it is crucial to investigate how herbal medicine affects SARS-CoV-2 infection by studying its active ingredients. To elucidate the underlying molecular mechanisms, a crystal structure of SARS-CoV-2 M pro complexed with baicalein was constructed at a resolution of 2.2 Å (the Protein Data Bank (PDB) ID: 6M2N) [68] . Analysis of the core of the substrate-binding pocket revealed multiple interactions (such as hydrogen bonding with Leu141/Gly143 and Ser144/His163, π-π interactions with Cys145 and His4, and hydrophobic interactions with Met49 and His41), which effectively blocked SARS-CoV-2 replication via noncovalent incorporation [68] . The relevant studies [70] [71] [72] provided direct data for a better understanding of the molecular mechanisms of Chinese herbal medicine by studying its active ingredients. 

Ingredient of Huangqin)

RdRp inhibitor via noncovalent incorporation [73] , potent antagonists against TMPRSS2 [70] , improving respiratory function, decreasing IL-1β and TNF-α levels, and inhibiting cell infiltration [71, 72] . 

There is no doubt that natural products have always been recognized as promising anti-lung cancer agents. Daurisoline, an autophagy blocker, is a bisbenzylisoquinoline alkaloid extracted from the herbal medicine Nelumbo nucifera Gaertn [74] . The chemical structures of the molecules discussed in this section are shown in Figure 2 . Daurisoline increases the degradation of β-catenin by targeting heat shock protein 90 (HSP90) directly and decreases the expression of MYC proto-oncogene (c-MYC) and cyclin D1, which resulted in cell cycle arrest at the G1 phase in human lung cancer A549 cells and Hop62 cells lines to exert its anti-lung cancer activity [75] . More importantly, in animals, daurisoline has been reported to be a promising anti-lung cancer agent (by inhibiting tumor growth in lung cancer xenografts) with no observable side effects, thus highlighting a potential role for daurisoline in the treatment of lung cancer [75] . Another recent study has shown that daurisoline can effectively inhibit SARS-CoV-2 replication at IC50 values of 3.664 μM RdRp inhibitor via noncovalent incorporation [73] , potent antagonists against TMPRSS2 [70] , improving respiratory function, decreasing IL-1β and TNF-α levels, and inhibiting cell infiltration [71, 72] . 

There is no doubt that natural products have always been recognized as promising antilung cancer agents. Daurisoline, an autophagy blocker, is a bisbenzylisoquinoline alkaloid extracted from the herbal medicine Nelumbo nucifera Gaertn [74] . The chemical structures of the molecules discussed in this section are shown in Figure 2 . Daurisoline increases the degradation of β-catenin by targeting heat shock protein 90 (HSP90) directly and decreases the expression of MYC proto-oncogene (c-MYC) and cyclin D1, which resulted in cell cycle arrest at the G1 phase in human lung cancer A549 cells and Hop62 cells lines to exert its anti-lung cancer activity [75] . More importantly, in animals, daurisoline has been reported to be a promising anti-lung cancer agent (by inhibiting tumor growth in lung cancer xenografts) with no observable side effects, thus highlighting a potential role for daurisoline in the treatment of lung cancer [75] . Another recent study has shown that daurisoline can effectively inhibit SARS-CoV-2 replication at IC 50 values of 3.664 µM and 0.875 µM in Vero E6 cells and in human pulmonary alveolar epithelial cells (HPAEpiC), respectively [49] .

1.9 μM by inducing cell cycle arrest in phase G0/G1 [76] . Deguelin, a protein kinase B (AKT) kinase inhibitor, is isolated from the African plant Mundulea sericea (Leguminosae) and is commonly used to inhibit the growth of several types of human cancer cell lines [77] . Deguelin promoted the phosphorylation of myeloid cell leukemia sequence-1 (Mcl-1) protein and induced the inhibition of the wildtype and mutated epidermal growth factor receptor (EGFR)-Akt signaling pathway, which resulted in activation of downstream GSK3β/FBW7 and profound anti-NSCLC activity with no obvious side effects in vivo [78] . Licochalcone A is a natural flavonoid derived from Xinjiang licorice and Glycyrrhiza inflata. Licochalcone A is known to possess a broad spectrum of activities with important pharmacological effects in various cancer cell lines [79] . Licochalcone A can significantly increase autophagic cytotoxicity (in both A549 and H460 cell lines) and downregulated the expression of c-IAP1, c-IAP2, XIAP, survivin, c-FLIPL, and RIP1, apoptosis-related proteins via inhibiting the activity of phosphorylated extracellular signal-regulated kinase (ERK) and autophagy [80] . In addition, licochalcone A has been reported to abolish the expression of programmed death ligand-1 (PD-L1) by increasing reactive oxygen species (ROS) levels in a time-dependent manner and interfering with protein translation in cancer cells [81] . Further, licochalcone A can inhibit PD-L1 translation likely through the inhibition of the phosphorylation of 4EBP1 and activation of the PERK-eIF2α signaling pathway [81] . Licochalcone A plays a vital role in reversing the ectopic expression of key mi-croRNA (miR-144-3p, miR-20a-5p, miR-29c-3p, let-7d-3p, and miR-328-3p) to elicit lung cancer chemopreventive activities both in vivo and in vitro [82] . In addition, licochalcone A has been reported to inhibit EGFR signaling and reduced the expression of Survivin protein in a cap-dependent translation manner to exhibit profound activity in mutated NSCLC cells [83] . Graveospene A, isolated from the leaves of Casearia graveolens, is a new clerodane diterpenoid that has been reported to induce apoptosis in A549 cells with an IC 50 value of 1.9 µM by inducing cell cycle arrest in phase G0/G1 [76] . Deguelin, a protein kinase B (AKT) kinase inhibitor, is isolated from the African plant Mundulea sericea (Leguminosae) and is commonly used to inhibit the growth of several types of human cancer cell lines [77] . Deguelin promoted the phosphorylation of myeloid cell leukemia sequence-1 (Mcl-1) protein and induced the inhibition of the wildtype and mutated epidermal growth factor receptor (EGFR)-Akt signaling pathway, which resulted in activation of downstream GSK3β/FBW7 and profound anti-NSCLC activity with no obvious side effects in vivo [78] .

Licochalcone A is a natural flavonoid derived from Xinjiang licorice and Glycyrrhiza inflata. Licochalcone A is known to possess a broad spectrum of activities with important pharmacological effects in various cancer cell lines [79] . Licochalcone A can significantly increase autophagic cytotoxicity (in both A549 and H460 cell lines) and downregulated the expression of c-IAP1, c-IAP2, XIAP, survivin, c-FLIPL, and RIP1, apoptosis-related proteins via inhibiting the activity of phosphorylated extracellular signal-regulated kinase (ERK) and autophagy [80] . In addition, licochalcone A has been reported to abolish the expression of programmed death ligand-1 (PD-L1) by increasing reactive oxygen species (ROS) levels in a time-dependent manner and interfering with protein translation in cancer cells [81] . Further, licochalcone A can inhibit PD-L1 translation likely through the inhibition of the phosphorylation of 4EBP1 and activation of the PERK-eIF2α signaling pathway [81] . Licochalcone A plays a vital role in reversing the ectopic expression of key microRNA (miR-144-3p, miR-20a-5p, miR-29c-3p, let-7d-3p, and miR-328-3p) to elicit lung cancer chemopreventive activities both in vivo and in vitro [82] . In addition, licochalcone A has been reported to inhibit EGFR signaling and reduced the expression of Survivin protein in a cap-dependent translation manner to exhibit profound activity in mutated NSCLC cells [83] .

Erianin, a novel dibenzyl compound, can be isolated from the traditional herbal medicine Dendrobium chrysotoxum Lindl and has been proposed as an apoptosis-inducing agent in human lung cancer cells [84] . The main mechanisms of its anti-lung cancer activity involve the induction of ferroptosis by activating Ca 2+ /calmodulin signaling, inhibition of cell proliferation and metastasis, and induction of cell cycle arrest in phase G2/M [85] .

Tutuilamide A, isolated from marine cyanobacteria Schizothrix sp., is a novel cyclic peptide reported to exhibit moderate cytotoxicity activity in the H-460 human lung cancer cell line with an IC 50 value of 0.53 µM [86] . Tutuilamide A, with the help of the vinyl chloride side chain, showed enhanced inhibitory potency with high selectivity (IC 50 0.73 nM) for human neutrophil elastase, which is associated mainly with the migration and metastasis of lung cancer cells [87] . Besides the above-mentioned molecules, Table 3 also exhibits other natural products (including their underlying molecular mechanisms) with notable anti-lung cancer activities reported since 2020. Erianin, a novel dibenzyl compound, can be isolated from the traditional herbal medicine Dendrobium chrysotoxum Lindl and has been proposed as an apoptosis-inducing agent in human lung cancer cells [84] . The main mechanisms of its anti-lung cancer activity involve the induction of ferroptosis by activating Ca 2+ /calmodulin signaling, inhibition of cell proliferation and metastasis, and induction of cell cycle arrest in phase G2/M [85] .

Tutuilamide A, isolated from marine cyanobacteria Schizothrix sp., is a novel cyclic peptide reported to exhibit moderate cytotoxicity activity in the H-460 human lung cancer cell line with an IC50 value of 0.53 μM [86] . Tutuilamide A, with the help of the vinyl chloride side chain, showed enhanced inhibitory potency with high selectivity (IC50 0.73 nM) for human neutrophil elastase, which is associated mainly with the migration and metastasis of lung cancer cells [87] . Besides the above-mentioned molecules, Table 3 also exhibits other natural products (including their underlying molecular mechanisms) with notable anti-lung cancer activities reported since 2020. Erianin, a novel dibenzyl compound, can be isolated from the traditional herbal medicine Dendrobium chrysotoxum Lindl and has been proposed as an apoptosis-inducing agent in human lung cancer cells [84] . The main mechanisms of its anti-lung cancer activity involve the induction of ferroptosis by activating Ca 2+ /calmodulin signaling, inhibition of cell proliferation and metastasis, and induction of cell cycle arrest in phase G2/M [85] .

Tutuilamide A, isolated from marine cyanobacteria Schizothrix sp., is a novel cyclic peptide reported to exhibit moderate cytotoxicity activity in the H-460 human lung cancer cell line with an IC50 value of 0.53 μM [86] . Tutuilamide A, with the help of the vinyl chloride side chain, showed enhanced inhibitory potency with high selectivity (IC50 0.73 nM) for human neutrophil elastase, which is associated mainly with the migration and metastasis of lung cancer cells [87] . Besides the above-mentioned molecules, Table 3 also exhibits other natural products (including their underlying molecular mechanisms) with notable anti-lung cancer activities reported since 2020. Erianin, a novel dibenzyl compound, can be isolated from the traditional herbal medicine Dendrobium chrysotoxum Lindl and has been proposed as an apoptosis-inducing agent in human lung cancer cells [84] . The main mechanisms of its anti-lung cancer activity involve the induction of ferroptosis by activating Ca 2+ /calmodulin signaling, inhibition of cell proliferation and metastasis, and induction of cell cycle arrest in phase G2/M [85] .

Tutuilamide A, isolated from marine cyanobacteria Schizothrix sp., is a novel cyclic peptide reported to exhibit moderate cytotoxicity activity in the H-460 human lung cancer cell line with an IC50 value of 0.53 μM [86] . Tutuilamide A, with the help of the vinyl chloride side chain, showed enhanced inhibitory potency with high selectivity (IC50 0.73 nM) for human neutrophil elastase, which is associated mainly with the migration and metastasis of lung cancer cells [87] . Besides the above-mentioned molecules, Table 3 also exhibits other natural products (including their underlying molecular mechanisms) with notable anti-lung cancer activities reported since 2020. Erianin, a novel dibenzyl compound, can be isolated from the traditional herbal medicine Dendrobium chrysotoxum Lindl and has been proposed as an apoptosis-inducing agent in human lung cancer cells [84] . The main mechanisms of its anti-lung cancer activity involve the induction of ferroptosis by activating Ca 2+ /calmodulin signaling, inhibition of cell proliferation and metastasis, and induction of cell cycle arrest in phase G2/M [85] .

Tutuilamide A, isolated from marine cyanobacteria Schizothrix sp., is a novel cyclic peptide reported to exhibit moderate cytotoxicity activity in the H-460 human lung cancer cell line with an IC50 value of 0.53 μM [86] . Tutuilamide A, with the help of the vinyl chloride side chain, showed enhanced inhibitory potency with high selectivity (IC50 0.73 nM) for human neutrophil elastase, which is associated mainly with the migration and metastasis of lung cancer cells [87] . Besides the above-mentioned molecules, Table 3 also exhibits other natural products (including their underlying molecular mechanisms) with notable anti-lung cancer activities reported since 2020. Erianin, a novel dibenzyl compound, can be isolated from the traditional herbal medicine Dendrobium chrysotoxum Lindl and has been proposed as an apoptosis-inducing agent in human lung cancer cells [84] . The main mechanisms of its anti-lung cancer activity involve the induction of ferroptosis by activating Ca 2+ /calmodulin signaling, inhibition of cell proliferation and metastasis, and induction of cell cycle arrest in phase G2/M [85] .

Tutuilamide A, isolated from marine cyanobacteria Schizothrix sp., is a novel cyclic peptide reported to exhibit moderate cytotoxicity activity in the H-460 human lung cancer cell line with an IC50 value of 0.53 μM [86] . Tutuilamide A, with the help of the vinyl chloride side chain, showed enhanced inhibitory potency with high selectivity (IC50 0.73 nM) for human neutrophil elastase, which is associated mainly with the migration and metastasis of lung cancer cells [87] . Besides the above-mentioned molecules, Table 3 also exhibits other natural products (including their underlying molecular mechanisms) with notable anti-lung cancer activities reported since 2020. Erianin, a novel dibenzyl compound, can be isolated from the traditional herbal medicine Dendrobium chrysotoxum Lindl and has been proposed as an apoptosis-inducing agent in human lung cancer cells [84] . The main mechanisms of its anti-lung cancer activity involve the induction of ferroptosis by activating Ca 2+ /calmodulin signaling, inhibition of cell proliferation and metastasis, and induction of cell cycle arrest in phase G2/M [85] .

Tutuilamide A, isolated from marine cyanobacteria Schizothrix sp., is a novel cyclic peptide reported to exhibit moderate cytotoxicity activity in the H-460 human lung cancer cell line with an IC50 value of 0.53 μM [86] . Tutuilamide A, with the help of the vinyl chloride side chain, showed enhanced inhibitory potency with high selectivity (IC50 0.73 nM) for human neutrophil elastase, which is associated mainly with the migration and metastasis of lung cancer cells [87] . Besides the above-mentioned molecules, Table 3 also exhibits other natural products (including their underlying molecular mechanisms) with notable anti-lung cancer activities reported since 2020. Erianin, a novel dibenzyl compound, can be isolated from the traditional herbal medicine Dendrobium chrysotoxum Lindl and has been proposed as an apoptosis-inducing agent in human lung cancer cells [84] . The main mechanisms of its anti-lung cancer activity involve the induction of ferroptosis by activating Ca 2+ /calmodulin signaling, inhibition of cell proliferation and metastasis, and induction of cell cycle arrest in phase G2/M [85] .

Tutuilamide A, isolated from marine cyanobacteria Schizothrix sp., is a novel cyclic peptide reported to exhibit moderate cytotoxicity activity in the H-460 human lung cancer cell line with an IC50 value of 0.53 μM [86] . Tutuilamide A, with the help of the vinyl chloride side chain, showed enhanced inhibitory potency with high selectivity (IC50 0.73 nM) for human neutrophil elastase, which is associated mainly with the migration and metastasis of lung cancer cells [87] . Besides the above-mentioned molecules, Table 3 also exhibits other natural products (including their underlying molecular mechanisms) with notable anti-lung cancer activities reported since 2020. Inhibited tumor growth, increased p-AMPK, and suppressed hypoxia-inducible factor 1α levels [99] Reduced proliferation, and induced apoptosis and cell cycle arrest, inhibited the progression of the cell cycle from the G1 to the S phase [114] Restriction of β-catenin nuclear transportation [102] 11 Formononetin Reduced proliferation, and induced apoptosis and cell cycle arrest, inhibited the progression of the cell cycle from the G1 to the S phase [114] Downregulated the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulated chemotaxis (CXCL9 and CXCL10) [111] 17 Isoharringtonine Reduced proliferation, and induced apoptosis and cell cycle arrest, inhibited the progression of the cell cycle from the G1 to the S phase [114] Induced death tumor spheroids by activating the intrinsic apoptosis pathway [112] 18 Kaempferol Inhibited tumor growth, increased p-AMPK, and suppressed hypoxia-inducible factor 1α levels [99] 9 Erianthridin

Attenuated extracellular signal-regulated kinase activity and mediated apoptosis, matrixdegrading metalloproteinases (MMPs) expression [100, 101] 10 Eugenol Restriction of β-catenin nuclear transportation [102] 11 Formononetin

Inhibited EGFR-Akt signaling, which in turn activates GSK3β and promotes Mcl-1 phosphorylation in NSCLC cells [103, 104] 12 Gallic Acid

Inhibited of EGFR activation and impairment, inhibition of phosphoinositide 3-kinase (PI3K) and AKT phosphorylation [105, 106] 13 Glochidiol Inhibited tubulin polymerization [107] 14 Gracillin

Inhibited both glycolysis and mitochondriamediated bioenergetics, induced apoptosis through the mitochondrial pathway [108, 109] 15 Hispidulin Promoted apoptosis by hispidulin via increased generation of ROS [110] 16 Icaritin Downregulated the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulated chemotaxis (CXCL9 and CXCL10) [111] 17 Isoharringtonine Induced death tumor spheroids by activating the intrinsic apoptosis pathway [112] 18 Kaempferol Inhibitor of nuclear factor erythroid 2-related factor 2 [113] 19

Liriopesides B

Reduced proliferation, and induced apoptosis and cell cycle arrest, inhibited the progression of the cell cycle from the G1 to the S phase [114] Inhibitor of nuclear factor erythroid 2-related factor 2 [113] 19

Liriopesides B Inhibited tumor growth, increased p-AMPK, and suppressed hypoxia-inducible factor 1α levels [99] 9 Erianthridin

Attenuated extracellular signal-regulated kinase activity and mediated apoptosis, matrixdegrading metalloproteinases (MMPs) expression [100, 101] 10 Eugenol Restriction of β-catenin nuclear transportation [102] 11 Formononetin

Inhibited EGFR-Akt signaling, which in turn activates GSK3β and promotes Mcl-1 phosphorylation in NSCLC cells [103, 104] 12 Gallic Acid

Inhibited of EGFR activation and impairment, inhibition of phosphoinositide 3-kinase (PI3K) and AKT phosphorylation [105, 106] 13 Glochidiol Inhibited tubulin polymerization [107] 14 Gracillin

Inhibited both glycolysis and mitochondriamediated bioenergetics, induced apoptosis through the mitochondrial pathway [108, 109] 15 Hispidulin Promoted apoptosis by hispidulin via increased generation of ROS [110] 16 Icaritin Downregulated the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulated chemotaxis (CXCL9 and CXCL10) [111] 17 Isoharringtonine Induced death tumor spheroids by activating the intrinsic apoptosis pathway [112] 18 Kaempferol Inhibitor of nuclear factor erythroid 2-related factor 2 [113] 19

Liriopesides B

Reduced proliferation, and induced apoptosis and cell cycle arrest, inhibited the progression of the cell cycle from the G1 to the S phase [114] Reduced proliferation, and induced apoptosis and cell cycle arrest, inhibited the progression of the cell cycle from the G1 to the S phase [114] 24 Polyphyllin I Induced autophagy by activating AMPK and then inhibited mTOR signaling, promoted apoptosis, modulated the PI3K/Akt signaling [122, 123] 25

Quercetin Inhibited proliferation and induced apoptosis [124] 26 Silibinin Inhibited cell proliferation, migration, invasion, and EMT expression [125] 27 Sinomenine Downregulated expression of MMPs and miR-21, suppressed α7 nicotinic acetylcholine receptors expression [126] [127] [128] 28

Toxicarioside O Decreased the expression of trophoblast cell surface antigen 2, resulting in inhibition of the PI3K/Akt pathway and EMT program [129] 29 Vincamine Interaction with the apoptotic protein caspase-3 [130] 30 Xanthohumol

Suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1, decreased the mRNA level of cyclin D1

[131]

Induced autophagy by activating AMPK and then inhibited mTOR signaling, promoted apoptosis, modulated the PI3K/Akt signaling [122, 123] 25

Quercetin 24 Polyphyllin I Induced autophagy by activating AMPK and then inhibited mTOR signaling, promoted apoptosis, modulated the PI3K/Akt signaling [122, 123] 25

Quercetin Inhibited proliferation and induced apoptosis [124] 26 Silibinin Inhibited cell proliferation, migration, invasion, and EMT expression [125] 27 Sinomenine Downregulated expression of MMPs and miR-21, suppressed α7 nicotinic acetylcholine receptors expression [126] [127] [128] 28

Toxicarioside O Decreased the expression of trophoblast cell surface antigen 2, resulting in inhibition of the PI3K/Akt pathway and EMT program [129] 29 Vincamine Interaction with the apoptotic protein caspase-3 [130] 30 Xanthohumol

Suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1, decreased the mRNA level of cyclin D1

[131]

Inhibited proliferation and induced apoptosis [124] 26 Silibinin 24 Polyphyllin I Induced autophagy by activating AMPK and then inhibited mTOR signaling, promoted apoptosis, modulated the PI3K/Akt signaling [122, 123] 25

Quercetin Inhibited proliferation and induced apoptosis [124] 26 Silibinin Inhibited cell proliferation, migration, invasion, and EMT expression [125] 27 Sinomenine Downregulated expression of MMPs and miR-21, suppressed α7 nicotinic acetylcholine receptors expression [126] [127] [128] 28

Toxicarioside O Decreased the expression of trophoblast cell surface antigen 2, resulting in inhibition of the PI3K/Akt pathway and EMT program [129] 29 Vincamine Interaction with the apoptotic protein caspase-3 [130] 30 Xanthohumol

Suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1, decreased the mRNA level of cyclin D1

[131]

Inhibited cell proliferation, migration, invasion, and EMT expression [125] 27 Sinomenine 24 Polyphyllin I Induced autophagy by activating AMPK and then inhibited mTOR signaling, promoted apoptosis, modulated the PI3K/Akt signaling [122, 123] 25

Quercetin Inhibited proliferation and induced apoptosis [124] 26 Silibinin Inhibited cell proliferation, migration, invasion, and EMT expression [125] 27 Sinomenine Downregulated expression of MMPs and miR-21, suppressed α7 nicotinic acetylcholine receptors expression [126] [127] [128] 28

Toxicarioside O Decreased the expression of trophoblast cell surface antigen 2, resulting in inhibition of the PI3K/Akt pathway and EMT program [129] 29 Vincamine Interaction with the apoptotic protein caspase-3 [130] 30 Xanthohumol

Suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1, decreased the mRNA level of cyclin D1

[131] 24 Polyphyllin I Induced autophagy by activating AMPK and then inhibited mTOR signaling, promoted apoptosis, modulated the PI3K/Akt signaling [122, 123] 25

Quercetin Inhibited proliferation and induced apoptosis [124] 26 Silibinin Inhibited cell proliferation, migration, invasion, and EMT expression [125] 27 Sinomenine Downregulated expression of MMPs and miR-21, suppressed α7 nicotinic acetylcholine receptors expression [126] [127] [128] 28

Toxicarioside O Decreased the expression of trophoblast cell surface antigen 2, resulting in inhibition of the PI3K/Akt pathway and EMT program [129] 29 Vincamine Interaction with the apoptotic protein caspase-3 [130] 30 Xanthohumol

Suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1, decreased the mRNA level of cyclin D1

[131]

Decreased the expression of trophoblast cell surface antigen 2, resulting in inhibition of the PI3K/Akt pathway and EMT program [129] 29 Vincamine 24 Polyphyllin I Induced autophagy by activating AMPK and then inhibited mTOR signaling, promoted apoptosis, modulated the PI3K/Akt signaling [122, 123] 25

Quercetin Inhibited proliferation and induced apoptosis [124] 26 Silibinin Inhibited cell proliferation, migration, invasion, and EMT expression [125] 27 Sinomenine Downregulated expression of MMPs and miR-21, suppressed α7 nicotinic acetylcholine receptors expression [126] [127] [128] 28

Toxicarioside O Decreased the expression of trophoblast cell surface antigen 2, resulting in inhibition of the PI3K/Akt pathway and EMT program [129] 29 Vincamine Interaction with the apoptotic protein caspase-3 [130] 30 Xanthohumol

Suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1, decreased the mRNA level of cyclin D1

[131]

Interaction with the apoptotic protein caspase-3 [130] 30 Xanthohumol 24 Polyphyllin I Induced autophagy by activating AMPK and then inhibited mTOR signaling, promoted apoptosis, modulated the PI3K/Akt signaling [122, 123] 25

Quercetin Inhibited proliferation and induced apoptosis [124] 26 Silibinin Inhibited cell proliferation, migration, invasion, and EMT expression [125] 27 Sinomenine Downregulated expression of MMPs and miR-21, suppressed α7 nicotinic acetylcholine receptors expression [126] [127] [128] 28

Toxicarioside O Decreased the expression of trophoblast cell surface antigen 2, resulting in inhibition of the PI3K/Akt pathway and EMT program [129] 29 Vincamine Interaction with the apoptotic protein caspase-3 [130] 30 Xanthohumol

Suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1, decreased the mRNA level of cyclin D1

[131]

Suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1, decreased the mRNA level of cyclin D1 [131] 

The bisbenzylisoquinoline alkaloid cepharanthine can be isolated from the traditional herbal medicine Stephania cephalantha Hayata [132] . Cepharanthine exhibits a range of promising bioactivity. It has IC 50 values of 0.026 µM, 9.5 µg/mL, and 0.83 µM against the human immunodeficiency virus type 1 (HIV-1) [133] , SARS-CoV [134] , and human coronavirus OC43 (HCoV-OC43) [135] , respectively. This alkaloid inhibits SARS-CoV-2 entry in vitro at an IC 50 of 0.35 µM without any evident toxicity profile (selectivity index, [SI] > 70) [136] . Furthermore, the cell death cascade induced by the cellular stress response is another key target for SARS-CoV-2 [137] . It is worth noting that this bisbenzylisoquinoline alkaloid, with a good safety profile, is an approved drug in Japan since the 1950s and is used to treat acute and chronic diseases [132] , highlighting that cepharanthine can serve as a potential therapeutic candidate for the treatment of SARS-CoV-2 infection.

Nelfinavir (Viracept), the first HIV-1 protease inhibitor developed by Agouron Pharmaceuticals, was approved by the FDA in March 1997 for the treatment of HIV-AIDS [138] . Recently, nelfinavir was shown to be effective at inhibiting SARS-CoV-2 M pro infection (IC 50 = 3.3 µM) with a low level of toxicity (SI = 3.7) [139] . In addition, nelfinavir inhibited SARS-CoV-2 replication in vitro with an EC 50 of 1.13 µM [140] . Nelfinavir was also effective at dose-dependently inhibiting SARS-CoV-2 S protein-complete inhibition at the concentration of 10 µM-with no evidence of cellular cytotoxicity [141] . Remarkably, nelfinavir can also improve lung pathology caused by SARS-CoV-2 infection [142] . Nonetheless, nelfinavir might not benefit SARS-CoV-2-infected patients by reducing viral loads in the lungs, just as it does not reduce viral load in hamsters [142] .

Taken together, numerous studies have demonstrated the in vitro anti-SARS-CoV-2 activity of cepharanthine (via inhibition of SARS-CoV-2 S protein) and nelfinavir (via inhibition SARS-CoV-2 M pro and partly S protein). To reveal the synergistic efficacy (Figure 3 ) of the above two molecules in SARS-CoV-2 infected patients, based on models of pharmacokinetics, pharmacodynamics, and viral-dynamics, Ohashi et al. constructed a mathematical prediction model of the therapeutic effects and revealed that the combination of cepharanthine (intravenous) and nelfinavir (oral) showed excellent synergistic effects in COVID-19 patients (with viral clearance occurring 1.23 days earlier than with nelfinavir alone; cepharanthine alone showed a minimal effect) [136] . Considering all these factors, including the critical value of cepharanthine and nelfinavir in anti-SARS-CoV-2 infection, both in vitro and in animal models and mathematical prediction modeling, further research is needed to explore whether these molecules exert synergistically augmented activity for the treatment of SARS-CoV-2 infection in patients. It is worth noting that further research is needed to explore whether they have anti-SARS-CoV-2 activity in vivo.

Remdesivir (GS-5734, Veklury ® ), an RdRp inhibitor developed by Gilead Science, was the first, and currently the only, anti-SARS-CoV-2 drug approved by the FDA (approval on 22 October 2020) for the treatment of COVID-19 [143] [144] [145] . Remdesivir exhibits broadspectrum activity against multiple viral infections in vitro, including SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), and SARS-CoV-2, with EC 50 values of 0.069 µM, 0.090 µM, 0.012 µM, and 0.77 µM, respectively [146] [147] [148] [149] . Furthermore, remdesivir has also been thoroughly explored in animal models. Remdesivir reduced lung viral loads in MERS-CoV-infected rhesus monkeys [150] and transgenic Ces1c − / − hDPP4 mice [147] , protected Nipah virus-infected African green monkeys [151] and rhesus macaques from SARS-CoV-2 infection [152] . Moreover, since 2016, the efficacy and safety of remdesivir have been clinically investigated for the treatment of EBOV infection [153] . Nonetheless, the FDA-approved remdesivir does not appear highly effective in the fight against the COVID-19 pandemic [154] [155] [156] . In this scenario, the combination of remdesivir with other small molecules, including natural products and natural-productinspired potential anti-SARS-CoV-2 agents, may exhibit a synergistic effect, compared to remdesivir alone in COVID-19 patients. ines 2021, 9, x FOR PEER REVIEW 13 of 27 Remdesivir (GS-5734, Veklury ® ), an RdRp inhibitor developed by Gilead Science, was the first, and currently the only, anti-SARS-CoV-2 drug approved by the FDA (approval on 22 October 2020) for the treatment of COVID-19 [143] [144] [145] . Remdesivir exhibits broad-spectrum activity against multiple viral infections in vitro, including SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), and SARS-CoV-2, with EC50 values of 0.069 μM, 0.090 μM, 0.012 μM, and 0.77 μM, respectively [146] [147] [148] [149] . Furthermore, remdesivir has also been thoroughly explored in animal models. Remdesivir reduced lung viral loads in MERS-CoV-infected rhesus monkeys [150] and transgenic Ces1c − / − hDPP4 mice [147] , protected Nipah virus-infected African green monkeys [151] and rhesus macaques from SARS-CoV-2 infection [152] . Moreover, since 2016, the efficacy and safety of remdesivir have been clinically investigated for the treatment of EBOV infection [153] . Nonetheless, the FDA-approved remdesivir does not appear highly effective in the fight against the COVID-19 pandemic [154] [155] [156] . In this scenario, the combination of remdesivir with other small molecules, including natural products and natural-product-inspired potential anti-SARS-CoV-2 agents, may exhibit a synergistic effect, compared to remdesivir alone in COVID-19 patients.

Linoleic acid, an inflammatory response modulator [157] isolated from the traditional meal Vicia faba [158] , significantly suppresses MERS-CoV replication [159] . Toelzer et al. hypothesized that the combination of remdesivir and linoleic acid, an essential diunsaturated fatty acid, may be superior for treating COVID-19 patients over remdesivir alone [160] . Indeed, the combination of linoleic acid (50 μM) and remdesivir (20 to 200 nM) exerted a synergistic effect on SARS-CoV-2 replication in human Caco-2 ACE2+ cells in vitro [160] . Linoleic acid, an inflammatory response modulator [157] isolated from the traditional meal Vicia faba [158] , significantly suppresses MERS-CoV replication [159] . Toelzer et al. hypothesized that the combination of remdesivir and linoleic acid, an essential diunsaturated fatty acid, may be superior for treating COVID-19 patients over remdesivir alone [160] . Indeed, the combination of linoleic acid (50 µM) and remdesivir (20 to 200 nM) exerted a synergistic effect on SARS-CoV-2 replication in human Caco-2 ACE2+ cells in vitro [160] .

The synergistic mechanisms involved in the combination of linoleic acid and remdesivir shown in Figure 4 . To clarify the underlying inhibitory mechanisms of action of linoleic acid, a cryo-electron microscopy (cryo-EM) model of SARS-CoV-2 S protein complexed with linoleic acid was determined at 2.85 Å resolution (Electron Microscopy Data (EMD) ID: 11145) [160] . Further analysis of the linoleic acid binding pocket within the S protein revealed that the hydrocarbon tail of linoleic acid binds to hydrophobic amino acids. At the same time, the acidic headgroup interacts with a positively charged anchor (Arg408 and Gln409) to lock the S protein irreversibly. The hydrophobic pocket with a tube-like shape of the S protein allows a good fit for linoleic acid, and results in reduced ACE2 interactions, and thus sets the stage for an intervention strategy that targets linoleic acid binding to SARS-CoV-2 S protein [160] .

As for remdesivir, it is a phosphoramidate prodrug, which requires conversion from the parent drug into the active triphosphate form (GS-443902) [161] . In cells, the triphosphate form, GS-443902, can block SARS-CoV-2 replication by evading the "proofreading" activity of viral RNA sequences [162] . In addition, Yin et al. [34] revealed the cryo-EM structure of SARS-CoV-2 RdRp in complex with remdesivir (using its triphosphate metabolite GS-443902) at 2.5 Å resolution (PDB ID: 7BV2) [34] . The cryo-EM structure unambiguously demonstrated that GS-443902 could positioned itself at the center of the catalytic site of the primer RNA, covalently binding to the primer at the 1+ position of the template strand to terminate chain elongation. Three strong H-bonds with active site residues (ribose -OH groups: Asp623, Ser682, and Asn691; sugar 2 -OH: Asn691) were identified [34] . Further research is warranted to establish whether linoleic acid and remdesivir exert synergistic anti-SARS-CoV-2 effects in vivo. At present, a more well-designed combination drug therapy that exhibits better additive or synergistic effects against COVID-19 is a promising strategy. However, for COVID-19, the nanodrug strategy (containing natural products and FDA-approved drugs) remains an open question, and undoubtedly, it has a long way to go. The synergistic mechanisms involved in the combination of linoleic acid and remdesivir shown in Figure 4 . To clarify the underlying inhibitory mechanisms of action of linoleic acid, a cryo-electron microscopy (cryo-EM) model of SARS-CoV-2 S protein complexed with linoleic acid was determined at 2.85 Å resolution (Electron Microscopy Data (EMD) ID: 11145) [160] . Further analysis of the linoleic acid binding pocket within the S protein revealed that the hydrocarbon tail of linoleic acid binds to hydrophobic amino acids. At the same time, the acidic headgroup interacts with a positively charged anchor (Arg408 and Gln409) to lock the S protein irreversibly. The hydrophobic pocket with a tube-like shape of the S protein allows a good fit for linoleic acid, and results in reduced ACE2 interactions, and thus sets the stage for an intervention strategy that targets linoleic acid binding to SARS-CoV-2 S protein [160] . As for remdesivir, it is a phosphoramidate prodrug, which requires conversion from the parent drug into the active triphosphate form (GS-443902) [161] . In cells, the triphosphate form, GS-443902, can block SARS-CoV-2 replication by evading the "proofreading" activity of viral RNA sequences [162] . In addition, Yin et al. [34] revealed the cryo-EM structure of SARS-CoV-2 RdRp in complex with remdesivir (using its triphosphate metabolite GS-443902) at 2.5 Å resolution (PDB ID: 7BV2) [34] . The cryo-EM structure unambiguously demonstrated that GS-443902 could positioned itself at the center of the catalytic site of the primer RNA, covalently binding to the primer at the 1+ position of the template strand to terminate chain elongation. Three strong H-bonds with active site residues (ribose -OH groups: Asp623, Ser682, and Asn691; sugar 2′-OH: Asn691) were identified [34] . Further research is warranted to establish whether linoleic acid and remdesivir exert synergistic anti-SARS-CoV-2 effects in vivo. At present, a more well-designed combination drug therapy that exhibits better additive or synergistic effects against COVID-19 is a promising strategy. However, for COVID-19, the nanodrug strategy (containing natural products and FDA-approved drugs) remains an open question, and undoubtedly, it has a long way to go. 

As regards lung cancer, significant progress has been made in the research of natural product-based nanomedicines [163, 164] and combination drug therapies [165, 166] , which can provide some reference for the related drug discovery and development for COVID-19. In this section, we mainly focused on the nanodrug strategy (containing natural products and FDA-approved drugs) to reveal its unique advantage in the research and development of anti-lung cancer drugs.

Curcumin is one of the main products of the Curcuma longa L. (turmeric) rhizome extract and has been proposed for its antimicrobial, antimutagenic, antiproliferative, and neuroprotective activities [167] . Curcumin is considered an ideal scaffold for lung cancer drug discovery due to its potent antitumor effects against NSCLC [168] . In particular, several crucial molecular pathways involved in the efficacy of curcumin as an anti-lung cancer drug involve the vascular endothelial growth factor (VEGF), EGFR, nuclear factor-κB (NF-κB), and mammalian target of rapamycin (mTOR) pathways [169] . Nonetheless, the biomedical application of curcumin is currently hindered by its poor aqueous solubility and low bioavailability [170] . In contrast, cisplatin, already marketed as the first platinumbased complex approved by the US FDA, has been used therapeutically for a broad range of cancers such as lung, lymphomas, melanoma, head, and neck cancer [171] . Unfortunately, the routine clinical practice of cisplatin is often coupled with severe toxic side effects (such as nephrotoxicity [172] , severe hearing loss [173] , and cardiotoxicity [174] ) and intrinsic or acquired drug resistance [175] .

Indeed, an efficacy study in NSCLC cells evidenced improved effects of the drug combination of curcumin and cisplatin [176] . An in vitro study showed that curcumin enhanced cisplatin-induced therapeutic efficacy in lung cancer cell lines A549, H460, and H1299 by regulating the Cu-Sp1-CTR1 regulatory loop. Furthermore, the promotion of active targeting ability with β-cyclodextrin (β-CD)-modified hyaluronic acid (HA) was identified as an effective strategy to address cellular uptake, intracellular trafficking, and therapy performance of the drug delivery systems [177] . Taking all these factors into account, Bai et al. [178] designed and constructed a β-cyclodextrin-modified hyaluronic acid-based pHand esterase-dual-responsive supramolecular codrug combining curcumin and cisplatin ( Figure 5 ). In detail, the designed guest moiety Cur-Pt was prepared via esterification reactions between curcumin, oxoplatin, and a molecule of succinic acid. The scheduled host moiety β-CD-modified hyaluronic acid (HA-CD) was prepared via amidation of the carboxylate salt sodium hyaluronate with free amine mono-6-deoxy-6-ethylenediamino-β-CD (β-CD-EDA). Eventually, the desired curcumin and cisplatin nanoparticles (HCPNs) were developed through a host-guest inclusion strategy and subsequent self-assembled. Interestingly, in this targeting system, curcumin acted as both the guest molecule and the chemical anticancer drug. The disulfide bond, a promising redox-reactive switch in vivo, plays an essential role in many biological processes [179] . To reduce adverse effects resulting from chemotherapy regimens, the disulfide-based drug design has attracted great enthusiasm in the synthesis of prodrug or codrug, and especially for the preparation of functional nanodrugs due to their high selectivity and biocompatibility [180, 181] . The nontoxic nanodrugs are activated by the excess of GSH in the tumor microenvironment, which provides an essential strategy for lung cancer-targeting treatment [182] . In vitro evaluation revealed that the HCPNs could be internalized by cancer cells. Once inside the cell, curcumin is released under acidic endosomal conditions (pH-responsive), and cisplatin is released via reducing of oxoplatin under higher expressed glutathione (GSH) conditions (esterase-responsive). Moreover, cell-based experiments revealed the effective cellular toxicity (high efficiency, the IC 50 value of 5.4 µM in A549 cells) and active targeting ability (low toxicity, with low expression levels in normal LO-2 cells) of this novel drugdelivery system. Given the observed positive synergistic effect in the study, the authors concluded that HCPNs exhibited improved effects, compared with either monotherapy with curcumin or cisplatin [178] . The drug delivery and sustained release behavior of Cur from HCPNs were investigated in vitro at pH 7.4 after 48 h (11% Cur was released) and pH 5.0 after 48 h (79% Cur was released), respectively, proving the better stability than Cur alone [178] . Meanwhile, although the Tian group did not proceed further with their in vivo studies; we suggest additional in vivo studies should be performed to identify the pharmacokinetic or pharmacodynamic profile of the HCPNs and the synergistic activity against lung cancer of this codrug.

The disulfide bond, a promising redox-reactive switch in vivo, plays an essential role in many biological processes [179] . To reduce adverse effects resulting from chemotherapy regimens, the disulfide-based drug design has attracted great enthusiasm in the synthesis of prodrug or codrug, and especially for the preparation of functional nanodrugs due to their high selectivity and biocompatibility [180, 181] . The nontoxic nanodrugs are activated by the excess of GSH in the tumor microenvironment, which provides an essential strategy for lung cancer-targeting treatment [182] .

Celastrol, a typical pentacyclic triterpenoid, can be extracted from traditional herbal medicines of the Celastraceae family [183] . Celastrol is considered another up-and-coming natural product for lung cancer treatment due to its potent anti-NSCLC activity via its suppression of Axl protein expression [184] , initiating tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-mediated apoptotic cell death [185] , and suppressing cell invasion [186] . However, the clinical translation and biomedical application of celastrol are hindered due to its low bioavailability and physiological instability [187] .

Gefitinib, approved by US FDA, has been used therapeutically as the first-line agent in patients with advanced lung cancer [188] . Unfortunately, the routine clinical practice of gefitinib is often coupled with severe adverse effects, such as pulmonary toxicity [189] , respiratory failure, and severe comorbidities [190] . Following a reasonable design, Wu et al. developed a GSH-responsive nanodrug (identified as CEL@G-SS-NIR in Figure 6 ), which possesses unique therapeutic efficacy for NSCLC in mice models by inhibiting upstream and downstream EGFR signaling pathways [191] . The nanodrug CEL@G-SS-NIR was prepared in two steps: preparation of the prodrug and acquisition of the nanocomplex. As shown in Figure 6 , the main molecule G-SS-NIR of the nanodrug CEL@G-SS-NIR was synthesized through a two-step reaction. First, the key intermediate G-SS was synthesized successfully in the presence of gefitinib (G), 2-hydroxyethyl disulfide (-SS-), and tiphosgene via covalent linkage. Next, the near-infrared (NIR-OH) chromophore was bound to the side chain of the G-SS to form the prodrug G-SS-NIR. The amphiphilic G-SS-NIR readily self-assembled into spherical nanomicelles in an aqueous medium (driven by the disulfide bond and the π-π interaction) and was encapsulated concomitantly the hydrophobic serinethreonine protein kinase (Akt) inhibitor celastrol (marked as CEL) to form CEL@G-SS-NIR.

This novel nanodrug CEL@G-SS-NIR possesses a suitable size (average diameter 119 ± 6 nm), outstanding overall drug loading (64.0 ± 1.4 wt.%), and excellent stability in the blood circulation, and has a rapid release rate of the free molecules (gefitinib, celastrol, and NIR-OH) at tumor region due to the breaking of the disulfide bonds in the presence of high levels of GSH [191] .

thesized successfully in the presence of gefitinib (G), 2-hydroxyethyl disulfide (-SS-), and tiphosgene via covalent linkage. Next, the near-infrared (NIR-OH) chromophore was bound to the side chain of the G-SS to form the prodrug G-SS-NIR. The amphiphilic G-SS-NIR readily self-assembled into spherical nanomicelles in an aqueous medium (driven by the disulfide bond and the π-π interaction) and was encapsulated concomitantly the hydrophobic serine-threonine protein kinase (Akt) inhibitor celastrol (marked as CEL) to form CEL@G-SS-NIR. This novel nanodrug CEL@G-SS-NIR possesses a suitable size (average diameter 119 ± 6 nm), outstanding overall drug loading (64.0 ± 1.4 wt.%), and excellent stability in the blood circulation, and has a rapid release rate of the free molecules (gefitinib, celastrol, and NIR-OH) at tumor region due to the breaking of the disulfide bonds in the presence of high levels of GSH [191] .

In vitro, the nanodrug CEL@G-SS-NIR formulation could effectively target the tumor region due to its enhanced permeability and retention effect and also allowed fluorescent imaging in vivo, at a predetermined timepoint after tail vein injection, in orthotopic lung In vitro, the nanodrug CEL@G-SS-NIR formulation could effectively target the tumor region due to its enhanced permeability and retention effect and also allowed fluorescent imaging in vivo, at a predetermined timepoint after tail vein injection, in orthotopic lung tumors [191] . In the treatment protocol, the mice were randomly divided into five groups (five mice per treatment group), and after a single treatment cycle, the CEL@G-SS-NIR group (13.4 mg/kg, intravenously, for 20 days), compared to the control groups, exhibited stronger NSCLC tumor-suppressive effects [191] . As for the response mechanism involved, the entire process can be divided into four steps: (i) CEL@G-SS-NIR accumulates in the lung tumor region, (ii) CEL@G-SS-NIR releases the drug celastrol and the protonated intermediates (and) through the deprotonated glutathione (GS ) nucleophilic attack of the disulfide bond on G-SS-NIR bonds, (iii) this further induces the synchronous releases of the parent drug gefitinib and the fluorescent dye NIR-OH via an intramolecular cyclization reaction (thiolate anion moiety reacts with the adjacent carbonyl group), and (iv) finally, the synergistic anticancer activity is activated by suppressing the phosphatidylinositol 3-kinase/serine threonine protein kinase (PI3K/Akt) signaling pathway by celastrol and downregulating EGFR signaling pathway by gefitinib. Simultaneously, a fluorescent and multispectral optoacoustic tomography imaging signal is generated by NIR-OH [192] . This study showed that disulfide-based and targeted fluorescent nano-prodrugs for treating NSCLC and tracking drug delivery systems are particularly advantageous.

COVID-19 and lung cancer, the two most critical lung diseases presenting high mortality rates, have posed a great challenge and a serious threat to human health and economic development. Since 2020, as is well-known, the scientific community has made great efforts and remarkable inroads in developing promising anti-SARS-CoV-2 and anti-lung cancer agents through various approaches. In this scenario, numerous natural products have fueled significant attention and have shown good results as potential therapeutics for the above-mentioned lung diseases. This review highlighted state-of-the-art of important natural products (including their underlying molecular mechanisms), covering studies published between 1 January 2020 and 31 May 2021, in the treatment of the above-mentioned lung diseases. We found that natural products can be applied in vitro as monotherapy for the treatment of SARS-CoV-2 (ginkgolic acid, resveratrol, and baicalein) and lung cancer (graveospene A, deguelin, and erianin), as well as in combination with the FDA-approved drug inhibit SARS-CoV-2 (cepharanthine plus nelfinavir, linoleic acid plus remdesivir) and as codrug formulations with anti-lung cancer activity in vitro (codrug of curcumin and cisplatin). The evidence revealed herein that natural products could serve as a starting point for further drug development both in COVID-19 and lung cancer. It is worth noting, however, that some natural products could be pan-assay interference compounds, which can give false readouts, and close attention should be paid to decrease futile attempts [193, 194] . There is currently very little direct data associated with the clinical effect of natural products against SARS-CoV-2 infection. To understand better and explore systematically the activity of natural products, more validation studies, with high-quality evidence (both in vitro and in animal models as well as on humans), are now needed.

To improve the use of natural products, many intensive research efforts (both in vitro and in vivo) are still needed to explore the limitations of these agents, such as poor water solubility, limited oral absorption, low bioavailability, and the poor first-pass effect, which represent the first step to develop promising anti-COVID-19 or anti-lung cancer agents. It is clear that a long way is still ahead for us to realize natural product-based drug discovery and development, as only phase 1-3 clinical trials can ensure that any small molecule inhibitor can be used as a drug.

More aggressive and well-designed combination drug therapies that exhibit better additive or synergistic effects against COVID-19 and lung cancer are a promising strategy. For example, shiraiachrome A exhibits potent effects in Vero E6 cells by inhibiting the activity of the SARS-CoV-2 S protein at EC 50 values of 0.21 µM; bafilomycin B 2 presents enhanced inhibitory potency against SARS-CoV-2 at IC 50 values of 5.11 nM in Vero E6 cells by inhibiting the viral entry process; ginkgolic acid has IC 50 values of 1.79 µM and 16.3 µM against SARS-CoV-2 M pro and SARS-CoV-2 PL pro . Combining the properties of the above-mentioned natural products with FDA-approved drugs (for example, with nelfinavir or remdesivir) could achieve optimal COVID-19 treatment through multitargeted mechanisms of action. In addition, a codrug of a natural product with an FDA-approved drug could achieve a combination booster through multitargeted activity. However, the codrug strategy remains an open question in the treatment of patients with COVID-19. Thus, we suggest researchers pay considerable attention to the development of emerging codrug therapy strategies.

In contrast, precisely fabricated nanodrugs may be a more potent weapon to enhance biocompatibility, minimize toxicity as well as side effects, achieve long-term circulation in the body, as well as sustained release, overcome undesired adverse effects, and expand the modalities of administration (intravenous injection or inhalation). However, for COVID-19, the nanodrug strategy (containing natural products and FDA-approved drugs) remains another open question. Fortunately, significant progress has been made in the research of lung cancer nanomedicines, which can provide some reference for the related drug discovery and development for COVID-19. There is no doubt that there is a long way to go and many difficulties to overcome. Nonetheless, natural products have their advantages. We sincerely hope natural products will be proven a safe and effective "natural remedy" for the treatment of the above-mentioned lung diseases with the assistance of multiple techniques and strategies. 

Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019

Natural products in drug discovery: Advances and opportunities

Ethnobotany and the role of plant natural products in antibiotic drug discovery

The role of natural products in the prevention and treatment of pulmonary fibrosis: A review

Active ingredients from Chinese medicine plants as therapeutic strategies for asthma: Overview and challenges

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

Microbiome in chronic obstructive pulmonary disease: Role of natural products against microbial pathogens

Targeting defective pulmonary innate immunity-A new therapeutic option? Pharmacol

Natural products with potential to treat RNA virus pathogens including SARS-CoV-2

Perspectives and controversies regarding the use of natural products for the treatment of lung cancer

Post-acute COVID-19 syndrome

Note from the editors: World Health Organization declares novel coronavirus (2019-nCoV) sixth public health emergency of international concern

A novel coronavirus outbreak of global health concern

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster

Importation and human-to-human transmission of a novel coronavirus in Vietnam

COVID-19: Discovery, diagnostics and drug development

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

A grafted peptidomimetic for EGFR heterodimerization inhibition: Implications in NSCLC models

The small-cell lung cancer drug market

Anti-SARS-CoV natural products with the potential to inhibit SARS-CoV-2 (COVID-19)

Turning the tide: Natural products and natural-product-inspired chemicals as potential counters to SARS-CoV-2 infection

SARS-CoV-2 M pro inhibitors with antiviral activity in a transgenic mouse model

Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity

Exogenous hormone on episperm development and ginkgolic acid accumulation in Ginkgo biloba L

Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases

ACE2: The molecular doorway to SARS-CoV-2

Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion

Axial chiral binaphthoquinone and perylenequinones from the stromata of hypocrella bambusae are SARS-CoV-2 entry inhibitors

Serendipity or opportunity for intervention? Cancer Discov. 2020

Platycodin D prevents both lysosome-and TMPRSS2-driven SARS-CoV-2 infection in vitro by hindering membrane fusion

Resveratrol inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cultured Vero cells

Resveratrol and pterostilbene potently inhibit SARS-CoV-2 replication in vitro

Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir

Anti-esophageal cancer effect of corilagin extracted from Phmllanthi fructus via the mitochondrial and endoplasmic reticulum stress pathways

Corilagin inhibits SARS-CoV-2 replication by targeting viral RNA-dependent RNA polymerase

Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay

Antiviral bafilomycins from a feces-inhabiting Streptomyces sp

Repurposing of Some Natural Product Isolates as SARS-COV-2 Main Protease Inhibitors via In Vitro Cell Free and Cell-Based Antiviral Assessments and Molecular Modeling Approaches

Anti-SARS-CoV-2 Aactivity of Andrographis paniculata extract and its major component andrographolide in human lung epithelial cells and cytotoxicity evaluation in major organ cell representatives

Artemether, artesunate, arteannuin B, echinatin, licochalcone B and andrographolide effectively inhibit SARS-CoV-2 and related viruses in vitro

Anti-SARS-CoV-2 potential of artemisinins in vitro

In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication

Epigallocatechin gallate inhibits the uridylate-specific endoribonuclease Nsp15 and efficiently neutralizes the SARS-CoV-2 strain

Assessment of antiviral potencies of cannabinoids against SARSCoV-2 using computational and in vitro approaches

Cannabidiol inhibits SARS-CoV-2 replication and promotes the host innate immune response

Docking characterization and in vitro inhibitory activity of flavan-3-ols and dimeric proanthocyanidins against the main protease activity of SARS-CoV-2. Front

Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CLpro

A cross-talk between epithelium and endothelium mediates human alveolar-capillary injury during SARS-CoV-2 infection

Epigallocatechin-3-gallate, an active ingredient of Traditional Chinese Medicines, inhibits the 3CLpro activity of SARS-CoV-2

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

Emetine suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E

Potent in vitro anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L

The natural stilbenoid (-)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA

Ipomoeassin-F inhibits the in vitro biogenesis of the SARS-CoV-2 spike protein and its host cell membrane receptor

Kobophenol A inhibits binding of host ACE2 receptor with Spike RBD domain of SARS-CoV-2, a lead compound for blocking COVID-19

Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in-vitro repurposing screen

Myricetin inhibit SARS-CoV-2 viral replication by targeting Mpro and ameliorates pulmonary inflammation

Naringenin is a powerful inhibitor of SARS-CoV-2 infection in vitro

Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs

Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

Tea polyphenols EGCG and theaflavin inhibit the activity of SARS-CoV-2 3CL-protease in vitro

Chinese Therapeutic Strategy for Fighting COVID-19 and Potential Small-Molecule Inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Chinese herbal medicine: Fighting SARS-CoV-2 infection on all fronts

Traditional Chinese Medicine (TCM) in the treatment of viral infections: Efficacies and mechanisms

National Health Commission of the People's Republic of China. Notice on the Issunance of Guidelines of Diagnosis and Treatment for 2019-nCoV Infected Pneumonia

Academician Xiaolin Tong: The Total Effective Rate of Qingfeipaidu Formula was 97%, none Transfer from Mild to Severe Cases

Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients

Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro

Unravelling high-affinity binding compounds towards transmembrane protease serine 2 enzyme in treating SARS-CoV-2 infection using molecular modelling and docking studies

The comprehensive study on the therapeutic effects of baicalein for the treatment of COVID-19 in vivo and in vitro

Rutin and flavone analogs as prospective SARS-CoV-2 main protease inhibitors: In silico drug discovery study

Baicalein and baicalin inhibit SARS-CoV-2 RNA-dependent-RNA polymerase

Cardiovascular pharmacological effects of bisbenzylisoquinoline alkaloid derivatives

Direct targeting of HSP90 with daurisoline destabilizes β-catenin to suppress lung cancer tumorigenesis

Clerodane diterpenoids isolated from the leaves of Casearia graveolens

Deguelin targets multiple oncogenic signaling pathways to combat human malignancies

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Licochalcone A selectively resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs

ERK activation-mediated autophagy induction resists licochalcone A-induced anticancer activities in lung cancer cells in vitro

Licochalcone A inhibits interferon-gamma-induced programmed death-ligand 1 in lung cancer cells

Licochalcone A reverses NNK-induced ectopic miRNA expression to elicit in vitro and in vivo chemopreventive effects

Licochalcone A inhibits EGFR signalling and translationally suppresses survivin expression in human cancer cells

Erianin regulates programmed cell death ligand 1 expression and enhances cytotoxic T lymphocyte activity

Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis

Tutuilamides A-C: Vinyl-chloride-containing cyclodepsipeptides from marine cyanobacteria with potent elastase inhibitory properties

Ahp-Cyclodepsipeptides as tunable inhibitors of human neutrophil elastase and kallikrein 7: Total synthesis of tutuilamide A, serine protease selectivity profile and comparison with lyngbyastatin 7

The cardenolide glycoside acovenoside A interferes with epidermal growth factor receptor (EGFR) trafficking in non-small cell lung cancer cells

Triterpenoids from the leaves of Centella asiatica inhibit ionizing radiation-induced migration and invasion of human lung cancer cells. Evid. Based Compl

Baicalein inhibits non-small-cell lung cancer invasion and metastasis by reducing ezrin tension in inflammation microenvironment

Baicalein suppresses vasculogenic mimicry through inhibiting RhoA/ROCK expression in lung cancer A549 cell line

Baicalein suppresses growth of non-small cell lung carcinoma by targeting MAP4K3

Baicalin induces apoptosis and suppresses the cell cycle progression of lung cancer cells through downregulating Akt/mTOR signaling pathway

Effects of wogonoside on invasion and migration of lung cancer A549 cells and angiogenesis in xenograft tumors of nude mice

Casticin induces DNA damage and affects DNA repair associated protein expression in human lung cancer A549 cells

Dioscin elicits anti-tumour immunity by inhibiting macrophage M2 polarization via JNK and STAT3 pathways in lung cancer

EGCG regulates CTR1 expression through its pro-oxidative property in non-small-cell lung cancer cells

EGCG sensitizes chemotherapeutic-induced cytotoxicity by targeting the ERK pathway in multiple cancer cell lines

Phenolic compound ellagic acid inhibits mitochondrial respiration and tumor growth in lung cancer

Erianthridin induces non-small cell lung cancer cell apoptosis through the suppression of extracellular signal-regulated kinase activity

Erianthridin suppresses non-small-cell lung cancer cell metastasis through inhibition of Akt/mTOR/p70 S6K signaling pathway

Eugenol emerges as an elixir by targeting β-catenin, the central cancer stem cell regulator in lung carcinogenesis: An in vivo and in vitro rationale

Formononetin inhibits tumor growth by suppression of EGFR-Akt-Mcl-1 axis in non-small cell lung cancer

An integrated strategy for effectivecomponent discovery of Astragali Radix in the treatment of lung cancer

The inhibitory mechanisms of tumor PD-L1 expression by natural bioactive gallic acid in non-small-cell lung cancer (NSCLC) cells. Cancers

Gallic acid impedes non-small cell lung cancer progression via suppression of EGFR-dependent CARM1-PELP1 complex. Drug Des. Dev

Glochidiol, a natural triterpenoid, exerts its anti-cancer effects by targeting the colchicine binding site of tubulin

Potent anticancer effect of the natural steroidal saponin gracillin is produced by inhibiting glycolysis and oxidative phosphorylation-mediated bioenergetics

Gracillin isolated from Reineckia carnea induces apoptosis of A549 Cells via the mitochondrial pathway. Drug Des. Dev

Hispidulin exhibits potent anticancer activity in vitro and in vivo through activating ER stress in non-small-cell lung cancer cells

Icaritin inhibits lung cancer-induced osteoclastogenesis by suppressing the expression of IL-6 and TNF-a and through AMPK/mTOR signaling pathway. Anti-Cancer Drug

Isoharringtonine induces apoptosis of non-small cell lung cancer cells in tumorspheroids via the intrinsic pathway

Kaempferol inhibits Nrf2 signalling pathway via downregulation of Nrf2 mRNA and induces apoptosis in NSCLC cells

Liriopesides B induces apoptosis and cell cycle arrest in human non-small cell lung cancer cells

Nagilactone E increases PD-L1 expression through activation of c-Jun in lung cancer cells

Identification of nagilactone E as a protein synthesis inhibitor with anticancer activity

Natural alkaloid 8-oxo-epiberberine inhibited TGF-β1-triggred epithelial-mesenchymal transition by interfering Smad3

Parthenolide inhibits the growth of non-small cell lung cancer by targeting epidermal growth factor receptor

Parthenolide inhibits human lung cancer cell growth by modulating the IGF-1R/PI3K/Akt signaling pathway

Parthenolide augments the chemosensitivity of non-small-cell lung cancer to cisplatin via the PI3K/AKT signaling pathway

PDB-1 from potentilla discolor bunge suppresses lung cancer cell migration and invasion via FAK/Src and MAPK signaling pathways

Polyphyllin I activates AMPK to suppress the growth of non-small-cell lung cancer via induction of autophagy

Polyphyllin I reverses the resistance of osimertinib in non-small cell lung cancer cell through regulation of PI3K/Akt signaling

Quercetin induces pro-apoptotic autophagy via SIRT1/AMPK signaling pathway in human lung cancer cell lines A549 and H1299 in vitro

Silibinin suppresses epithelial-mesenchymal transition in human non-small cell lung cancer cells by restraining RHBDD1

Sinomenine inhibits migration and invasion of human lung cancer cell through downregulating expression of miR-21 and MMPs

Inhibitory effect of sinomenine on lung cancer cells via negative regulation of α7 nicotinic acetylcholine receptor

Sinomenine inhibits non-small cell lung cancer via downregulation of hexokinases II-mediated aerobic glycolysis

Toxicarioside O inhibits cell proliferation and epithelial-mesenchymal transition by downregulation of Trop2 in lung cancer cells

Vincamine, a safe natural alkaloid, represents a novel anticancer agent

Xanthohumol targets the ERK1/2-Fra1 signaling axis to reduce cyclin D1 expression and inhibit non-small cell lung cancer

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

Potent inhibition of HIV type 1 replication by an antiinflammatory alkaloid, cepharanthine, in chronically infected monocytic cells

Antiviral activity of cepharanthine against severe acute respiratory syndrome coronavirus in vitro

Natural bis-benzylisoquinoline alkaloids-tetrandrine, fangchinoline, and cepharanthine, inhibit human coronavirus OC43 infection of MRC-5 human lung cells

Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment

Transcriptome analysis of cepharanthine against a SARS-CoV-2-related coronavirus

Molecular basis for reduced cleavage activity and drug resistance in D30N HIV-1 protease. bioRxiv 2021

Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection

Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro

The anti-HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV-2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID-19 infections

Nelfinavir markedly improves lung pathology in SARS-CoV-2-infected Syrian hamsters despite lack of an antiviral effect

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Remdesivir metabolite GS-441524 effectively inhibits SARS-CoV-2 infection in mouse models

FDA approval of remdesivir-A step in the right direction

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Characterisation of infectious Ebola virus from the ongoing outbreak to guide response activities in the Democratic Republic of the Congo: A phylogenetic and in vitro analysis

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

GS-5734) protects African green monkeys from Nipah virus challenge

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

Late Ebola virus relapse causing meningoencephalitis: A case report

Remdesivir: A pendulum in a pandemic

Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial

Efficacy of remdesivir in COVID-19

Characterization of lipidomic profile of human coronavirus -infected cells: Implications for lipid metabolism remodeling upon coronavirus replication

Broad beans (Vicia faba) and the potential to protect from COVID-19 coronavirus infection

The need for precision nutrition, genetic variation and resolution in Covid-19 patients

Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein

GS-5734: A potentially approved drug by FDA against SARS-CoV-2

Advantages of the parent nucleoside GS-441524 over remdesivir for Covid-19 treatment

Engineering EHD1-targeted natural borneol nanoemulsion potentiates therapeutic efficacy of gefitinib against non-small lung cancer

Targeted delivery of quercetin by nanoparticles based on chitosan sensitizing paclitaxel-resistant lung cancer cells to paclitaxel

Overcoming acquired resistance of EGFRmutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol

Celastrol acts synergistically with afatinib to suppress non-small cell lung cancer cell proliferation by inducing paraptosis

Impact of curcumin nanoformulation on its antimicrobial activity

Identification of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor effect against non-small cell lung cancer

Versatile role of curcumin and its derivatives in lung cancer therapy

Structural and therapeutic properties of curcumin solubilized pluronic F127 micellar solutions and hydrogels

The first metal based anticancer drug

The circadian clock gene Bmal1 facilitates cisplatin-induced renal injury and hepatization

Progress in the development of preventative drugs for cisplatin-induced hearing loss

Molecular mechanisms of cardiomyocyte death in drug-induced cardiotoxicity

Ring finger protein 38 induces the drug resistance of cisplatin in non-small cell lung cancer

Curcumin enhances cisplatin sensitivity of human NSCLC cell lines through influencing Cu-Sp1-CTR1 regulatory loop

Targeted polysaccharide nanoparticle for adamplatin prodrug delivery

β-Cyclodextrin-modified hyaluronic acid-based supramolecular self-assemblies for pH-and esterase-dual-responsive drug delivery

Self-Assembled disulfide bond bearing paclitaxelcamptothecin prodrug nanoparticle for lung cancer therapy

Pure redox-sensitive paclitaxel-maleimide prodrug nanoparticles: Endogenous albumin-induced size switching and improved antitumor efficiency

Comparison of redox responsiveness and antitumor capability of paclitaxel dimeric nanoparticles with different linkers

Tumor-specific carrier-free nanodrugs with GSH depletion and enhanced ROS generation for endogenous synergistic anti-tumor by a chemotherapyphotodynamic therapy

Control of autoimmune inflammation by celastrol, a natural triterpenoid

Axl is a novel target of celastrol that inhibits cell proliferation and migration, and increases the cytotoxicity of gefitinib in EGFR mutant non-small cell lung cancer cells

Autophagy flux inhibition mediated by celastrol sensitized lung cancer cells to TRAIL-induced apoptosis via regulation of mitochondrial transmembrane potential and reactive oxygen species

Celastrol improves the therapeutic efficacy of EGFR-TKIs for non-small-cell lung cancer by overcoming EGFR T790M drug resistance. Anti-Cancer Drug

Enhanced solubility, stability, permeation and anti-cancer efficacy of Celastrol-β-cyclodextrin inclusion complex

Cryptotanshinone strengthens the effect of gefitinib against non-small cell lung cancer through inhibiting transketolase

Crosstalk between alveolar macrophages and alveolar epithelial cells/fibroblasts contributes to the pulmonary toxicity of gefitinib

Fatal toxic effects related to EGFR tyrosine kinase inhibitors based on 53 cohorts with 9569 participants

An activatable nano-prodrug for treating tyrosine-kinase-inhibitor-resistant non-small cell lung cancer and for optoacoustic and fluorescent imaging

Fluorescent probe for sensitive discrimination of Hcy and Cys/GSH in living cells via dual-emission

Chemistry: Chemical con artists foil drug discovery

Best practice in research-Overcoming common challenges in phytopharmacological research