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Since the outbreak of coronavirus disease 2019 (COVID-19) in December 2019, millions of people have been infected and died worldwide. However, no drug has been approved for the treatment of this disease and its complications, which urges the need for finding novel therapeutic agents to combat. Among the complications due to COVID-19, lung injury has attained special attention. Besides, phytochemicals have shown prominent anti-inflammatory effects and thus possess significant effects in reducing lung injury caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Also, the prevailing evidence reveales the antiviral effects of those phytochemicals, including anti-SARS-CoV activity, which could pave the road in providing suitable lead compounds in the treatment of COVID-19. In the present study, candidate phytochemicals and related mechanisms of action have been shown in the treatment/protection of lung injuries induced by various methods. In terms of pharmacological mechanism, phytochemicals have shown potential inhibitory effects on inflammatory and oxidative pathways/mediators, involved in the pathogenesis of lung injury during COVID-19 infection. Also, a brief overview of phytochemicals with anti-SARS-CoV-2 compounds has been presented.
The complex pathophysiological mechanisms behind viral diseases, along with the associated side effects of the present conventional drugs, urge the need for introducing alternative treatments. Among viral infections, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS-CoV), and the newest human CoVs (HCoVs) associated with the outbreak of coronavirus disease 2019-SARS-CoV-2 (COVID-19) have caused acute respiratory distress syndrome (
In striking contrast to the history of HCoVs, as relatively harmless respiratory pathogens, the outbreak of SARS and the emergence of MERS pose the CoVs as important pathogens in respiratory tract infections. SARS-CoV, MERS-CoV, and SARS-CoV-2 can cause clinical complications leading to severe diseases presented as acute respiratory distress syndrome (ARDS) (
The most common clinical symptoms in SARS-CoV-2 include fever, cough, dyspnea, fatigue, headache, myalgia, and diarrhea. Some patients afterward suffer from shortness of breath and recurrent or ongoing fever. In nearly 13% of patients, intense care treatment (e.g., mechanical ventilation) should be applied (
Since the outbreak of COVID-19 happened, several researchers have focused on the use of natural compounds for the treatment of related complications. Most of those studies are
Selected chemical structures of some phytochemicals with potential anti-CoV effects.
Medicinal plants and isolated phytochemicals can cover multiple therapeutic targets at the same time and lie in the fact that they are widely used in the treatment of various diseases, including viral diseases and related complications. Since infection with any of the viruses of the Coronaviridae family, including SARS-CoV-2, can cause severe damage to the pulmonary system (
Alkaloids are one of the largest classes of natural products that are mainly found in several plant families such as Solanaceae, Ranunculaceae, Rubiaceae, Papaveraceae, Amaryllidaceae, and Fabaceae. The main feature of this group is the presence of the nitrogen atom in their structure (
Selected chemical structures of polyphenols with potential protective effects against lung injury.
Toll-like receptor 4 (TLR4) is an inflammatory signaling pathway whose expression is increased in acute lung injury (
Zhang et al. reported that tabersonine, as a monoterpenoid indole alkaloid isolated from the root of
Berberine, an isoquinoline alkaloid isolated from different species such as
Matrine (tetracycloquinolizindine) (
Phytochemicals and their mechanisms of action against lung injury.
Phytochemical class | Compounds | Natural source | Mechanisms | Type of study | Lung injury model | Antiviral activity | References |
---|---|---|---|---|---|---|---|
Alkaloid | Antidesmone | |
↓TNF-α, ↓IL-6, ↓IL-1β, ↓NF-κB, ↓MAPK, ↓COX-2, ↓iNOS, ↓wet/dry ratio of lungs, ↓JNK, ↓ p38 | |
LPS | NR | |
Alkaloid | Berberine | |
↑Nrf2, ↑HO-1, ↓MPO, ↓TGF-β1, ↓ROS, ↓wet/dry ratio of lungs | |
LPS, radiation | Yes |
|
Alkaloid | Cepharanthine |
|
↓TNF-a, ↓IL-6, ↓IL-1β, ↓NF-κB, ↓IκBα, ↓ERK, ↓MAPK,↓ MPO | |
LPS | Yes |
|
Alkaloid | Epigoitrin | |
↓Viral replications, ↓MFN2, ↑MAVS, ↑IFN-b, ↑IFITM3, ↓TNF-a, ↓IL-1β | |
Influenza virus | Yes |
|
Alkaloid | Isotetrandrine | |
↓TNF-a, ↓IL-6, ↓IL-1β, ↓NF-κB, ↓NF-κB. ↓MAPK, ↓MPO, ↓wet/dry ratio of lungs | |
LPS | NR |
|
Alkaloid | Matrine |
|
↓TNF-a, ↓IL-6, ↓HMGB1, ↓MPO, ↓wet/dry ratio of lungs, ↓MDA, ↓ROS, ↓NF-κB | |
LPS | Yes |
|
Alkaloid | Neferine |
|
↑SOD,↑MDA, ↓MPO, ↓TNF-a, ↓IL-6, ↓NF-κB, ↓TGF-b1 | |
Bleomycin | NR |
|
Alkaloid | Oxysophoridine | |
↓TNF-α, ↓IL-6, ↓IL1β, ↓wet/dry ratio of lungs, ↓NF-κB, ↓pulmonary cell apoptosis | |
LPS | Yes |
|
Alkaloid | Sinomenine | |
↓IL-6, ↓IL-1β, ↓TNF-α, ↓NF-κB, ↓iNOS, ↓COX-2, ↑SOD, ↓MDA, ↑Nrf2, ↑ LC-3II, ↑Beclin1, ↓lung wet/dry ratio, ↓pulmonary edema, ↓BALF | |
LPS, sepsis | NR |
|
Alkaloid | Tabersonine | |
↓TRAF6, ↓MAPK/MK2, ↓NF-κB, ↓TNF-α, ↓IL-6, ↓IL-1β, ↓MPO, ↓iNOS, ↓NO | |
LPS | NR |
|
Anthocyanin | Cyanidin | |
↓TNF-α, ↓IL-6,↓IL-1β, ↓NF-κB, ↓COX-2, ↓PGE2 | |
Sepsis | Yes |
|
Anthocyanin | Malvidin | |
↓Bax/Bcl-2, ↓Caspase-3, ↓IL-1β, ↓TNF-α | |
Radiation | Yes |
|
Carbohydrate | Polysaccharides |
|
↓TNF-α, ↓wet/dry ratio of lungs, ↓TLR4,.↓TNF-α, ↓IL-6, ↓IL-1β, ↓MPO |
|
LPS | NR |
|
Chalcone | Cardamonin |
|
↓TNF-α, ↓IL-6, ↓IL-1β, ↓P38 MAPK, ↓MPO, ↓wet/dry ratio of lungs |
|
Sepsis | NR |
|
Coumarin | Anomalin | |
↓IL-1β, ↓IL-6, ↓TNF-α, ↑GST, ↑GSH, ↑catalase, ↓MDA, ↓NO, ↓wet/dry ratio of lungs | |
LPS | NR |
|
Coumarin | Daphnetin |
|
↓NF-κB, ↓TNF-α, ↓IL-6, ↓IL-1β, ↓JAK/STATs, ↓ROS, ↓MPO, ↓MAPK | |
LPS | NR |
|
Coumarin | Esculetin |
|
↓IL-23, ↓TNF-α, ↓IL-6, ↓IL-1β, ↓MAPK, ↓neutrophils, ↓NF-κB, ↓macrophages, ↓ERK, ↓Akt | |
LPS | Yes |
|
Coumarin | Fraxin | |
↓NLRP3, ↓wet/dry ratio of lungs, ↓NF-κB, ↓MPO, ↓MDA, ↓SOD, ↓IL-1β, ↓ IL-6, ↓TNF-α | |
LPS | NR |
|
Coumarin | Isofraxidin | |
↓PGE2, ↓COX-2, ↓NF-κB, ↓IL-1β, ↓IL-6, ↓MIP-2, ↓wet/dry ratio of lungs, ↓MPO, ↓MAPK, ↓AKT | |
LPS, influenza virus | Yes |
|
Coumarin | Osthole | |
↓IL-1β, ↓IL-6, ↓TNF-α, ↓NF-κB, ↓ERK, ↓Akt, ↓wet/dry ratio of lungs | |
LPS, neutrophil oxidative stress, hemorrhagic shock, intestinal ischemia reperfusion | Yes |
|
Coumarin | Praeruptorin D and E |
|
↓NF-κB, ↓IL-6, ↓TNF-α, ↓neutrophils, ↓cells infiltration in BALF, ↓MPO |
|
LPS, hydrochloric acid | NR |
|
Coumarin | Psoralidin |
|
↓COX-2, ↓5-LOX, ↓IL-1β, ↓IL-6, ↓TNF-α, ↓TGF-b |
|
Ionizing radiation | Yes |
|
Coumarin | Scoparone |
|
↓wet/dry ratio of lungs, ↓TLR4, ↓NF-κB, ↓IL-1β, ↓IL-6, ↓TNF-α, ↓MPO |
|
LPS | NR |
|
Coumarin | Umbelliferone |
|
↓MCP-1, ↓MPO, ↓MDA, ↑SOD, ↓TLR4, ↓MyD88, ↓NF-κB, ↓wet/dry ratio of lungs |
|
LPS | NR |
|
Flavonoid | Apigenin |
|
↓TNF-α, ↓wet/dry ratio of lungs, ↓IL-6, ↓IL-1β, ↓NF-κB, ↓TLR4, ↓ MPO |
|
LPS | Yes |
|
Flavonoid | Breviscapine |
|
↓ICAM-1, ↓IL-18 |
|
Left heart ischemic reperfusion | NR |
|
Flavonoid | Daidzein | |
↓TLR4, ↓MyD88, ↓NF-κB, ↓MPO, ↓wet/dry ratio of lungs, ↓IL-6, ↓TNF-α | |
LPS | Yes | |
Flavonoid | Eriodictyol |
|
↑Nrf2, ↓MPO, ↓TNF-α, ↓IL-6, ↓IL-1β, ↓MIP-2, ↓wet/dry ratio of lungs | |
LPS | NR | |
Flavonoid | Fisetin | |
↓Neutrophils, ↓macrophages, ↓TNF-α, ↓IL-6, ↓IL-1β, ↑Nrf2, ↑GPx, ↑SOD, ↑CAT | |
Cigarette smoke | Yes | |
Flavonoid | Hesperetin | |
↓TNF-α, ↓IL-6, ↓MPO, ↓LDH, ↑SOD, ↓TLR4, ↓MyD88, ↓NF-κB | |
LPS | NR | |
Flavonoid | Hyperin |
|
↓inflammatory cell infiltration, ↓MPO activity, ↓TNF-α, ↓IL-6, ↓ IL-1β, ↓NF-κB, ↓wet/dry ratio of lungs |
|
LPS | Yes |
|
Flavonoid | Isorhamnetin | |
↓Pulmonary edema, ↓TNF-α, ↓IL-6, ↓IL-1β, ↓ERK, ↓JNK, ↓NF-κB | |
LPS | Yes | |
Flavonoid | Kaempferol | |
↓Pulmonary edema, ↓TNF-α, ↓IL-6, ↓IL-1β, ↓alveolar wall thickness, ↓alveolar ↓hemorrhage, ↓leukocytes infiltration, ↑SOD,↓NF-κB,↓MAPKs, ↓MPO, ↓wet/dry ratio of lungs | |
LPS | Yes | |
Flavonoid | Luteolin |
|
↓Neutrophil chemotaxis, ↓MPO, ↓respiratory, ↓Akt, ↓ERK, ↑Nrf2, ↓NF-κB, ↑GPx, ↑SOD, ↑CAT | |
Mercuric chloride, LPS | Yes | |
Flavonoid | Myricetin |
|
↓TLR4, ↓MyD88, ↓NF-κB, ↓MPO,↓inflammatory cell migration, ↑SOD, ↑GPx, ↑CAT, ↓MPO, ↓wet/dry ratio of lungs, ↓IL-6, ↓TNF-α | |
LPS | Yes | |
Flavonoid | Naringenin | |
↓PI3K, ↓Akt, ↓MAPK, ↓pulmonary edema, ↓ROS, ↓TNF-α, ↓MPO, ↓IL-6, ↓IL-1β | |
LPS, acid | Yes | |
Flavonoid | Quercetin | |
↓NF-κB, ↓JNK/SAPK, ↓p38, ↓p44/p42, ↑caspase-3 | |
Radiation | Yes | |
Flavonoid | Rutin |
|
↓NF-κB, ↓MAPK, ↑GPx, ↑SOD, ↑CAT, ↓MIP, ↓MMP-9, ↓Akt | |
LPS | Yes | |
Flavonoid | Silymarin |
|
↑Nrf2, ↑HO-1, ↑GPx, ↑SOD, ↑CAT, ↓ MPO |
|
|
Yes | |
Flavonoid | Wogonin | |
↓NO, ↓TNF-α, ↓IL-6, ↓IL-1β, ↓iNOS, ↓NF-κB,↓ MPO | |
LPS | Yes | |
Iridoid | Geniposide | |
↓NF-κB, ↓MAPKs,↓ TNF-α, ↓IL-6, ↓alveolar hemorrhage, ↓MPO, ↓wet/dry ratio of lungs |
|
LPS | Yes | |
Isothiocyanate | Sulforaphane |
|
↑Nrf2, ↓PGE2, ↓COX-2, ↓MMP-2, ↓NO, TNF-α, ↓IL-6 |
|
LPS | Yes | |
Phenolic acid | Caffeic acid |
|
↓MDA, ↑SOD, ↑CAT | |
Radiation | Yes | |
Phenolic acid | Chicoric acid |
|
↑Nrf2, ↑HO-1, ↓wet/dry ratio of lungs, ↓MPO, ↓MAPK,↓ NLRP3, ↑SOD, ↓NF-κB |
|
LPS | Yes | |
Phenolic acid | Chlorogenic acid |
|
↓iNOS, ↓NO, ↓leukocytes, ↓MPO | |
LPS | Yes | |
Phenolic acid | Ellagic acid |
|
↓NF-κB, ↓COX-2, ↑IL-10, ↓IL-6, ↓TNF-α, ↓IL-1β, ↓NF-κB |
|
LPS, hydrochloric acid | Yes | |
Phenolic acid | Rosmarinic acid |
|
↓ERK/MAPK, ↓IL-6, ↓TNF-α, ↓IL-1β, ↑SOD | |
LPS | Yes | |
Phenolic compound | Apocynin |
|
↓TNF-α, ↑ SOD, ↓pulmonary vascular permeability, ↓MDA, ↓NADPH | |
LPS | NR | |
Phenolic glycoside | Salidroside |
|
|
|
LPS, paraquat | Yes | |
Phenolic terpene | Cannabidiol | |
|
|
LPS | Yes | |
Polyphenol | Curcumin |
|
|
|
Diabetes, bleomycin, LPS | Yes |
|
Polyphenol | Gossypol |
|
|
|
LPS | Yes |
|
Polyphenol | Magnolol |
|
|
|
LPS | Yes |
|
Polyphenol | Resveratrol |
|
|
|
LPS, hypoxia, sepsis, staphylococcal enterotoxin B, nickel, methamphetamine, bleomycin, chest trauma, cigarette smoke | Yes |
|
Polyphenol | Tannic acid |
|
|
|
LPS, sepsis | Yes |
|
Quinone | Emodin |
|
Activating autophagy, |
|
LPS | Yes |
|
Quinone | Shikonin |
|
|
|
LPS | Yes |
|
Quinone | Tanshinone IIA |
|
|
|
Oleic acid | Yes |
|
Quinone | Thymoquinone |
|
|
|
Chronic toluene | Yes |
|
Saponin | Dioscin |
|
|
|
LPS | Yes |
|
Saponin | Ginsenoside Rg1 |
|
|
|
LPS | Yes |
|
Saponin | Ginsenoside Rg3 |
|
|
|
LPS | Yes |
|
Saponin | Sodium aescinate |
|
|
|
Oleic acid | NR |
|
Saponin | Soyasaponin |
|
|
|
LPS | Yes |
|
Terpenoid | Andrographolide |
|
|
|
Cigarette smoke | Yes |
|
Terpenoid | Artemisitene |
|
|
|
Bleomycin | NR |
|
Terpenoid | Betulinic acid |
|
|
|
Sepsis | Yes |
|
Terpenoid | Costunolide |
|
|
|
Heat-killed |
Yes |
|
Terpenoid | Eugenol |
|
|
|
LPS | Yes |
|
Terpenoid | Farnesol |
|
|
|
Cigarette smoke | Yes |
|
Terpenoid | Geraniol |
|
|
|
LPS | NR |
|
Terpenoid | Glycyrrhizin |
|
|
|
Carrageenan | Yes |
|
Terpenoid | Isoforskolin |
|
|
|
LPS | NR |
|
Terpenoid | Linalool |
|
|
|
LPS | NR |
|
Terpenoid | Oridonin |
|
|
|
LPS | Yes |
|
Terpenoid |
|
|
|
|
LPS | Yes |
|
Terpenoid | Rubriflordilactone A |
|
|
|
LPS | Yes |
|
Terpenoid | Taraxasterol |
|
|
|
LPS | Yes |
|
Terpenoid | Thymol |
|
|
|
LPS | Yes |
|
Terpenoid | Triptolide |
|
|
|
LPS | Yes |
|
Terpenoid | Zerumbone |
|
|
|
LPS | Yes |
|
5-LOX, 5-Lipoxygenase; Akt, protein kinase B; BALF, bronchoalveolar lavage fluid; Bcl-2/Bax, B-cell lymphoma protein 2/associated X; CAT, catalase; CO2, carbon dioxide; COX-2, cyclooxygenase-2; ERK, extracellular signal-regulated kinase; GPx, glutathione peroxidase; GSH, glutathione; GST, glutathione S-transferase; HMGB1, high-mobility group box 1 protein; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule 1; IFITM3, interferon-induced transmembrane protein 3; IFN-b, interferon Beta 1; IL, interleukin; iNOS, inducible nitric oxide synthase; IκBα, inhibitor of nuclear factor-kappa B α; JAK/STATs, janus kinase-signal transducers and activator of transcription; JNK, jun N-terminal kinases; JNK/SAPK, JNK/stress-activated protein kinases; LDH, lactate dehydrogenase; LPS, lipopolysaccharides; MAPK, mitogen-activated protein kinase; MAPK/MK2, MAPK/activated protein kinase 2; MAVS, mitochondrial antiviral signaling; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MFN2, mitofusin-2; MIP-2, macrophage inflammatory protein 2; MMPs, matrix metalloproteinases; MPO, myeloperoxidase; MyD88, myeloid differentiation factor 88; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain-like receptors pyrin domain-containing protein 3; NR, not reported; Nrf2, nuclear factor erythroid 2- related factor two; O2, oxygen; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinases; ROS, reactive oxygen species; SOD, superoxide dismutase; TGF-β1, transforming growth factor β1; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α; TRAF6, TNF receptor-associated factor six.
Selected chemical structures of alkaloids, coumarins, terpenes, quinones, and other phytochemicals with potential protective effects against lung injury.
The pharmacological mechanisms and therapeutic targets of phytochemicals against coronavirus-associated lung injury. ACE, angiotensin-converting enzyme; Ag, angiotensin; Akt, protein kinase B; ARE, antioxidant response element; Anti-SARS-CoV, anti-severe acute respiratory syndrome coronavirus; Ca2+, calcium; CalM, calmodulin; NAFT, nuclear factor of activated T cells; CAT, catalase; COX-2, cyclooxygenase-2; ERK, extracellular signal-regulated kinase; GSH, glutathione; GST-1α, glutathione S-transferase; HO-1, heme oxygenase-1; IFNγ, interferon γ; IL, interleukin; IKK, inhibitor of nuclear factor-κB (IκB) kinase; MAPK, mitogen-activated protein kinase; MMPs, matrix metalloproteinases; NF-κB, nuclear factor-κB; Nrf2, nuclear factor erythroid 2-related factor 2; SOD, superoxide dismutase; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α; TNFR, TNF receptor.
Coumarins are the heterocyclic phytochemicals with 2
Daphnetin, as a hydroxy coumarin isolated from
Another study showed that the praeruptorins D and E (80 mg/kg, gavage), as pyranocoumarins found in
IL-17 as one of the prominent inflammatory cytokines is produced by T lymphocyte helper cells whose production is regulated by retinoic acid-related orphan receptor gamma t (RORγt). Esculetin (20 and 40 mg/kg, i.p.) as a hydroxycoumarin is widely found in
Besides, the protective effects of osthole, as prenylated coumarins purified first from the fruit of
Isofraxidin is another hydroxycoumarin, isolated from
Consistently, anomalin (
According to the prominent anti-inflammatory effects of natural coumarins, along with their other pharmacological effects, these compounds can be introduced as one of the new sources of drug discovery for the protection and treatment of lung injury.
Structurally, polyphenols are divided into several categories, including flavonoids (flavonols, flavones, flavanones, flavanols, anthocyanins, and isoflavones), phenolic acids (hydroxybenzoic acid and hydroxycinnamic acids), stilbenes, catechins, tannins, and lignans (
Flavonoids are another class of polyphenolic compounds whose effects on lung injuries have been extensively studied. Li et al. reported that apigenin C-glycoside, a trihydroxyflavone extracted from
Phenolic acid derivatives such as curcumin, chlorogenic acid, caffeic acid, salidroside, rosmarinic acid, and apocynin are other compounds with protective effects on lung injury with various mechanisms (
In general, due to the anti-inflammatory and antioxidant effects of polyphenol compounds, as well as their antiviral effects (
Quinones are another class of phytochemicals with an aromatic ring attached to two carbonyl groups in their structure, including anthraquinones, benzoquinones, naphthoquinones, phenanthrenequinones, and polycyclic quinones derivatives (
Terpenoids are natural carbohydrate compounds, divided into seven categories based on the number of carbons in their structure (
Geniposide (20, 40, or 80 mg/Kg, i.p., mice), as an iridoid found in
In general, due to the protective effects of the aforementioned phytochemicals on lung injuries, these compounds can be used as a protector and treatment in lung injuries leftover from coronavirus activity, including COVID-19. Given the antiviral effects (especially anticoronavirus) of some of the compounds listed in
Since the World Health Organization (WHO) announced the pandemic of COVID-19 disease (March 11, 2020), no effective treatment or vaccine has been introduced to treat this disease. Besides, to eliminate the SARS-CoV-2, conventional medications have either failed or been used taking them in doses higher than their therapeutic index leading to side effects (
MM and MF contributed to conceptualization; MM, SF, and MF contributed to designing the structure of the paper; MM and SF contributed to software; MM, SF, YS, NK, KS, PM, MG, MF, and JE contributed to drafting the manuscript; and MM, SF, MF, and JE contributed to reviewing and editing the paper.
JE gratefully acknowledges funding from CONICYT (PAI/ACADEMIA No. 79160109).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.