Plant phytochemicals as potential candidates for treating post‐COVID‐19 lung infections

To the Editor,

The rapid spread of coronavirus disease 2019 (COVID‐19) caused by Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2, Coronaviridae family) has infected over 500 million cases, with 6.5 million deaths reported globally since December 2020 (He, Deng, & Li, 2020). The lack of an effective therapy approved by the World Health Organization (WHO) has potentially increased the number of infected individuals worldwide. The respiratory quality of life and the level of pulmonary functional damage can greatly affect the intensity of respiratory failure during COVID‐19 infections (Steinbeis et al., 2022). Moreover, COVID‐19 infections weaken the immune system resulting in further bacterial or viral infection. Consequently, the virus exposure has caused many patients to develop adverse complications during COVID‐19 infections, including pneumonia, acute respiratory distress syndrome, or sepsis (Myall et al., 2021). SARS‐CoV‐2 used angiotensin‐converting enzyme 2 (ACE2) as a binding site receptor for the fusion of the viral and host membranes, thereby invading the host cell. Even though the exact mechanism of infection remains largely unidentified, SARS Covid‐2 Spike Protein (S1 protein) alone is reported to initiate severe lung disorders (Schroeder & Bieneman, 2022; Suzuki et al., 2021). Therefore, modulating the pulmonary and cardiovascular symptoms of COVID‐19 infections could be the key to lowering disease morbidity and mortality.

Plant phytochemicals are potent secondary metabolites that include various chemical entities such as polyphenols, flavonoids, steroidal saponins, organ sulfur compounds, and vitamins, with antioxidant, antiinflammatory, anticancer, antibacterial, antifungal, and antiviral properties (George, Dellaire, & Rupasinghe, 2017; Naveen Kumar, George, Suresh, & Kumar, 2013; Rahman, Mathew, Nair, Ramadan, & Vazhappilly, 2021). The most promising small molecules outlined as coronavirus antagonists were found to have a covalently melded cyclic structure, with the majority classified as polyphenols (Mani et al., 2020). With the rise in COVID‐19 cases, a surge in research analyzing the plausible use of polyphenols in treating COVID‐19 infections has been reported. Few clinical trials have also reported the effectiveness of plant polyphenols in patients with COVID‐19.

A recent in silico study has shown the effectiveness of 11 phytochemicals, targeting the SARS‐CoV‐2 essential proteins, including spike glyco‐protein (PDB id 5WRG), Nsp9 RNA binding protein (PDBid 6W4B), main protease (PDB id 6Y84), and RNA dependent RNA polymerase (PDB id 6M71), highlighting them as potential drugs against SARS‐CoV‐2 (Nag et al., 2021). Nigella sativa oil (NSO) is a herbal medicine with known antiviral and immunomodulatory properties. Patients with mild COVID‐19 symptoms, when administered with 500 mg of NSO, showed a faster recovery than patients who received standard care, with 63% of patients recovering within 14 days (Koshak et al., 2021). Persian medicine uses herbal formulations based on patients' symptoms and has reported clinical benefits for treating respiratory diseases. When administered with polyherbal formulations along with the standard care, patients with COVID‐19 demonstrated a significant reduction of symptoms, including dry cough, fatigue, headache, muscle pain, dyspnea, runny nose, and sputum cough (Karimi et al., 2021). Squalene belongs to a class of triterpenes and has demonstrated antiviral effects and acts by inhibiting viral DNA synthesis. An intravenous injection of 5 mg squalene microemulsion improved the symptoms of COVD‐19 within 7 days with significant improvement in lung elevated computed tomography (Ebrahimi et al., 2022). Similarly, in hospitalized‐COVID‐19 patients, administration of 400–800 g of green propolis extract along with the standard care protocols significantly reduced the length of hospital stay. Interestingly, patients treated with a higher dose of propolis showed a lower incidence of acute lung injury, also identified as a common complication in COVID‐19 infections. The mechanism of action of propolis remains unclear; however, quercetin, a component of propolis, has also demonstrated effectiveness against lung cell damage and inhibits cancer cell growth (Silveira et al., 2021). The effect of quercetin on patients with Chronic Obstructive Pulmonary Disease (COPD) with mild‐to‐severe lung damage showed that patients administrated with 500–2000 mg/day of plant flavonoid limited cell damage and lung inflammation, and rhinovirus‐induced lung tumor growth (Han, Barreto, Martinez, Comstock, & Sajjan, 2020). Zataria multiflora (Z) is a traditional medicine widely used to treat respiratory diseases and has potent antiinflammatory and antioxidative effects. Two months of treatment with Zataria multiflora improved the respiratory symptoms in asthmatic patients, as observed by improved pulmonary function tests, and effectively reduced inflammatory cells and a high‐sensitivity C‐reactive protein (hs‐CRP) while increasing IL‐10 (Alavinezhad, Ghorani, Rajabi, & Boskabady, 2022).

Further, several in vitro and in vivo studies have described the effect of plant polyphenols in lung cells. The alveolar epithelial cells, when treated with the Cannabis Sativa Arbel extract fraction, FCBD, in vitro, showed a significant reduction in COVID‐19‐related immune response markers, interleukin (IL)‐6 and ‐8. FCBD boosted CD36 and type II receptors for the Fc region of IgG (FcRII) expression and polarization and phagocytosis in macrophages (differentiated KG1 cell line) (Anil et al., 2021). The aqueous extract of Adhatoda vasica (AV) was shown to inhibit steroid‐resistant asthmatic molecules such as IL‐17A, KC (murine IL‐8 homolog), and hypoxia‐inducible factor (HIF)‐1 and demonstrated an increased negative binding affinity for C and O‐glycosides for HIF‐1, IL‐6, Janus kinase 1/3, tumor necrosis factor (TNF), and transforming growth factor (TGF)‐key factors in hypoxia inflammation (Gheware et al., 2021). Qu zhi qiao (QZQ), dry and immature fruit of Citrus paradisi cv. Changshanhuyou protects from allergic airway inflammation on ovalbumin (OVA)‐induced mice model. The flavonoids from QZQ suppress airway remodeling and prevent allergic asthma through MAPKs and Smad2/3 signaling pathway on inflammatory cells (Wang et al., 2021). The phenanthrene compounds, 2,7‐dihydroxy‐4,6‐dimethoxyphenanthrene and 6,7‐dihydroxy‐2,4‐dimethoxyphenanthrene extracted from Dioscorea batatas Decne (Chinese yam) demonstrated significant scavenging activity against PM2.5‐induced ROS and inhibited ROS‐induced activation of p38 mitogen‐activated protein kinase in lungs tissue (Lee et al., 2019). In a female Wistar rat model, the tamarind seed coat extract (TSCE) works against fluoride (F‐)‐induced pulmonary toxicity. In addition, TSCE modulates oxidative stress (NOX4 and p38α MAPK), inflammation (NF‐κB, COX‐2, and HO‐1), apoptosis (Hsp27, Hsp60, caspase3p20, and PARP1), and fibrosis (TGF‐β1, psmad3, Col1αl, and hydroxyproline level) markers in the lungs (Ameeramja & Perumal, 2018). A summary of potential plant extracts/compounds in treating lung disorders/diseases including COVID‐19 infections are shown in Table 1.

TABLE 1.

Potential plant phytochemicals/ extracts in treating lung disorders/diseases including COVID‐19 infections

Type of studies	Plant extract/compound	Key findings	References
Clinical trials	Nigella sativa oil	Studied the antiviral and immunomodulatory effects of Nigella sativa oil (NSO). Consuming 500 mg of NSO resulted in a 63% recovery from Covid‐19 post lung infections within 10 days.	Koshak et al. (2021))
	Persian herbal medicine	Administration of polyherbal decoction every 8 hr and two herbal capsules every 12 hr along with standard care significantly reduced COVID‐19 symptoms, including dry cough, fatigue, headache, muscle pain, dyspnea, runny nose, and sputum cough.	Karimi et al. (2021))
	Squalene	Studied the effect of squalene microemulsion on patients with COVID‐19. The patients were administered 5 mg of intravenous squalene two times a day for 6 days along with standard care. The symptoms improved within 7 days of admission, with no fever, cough relief, and lung elevated computed tomography showing significant improvement.	Ebrahimi et al. (2022))
	Quercetin	In COVID‐19 symptomatic patients, adjuvant supplementation of a daily dose of 1,500 mg/day (first week) and 1,000 mg/day (second week) of quercetin Phytosome improved the viral clearance and symptom frequency and was well tolerated by the patients.	Pierro et al. (2021)
	Zataria multiflora	Treatment with 5, and 10 mg/kg/day of Zataria multiflora (Z) plant improved respiratory symptoms and increased pulmonary function tests in asthmatic patients. The plant's leaf and stem extract showed significant effect on respiratory symptoms and pulmonary function test by reducing inflammatory cells and hs‐CRP while increasing IL‐10.	Alavinezhad et al. (2022))
	Standardized Brazilian green propolis extract	Hospitalized covid‐19 patients when treated with oral doses of 400–‐800 mg per day of green propolis extract (EPP‐AF) for 7 days improved the patient symptoms, with reduced length of hospital stay.	Silveira et al. (2021)
In vitro	FCDB	A reduction of interleukin (IL)‐6 and ‐8 levels was observed in an alveolar epithelial (A549) cell line when treated with an extract fraction from Cannabis sativa Arbel strain (FCBD). In vitro, FCBD boosted CD36 and type II receptors for the Fc region of IgG (FcRII) expression and polarization and phagocytosis in macrophages (differentiated KG1 cell line).	Anil et al. (2021))
	Adhatoda vasica	Studied the effects of Adhatoda vasica (AV) aqueous extract on an asthmatic mice model. AV inhibits steroid‐resistant asthmatic molecules such as IL‐17A, KC (murine IL‐8 homolog), and HIF‐1 (hypoxia‐inducible factor‐1), and demonstrated an increased negative binding affinity for C and O‐glycosides for HIF‐1, IL‐6, Janus kinase 1/3, TNF‐, and TGF‐key factors in hypoxia inflammation.	Gheware et al. (2021))
In vivo	Green tea extract	Green tea extract (GTE) reduces serum levels of pro‐inflammatory (IL‐1β, TNF‐α, IL‐6) and antiinflammatory (IL‐10) cytokines in vivo (male albino rats) model of pulmonary aflatoxicosis. The administration of GTE improved total glutathione (tGSH) and catalase (CAT) antioxidant enzyme activity.	El‐Sayed Mostafa et al. (2021)
	Citrus paradisi cv. Changshanhuyou	Qu zhi qiao (QZQ), a dry and immature fruit of Citrus paradisi cv. Changshanhuyou protects from allergic airway inflammation on ovalbumin (OVA)‐induced mice model. The flavonoids from QZQ suppress airway remodeling and prevent allergic asthma through MAPKs and Smad2/3 signaling pathway on inflammatory cells.	Wang et al. (2021))
	Tamarind seed coat extract	In a female Wistar rat model, the tamarind seed coat extract (TSCE) works against fluoride (F‐)‐induced pulmonary toxicity. In addition, TSCE modulates oxidative stress (NOX4 and p38α MAPK), inflammation (NF‐κB, COX‐2, and HO‐1), apoptosis (Hsp27, Hsp60, caspase3p20, and PARP1), and fibrosis (TGF‐β1, psmad3, Col1αl, and hydroxyproline level) markers in the lungs.	Ameeramja and Perumal (2018))
	Dioscorea batatas Decne	Dioscorea batatas Decne (Chinese yam) is a potential source of PM2.5 inhibition of induced pulmonary inflammation in a mouse model. The 2,7‐dihydroxy‐4,6‐dimethoxyphenanthrene and 6,7‐dihydroxy‐2,4‐dimethoxyphenanthrene compounds were extracted and demonstrated significant PM2.5‐induced ROS activity and inhibited ROS‐induced activation of p38 mitogen‐activated protein kinase in lungs tissue.	Lee et al. (2019))

Herein, we hypothesize that administering polyphenols along with the standard care protocols would be an effective strategy to alleviate symptoms related to post COVID‐19 lung infections. From the available data, plant polyphenols are reported to ascertain their protective effect by regulating the inflammatory and oxidative pathway/mediators involved in the pathogenesis of lung injury/disorders, particularly in related to COVID‐19 infections (Figure 1). Above studies have indicated that moderate to mild lung disorders can be improved by the use of phytochemicals and therefore, identifying potential candidate polyphenols for treating patients with COVID‐19 would have beneficial treatment outcomes along with standard care protocols. However, placebo‐controlled or double‐blinded clinical studies involving a larger number of COVID‐19 patients are essential in determining the effectiveness of polyphenols either alone or as cocktail against SARS‐CoV‐2 post lung infections.

FIGURE 1.

Potential targets of polyphenols against SARS‐CoV‐2 infection. Polyphenols targets viral proteins and the host immune system to exert a protective effect against SARS‐CoV‐2 infection. They modulates essential viral proteins and inhibit the binding of SARS‐CoV‐2 to the ACE receptors, preventing viral entry into the host cells. They also inhibits several processes of viral replication and assembly. Further, polyphenols are potent antiinflammatory and anti‐oxidant agents and could prevent the cell from virus‐induced oxidative stress and inflammation. Figure created in Biorender.com

CONFLICT OF INTEREST

There are no competing interests to declare.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study