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. 2023 Jan 26;38:100635. doi: 10.1016/j.hermed.2023.100635

Thymus vulgaris, a natural pharmacy against COVID-19: A molecular review

Ali Nadi a, Amir Abbas Shiravi b, Zahra Mohammadi c, Amin Aslani b, Mehrdad Zeinalian b,d,⁎
PMCID: PMC9877322  PMID: 36718131

Abstract

Introduction

A worldwide pandemic infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a deadly disease called COVID-19. Interaction of the virus and the Angiotensin converting-enzyme 2 (ACE2) receptor leads to an inflammatory-induced tissue damage. Thymus vulgaris L. (TvL) is a plant with a long history in traditional medicine that has antimicrobial, antiseptic, and antiviral properties. Thymol and Carvacrol are two important biological components in Thyme that have anti-inflammatory, antioxidant, and immunomodulatory properties. This study is a molecular review on the potential effects of TvL and its active compounds on SARS-COV2 infection.

Method

This is a narrative review in which using PubMed, Scopus, ISI, Cochrane, ScienceDirect, Google scholar, and Arxiv preprint databases, the molecular mechanisms of therapeutic and protective effects of TvL and its active compounds have been discussed regarding the molecular pathogenesis in COVID-19.

Results

Thyme could suppress TNF-alpha, IL-6, and other inflammatory cytokines. It also enhances the anti-inflammatory cytokines like TGF-beta and IL-10. Thyme extract acts also as an inhibitor of cytokines IL-1-beta and IL-8, at both mRNA and protein levels. Thymol may also control the progression of neuro-inflammation toward neurological disease by reducing some factors. Thyme and its active ingredients, especially Thymol and Carvacrol, have also positive effects on the renin-angiotensin system (RAS) and intestinal microbiota.

Conclusions

Accordingly, TvL and its bioactive components may prevent COVID-19 complications and has a potential protective role against the deleterious consequences of the disease.

Abbreviations: RAS, renin-angiotensin system; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme II; AngII, angiotensin II; ACEIs, ACE inhibitors; TMPRSS2, transmembrane serine protease 2; AT1R, angiotensin II receptor type 1; ARBs, angiotensin receptor blockers; TNF, tumor necrosis factor; Th, T helper; IL, Interleukin; TvL, Thymus vulgaris L.; CVD, cardio vascular disease; ARDS, acute respiratory distress syndrome; ALI, acute lung injury; BALF, brochalveolar lavage fluid; TGF-β, Transforming growth factor beta

Keywords: Thymus vulgaris L, Thyme, COVID-19, SARS-COV2, Infection, Treatment

1. Introduction

A large number of medicinal plant species have been traditionally used in the treatment of several diseases, including cardiovascular diseases, diabetes, intestinal inflammatory diseases, inflammatory bowel disease, Alzheimer’s diseases, and other illnesses (Juhás et al., 2008, Khouya et al., 2015, Ocaña and Reglero, 2012).

Thyme is a plant with a long history in traditional medicine that has antimicrobial, antiseptic, and antiviral properties (Hosseinzadeh et al., 2015, Ocaña and Reglero, 2012). It also has beneficial effects on the respiratory and cardiovascular system (Dauqan and Abdullah, 2017, Yu et al., 2016). Thymus vulgaris L (TvL) belongs to the Thyme L genus and the Lamiaceae family. This plant is small and perennial which grows in hot and dry climates (Prasanth Reddy et al., 2014). The most important compounds in TvL include thymol, carvacrol, linalool, γ-terpinene, p-cymene, β-myrcene, and terpinen-4-ol (Dauqan and Abdullah, 2017). Some of the health beneficial properties of Thyme are strongly related to its bioactive compounds which include phenols (thymol and carvacrol), phenolic acids (rosmarinic and caffeic acids), and flavonoids (luteolin, quercetin, and apigenin derivatives) (Dauqan and Abdullah, 2017, Hashemian et al., 2015, Oliviero et al., 2016, Yu et al., 2016). This plant is a rich source of vitamins, especially vitamin A, vitamin C, and vitamin B6. Moreover, there is a plethora of minerals, such as potassium, calcium, iron, manganese, magnesium, and selenium in the leaves of this plant (Dauqan and Abdullah, 2017).

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported for the first time in Wuhan, China (Zu et al., 2020). SARS-COV2 is a novel coronavirus, thus named because of its similar symptoms, biological behavior, and clinical manifestation to the severe acute respiratory syndrome virus (SARS-Cov). SARS-Cov2 causes coronavirus disease-2019 (COVID-19) which, as a pandemic infection, has so far affected millions of people, leading to hundreds thousands of deaths worldwide (Xu et al., 2020). The SARS-CoV-2 binds to the ACE2 receptor in human cells through its spike glycoprotein and enters host cells. As a consequence, this mechanism leads to respiratory infection, cardiovascular, gastrointestinal, and central neural system involvement (Utomo and Meiyanto, 2020). The most common clinical characteristics of SARS-COV2 are fever, cough, shortness of breath, muscle pain, confusion, sore throat, rhinorrhea, chest pain, and nausea (Chen et al., 2020). Although the molecular story of COVID-19 has been greatly identified, no definite treatment has been so far confirmed for this disease. Accordingly, in the current study, the potential therapeutic effects of Thymus vulgaris L and its compounds against COVID-19 and other similar viral infections have been molecularly described. ( Table 1).

Table 1.

The main chemical components of the essential oil of Thymus vulgaris L. (Karpinski TM, 2020).

Chemical Component Percent in essential oil extract
Carvacrol 3.5–70.3
Thymol 0.6–51.8
Borneol 0.0–40.6
p-Cymene 2.9–38.9
o-Cymene 0.0–31.7
Terpineol 0.0–19.9
Linalool 0.0–16.0
Terpinene 0.3–12.65
Camphene 0.0–12.3
1,8-Cineole 0.0–11.3
Pinene 0.2–6.1
Caryophyllene 0.0–3.5
Neomenthol 0.0–2.8
Cubebene 0.0–2.4
Geraniol 0.0–2.32
Menthone 0.0–2.2
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1.1. Research Methodology

The current study is a narrative review in which using some authentic resources, including PubMed, ISI, Scopus, ScienceDirect, Cochrane, Google Scholar, and Arxiv preprint databases, the relevant articles were searched within 2000–2021. Using sensitive keywords, including COVID, coronavirus infection, COVID19, COVID-19, SARS, SARS-CoV-2, molecular, thyme, Thymus vulgaris L, and viral infection, the most authentic articles were found and classified. Finally, the screened full-text articles were evaluated and analyzed using thematic analysis, regarding to the molecular mechanisms of thyme and its ingredients against COVID-19 and other similar viral infections.

2. Results and discussion

2.1. The pathophysiology of COVID-19

SARS-CoV2 is an enveloped positive single-stranded RNA virus belonging to beta coronaviruses (Xu et al., 2020). This virus fuses with the membrane of human respiratory system cells especially type II alveolar cells (AT2) via binding of its spike protein to the ACE2 receptor. It leads to ACE2 cleavage by transmembrane serine protease 2 (TMPRSS2) and causes alveolar damage after infection (Hoffmann et al., 2020, Zhao et al., 2020). ACE2 is an important molecule in the cellular entry of SARS-COV-2; the ACE2 expression in human cells could be an important factor in cell susceptibility to SARS-COV-2 (Hamming et al., 2004). ACE2 is a component of the renin-angiotensin system (RAS) in the human body which converts angiotensin II (AngII) to angiotensin(1−7) (Santos et al., 2003), a heptapeptide with various functions, including vasodilation, antifibrotic and antiproliferative effects (Clarke and Turner, 2011). ACE2 is most commonly expressed in the liver, kidneys, and heart (Akhmerov and Marban, 2020), and its level is decreased in COVID-19 due to the interaction of virus-ACE2, leading to raising the AngII level (Fakhrolmobasheri et al., 2020). Angiotensin II is a pre-inflammatory factor which in high level can increase oxidative stress and nuclear factor-kappa B (NF-κB) expression. These events could lead to cardiovascular, pulmonary, and renal disorders (Ferrario and Strawn, 2006, Phillips and Kagiyama, 2002). Accordingly, SARS-COV2 induces acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) through increasing the activity of ACE and Ang II via down-regulating the ACE2 and Ang(1−7) (South et al., 2020).

NOX1, a homologous enzyme of NADPH oxidase is expressed in endothelial cells, epithelial cells, smooth muscle cells, and interstitial fibroblasts, while NOX2, another homologous enzyme of NADPH oxidase, is expressed in phagocyte cells, and some organ tissue cells in cardiovascular, renal, CNS, and GI tracts. The overactivation of AngII in some of the pathological conditions, like COVID-19, leads to upregulating the NOX1 and NOX2 enzymes, the events that result in overproducing the Reactive Oxygen Species (ROS) molecules (Ago et al., 2011; Montezano et al., 2018). Fig. 1.

Fig. 1.

Fig. 1

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An infographic picture illustrating the molecular pathway of SARS-CoV-2 pathogenesis and also the molecular pathway of Thymus vulgaris L. potencies against COVID-19. (ANG: Angiotensin). (a). This virus causes body organ damage by increasing oxidative stress, inflammation, and disturbance in RAS. (ACE: Angiotensin-converting enzyme). (b). Thyme affects the renin-angiotensin system by both ACE suppression and inhibition of AngII binding to its receptor (AT1R: Angiotensin II receptor type 1). (c). NF-kB, which is down-regulated by Thyme, plays a vital role in the regulation of several pro-inflammatory genes. (d). Increased cytokines (IL-6, IL-2, IL-7, interferon- γ, TNF-α), oxidative stress, and hypoxemia, which are induced by SARS-CoV-2, lead to myocardial injury. On the other hand, Thymus vulgaris contains antioxidant and anti-inflammatory components which can improve the heart damage caused by COVID-19 infection. (e). Cytokines such as TNF-α and IL-6 recruit inflammatory cells into the lung and increase their response to activators. Cytokine storm leads to respiratory endothelial dysfunction which results in microvascular permeability and protein leakage followed by hypoxemia. Otherwise, Thyme suppresses TNF-α and IL-6. (f). Thyme decreases the level of IL-1β, IL-6, and TNF-α and downregulates the activation of NF-Κb. It also enhances the anti-inflammatory cytokines like TGF-β and IL-10, reducing the release of inflammatory cytokines. (g). Some inflammatory molecules like IL-6, IL-12, IL-15, and TNF-α may have an immunopathological role in infected brains. Otherwise, Thyme extract acts as an inhibitor of cytokines IL-1-beta and IL-8, at both mRNA and protein levels. (h). Thymol may also reduce the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3 (NLRP3) inflammasome components, which promote caspase-1-mediated interleukin-1ß and interleukin-18 maturation and thus the progression of neuro-inflammation toward neurological disease.

2.1.1. Chemical compounds of Thymus vulgaris

The essential oil of TvL contains several natural chemical components which carvacrol (3.5–70.3%), thymol (0.6–51.8%), borneol (0.0–40.6%), and p-Cymene (2.9–38.9%) are the most common components (Karpinski TM, 2020).

Carvacrol [C6H3CH3(OH)(C3H7)] is a liquid phenolic monoterpenoid which is also named 5–isopropyl‐ 2–methyl-phenol by the International Union of Pure and Applied Chemistry. This small molecule is the major component in the essential oil of oregano (Origanum vulgare), thyme (Thymus vulgaris), pepperwort (Lepidium flavum), and some other plants (de Carvalho et al., 2020, Sharifi‐Rad et al., 2018). Thymol (2-isopropyl-5-methyl-phenol) also known as “hydroxy cymene” is a colorless crystalline monoterpene phenol that is the main constituent of essential oils derived from the Lamiaceae family, including Thymus, Ocimum, Origanum, and other plants belonging to other families like Verbenaceae and Scrophulariaceae (Evans and Martin, 2000, Marchese et al., 2016, Meeran et al., 2017). Similar to carvacrol, thymol also has a hydroxyl group at a distinct position on the phenolic ring. Although thymol is slightly soluble in water, it is soluble in alcohols, alkaline solutions, and other organic solvents (Evans and Martin, 2000, Jafri et al., 2019, Meeran et al., 2017). Thymol exhibits several biological effects such as anti-inflammatory, antioxidant, immunomodulating, and free radical scavenging properties. Carvacrol also exhibits antioxidant activities, antimicrobial, and anticarcinogenic effects (Hashemian et al., 2015, Ocaña and Reglero, 2012). Moreover, many studies have demonstrated the reductive effect of thymol and carvacrol on the levels of the proinflammatory cytokines: Interleukin (IL)− 1β, IL-6, and tumor necrosis factor (TNF)-α (Ocaña and Reglero, 2012, Yu et al., 2016).

Borneol is a highly lipid-soluble bicyclic terpene which is mainly extracted from Cinnamomum camphora (L.) and Blumea balsamifera (L.) (Zhang et al., 2017, Zheng et al., 2018). In Traditional Chinese Medicine, borneol as a messenger drug is a well-known prescription to treat strokes (Guo et al., 2014). Borneol is known as a ‘Courier herb’ that helps to direct the herbs upward to the target organ, particularly in the brain. According to different studies, borneol can increase the penetration of drugs through the corneal (Yang et al., 2009), intestinal membrane (Zhang et al., 2012), and nasal cavity mucosa (Lu et al., 2011). It can overcome the brain blood barrier, leading to enhanced access to the brain (Wang et al., 2014).

p-Cymene, 1-methyl-4-isopropylbenzene, is a monoterpene found in many plant species such as TvL, and also belongs to the volatile organic compounds which may significantly be detected in some food products. Moreover, p-Cymene, as a natural flavouring agent in foods, has shown predominant antioxidant and antimicrobial properties, according to different studies (De Oliveira et al., 2015, Marchese et al., 2017, Cao et al., 2019).

2.2. Thymus vulgaris L., COVID-19, and the renin-angiotensin system (RAS)

RAS consists of an enzymatic cascade which plays a crucial role in multiple physiological and inflammatory events. Several studies have shown that RAS activation is strictly related to an increase in the inflammatory status, such as upregulating several cytokines, chemokines, and cell adhesion molecules (Brasier et al., 2002; S.A. Capettini et al., 2012; Satou et al., 2018). Some dietary factors have a considerable in vitro effect on regulating the RAS elements, however, the major event is ACE inhibition by a range of dietary peptides from plant, dairy, and fish (Loizzo et al., 2008, Patten et al., 2012). Glen S et al. showed that among the plants studied, a small selection of plants such as thyme and tea have potential for both ACE suppression and AngII inhibition through binding to its receptor (AT1R). They also demonstrated that the ACE inhibitory effect of these herbs was correlated with their polyphenolic component, as demonstrated by other researchers in this field. On the other hand, the correlation between AT1R suppression and these components was non-significant, largely associated with the herbal metabolites of several chemical classes. It is expected that the herbal components associated with AT1R inhibition are likely distinct from those associated with ACE-blockade (Marchesi et al., 2008, Patten et al., 2012). Initial reports recommended that some conditions, including heart disease, hypertension, diabetes mellitus, and cardiovascular diseases increase the COVID-19-induced morbidities. Meanwhile, many of these patients are often undertreated with RAS blockers, such as ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) (Bavishi et al., 2020, Danser et al., 2020). Nevertheless, the therapeutic potential of ACEIs/ARBs drugs in COVID-19 is controversial. As the ACE2 receptor facilitates SARS-CoV-2 to invade target cells, SARS-CoV-2 binding to ACE2 leads to reduce ACE2 expression (Fakhrolmobasheri et al., 2020). Some studies have also shown that in the patients undertreated with ACEIs/ARBs, the expression of ACE2 is elevated. Accordingly, some experts speculated that treatment with ACEIs/ARBs could potentially enhance the risk of infection with COVID-19 (Bavishi et al., 2020, Ferrario et al., 2005). There is, however, no evidence to confirm the notion that ACEIs/ARBs can facilitate coronavirus entry by increasing the ACE2 expression (Danser et al., 2020). On the other hand, some other studies have illustrated that in COVID-19 patients, serum AngII level is higher than healthy people which can upregulate the expression of inflammatory cytokines through AT1R activation (Bavishi et al., 2020, Meng et al., 2020). Therefore, the usage of ACEIs/ARBs, such as thyme, could be beneficial for COVID-19 patients.

2.3. The Anti-inflammatory effects of Thymus vulgaris L. in COVID-19

In SARS-CoV-2 infection, the serum level of AngII is increased (Shiravi et al., 2020). The binding of AngII to AngII type 1 receptor (AT1R) is a crucial mediator for most of the pro-inflammatory effects. The AngII type 2 receptor (AT2R) is also activated by AngII which leads to the activation of some inflammatory cells. AT1R activation induces the overexpression of adhesion molecules, chemokines, and cytokines via different pathways such as NF-kB up-regulation. NF-kB plays a vital role in the regulation of several pro-inflammatory genes (Husain, 2015; S.A. Capettini et al., 2012; Tan et al., 2018). As previously described, thyme also acts as a negative regulator of NF-kB (Wan et al., 2018). Moreover, the plasma levels of most pro-inflammatory cytokines, such as IL1B, IL1RA, IL7, IL8, IL9, IL10, TNF, basic fibroblast growth factor (FGF), and other pro-inflammatory factors, are increased in COVID-19, according to some recent studies (Gharebaghi et al., 2020, Monteleone et al., 2020). Therefore, thyme as an inhibitory agent of pro-inflammatory cytokines may be considered in the therapeutic approach of the patients with COVID-19 (Chamanara et al., 2019, Oliviero et al., 2016, Yu et al., 2016). Fig. 2.

Fig. 2.

Fig. 2

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An infographic diagram illustrating the potential therapeutic effects of Thymus vulgaris L. in COVID-19. ACE: Angiotensin-converting enzyme, AngII: Angiotensin II, AT1R: Angiotensin II receptor type 1, TNF: tumor necrosis factor, IL: Interleukin, TGF-β: Transforming growth factor-beta, NLRP3: nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3.

Some thyme compounds, such as thymol and carvacrol, are traditionally used to treat chronic bronchitis, cough, sore throat, colds, asthma, and other respiratory infections. Thyme is an antiseptic, expectorant, and antispasmodic herbal medicine with respiratory clearance characteristics (Ernst et al., 1997, Inouye et al., 2001, Kohlert et al., 2002). As mentioned, acute lung injury (ALI) and its severest form, acute respiratory distress syndrome (ARDS), are the main reasons for COVID-19 mortality. The characteristics of ARDS include damage of endothelial and epithelial respiratory cells, neutrophil infiltration, an extended-release of pro-inflammatory mediators, and pulmonary edema and inflammation (Mendez and Hubmayr, 2005, Thiagarajan, 2011, Ware and Matthay, 2000). The severe COVID-19 patients represent cytokine storm characteristics. In cytokine storm, the serum levels of pro-inflammatory cytokines, such as IL-6, IL-1β, IL-2, IL-8, IL-17, and TNF-α, are suddenly increased (Cao, 2020). Some cytokines such as TNF-α and IL-6 recruit neutrophils and other inflammatory cells into the lung and increase their response to activators. This cytokine release leads to the respiratory endothelial dysfunction resulting in microvascular permeability and protein leakage, followed by hypoxemia (Herold et al., 2013, Sawa, 2014). TNF-α and IL-6 have an essential role in inflammatory response and can induce the occurrence of ARDS/ALI (Bhatia and Moochhala, 2004). Wan et al. indicated the immunomodulatory effect of thymol in lipopolysaccharide-induced ARDS through TNF-α and IL-6 suppression in the broncho-alveolar lavage fluid (BALF) (Wan et al., 2018).

NF-κB, a protein complex that triggers a pro-inflammatory signaling pathway in the lung leading to cytokine release, is overexpressed in ALI and ARDS (Fudala et al., 2011). NF-kB pathway is activated through two distinct ways, the canonical and non-canonical pathways. p65 and p50 are members of the canonical pathway triggered by pro-inflammatory cytokines (as IL-1). On the other hand, p52 and RelB are members of the non-canonical pathway, associated with the normal lymphoid organ development. Some studies have shown that the Thyme extract is a negative regulator of NF-kB p65 and NF-kB p52 transcription factors whereby pro-inflammatory cytokines (IL-1 beta and IL-8) are reduced. Studies also demonstrated that the thyme extract acts as an inhibitor of cytokines IL-1-beta and IL-8, at both mRNA and protein levels in normal human epithelial cells (Bae et al., 2014, Mezzano et al., 2003, Oliviero et al., 2016). Thymol can also decrease the recruitment of inflammatory cells like neutrophils into BALF. Thymol inhibits NF-κB activation (Wan et al., 2018) which is a transcription regulator of inflammatory and immune response genes (Schuliga, 2015), an event that can decrease the severity of ALI/ARDS. Carvacrol, another active constituent of thyme has been also shown to have a therapeutic effect on ALI/ARSD. The remedial effect of carvacrol on ARDS is through decreasing the inflammatory cytokines, reducing the number of inflammatory cells in BALF, and inhibition of NF-κB (Feng and Jia, 2014). As a result, thyme could be effective in improving the respiratory symptoms of COVID-19 patients.

2.4. The Cardio-protective effects of Thymus vulgaris L. in COVID-19

Thyme has been used as a remedy for hypertension and other cardiovascular diseases in traditional medicine from ancient times. Thyme has effective components, such as thymol and carvacrol, against oxidative agents causing cardiovascular disease (Castillo-España et al., 2012). Cardiovascular damages are prevalent in morbidity in COVID-19 patients. Meanwhile, patients with cardiovascular disease (CVDs) are more susceptible to severe COVID-19 symptoms, especially acute myocardial injury (Huang et al., 2020; D. Wang et al., 2020, Wang et al., 2020). SARS-COV2 might induce myocardial injury through the cytokine storm associated with a severe response by type 1 and type 2 T helper cells. Moreover, COVID-19-induced hypoxemia and respiratory failure could lead to myocardial dysfunction (Zheng et al., 2020). Cytokine storms could induce multiple organ failure because of increasing the inflammatory chemokines, such as IL-6, IL-2, IL-7, interferon- γ, and (TNF)-α. It has been shown that cardiovascular injury correlates with elevated inflammatory markers (Akhmerov and Marban, 2020). Moreover, the oxidative stress generated by SARS-CoV-2 could cause the heart damage (J.-Z. Wang et al., 2020, Wang et al., 2020). Thymus vulgaris L. contains antioxidant components and studies show that a proper dose of antioxidants can improve the heart damage caused by COVID-19 infection (Dauqan and Abdullah, 2017; J.-Z. Wang et al., 2020, Wang et al., 2020). It has also been demonstrated in many studies that thymol and carvacrol, derivatives of TvL, have anti-inflammatory effects (Braga et al., 2007, Liang et al., 2007, Ocaña and Reglero, 2012). So it seems TvL and its derivatives can protect cardiovascular damage induced by SARS-COV2.

2.4.1. The Neuroprotective effects of Thymus vulgaris L. in COVID-19

Some COVID-19 patients have neurologic symptoms such as dizziness, headache, hypogeusia/hyposmia, and vomiting (Mao et al., 2020). These symptoms are suggestive for neuroinvasive potencies of the virus (Wu et al., 2020). Past studies on SARS-CoV revealed that it could reach the CNS through the bloodstream or olfactory bulb neuronal circuits. Moreover, ACE2, the receptor of SARS-CoV2, is expressed in astroglial cells and neurons in different regions of the CNS (Netland et al., 2008). Interaction of ACE2 with SARS-CoV2 spike protein leads to an increase in the AngII/Ang(1−7) ratio, which is the main reason for cytokine storm in patients (Fakhrolmobasheri et al., n.d.). Other studies represent that increasing the secretion of some inflammatory molecules like IL-6, IL-12, IL-15, and TNF-α in CoV-infected glial cells can have an immunopathological role in inflamed brains (Bohmwald et al., 2018, Netland et al., 2008).

Otherwise, thymol and carvacrol, two bioactive molecules isolated from TvL, could down-regulate the activation of NF-κB signaling in lipopolysaccharide-treated macrophages (Gholijani et al., 2016). TvL also enhances the anti-inflammatory cytokines like TGF-β and IL-10 which can reduce the release of inflammatory cytokines by astrocytes (Mahmoodi et al., 2019). Thymol may also reduce the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3 (NLRP3) inflammasome components, which promote caspase-1-mediated interleukin-1ß and interleukin-18 maturation in microglia, resulting in the progression of neuro-inflammation toward neurological disease (Hung et al., 2019). Altogether, TvL can inhibit the pathogenic pathway of the virus through some anti-inflammatory potencies that counteract the destructive effects of SARS-CoV2 on the brains of the patients.

2.4.2. Gut microbiota, COVID-19, and Thymus vulgaris L

The intestinal microbiota is a vast collection of microorganisms in the human gastrointestinal tract with a determinant role in disease and health (Sekirov et al., 2010). Dysbiosis, an imbalance in human microbiota, can lead to some respiratory problems, such as asthma, COPD (Chronic obstructive pulmonary disease), and CF (Cystic fibrosis) (Shukla et al., 2017). In patients with respiratory disorders such as COVID-19, the association between lungs and intestines can lead to gut disturbance. Thus, improving the gut microbiota can be considered as a therapeutic approach for COVID-19 patients (Gao et al., 2020). An experimental study indicated that thyme extract improved the gut microbial population (Mehdipour et al., 2014). The mixture of virgin olive oil and thyme phenolic compounds could increase the populations of bifidobacteria in another study. Therefore, a mixture of virgin olive oil and thyme phenolic compounds have prebiotic properties (Martín-Peláez et al., 2017). Apparently, more detailed studies should be performed to explore the exact effect of thyme on the intestinal microbiota (Almanea et al., 2019). Altogether, it seems TvL can be effective in the treatment of the patients with COVID-19 through improving the gut microbiota. (Fig. 1, Fig. 2).

3. Conclusions

SARS-CoV-2 virus, an agent of COVID-19, can affect different body organs, including respiratory, gastrointestinal, cardiovascular, and neurologic tracts by increasing oxidative stress, inflammation, and disturbance in RAS. Thymus vulgaris L. and its bioactive components such as thymol and carvacrol can suppress the negative effects of the RAS in COVID-19 patients. Moreover, thyme can decrease the pro-inflammatory cytokines such as IL-6 and TNF-α, resulting in the reduction of the severity of ALI/ARDS. TvL can also decrease oxidative stress due to its antioxidant properties that can protect the cardiovascular system in COVID-19 infection. Meanwhile, it has also neuro-protective effects by enhancing anti-inflammatory cytokines like TGF-β and inhibition of inflammatory pathways. In conclusion, thyme has anti-inflammatory, antioxidant, and immunomodulating properties which can reduce the side effects of COVID-19 in patients.

Credit Author Statement

The authors of the manuscript entitled: Thymus vulgaris, a natural pharmacy against COVID-19: A molecular review, are committed to abide by the trust in their article and have not submitted their work to another journals.

References

  1. Ago T., Kuroda J., Kamouchi M., Sadoshima J., Kitazono T. Pathophysiological Roles of NADPH oxidase/nox family proteins in the vascular system. Circ. J. advpub. 2011 doi: 10.1253/circj.CJ-11-0388. 1106131269–1106131269. [DOI] [PubMed] [Google Scholar]
  2. Akhmerov A., Marban E. COVID-19 and the heart. Circ. Res. 2020 doi: 10.1161/CIRCRESAHA.120.317055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Almanea A., El-Aziz G.S.A., Ahmed M.M.M. The potential gastrointestinal health benefits of Thymus vulgaris essential oil: a review. Biomed. Pharmacol. J. 2019;12:1793–1799. doi: 10.13005/bpj/1810. [DOI] [Google Scholar]
  4. Bae E.H., Kim I.J., Joo S.Y., Kim E.Y., Choi J.S., Kim C.S., Ma S.K., Lee J., Kim S.W. Renoprotective effects of the direct renin inhibitor aliskiren on gentamicin-induced nephrotoxicity in rats. J. Renin Angiotensin Aldosterone Syst. 2014;15:348–361. doi: 10.1177/1470320312474853. [DOI] [PubMed] [Google Scholar]
  5. Bavishi C., Maddox T.M., Messerli F.H. Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers. JAMA Cardiol. 2020 doi: 10.1001/jamacardio.2020.1282. [DOI] [PubMed] [Google Scholar]
  6. Bhatia M., Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J. Pathol. 2004;202:145–156. doi: 10.1002/path.1491. [DOI] [PubMed] [Google Scholar]
  7. Bohmwald K., Galvez N., Ríos M., Kalergis A.M. Neurologic alterations due to respiratory virus infections. Front. Cell. Neurosci. 2018;12:386. doi: 10.3389/fncel.2018.00386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Braga P.C., Alfieri M., Culici M., Dal Sasso M. Inhibitory activity of Thymol against the formation and viability of Candida albicans hyphae. Mycoses. 2007;50:502–506. doi: 10.1111/j.1439-0507.2007.01412.x. [DOI] [PubMed] [Google Scholar]
  9. Brasier A.R., Recinos A., Eledrisi M.S. Vascular inflammation and the renin-angiotensin system. ATVB. 2002;22:1257–1266. doi: 10.1161/01.ATV.0000021412.56621.A2. [DOI] [PubMed] [Google Scholar]
  10. Cao X. COVID-19: immunopathology and its implications for therapy. Nat. Rev. Immunol. 2020 doi: 10.1038/s41577-020-0308-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cao X.L., Sparling M., Dabeka R. p-Cymene, a natural antioxidant, in Canadian total diet foods: occurrence and dietary exposures. J. Sci. Food Agric. 2019;99:5606–5609. doi: 10.1002/jsfa.9854. [DOI] [PubMed] [Google Scholar]
  12. de Carvalho F.O., Silva É.R., Gomes I.A., Santana H.S.R., do Nascimento Santos D., de Oliveira Souza G.P., de Jesus Silva D., Monteiro J.C.M., de Albuquerque Júnior R.L.C., de Souza Araújo A.A. Anti‐inflammatory and antioxidant activity of Carvacrol in the respiratory system: A systematic review and meta‐analysis. Phytother. Res. 2020 doi: 10.1002/ptr.6688. [DOI] [PubMed] [Google Scholar]
  13. Castillo-España P., Perea-Arango I., Hernández-Abreu O., Ramírez R., Estrada-Soto S. Preliminary ethnopharmacological survey of plants used in Mexico for the treatment of hypertension. Planta Med. 2012;78 doi: 10.1055/s-0032-1320581. [DOI] [Google Scholar]
  14. Chamanara M., Abdollahi A., Rezayat S.M., Ghazi-Khansari M., Dehpour A., Nassireslami E., Rashidian A. Thymol reduces acetic acid-induced inflammatory response through inhibition of NF-kB signaling pathway in rat colon tissue. Inflammopharmacology. 2019;27:1275–1283. doi: 10.1007/s10787-019-00583-8. [DOI] [PubMed] [Google Scholar]
  15. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y., Qiu Y., Wang J., Liu Y., Wei Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–513. doi: 10.1016/S0140-6736(20)30211-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Clarke N.E., Turner A.J. Angiotensin-converting enzyme 2: the first decade. Int. J. Hypertens. 2011:2012. doi: 10.1155/2012/307315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Danser A.H.J., Epstein M., Batlle D. Renin-Angiotensin system blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin-angiotensin system blockers. Hypertension. 2020 doi: 10.1161/HYPERTENSIONAHA.120.15082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dauqan E.M., Abdullah A. Medicinal and functional values of Thyme (Thymus vulgaris L.) herb. J. Appl. Biol. Biotechnol. 2017;5:17–22. [Google Scholar]
  19. De Oliveira T.M., de Carvalho R.B.B., de Costa I.H.F., de Oliveira G.A.L., de Souza A.A., de Lima S.G., et al. Evaluation of p-cymene, a natural antioxidant. Pharm. Biol. 2015;53:423–428. doi: 10.3109/13880209.2014.923003. [DOI] [PubMed] [Google Scholar]
  20. Ernst E., März R., Sieder C. A controlled multi-centre study of herbal versus synthetic secretolytic drugs for acute bronchitis. Phytomedicine. 1997;4:287–293. doi: 10.1016/S0944-7113(97)80035-9. [DOI] [PubMed] [Google Scholar]
  21. Evans J.D., Martin S.A. Effects of thymol on ruminal microorganisms. Curr. Microbiol. 2000;41:336–340. doi: 10.1007/s002840010145. [DOI] [PubMed] [Google Scholar]
  22. Feng X., Jia A. Protective effect of carvacrol on acute lung injury induced by lipopolysaccharide in mice. Inflammation. 2014;37:1091–1101. doi: 10.1007/s10753-014-9833-1. [DOI] [PubMed] [Google Scholar]
  23. Ferrario C.M., Strawn W.B. Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am. J. Cardiol. 2006;98:121–128. doi: 10.1016/j.amjcard.2006.01.059. [DOI] [PubMed] [Google Scholar]
  24. Ferrario C.M., Jessup J., Chappell M.C., Averill D.B., Brosnihan K.B., Tallant E.A., Diz D.I., Gallagher P.E. Effect of angiotensin-converting enzyme inhibition and angiotensin ii receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111:2605–2610. doi: 10.1161/CIRCULATIONAHA.104.510461. [DOI] [PubMed] [Google Scholar]
  25. Fudala R., Allen T.C., Krupa A., Cagle P.T., Nash S., Gryczynski Z., Gryczynski I., Kurdowska A.K. Increased levels of nuclear factor kb and fos-related antigen 1 in lung tissues from patients with acute respiratory distress syndrome. Arch. Pathol. Lab Med. 2011;135:8. doi: 10.5858/2009-0660-OAR1.1. [DOI] [PubMed] [Google Scholar]
  26. Gao Q.Y., Chen Y.X., Fang J.Y. 2019 novel coronavirus infection and gastrointestinal tract. J. Dig. Dis. 2020 doi: 10.1111/1751-2980.12851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Gharebaghi R., Heidary F., Moradi M., Parvizi M. Metronidazole a potential novel addition to the COVID-19 treatment regimen. SSRN J. 2020 doi: 10.2139/ssrn.3559020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Gholijani N., Gharagozloo M., Farjadian S., Amirghofran Z. Modulatory effects of Thymol and Carvacrol on inflammatory transcription factors in lipopolysaccharide-treated macrophages. J. Immunotoxicol. 2016;13:157–164. doi: 10.3109/1547691X.2015.1029145. [DOI] [PubMed] [Google Scholar]
  29. Guo Y., Yan S., Xu L., et al. Use of angong niuhuang in treating central nervous system diseases and related research. Evid. Based Complement Altern. Med. 2014;2014 doi: 10.1155/2014/346918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hamming I., Timens W., Bulthuis M., Lely A., Navis G., van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol.: A J. Pathol. Soc. Gt. Br. Irel. 2004;203:631–637. doi: 10.1002/path.1570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hashemian Farnaz, Baghbanian N., Majd Z., Rouini M.-R., Jahanshahi J., Hashemian Farshad. The effect of Thyme honey nasal spray on chronic rhinosinusitis: a double-blind randomized controlled clinical trial. Eur. Arch. Oto-Rhino-Laryngol. 2015;272:1429–1435. doi: 10.1007/s00405-014-3233-x. [DOI] [PubMed] [Google Scholar]
  32. Herold S., Gabrielli N.M., Vadász I. Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction. Am. J. Physiol. -Lung Cell. Mol. Physiol. 2013;305:L665–L681. doi: 10.1152/ajplung.00232.2013. [DOI] [PubMed] [Google Scholar]
  33. Hoffmann M., Kleine-Weber H., Schroeder S., Krüger N., Herrler T., Erichsen S., Schiergens T.S., Herrler G., Wu N.-H., Nitsche A. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020 doi: 10.1016/j.cell.2020.02.052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Hosseinzadeh S., Jafarikukhdan A., Hosseini A., Armand R. The application of medicinal plants in traditional and modern medicine: a review of Thymus vulgaris. Int. J. Clin. Med. 2015;6:635. [Google Scholar]
  35. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X., Cheng Z., Yu T., Xia J., Wei Y., Wu W., Xie X., Yin W., Li H., Liu M., Xiao Y., Gao H., Guo L., Xie J., Wang G., Jiang R., Gao Z., Jin Q., Wang J., Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hung W., Ho C., Pan M. Targeting the NLRP3 inflammasome in neuroinflammation: health promoting effects of dietary phytochemicals in neurological disorders. Mol. Nutr. Food Res. 2019:1900550. doi: 10.1002/mnfr.201900550. [DOI] [PubMed] [Google Scholar]
  37. Husain K. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis. WJBC. 2015;6:209. doi: 10.4331/wjbc.v6.i3.209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Inouye S., Takizawa T., Yamaguchi H. Antibacterial activity of essential oils and their major constituents against respiratory tract pathogens by gaseous contact. J. Antimicrob. Chemother. 2001;47:565–573. doi: 10.1093/jac/47.5.565. [DOI] [PubMed] [Google Scholar]
  39. Jafri H., Ansari F.A., Ahmad I. New Look to Phytomedicine. Elsevier; 2019. Prospects of Essential Oils in Controlling Pathogenic Biofilm; pp. 203–236. [Google Scholar]
  40. Juhás Š., Bujňáková D., Rehák P., Čikoš Š., Czikková S., Veselá J., Iłková G., Koppel J. Anti-inflammatory effects of Thyme essential oil in mice. Acta Vet. Brno. 2008;77:327–334. [Google Scholar]
  41. Karpinski T.M. Essential oils of lamiaceae family plants as antifungals. Biomolecules. 2020;10:103. doi: 10.3390/biom10010103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Khouya T., Ramchoun M., Hmidani A., Amrani S., Harnafi H., Benlyas M., Zegzouti Y.F., Alem C. Anti-inflammatory, anticoagulant and antioxidant effects of aqueous extracts from Moroccan Thyme varieties. Asian Pac. J. Trop. Biomed. 2015;5:636–644. [Google Scholar]
  43. Kohlert C., Schindler G., März R.W., Abel G., Brinkhaus B., Derendorf H., Gräfe E., Veit M. Systemic availability and pharmacokinetics of Thymol in humans. J. Clin. Pharmacol. 2002;42:731–737. doi: 10.1177/009127002401102678. [DOI] [PubMed] [Google Scholar]
  44. Liang H., Bao F., Dong X., Tan R., Zhang C., Lu Q., Cheng Y. Antibacterial thymol derivatives isolated from centipeda minima. Molecules. 2007;12:1606–1613. doi: 10.3390/12081606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Loizzo M.R., Saab A.M., Tundis R., Menichini Federica, Bonesi M., Piccolo V., Statti G.A., de Cindio B., Houghton P.J., Menichini Francesco. In vitro inhibitory activities of plants used in Lebanon traditional medicine against angiotensin converting enzyme (ACE) and digestive enzymes related to diabetes. J. Ethnopharmacol. 2008;119:109–116. doi: 10.1016/j.jep.2008.06.003. [DOI] [PubMed] [Google Scholar]
  46. Lu Y., Du S.Y., Chen X.L., et al. Enhancing effect of natural borneol on the absorption of geniposide in rat via intranasal administration. J. Zhejiang Univ. Sci. B. 2011;12:143–148. doi: 10.1631/jzus.B1000121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Mahmoodi M., Ayoobi F., Aghaei A., Rahmani M., Taghipour Z., Hosseini A., Jafarzadeh A., Sankian M. Beneficial effects of Thymus vulgaris extract in experimental autoimmune encephalomyelitis: clinical, histological and cytokine alterations. Biomed. Pharmacother. 2019;109:2100–2108. doi: 10.1016/j.biopha.2018.08.078. [DOI] [PubMed] [Google Scholar]
  48. Mao L., Wang M., Chen S., He Q., Chang J., Hong C., Zhou Y., Wang D., Miao X., Hu Y. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan. China.: a Retrosp. case Ser. Study. 2020 doi: 10.1001/jamaneurol.2020.1127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Marchese A., Orhan I.E., Daglia M., Barbieri R., Di Lorenzo A., Nabavi S.F., Gortzi O., Izadi M., Nabavi S.M. Antibacterial and antifungal activities of thymol: a brief review of the literature. Food Chem. 2016;210:402–414. doi: 10.1016/j.foodchem.2016.04.111. [DOI] [PubMed] [Google Scholar]
  50. Marchese A., Arciola C.R., Barbieri R., Silva A.S., Nabazi S.F., Sokeng A.J.T., et al. Update on monoterpenes as antimicrobial agents: a particular focus on p-cymene. Materials. 2017;10:947. doi: 10.3390/ma10080947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Marchesi C., Paradis P., Schiffrin E.L. Role of the renin–angiotensin system in vascular inflammation. Trends Pharmacol. Sci. 2008;29:367–374. doi: 10.1016/j.tips.2008.05.003. [DOI] [PubMed] [Google Scholar]
  52. Martín-Peláez S., Mosele J.I., Pizarro N., Farràs M., de la Torre R., Subirana I., Pérez-Cano F.J., Castañer O., Solà R., Fernandez-Castillejo S. Effect of virgin olive oil and Thyme phenolic compounds on blood lipid profile: implications of human gut microbiota. Eur. J. Nutr. 2017;56:119–131. doi: 10.1007/s00394-015-1063-2. [DOI] [PubMed] [Google Scholar]
  53. Meeran N., Fizur M., Javed H., Al Taee H., Azimullah S., Ojha S.K. Pharmacological properties and molecular mechanisms of Thymol: prospects for its therapeutic potential and pharmaceutical development. Front. Pharmacol. 2017;8:380. doi: 10.3389/fphar.2017.00380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Mehdipour Z., Afsharmanesh M., Sami M. Effects of supplemental Thyme extract (Thymus vulgaris L.) on growth performance, intestinal microbial populations, and meat quality in Japanese quails. Comp. Clin. Pathol. 2014;23:1503–1508. doi: 10.1007/s00580-013-1813-6. [DOI] [Google Scholar]
  55. Mendez J.L., Hubmayr R.D. New insights into the pathology of acute respiratory failure. Curr. Opin. Crit. Care. 2005;11:29–36. doi: 10.1097/00075198-200502000-00005. [DOI] [PubMed] [Google Scholar]
  56. Meng J., Xiao G., Zhang J., He X., Ou M., Bi J., Yang R., Di W., Wang Z., Li Z., Gao H., Liu L., Zhang G. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg. Microbes Infect. 2020;9:757–760. doi: 10.1080/22221751.2020.1746200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Mezzano S., Droguett A., Burgos M.E., Ardiles L.G., Flores C.A., Aros C.A., Caorsi I., Vío C.P., Ruiz-Ortega M., Egido J. Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy. Kidney Int. 2003;64:S64–S70. doi: 10.1046/j.1523-1755.64.s86.12.x. [DOI] [PubMed] [Google Scholar]
  58. Monteleone G., Sarzi-Puttini P.C., Ardizzone S. Preventing COVID-19-induced pneumonia with anticytokine therapy. Lancet Rheumatol. 2020 doi: 10.1016/S2665-9913(20)30092-8. S2665991320300928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Netland J., Meyerholz D.K., Moore S., Cassell M., Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol. 2008;82:7264–7275. doi: 10.1128/JVI.00737-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Ocaña A., Reglero G. Effects of thyme extract oils (from Thymus vulgaris, Thymus zygis, and Thymus hyemalis) on cytokine production and gene expression of oxLDL-stimulated THP-1-macrophages. J. Obes. 2012:2012. doi: 10.1155/2012/104706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Oliviero M., Romilde I., Beatrice M.M., Matteo V., Giovanna N., Consuelo A., Claudio C., Giorgio S., Filippo M., Massimo N. Evaluations of Thyme extract effects in human normal bronchial and tracheal epithelial cell lines and in human lung cancer cell line. Chem. -Biol. Interact. 2016;256:125–133. doi: 10.1016/j.cbi.2016.06.024. [DOI] [PubMed] [Google Scholar]
  62. Patten G.S., Abeywardena M.Y., Head R.J., Bennett L.E. Processed dietary plants demonstrate broad capacity for angiotensin converting enzyme and angiotensin II receptor binding inhibition in vitro. J. Funct. Foods. 2012;4:851–863. doi: 10.1016/j.jff.2012.06.002. [DOI] [Google Scholar]
  63. Phillips M., Kagiyama S. Angiotensin II as a pro-inflammatory mediator. Curr. Opin. Investig. Drugs (Lond., Engl.: 2000) 2002;3:569–577. [PubMed] [Google Scholar]
  64. Prasanth Reddy V., Ravi Vital K., Varsha P., Satyam S. Review on Thymus vulgaris traditional uses and pharmacological properties. Med Aroma Plants. 2014;3 2167–0412. [Google Scholar]
  65. S.A. Capettini L., Montecucco F., Mach F., Stergiopulos N., A.S. Santos R., F. da Silva R. Role of renin-angiotensin system in inflammation, immunity and aging. CPD. 2012;18:963–970. doi: 10.2174/138161212799436593. [DOI] [PubMed] [Google Scholar]
  66. Santos R.A., e Silva A.C.S., Maric C., Silva D.M., Machado R.P., de Buhr I., Heringer-Walther S., Pinheiro S.V.B., Lopes M.T., Bader M. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc. Natl. Acad. Sci. 2003;100:8258–8263. doi: 10.1073/pnas.1432869100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Satou R., Penrose H., Navar L.G. Inflammation as a regulator of the renin-angiotensin system and blood pressure. Curr. Hypertens. Rep. 2018;20:100. doi: 10.1007/s11906-018-0900-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Sawa T. The molecular mechanism of acute lung injury caused by Pseudomonas aeruginosa: from bacterial pathogenesis to host response. J. Intensive care. 2014;2:10. doi: 10.1186/2052-0492-2-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Schuliga M. NF-kappaB signaling in chronic inflammatory airway disease. Biomolecules. 2015;5:1266–1283. doi: 10.3390/biom5031266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Sekirov I., Russell S.L., Antunes L.C.M., Finlay B.B. Gut microbiota in health and disease. Physiol. Rev. 2010;90:859–904. doi: 10.1152/physrev.00045.2009. [DOI] [PubMed] [Google Scholar]
  71. Sharifi‐Rad M., Varoni E.M., Iriti M., Martorell M., Setzer W.N., del Mar Contreras M., Salehi B., Soltani‐Nejad A., Rajabi S., Tajbakhsh M. Carvacrol and human health: a comprehensive review. Phytother. Res. 2018;32:1675–1687. doi: 10.1002/ptr.6103. [DOI] [PubMed] [Google Scholar]
  72. Shiravi A.A., Saadat M., Abdollahi Z., Miar P., Khanahmad H., Zeinalian M. Vitamin D can be effective against COVID19 and other similar viral infections: a review on molecular aspects. Zenodo. 2020 doi: 10.5281/zenodo.3779934. [DOI] [Google Scholar]
  73. Shukla S.D., Budden K.F., Neal R., Hansbro P.M. Microbiome effects on immunity, health and disease in the lung. Clin. Transl. Immunol. 2017;6 doi: 10.1038/cti.2017.6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. South A.M., Tomlinson L., Edmonston D., Hiremath S., Sparks M.A. Controversies of renin–angiotensin system inhibition during the COVID-19 pandemic. Nat. Rev. Nephrol. 2020:1–3. doi: 10.1038/s41581-020-0279-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Tan W.S.D., Liao W., Zhou S., Mei D., Wong W.-S.F. Targeting the renin–angiotensin system as novel therapeutic strategy for pulmonary diseases. Curr. Opin. Pharmacol. 2018;40:9–17. doi: 10.1016/j.coph.2017.12.002. [DOI] [PubMed] [Google Scholar]
  76. Thiagarajan R.R. Extracorporeal membrane oxygenation to support cardiopulmonary resuscitation: Useful, but for whom?*. Crit. Care Med. 2011;39:190–191. doi: 10.1097/CCM.0b013e318202e658. [DOI] [PubMed] [Google Scholar]
  77. Utomo, R.Y., Meiyanto, E., 2020. Revealing the Potency of Citrus and Galangal Constituents to Halt SARS-CoV-2 Infection.
  78. Wan L., Meng D., Wang H., Wan S., Jiang S., Huang S., Wei L., Yu P. Preventive and therapeutic effects of thymol in a lipopolysaccharide-induced acute lung injury mice model. Inflammation. 2018;41:183–192. doi: 10.1007/s10753-017-0676-4. [DOI] [PubMed] [Google Scholar]
  79. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., Wang B., Xiang H., Cheng Z., Xiong Y., Zhao Y., Li Y., Wang X., Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020;323:1061. doi: 10.1001/jama.2020.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Wang J.-Z., Zhang R.-Y., Bai J. An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients. Int. J. Cardiol. 2020 doi: 10.1016/j.ijcard.2020.04.009. S0167527320313851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Wang L.P., Feng J.F., Hu K.L., et al. Progress in regulation effect of aromatic refreshing traditional Chinese medicine on BBB permeability and its mechanism. Zhongguo Zhong Yao Za Zhi. 2014;39:949–954. [PubMed] [Google Scholar]
  82. Ware L.B., Matthay M.A. The acute respiratory distress syndrome. N. Engl. J. Med. 2000;16 doi: 10.1056/NEJM200005043421806. [DOI] [PubMed] [Google Scholar]
  83. Wu Y., Xu X., Chen Z., Duan J., Hashimoto K., Yang L., Liu C., Yang C. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, Behav., Immun. 2020 doi: 10.1016/j.bbi.2020.03.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Xu H., Zhong L., Deng J., Peng J., Dan H., Zeng X., Li T., Chen Q. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int. J. Oral. Sci. 2020;12:1–5. doi: 10.1038/s41368-020-0074-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Yang H., Xun Y., Li Z., et al. Influence of borneol on in vitro corneal permeability and on in vivo and in vitro corneal toxicity. J. Int Med Res. 2009;37:791–802. doi: 10.1177/147323000903700322. [DOI] [PubMed] [Google Scholar]
  86. Yu Y.-M., Chao T.-Y., Chang W.-C., Chang M.J., Lee M.-F. Thymol reduces oxidative stress, aortic intimal thickening, and inflammation-related gene expression in hyperlipidemic rabbits. J. Food Drug Anal. 2016;24:556–563. doi: 10.1016/j.jfda.2016.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Zhang N., Liu P., He X.R. Effect of borneol, moschus, storax, and acorus tatarinowii on expression levels of four amino acid neurotransmitters in the rat corpus striatum. Neural Regen. Res. 2012;7:440–444. doi: 10.3969/j.issn.1673-5374.2012.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Zhang Q.L., Fu B.M., Zhang Z.J. Borneol, a novel agent that improves central nervous system drug delivery by enhancing blood–brain barrier permeability. Drug Deliv. 2017;24:1037–1044. doi: 10.1080/10717544.2017.1346002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Zhao, Y., Zhao, Z., Yuija, W., 2020. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. 2020.
  90. Zheng Q., Chen Z.X., Xu M.B., Zhou X.L., Huang Y.Y., Zheng G.Q., et al. Borneol, a messenger agent, improves central nervous system drug delivery through enhancing blood–brain barrier permeability: a preclinical systematic review and meta-analysis. Drug Deliv. 2018;25:1617–1633. doi: 10.1080/10717544.2018.1486471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Zheng Y.-Y., Ma Y.-T., Zhang J.-Y., Xie X. COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. 2020;17:259–260. doi: 10.1038/s41569-020-0360-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Zu Z.Y., Jiang M.D., Xu P.P., Chen W., Ni Q.Q., Lu G.M., Zhang L.J. Coronavirus disease 2019 (COVID-19): a perspective from China. Radiology. 2020 doi: 10.1148/radiol.2020200490. [DOI] [PMC free article] [PubMed] [Google Scholar]

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