Effects of Lamiaceae family plants and their bioactive ingredients on coronavirus‐induced lung inflammation

Abstract Coronaviruses (CoVs) are a family of viruses that cause infection in respiratory and intestinal systems. Different types of CoVs, those responsible for the SARS‐CoV and the new global pandemic of coronavirus disease 2019 in people, have been found. Some plants were used as food additives: spices and dietary and/or medicinal purposes in folk medicine. We aimed to provide evidence about possible effects of two Lamiaceae family plants on control or treatment of CoVs‐induced inflammation. The keywords including coronaviruses, Thymus vulgaris, Zataria multiflora, thymol, carvacrol, antivirus, and anti‐inflammatory and antioxidant effects were searched in various databases such as PubMed, Web of Sciences (ISI), and Google Scholar until September 2022. The medicinal herbs and their main ingredients, thymol and carvacrol, showed antiviral properties and reduced inflammatory mediators, including IL‐1β; IL‐6, and TNF‐α, at both gene and protein levels but increased the levels of IFN‐γ in the serum as anti‐inflammatory cytokine. These medicinal herbs and their constituents also reduce oxidative stress and enhance antioxidant capacity. The results of molecular docking analyses also indicated that polyphenol components such as thymol, carvone, and carvacrol could inhibit the entry of the viruses into the host cells in molecular docking analyses. The antiviral, anti‐inflammatory, and antioxidant effects of these plants may be due to actions of their phenolic compounds that modulate immune response and may be useful in the control and treatment of CoV‐induced lung disorder.

herbal products showed anti-inflammatory and immune-regulatory effects in folk medicine.So, the isolation of plants' bioactive components with various pharmacological effects occurred in the 19th century (Phillipson, 2001).
Almost 64% of population in the world use medicinal herbs for treatment of various diseases.In addition, almost 50% of synthetic drugs are derived from herbal sources (Newman & Cragg, 2016).The phytochemicals as anti-infective agents including flavonoids and hydroxylated phenols are effective against infections and could help to defense system to combat pathogens (Dixon et al., 1983).Moreover, alkaloids and flavonoids showed antimicrobial and larvicidal effects (Naghibi et al., 2005).The possible advantageous effects of Nigella sativa and its ingredients, thymoquinone, as well as natural products and flavonoids on SARS-CoV-2, were also reported (Khazdair, 2021;Khazdair, Anaeigoudari, et al., 2021).
The plants from Lamiaceae family are well known for the presence of diterpenoids and essential oils in many members of the plant family.Some species of this plant family such as Thymus vulgaris (TV) and Zataria multiflora Boiss (ZM) are used in culinary as well as used as spice, food additive, and flavorings (Naghibi et al., 2005).TV and ZM have been used to treat coughs due to cold, laryngitis, and bronchitis and are also used for the treatment of oral cavity disorders in Iranian folk medicine (Mozaffarian, 1996).
ZM is used for analgesic, antiseptic, anthelmintic, and antidiarrheal effects in folk medicine (Ghasemi Dehkordi et al., 2002).ZM has also been used for treatment of dyspepsia vomiting, headache, premature labor pain, and common cold (Amin, 1991).The essential oils of ZM also revealed inhibitory effect on growth of yeasts and showed antimicrobial activities against gram-positive and -negative bacteria (Zomorodian et al., 2011).
ZM and TV have similar chemical and pharmacological properties and are well known as medicinal plants (Amin, 1991).The aims of this review article are to explain the traditional and new pharmacological properties of some medicinal herbs on the respiratory system focusing on molecular immunomodulatory effects, which suggest the possible therapeutic effects on CoVs and suggest a reference for drug development of coronavirus infection.

| ME THODS
The data of the current review study were obtained by searching for the terms: coronavirus, Thymus vulgaris, Zataria multiflora, thymol, carvacrol, antiviral, anti-inflammatory, and antioxidant effect in the electronic databases, including PubMed, ISI, and Google Scholar until September 2022.

| IMMUN ORE G UL ATORY EFFEC TS OF MEDICINAL PL ANTS
It has been known that deregulation of immune system is the main cause of many diseases.So, the useful therapeutic approach for the management of various diseases is the management of immune responses (Su et al., 2012).Some natural products and medicinal herbs can affect the function of the immune system by modulation of immune cell activities as well as production of mediators (Das et al., 2004).The quantitative comparison of immunomodulatory properties with respect to T helper cells (Th1) and Th2 of saffron and black seed, as well as their main constituent, were reported (Khazdair, Gholamnezhad, et al., 2021).

| PHARMACOLOG IC AL EFFEC TS OF T V
TV is a perennial flowering plant that widely grows in western Mediterranean and southern Europe (Letchamo & Gosselin, 1996).
The plant has been used as a culinary herb, with antiseptic, analgesic, antimicrobial, and antioxidative properties (Baranauskiene et al., 2003).TV is used to treat diabetes, digestive upset, and cough due to cold and chest infections (Ekoh et al., 2014).The oils from TV contain terpenoid, carvacrol, and thymol as phenol compound that has antiviral, antibacterial, antispasmodic, and antioxidative effects (Höferl et al., 2009).Thymus spp.also are used for their antiviral, antifungal, antimicrobial, antispasmodic, and diaphoretic effects in traditional medicine (Fachini-Queiroz et al., 2012).The antibacterial effects of the TV oils against the gram-negative and gram-positive bacteria have been reported (Marino et al., 1999).

| Antiviral effects of TV
Some plants, their fractions, extracts, derivations, or essential oils, and their possible antiviral prosperities have been reported (Jassim & Naji, 2003).The antiviral effects of thyme spp.including T. vulgaris, T. hyemalis, and T. zygis extracts in contradiction of the herpes simplex virus 1 (HSV-1) at different stages during virus infection were evaluated.Results showed that pretreated cells with the thyme extract significantly reduced virus infectivity.
T. zygis extract was also more effective than the other plant extract.The antiviral activity of Thyme spp.could be related to the percentage of phenolic compounds (thymol and carvacrol) that are presented in these extracts.These combined extracts mostly inhibited intracellular replication of HSV-1, although they were able to disrupt the attachment step of the virus (Santoyo et al., 2014).The antiviral efficacy of TV essential oils on feline infectious peritonitis (FIP) (a disease caused by a Coronavirus) showed essential oils of the plant (27 μg/mL) significantly inhibited virus replication.Moreover, the plant essential oils (27 and 270 μg/ mL) reduced virucidal activity by reducing viral titer to 1 h of time contact (Catella et al., 2021).
Antiviral activity of monoterpene compounds including αterpinene, p-cymen, γ-terpinen, thymol, and citral against HSV-1 in vitro was examined.These monoterpenes reduced viral infectivity and inhibited HSV by >80%.In addition, these monoterpenes showed high anti-HSV-1 effects by direct inactivation with virus particles.The monoterpenes also interact with herpesvirus particles inactivating viral infection (Astani et al., 2010).The antiviral activity of some monoterpenes such as β-pinene and limonene against HSV-1 showed high anti-HSV-1 activity and reduced viral infectivity by 100% by interaction with free virus particles (Astani & Schnitzler, 2014).Essential oils from three plants including thyme, camomile, and ginger exhibited antiviral effects against HSV type 2 (HSV-2) using a plaque reduction on RC-37 cells.The essential oils at noncytotoxic concentrations significantly reduced plaque formation by about 90%.These results indicated that the obtained essential oils affected HSV-2 mostly before adsorption maybe by interaction with envelope of the viruses (Koch et al., 2008).
In a study, the antiviral properties of combination of honey and thyme extracts were evaluated.This combination therapy of monkey kidney cell (MKC) culture infected with the rubella virus showed good antirubella activity (Zeina et al., 1996).TV extracts (50 μg/mL) showed antiviral effects in embryonated eggs against Newcastle disease virus (NDV) (Rezatofighi et al., 2014).The results of a cohort study with 161 patients testing positive PCR for COVID-19 showed that TV (5 g in 100 mL in hot water) every 8 h has a positive effect on cough, anorexia, chest pain, dyspnea, fever, ageusia, and anosmia.
There was a significant decrease in blood urea levels and neutrophils.
In addition, the lymphocyte count and serum calcium level increased significantly after 3 days of treatment in 86 patients who were exposed compared to 75 patients who were not exposed (Yiagnigni Mfopou et al., 2021).The effect of TV on the clinical symptoms of COVID-19 patients (n = 83) showed consumption of thyme essential oils (5 mL) three times per day could be useful for reducing fever, cough, headache, dyspnea, weakness, muscular pain, anorexia, fatigue, and chest wall pain.Moreover, blood urea nitrogen, calcium, and neutrophil count were remarkably decreased, while lymphocyte count was increased (Sardari et al., 2021).
The effects of some medicinal herbs' essential oils on the expression of transient receptor potential (TRP) gene family as well as replication of coronavirus were reported (Ulasli et al., 2014).
The molecular douching study indicated that interaction between monoterpenoids such as carvone, carvacrol, thymol, and SARS-CoV-2 spike protein together with the cellular proteases TMPRSS2, cathepsin L (CatL), and cathepsin B (CatB) showed that the mentioned compounds have most effective molecule against all targets by inhibition entry of the virus on the host cells (Istifli et al., 2020).
Similarly, molecular interactions among carvacrol, carvone, and thymol and on borehole spike glycoprotein of SARS-CoV-2 showed the binding energy of these phenolic components was found to be in the range of −3.4/−3.7 kcal (Smith & Smith, 2020).The result of a molecular dynamic simulation (MDS) analysis showed that thymol and carvacrol as better inhibitors than camostat as a synthetic inhibitor of TMPRSS2 due to their stable binding 32 with TMPRSS2 in its oxyanion hole (Yadav et al., 2020).TV and its components such as thymol may be useful in COVID-19-infected patients by suppressing the destructive effects of the renin-angiotensin system (RAS).
Moreover, TV can decrease the pro-inflammatory mediators and oxidative stress in COVID-19 infection.The antiviral properties of TV and its bioactive ingredient are shown in Table 1.

| Anti-inflammatory effects of TV
The quantitatively immunoregulatory properties of TV and its main ingredients on inflammatory/anti-inflammatory mediators have been reported (Khazdair, Gholamnezhad, et al., 2021a).It was shown that TV aqueous extract (0.01 to 200 μg/mL) significantly reduced the proliferation of mitogen-induced lymphocytes.The extract also significantly increased expression of CD40 in dendritic cells (DCs) but reduced T-cell proliferation.The plant extracts did not influence the pattern of mediator secretion (IFNγ and IL-4) by T cells but suppressed proliferation of allogenic T cells (Amirghofran et al., 2012).
The effects of TV hydroalcoholic extract on lipopolysaccharide (LPS)-induced lung injury in primary human airway epithelial cell line (H460) significantly reduced protein levels of NF-κB p52 and NF-κB p65 transcriptions factors followed by reduction in proinflammatory mediators, IL-1β and IL-8, as well as reduced mucus secretion in tracheal epithelial cells and human normal bronchial (Oliviero et al., 2016).
Treatment of bursal disease of vaccinated and nonvaccinated male broilers with a mixture of crushed TV, N. sativa seeds, and Pimpinella anisum (P.anisum) improved antibody titer in broilers.
Furthermore, this mixture treatment improved lymphocytes and TA B L E 1 Antiviral effects of T. vulgaris and its constituent.

Vero cells
Significantly reduced virus infectivity in the pretreated cells.monocytes of vaccinated birds (Al-Beitawi et al., 2010).The supplementation with essential oil of TV (5000 ppm, p.o.) in induced colitis-inhibited mRNA expression of IL-1β and reduced macro-and microscopic scores of colitis in mice colon (Juhás et al., 2008).
Effects of TV essential oils on sodium hypochlorite induced lung damage in rats showed inhalation of TV (4%) twice a day (30 min) for 4 weeks repeated tissue damage and decreased the histopathological change in the lung tissue.Furthermore, the expression of TNFα and oxidative biomarkers were decreased but the total antioxidant status (TAS) was improved compared to control group (Bolatli et al., 2023).
The effects of thymol in LPS-induced lung inflammation in mice showed administration of thymol (100 mg/kg) inhibited the inflammatory cells influx, protein level in broncho-alveolar lavage fluid (BALF), TNFα and IL-6 releases, and improved pathological change in lung tissue.Furthermore, thymol inhibited the elevated levels of MPO and MDA and improved reduction in SOD activity (Wan et al., 2018).
Thymol also suppressed the gene expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as dose dependently.In addition, the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK); p38 mitogen-activated protein kinase (MAPKs), and inhibitor protein of NF-κB (IκBα) were also inhibited by thymol in stimulate cells (Liang et al., 2014).Treatment of MC/9 cells with thymol (500 to 750 μM) significantly increased gene transcription of IL-6 and IL-13 after 3hour incubation as dose dependently but did not affect remarkably IL-6 and IL-13 in the protein level (Wechsler et al., 2014) sheep red blood cells titer, but reduced the ratio of heterophile to lymphocyte in the birds (Hashemipour et al., 2013).Thymol and carvacrol (120 and 240 mg/kg) in dietary supplementation caused upregulation of mRNA expression of toll-like receptors (TLR)-2 and IL-1β in the ileum as well as mucosal secretory IgA in broiler chicken.
Moreover, the level of antibodies against NDV was increased in the serum but the mRNA expressions of TLR-2 and TNFα in ileum were inhibited by this supplementation (Du et al., 2016).
Oral administration of thymol at dose of 100 mg/kg or nicotine (2.5 mg/kg, p.o.) alone decreased the level of IL-1β, TNFα, IL-6, IFNγ, and IL-17 in rheumatoid arthritis induced in animal model in rats.In addition, treatment with thymol and nicotine as combination (half doses with each) more reduced IL-1β, CRP, IL-17, and MPO compared to individual thymol and nicotine treatments (Golbahari & Froushani, 2019).
These results indicate that TV and its ingredient, thymol, can alter the pattern of cytokine production and could be used for the treatment of inflammatory, allergic, and immunologic disorders.The anti-inflammatory and immunoregulatory effects of TV and its main bioactive ingredient are shown in Table 2.
ZM was also used for dyspepsia, cold, vomiting, headache, as well as premature labor pain in folk remedy.It has been reported that the major constituents of ZM were carvacrol, thymol, and pcymene.Moreover, the major constituents of ZM collected from the northeast of Iran are carvacrol, thymol, р cymene, γ-terpinene, and α-pinene about 80.19% (Aida et al., 2015).The safety and antiantispasmodic, as well as clinical benefit of medicinal plants such as ZM in relieving chronic cough, was also reported (Mortazavi Moghaddam et al., 2020).

| Antiviral properties of ZM
The positive properties of ZM in reducing replication of virus in the tissues of H9N2 influenza-infected broiler chickens were reported.These effects can lead to better performance and clinical symptoms in chickens (Shayeganmehr et al., 2018).Antiviral effect of ZM (800 and 1000 μg/mL) on HSV-1-infected vero cells remarkably reduced plaque formation up to 100% (Arabzadeh et al., 2013).The antiviral properties of ZM oil on HSV type 1 in vero cells showed noncytotoxic effect on the cell's viability.ZM oil inhibited virus plaque formation and suggested it could be used as herbal mouthwash (Gavanji et al., 2015).The chemical compositions and antiviral effects of ZM have been reported.The essential oil from ZM contains carvacrol (34.96%), thymol (38%), and paracymene (7.17%).The concentration of 1/10,000 of ZM oil has not inhibited the growth of HSV-I to Hela cell culture (Khanavi et al., 2010).The antiviral properties of "Oregano oils" and carvacrol against H1N1 virus in canine kidney cells (MDCK) and human lung epithelial cells (A549) showed oils, and carvacrol at concentration (0.01-100 μL/mL) showed antiviral effective (Vimalanathan & Hudson, 2012).
Treatment of RAW 264.7 cells with carvacrol (0.25% and 0.5%) within 15 min of exposure significantly reduced human noroviruses (NoVs) titers.In addition, with greater duration of exposure to carvacrol, the cell culture infectivity was reduced.Also, the particles of the virus are no longer intact, followed by 30 min expose to carvacrol due to the lack of cells binding in the RNase I protection assay (Gilling et al., 2014).
Treatment of infected BSC-1 cells by HSV-2 with carvacrol (1, 0.5, 0.25, 0.125, and 0.0625 mmol/L) inhibited the expressions of transcription genes (ICP27, VP16, ICP4, and UL30) and protein levels of cytokines such as RIP3, MLKL, and TNFα due to viral replication as dose dependently (Wang et al., 2020).It has been reported that carvacrol could serve as an inhibitor in regulating the main protease (M pro ) of COVID-19 functions and controlling viral replications (Kumar et al., 2021).Antiviral properties of ZM and its bioactive ingredient are shown in Table 3.

| Anti-inflammatory properties of ZM
The aqueous extract of ZM (0.1-100 μg/mL) reduced the proliferation of lymphocytes without affecting remarkable cytotoxic effect on DCs.The plant extract showed no effect on the secretions of IFNγ and IL-4 mediators, while increasing the expression of CD40 in DCs (Amirghofran et al., 2012).ZM extract (200-800 μg/mL) in splenocyte cell culture from sensitized mice significantly increases expressions of IFNγ and FOXP3 but decreases gene expressions of TGFβ and IL-17 (Kianmehr et al., 2017).ZM hydroethanolic extract (50) reduced expression of IL-4 at gene and protein but the higher dose of extract (200 μg/mL) increased remarkably the genes expression of IFNγ in PHA-stimulated peripheral blood mononuclear cell (PBMC) (Boskabady et al., 2013).
Treatment of OVA-sensitized guinea pigs with ZM extracts (0.2-0.8 mg/mL) enhanced the serum level of IFNγ, whereas decreased the level of IL-4 (Boskabady et al., 2013).Subcutaneous injection of ZM essences (200 mg/kg, p.o. and s.c.) stimulated the immune response against Candida albicans antigens and Con-A mitogen in the animals.Moreover, treatment with ZM (200 mg/kg, s.c.) at subcutaneous administration led to more stimulatory effect on the immune system in comparison to oral administrations (Khosravi et al., 2007).
The effects of ZM hydroalcoholic extracts (200 and 800 mg/ kg/day) on inhaled paraquat (PQ) induced lung inflammation significantly reduced levels of IL-6, malondialdehyde (MDA), and nitrite (NO 2 ), but enhanced the level of IFNγ compared to control animals (Amin et al., 2020).
Administration of hydroalcoholic extracts of ZM (200 and 800 mg/kg/day) on PQ-induced memory and lung injury in rats significantly reduced total and different WBC counts, IL-10, NO 2 , INFγ, and MDA levels, while enhancing the catalase (CAT) and superoxide dismutase (SOD) activities as well as thiol levels (Heydari et al., 2021).
The results of a randomized clinical study showed administration of ZM extract (5 and 10 mg/kg, p.o.) in sulfur mustard exposer patient (long-term) lung injury for 2 months remarkably reduced the levels of inflammatory mediators, IL-6, IL-2, and IL-8, but it increases the levels of mediators, IL-10 and IFNγ, compared to the placebotreated patient (Khazdair et al., 2019).
In the other clinical trial treatment of asthmatic and COPD patients with 5 and 10 mg/kg concentrations of ZM extract for 2 months, remarkably increased pulmonary function test values but reduced respiratory symptoms in treated groups.The laboratory results showed total WBC, monocyte and eosinophils, hemoglobin, and hematocrit were reduced in treated asthmatic and COPD patients.Furthermore, the levels of inflammatory mediators including TNFα, hs-CRP, and IL-8 declined in the treatment groups (Alavinezhad et al., 2022;Ghorani et al., 2022).
Treatment of splenocyte supernatant obtained from OVAimmunized mice with carvacrol (80 mg/kg, i.p.) decreased the mRNA expression of, IL-5, IL-17A, IL-4, and IL-23α, as well as the expression of Th1 cytokines (IL-2 and IFNγ).In addition, the gene expression of IL-10 and TGFβ also remarkably increased in the carvacrol-treated cells compared to the untreated cells (Gholijani & Amirghofran, 2016).Treatment of OVA -sensetized guinea pigs with carvacrol (40 to 160 μg/mL) cased to increases in the level of IFNγ, but reduction in the level of IL-4 and endothelin in the serum of animals (Jalali et al., 2013).
Administration of carvacrol (1000-5000 mg/kg) in rainbow fish showed no particular effect on the hematological parameter.
However, administration of carvacrol at higher doses significantly increased serum lysozyme activity after 30 days.Also, carvacrol TA B L E 3 Antiviral effects of Z. multiflora and its main constituents.significantly increased the myeloperoxidase activity on day 30.

Z. multiflora
Carvacrol (5000 mg/kg) significantly enhanced serum of total protein, myeloperoxidase activity, globulin, and triglyceride levels in the treated compared to the control group after day 60 (Yilmaz & Ergün, 2015).Carvacrol (40-160 μg/mL) significantly improved the levels of IgE and EPO in the serum of OVA-induced asthma in sensitized guinea pigs compared to control group (Boskabady, Tabatabaee, et al., 2014).
The results of the above studies indicated that ZM and its main ingredient, carvacrol, reduced pro-inflammatory cytokines production and suggested their use for treatment of inflammatory and allergic disorders.The anti-inflammatory effects of Z. multiflora and its main bioactive ingredient are shown in Table 4.

| ANTI OXIDANT EFFEC TS OF HERBS AND THEIR CON S TITUENTS
Oral treatment of aflatoxin-induced oxidative stress in rats with essential oil of TV (5 and 7.5 mg/kg) significantly decreased AST, ALP, ALT, Cho, TriG, total lipids, and creatinine in the serum, but significantly increased total antioxidant capacity (TAC) level in the liver tissue.The extract also significantly decreased MDA level in liver and kidney of treated animals compared to control group (El-Nekeety et al., 2011).Effects of TV extract (500 mg/kg/day, p.o.) against lead (Pb)-intoxicated rats remarkably improved all changes in Pb-induced toxicity, attenuated the levels of IL-6, IL-1β, and TNFα, while enhancing the levels of IFNγ and IL-10 in the serum.TV extract also increased SOD, CAT, GSH, and glutathione peroxidase (GPx) but reduced the level of MDA (El-Boshy et al., 2019).Administration of thyme water extract (100 mL/L) in their drinking water increased total oxidant status and total antioxidant response, while lowered the rate of DNA damage in Japanese quails (Sengül et al., 2008).ZM extract has high amount of phenolic compounds with potent antioxidant activities (Alizadeh & Shaabani, 2014).The hydroalcoholic extracts of ZM showed strong radical scavenging activity (~71%) compared to vitamin C (~48%) as a standard antioxidant agent.
The essential oils of ZM and its methanolic extract showed antioxidant properties using two standard methods for inhibition of free radicals such as ammonium thiocyanate systems and DPPH (Moshafi et al., 2007;Sharififar et al., 2007).Furthermore, the essential oils from five ecotypes of ZM showed the potential antioxidant capacity that was assessed by DPPH methods.These results indicate that all essential oils from the plant have remarkable antioxidant properties (Saei-Dehkordi et al., 2010).Therefore, the potent antioxidant activity of the plant was approved by different methods.
Treatment of human monocyte culture (HMC) in the presence of glucose with ZM showed antioxidant effects including: reduced H 2 O 2 and nitric oxide (NO) production, inhibited NO synthase (NOS) and NADH oxidase (NOX) activities, and prevented nitrosative stress and lipid peroxidation in these cells (Kavoosi & Teixeira da Silva, 2012).
Treatment of cyclophosphamide-induced oxidative stress by extract of ZM (50-200 mg/kg, b.w.) in mouse bone marrow cells showed antioxidant activity on DPPH and lipid peroxidation (Hosseinimehr et al., 2010).The possible beneficial effect of ZM extract (50-200 μL/kg) on cognitive function in Alzheimer's disease rat model showed that ZM treatment reduces total NO and nitrite levels in the serum of animals (Majlessi et al., 2012).
The ethanol extract of ZM on the hyperglycemia mice induced by bisphenol A (BPA) reduced the level of MDA content but increased GSH in the serum of animals.ZM (50-400 mg/kg, i.p.) caused pulmonoprotective effect by inhibition of MDA production and reduction in glutathione content, and SOD and CAT activities induced by cyclophosphamide (CP) in the lung (Habibi et al., 2014).
The potent antioxidant effects of carvacrol on MDA and NO scavenging activity (Karimian et al., 2012)  H 2 O 2 and NO production as well as NADH oxidase activity and NO synthase (Kavoosi et al., 2012).Administration of carvacrol at a dose of 73 mg/kg on methotrexate (MTX)-induced inflammation and oxidative stress significantly attenuated MDA, total oxidant status (TOS), and IL-1  and TNFα levels, while increasing the TAS compared to the MTX group (Celik et al., 2013).Treatment of animal model of Parkinson's disease with carvacrol (10 mg/ kg) reduced the level of nitrite and MDA as well as increased antioxidant enzyme compared to control animals (Hassanshahi et al., 2014).
Treatment of radiation-induced cytotoxicity in the cells (V79) with thymol significantly increased glutathione, CAT, and SOD enzyme levels, but reduced the level of MDA in V79 cells.Additionally, thymol could antagonize toxicity by normalizing the antioxidant levels (Archana et al., 2009).These results showed that the monoterpenes, thymol, and carvacrol contribute to antioxidant properties.
The antioxidant effects of medicinal herbs and their ingredients are summarized in Table 5.

| CON CLUS ION
This review study descriptively highlights the possible therapeu- CD40 but reduced T cells proliferation and did not influence the pattern of mediators secretion (IFN-γ and IL-4) Aqueous extract of T. vulgaris 5, 15 and 25 μg/mL THP-1-macrophages Remarkably reduced the levels IL-6; IL-1β; and TNF-α but increased the level of ILlevels of NF-κB p65 and NF-κB p52 transcription factors after decrease in IL-1-beta and IL-8 Oliviero et al. (2016) Reduced mucus secretion Essential oils of T. vulgaris, Cinnamomum verum, and Cymbopogon nardus (0.05 mL) Inhalation Mice Reduced myeloperoxidase (MPO) activity, inflammatory airway hyper-responsiveness, and certain cellular inflammatory parameters Csikós et al. (2020) T. vulgaris, N. sativa seeds, and Pimpinella anisum (P.anisum) crushed 2.0% crushed mixture (1:1:1) as feed additive Broilers Improved antibodies titer in broilers.Furthermore, this mixture treatment improved lymphocytes and monocytes of vaccinated birds Al-Beitawi et al. (2010) T. vulgaris essential oil 5000 ppm, p.o. Mice Inhibited mRNA expression of IL-1β and reduced macro-and microscopic scores of colitis in mouse colon (Juhás et al.Significantly increased gene transcription of IL-6 and IL-13 after 3-hour incubation but did not affect remarkably IL-6 and IL-13 in the protein levels Wechsler et al. of IL-1β, toll-like receptor (TLR)-2 in the ileum, and mucosal secretory IgA in broiler chickens Du et al. (2016) Thymol or nicotine 100 mg/kg, p.o. or 2.5 mg/ kg, p.o. Rat Reduced the levels of IL-1β; TNF-α; IL-6; IFN-γ; and IL-17 in rheumatoid arthritis in rats.The combination therapy with thymol and nicotine caused more reduction in IL-1β, CRP, IL-17, and MPO compared to individual thymol and nicotine treatmentsGolbahari and Froushani (2019) on the cell's viability.Z. multiflora oil inhibited virus plaque formation and suggested it could be used as herbal mouthwashGavanji et al. (2015) 1/10000 of Z. multiflora oil has not inhibited the growth of HSV-Treatment with carvacrol after 15 min of exposure reduced norovirus titers.In addition, cell culture infectivity was reduced.Virus particles are no longer intact following 30 min exposure to carvacrol Gilling et al.Inhibited the expressions of transcription genes and protein levels of cytokines due to viral replicationWang et al. (2020) Carvacrol (15 mg/kg, p.o.)  for 17 days reduces the value of absolute eosinophil counts (AEC), immunoglobulin E (IgE), IL-4, TNFα, IL-5, IFNγ, IL-13, iNOS, and MDA levels in the serum of OVA-induced asthma in rats.Moreover, it significantly improved histopathological changes and increased the value of SOD and GSH compared to control group(Ezz-Eldin et al., 2020).The effects of carvacrol on cadmium (Cd)-induced lung toxicity in rats showed that carvacrol (25 or 50 mg/kg) oral intake 30 min after Cd administration exhibited antioxidant properties and suppressed pro-inflammatory cytokines by lowering NF-κB and p38 mitogen-activated protein kinase (p38 MAPK) signaling.It also decreases the levels of Bax, cytochrome c, and caspase-3 that are increased by Cd.In addition, carvacrol reduces levels of 8-hydroxy-2′-deoxyguanosin (8-OHdG), matrix metallopeptidase (MMP)-2 and 9, which increased with Cd(Yesildag et al., 2022).The pharmacological effect of carvacrol on several clinical trials was investigated.Carvacrol reduced respiratory symptoms; serum levels of IL-2, IL-4, and IL-6; vascular endothelial growth factor (VEGF); and epidermal growth factor (EGF) remarkably, while improved the levels of IL-10 and IFNγ in the treatment of SM-exposed patients compared to control group(Khazdair & Boskabady, 2019a, 2019b).Treatment of asthmatic patients with carvacrol (1.2 mg/kg, p.o.) for 2 months improved oxidative stress markers and significantly increased pulmonary function test values after treatment.It also remarkably enhanced the levels of IL-10 and IFNγ in the serum, while remarkably decreasing the level of IL-4(Ghorani et al., 2021).The results of the other clinical study showed carvacrol (1.2 mg/kg, p.o.) improved pulmonary function test values, respiratory symptoms, and hematological indices.It also significantly reduces total and differential WBC and serum levels of hs-CRP(Alavinezhad

Clinical
, and antioxidant effects for thymol by reduction in H 2 O 2 and NO production and NO synthase activities in glucose-stimulated HMC were shown(Kavoosi   & Teixeira da Silva, 2012).Treatment of LPS-stimulated murine macrophages with thymol and carvacrol remarkably reduced TA B L E 4 Anti-inflammatory effects of Z. multiflora and its main component, carvacrol./mL, p.o. Guinea pig model of asthma Improved the levels of IgE and EPO in guinea pigs sensitized by ovalbumin Boskabadymg/kg/day, p.o. PQ-induced memory and lung damage in rat Significantly reduced total and different WBC count; IL-10; INFand CAT and SOD activities Syrup5 and 10 mg/kg/day, p.o Clinical, sulfur mustardinduced lung injury Significantly reduced the levels of IL-2, IL-6, and IL-8 Khazdair et al. (2019) Enhanced the levels of IL-10 and IFN-γ Syrup 5 and 10 mg/kg/day, p.o Clinical, asthmatic patients Significantly increased pulmonary function test values Alavinezhad et al. (2022) Reduced respiratory symptom Total WBC, monocyte and eosinophils, hemoglobin, and hematocrit were decreased Syrup 5 and 10 mg/kg/day, p.o of AEC, IgE, IL-4, IL-13, TNF-α, IL-5, IFN-γ, iNOS, and MDA Ezz-Eldin et al. (2020) Improved histopathological changes and increased the values of SOD and GSH 25 or 50 mg/kg Rat Exhibited antioxidant properties and suppressed NF-κB and p38 MAPK signaling Yesildag et al. (2022) Decreased the levels of Bax, caspase-3, and cytochrome c Reduce levels of 8-OHdG, MMP-2, and 9 1.2 mg/kg, p.o. Clinical, sulfur mustardinduced lung injury Decreased respiratory symptoms, and serum levels of VEGF, EGF, IL-6, IL-2test values after treatment Enhanced the levels of IL-10 and IFN-γ in serum Significantly decreased the concentration of IL-4 in serum 1.2 mg/kg, p.o. Clinical, COPD patients Improved respiratory symptoms and PFT as well as hematological indices Alavinezhad et al. (2018) Significantly reduced total and differential WBC and serum levels of hs-CRP TA B L E 4 (Continued) TA B L E 5 Antioxidant effects of T. vulgaris, Z. multiflora, and their constituents.
tic activities of some Lamiaceae family plants and their major bioactive components with their possible mechanisms of action on coronavirus-induced lung inflammation.According to our literature review, TV and ZM with their major ingredients have various properties such as antiviral effects in different studies, stimulation and modulation of immune responses, improvement in IgE serum levels and eosinophil counts, reduction in the levels of pro-inflammatory mediators (IL-1β, IL-17, IL-6, IL-4, and TGFβ), as well as enhancement of anti-inflammatory mediators (IFNγ and FOXP3).These medicinal herbs and their constituents also enhance antioxidant capacity.The plant constituents could inhibit the main protease (M pro ) of coronavirus functions and control viral replications and inhibition, as well as interaction with the cellular proteases TMPRSS2 could inhibit the entry of the virus on the host cells.In addition, these medicinal plants improved pulmonary function tests and respiratory symptoms in obstructive lung disease.In this regard, ARDS with cytokine storm of pro-inflammatory cytokines is the main death cause of coronavirus and these plants with anti-inflammatory and immunomodulatory effects as well as protective effects on obstructive diseases, it may be useful for treatment of coronavirus-induced lung inflammation.However, more clinical studies are required to support drug effectiveness.