**3.1 Medicinal plants**

### *3.1.1 Boswellia serrata (B. serrata)*

*B. serrata* is an ancient traditional plant that was used in the treatment of cough, asthma, and other inflammatory lung conditions. *B. serrata* and its abundant active ingredients downregulate pro-inflammatory cytokines, 5-lipoxygenase, and leukotriene [44, 45]. Boswellic acids and *B. serrata* extract inhibited human leukocyte elastase (HLE), the claimed agent of the pathogenesis of cystic fibrosis, chronic bronchitis,

#### *Complementary and Alternative Medicine in COVID-19 Infection, an Old Weapon… DOI: http://dx.doi.org/10.5772/intechopen.106866*

and emphysema [46–49]. Moreover, alpha-keto-beta-boswellic acids (AKBA) stimulated the production of anti-inflammatory LOX-isoform-selective modulators and inhibited 5-lipoxygenase [50]. *B. serrata* can help in pulmonary fibrosis, which is a common complication of SARS-CoV-2 infection [51]. It antagonized the effect of bleomycin-induced injury by reducing collagen accumulation and airway dysfunction in rats [52]. The anti-asthmatic potential of *B. serrata* was investigated in many studies [53–55]. Furthermore, boswellic acid and AKBA induced anti-platelet aggregation effect, anti-profibrotic mechanisms, and hastened vascular remodeling by the TGFβ1/ Smad3 pathway [56, 57]. Immune modulation is a promising property of boswellic acids [58], which is an important element in SARS-CoV-2 treatment. In small doses, boswellic acids enhanced lymphocyte proliferation, while higher doses had a blocking action. Similarly, at the level of the humoral response, primary antibody titers were decreased at big doses of boswellic acids, but lower doses elevated secondary antibody titers. Boswellic acids stimulate the phagocytosis of macrophages, as well [47, 59–61]. The anti-viral property of *B. serrata* was strongly emphasized against many viruses*.* It inhibited wild-type and a clinical isolate of HSV-1 via downregulation of nuclear factor-κB (NF-κB) [62]. In another study, the total Boswellia extract exerted a more potent anti-herpes activity than other compounds [63]. HIV, HCV, and influenza [64]. In a computational study on *B. serrata* bioactive ligands (compounds) against SARS-CoV-2 Mpro protein. Among the examined compounds, euphane, ursane, α-amyrin, phytosterols, and 2,3-dihydroxyurs-12-en-28-oic acid were found to have the ability of Mpro inhibition [65]. A clinical trial investigated the effect of combined glycyrrhizin (GR) capsule (60 mg) and boswellic acids (BA) (200 mg) versus placebo twice daily for 14 days in 50 patients with moderate SARS-CoV-2 or COVID-19 variants hospitalized. The group of GR + BA showed a significant shorter cure time, amelioration of clinical condition, and decrease in CRB compared to the placebo group [66].

#### *3.1.2* Pomegranate *(Punica granatum* L*.)*

It is an old fruit that is cultivated in many parts of the world. Its pharmacological activities are mediated mainly by phenolic compounds [67]. Anti-viral action is demonstrated against many viruses [25, 68, 69]. The immune modulation activity of pomegranate was illustrated in several studies. It inhibited phorbol-12-myristate 13-acetate plus calcium ionophore A23187 (PMACI) induced inflammatory gene expression and the release of interleukin (IL)-6 and IL-8 in the myeloid precursor cell line KU812 cells [70]. Pomegranate extract attenuated the activation of NF-κB/p65 in human chondrocyte by counteracting the IL-1β-mediated phosphorylation of IKKβ, expression of IKKβ mRNA, and degradation of IκBα [71]. In another *in vitro* study, pomegranate flower (PFE) ethanol extracts reduced IL-6, IL-1β, and TNF-α production in lipo-poly saccharides (LPS)-induced RAW264.7 macrophages [72]. Baricitinib is a janus kinase (JAK) inhibitor and is a numb-associated kinase (NAK) inhibitor that inhibits AP2-associated protein kinase-1 (AAK1), this protein enhances endocytosis of the virus [73, 74]. Pomegranate possessed a janus kinase inhibitory action. These findings encourage the use of pomegranate in SARS-CoV-2 treatment [75, 76]. The anti-SARS-CoV-2 activity of pomegranate was demonstrated by a computational study where ellagic acid, gallic acid and mainly punicalagin, punicalin interacted with SARS-CoV-2 spike glycoprotein, angiotensin-converting enzyme 2, furin and transmembrane serine protease2 [77]. Pomegranate peel extract interfered with the binding between SARS-CoV-2 spike glycoprotein and ACE2 receptor and showed a possible anti-replication action by inhibition of the virus 3-chymotrypsin-like cysteine protease (3CLPro) [78]. Moreover, anti-replication potential was demonstrated in tannins, which are pomegranate compounds via binding (3CLPro) catalytic site in a virtual study [79]. Triterpenoids, other pomegranate compounds blocked the spike protein binding site of SARS-CoV-2 [80]. Pomegranate was investigated with other herbs in 184 patients with SARS-CoV-2 infection plus standard care for 7days. There was a significant reduction in hospital duration and improvement of clinical symptoms in comparison to 174 patients in the standard-care group [81].

#### *3.1.3* Curcumin (*Curcuma longa*)

*C. longa* is known as turmeric, which is a common spice that was traditionally used to treat many health disorders. Curcumin, a secondary metabolite has a potent antioxidative, anti-inflammatory [82], and anti-viral activities [83, 84]. Which is mediated by its effect on multiple molecular targets and signaling pathways of apoptosis and inflammation. It inhibits viral replication by interfering with NF-κB, PI3K/ Akt signaling, post-transcriptional, and post-translational modifications. Moreover, it blocks viral attachment [85–88]. In silico docking study, curcumin interacted with SARS-CoV-2 protease, spike glycoprotein-RBD, and PD-ACE2, receptors that are vital in virus infection [89]. Curcumin also showed attenuation ability to SARS-CoV-2 protease (Mpro) in another study [90]. Stimulation of innate immunity, and hence, IFN production at the early stage of SARS-CoV-2 infection was investigated to reduce the fatality rate of the diseases [91, 92]. Immune modulation activity of curcumin was demonstrated in PEDV model of coronavirus where viral reproduction was hindered after treatment with cationic carbon dots based on curcumin. This effect was mediated by the activation of the innate immunity with subsequent production of interferon-stimulating genes (ISGs) and cytokines (IL-8 and IL-6) [93]. In addition to the anti-viral action of curcumin, its anti-inflammatory and anti-fibrotic potentials provide some help in pulmonary damage. It reduced the expression of IFN-γ, MCP-1, IL-6, and IL-2, which are involved in lung inflammation and fibrosis [94]. Curcumin decreased collagen in experimental models of pulmonary fibrosis, as well [95]. Furthermore, curcumin reduced pulmonary edema in hypoxic rats via attenuation of NF-кB activity and stabilizing hypoxia-inducible factor 1-alpha (HIF1-α) [96]. Many clinical trials have investigated the possible efficacy of curcumin on SARS-CoV-2 patients. Two studies used nanocurcumin 40 mg in a dose of 2 soft gels twice daily for 2 weeks in mild to moderate patients compared with the placebo group. Curcumin improved the clinical symptoms with a significant lowering of CRP level, elevation of lymphocyte count [97], and shortened the hospital duration [98]. In addition, nanocurcumin significantly reduced IL-6, IL-1β gene expression when it was given to 20 patients with SARS-CoV-2 in comparison to 20 patients in the placebo group [99]. Nanocurcumin 80 mg in a dose of 2 soft gels twice daily was introduced to 40 patients with mild and severe SARS-CoV-2 for 21 days versus placebo. Curcumin decreased the count of Th17 cells and the level of IL-17, IL-21, IL-23, and GM-CSF [100]. In another study, there was an increase in Treg cells count, expression levels of FoxP3, IL-10, IL-35, TGF-β, and cytokines serum level in the Nanocurcumin-treated group compared to the placebo [101]. Treg cells maintain the balance between inflammatory and regulatory responses. Dysfunction of Treg cells and related cytokines leads to hyperinflammation in SARS-CoV-2 patients [102, 103]. A combination of piperine (2.5 mg) and curcumin (252 mg) was introduced to 70 mild to severe SARS-CoV-2 patients twice daily in comparison with probiotics given group for two weeks. Rapid cure, less deaths, and short hospital stays were achieved by curcumin therapy [104].

*Complementary and Alternative Medicine in COVID-19 Infection, an Old Weapon… DOI: http://dx.doi.org/10.5772/intechopen.106866*

#### *3.1.4* Glycyrrhizin (*Glycyrrhiza glabra)*

Glycyrrhizin is an active constituent isolated from *G. glabra L. (Fabaceae), (licorice*) root, a common medicinal plant that grows in Mediterranean areas [105]. It has abundant phytochemicals, flavonoids, and triterpenoids [106]. The anti-viral action of licorice is mediated mostly by two triterpenoids, glycyrrhizin, and 18β-glycyrrhetinic acid [105, 107]. Glycyrrhizin exhibited an anti-viral effect against RNA and DNA viruses by acting on casein kinase II, protein kinase II and transcription factors [108–110]. Interestingly, glycyrrhizin and licorice extract have the ability to block SARS-CoV-2 and cell entry [111, 112]. Moreover, it has the ability to decrease the expression of type 2 transmembrane serine proteases (TMPRSS2), and hence, interfere with the virus entry and stimulate mineralocorticoid receptor (MR), by decreasing ACE2 expression [113]. In addition, glycyrrhizin interferes with receptor-binding domain (RBD) of SARS-COV2 and ACE2 [114]. Glycyrrhizic acid (GA) nanoparticles inhibited murine coronavirus MHV-A59 replication and attenuated pro-inflammatory cytokine release caused by MHV-A59 or the N protein of SARS-CoV-2 [115]. Regarding immunomodulation activity, glycyrrhizin upregulated lymphocytic proliferation in viral infection [116] which may help to manage SARS-CoV-2 associated lymphopenia. Licorice extract in a dose-dependent manner, induced an immune modulation of cell-mediated and humeral responses [117]. The antioxidative and anti-inflammatory potentials of licorice can protect against acute lung injury by inhibition of NF-κB and can increase the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), which decreases the inflammatory response [118]. Glycyrrhetinic acid derivative, diammonium glycyrrhizinate combined with vitamin C improved the clinical symptoms in severe suspected COVID-19 patients [119]. A clinical trial recorded amelioration of clinical state in SARS-CoV-2 patients who received glycyrrhizin and boswellic acids combined therapy [66].

#### *3.1.5 Nigella sativa (N. sativa)*

*N. sativa* is known as black cumin seed, black seed, Habbatul Barakah [120]. Since ancient times, It was widely used in traditional medicine for the treatment of asthma, common cold, headache, nasal congestion, and rheumatic diseases [121]. The Holy Bible mentioned it as "Curative black seed." Prophet Muhammad (PBUH) said that "In the black cumin, there is a cure for every disease except death." [122–124]. Among several pharmacological effects, antioxidant, anti-inflammatory, anti-viral, anticoagulant, and immunomodulatory properties make *N. sativa* an appropriate therapeutic agent in SARS-CoV-2 management [123, 125, 126]. *In vitro* and molecular docking studies reported the anti-SARS-CoV-2 potential of many *N. sativa* compounds; thymohydroquinone and dithymoquinone [127, 128], nigellidine α-hederin [129] thymol and thymoquinone [130]. The immunomodulatory importance of *N. sativa* to overcome cytokine storm was highlighted in a docking study where nigellidine showed affinity to TNFR1, IL1R, and TNFR2 [131]. In a multicenter, placebo-controlled, randomized clinical trial honey (1 gm/Kg/day), and *N. sativa* seeds (80 mg/Kg/day) were administrated to moderate or severe SARS-CoV-2 patients versus placebo group for 13 days along with standard care. *N. sativa* and honey-treated patients showed significant symptoms alleviation, rapid viral clearance and a decrease in mortality compared to placebo [132]. In another clinical trial, *N. sativa* oil was administered in a dose of 500 mg twice daily for 10 days to 86 patients compared to 87 patients as a

control. A significant higher percentage of recovered patients and shorter recovery time were observed in *N. sativa* treated group [133].

### *3.1.6* Thyme *(Thymus Vulgaris)*

*Thymus vulgaris* was commonly used for its flavoring and medicinal advantages for centuries [134]. Thyme contains variable flavonoids and phenolic antioxidants, such as zeaxanthin, lutein, pigenin, naringenin, luteolin, and thymonin. The antioxidant property of thyme is mainly attributed to thymol, a phenolic component [135]. Through its anti-viral potential, thyme attenuated the cytopathic effect of the influenza virus in a dose-dependent manner [136]. Thymol showed the ability of viral spike protein inhibition in a computational study [137]. Moreover, carvacrol, a monoterpenoid phenol of thyme oil blocked the attachment of SARS-CoV-2 spike (S) glycoprotein to the cell and inhibited the viral protease [138]. Furthermore, the essential oil of thyme improved the clinical symptoms and caused a significant rise in lymphocyte count and calcium level along with a lowering of neutrophil count and blood urea nitrogen (BUN) in SARS-COV-2 patients [139].
