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Complementary and Alternative Medicine in COVID-19 Infection, an Old Weapon against a New Enemy

Written By

Sally Elnawasany

Submitted: 21 July 2022 Reviewed: 29 July 2022 Published: 20 September 2022

DOI: 10.5772/intechopen.106866

Medicinal Plants IntechOpen
Medicinal Plants Edited by Sanjeet Kumar

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Medicinal Plants

Edited by Sanjeet Kumar

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Abstract

COVID-19 is a running story with an unexpected end. Despite the large effort to provide effective treatment and prophylaxis, many people are still getting infected. This may be explained by the continuous virus mutations, and hence, the attenuation of the vaccine’s efficacy. Therefore, long-life boosting of the body’s immunity is a hopeful way against SARS-CoV-2 infection. Medicinal plants and other complementary and alternative remedies were used effectively in treating numerous mankind’s health problems. Recently, a lot of studies have confirmed the effect of natural products, cupping therapy, and acupuncture against SARS-CoV-2. The aim of this chapter is to remind ourselves of the natural pharmacy that God gave us, by shedding the light on the importance of some herbs and traditional remedies in the management of SARS-CoV-2 infection.

Keywords

  • SARS-CoV-2
  • medicinal plants
  • cupping therapy
  • acupuncture
  • complementary and alternative medicine

1. Introduction

Coronavirus disease 2019 (COVID-19) was reported by the World Health Organization (WHO) as a pandemic in 2020 [1]. The spread of the infection is still ongoing in spite of the hard trials to provide potent drugs and vaccines [2]. There is a growing concern about the importance of complementary and alternative medicine (CAM) in treating many infectious diseases [3, 4]. The effect of CAM on the improvement of the symptoms and outcome of SARS-CoV-2 infection was highlighted in multiple reviews [5, 6, 7, 8].

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2. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has aroused the attention of the world since 2019 [9]. It is the third severe epidemic of beta-coronavirus (β-CoV) after the severe acute respiratory syndrome (SARS) and the middle east respiratory syndrome (MERS) [10]. SARS-CoV-2 is an enveloped, positive single-stranded RNA virus [11]. Its genome consists mainly of open reading frames (ORF). ORF1ab represents 67% of the viral genome which encodes the synthesis of polyproteins (nonstructural proteins) in the infected cell (1a, 1ab). The viral structural proteins are synthesized from the last 33% ORFs [12, 13, 14]. SARS-CoV-2 has four structure proteins: spike (S) glycoprotein, envelope glycoprotein (E), membrane glycoprotein (M), and nucleocapsid protein (N) [15, 16, 17]. The pathogenesis of SARS-CoV-2 starts by binding the spike protein (S) with angiotensin-converting enzyme 2, (ACE2). Then synthesis of different viral structural, nonstructural, and extra proteins take place in the infected cells. This is associated with inhibition of the host innate immunity at the early phase of the infection. Then the virus acts against adaptive immunity and spreads in the whole body with subsequent acute and chronic complications. Autoinflammation, immunosuppression, and hyperimmune response may occur [18]. The virulence of SARS-CoV-2 is mediated by the downregulation of pattern recognition receptors (PRRs), which triggers the anti-viral innate immunity mainly interferons (IFNs) release [18, 19]. In addition, the virus stimulates polyclonal activation and apoptosis of lymphocytes leading to pathological activation of macrophages, and immunosuppression [20]. The rapid replication rate of the RNA genome increases the incidence of mutations due to replication errors mediated by RNA polymerase or reverse transcriptase [21, 22]. Mutations in S-protein significantly alter viral pathogenesis [23]. This may impair the immune response to vaccines [24]. Treatment of SARS-CoV-2 has two pathways: the first is to overcome the viral infection either by blocking cell binding, replication, or direct viral effect on tissues. The second pathway is to counteract the overwhelming viral-induced immune response [25]. For blocking viral entry, many agents coexist, such as umifenovir [26, 27], soluble recombinant hACE2, and specific monoclonal antibodies [28, 29]. Several drugs were tried to inhibit viral replication, such as remdesivir [30] favipiravir [31], ribavirin, lopinavir, and ritonavir [32]. For immune modulation, a lot of drugs were introduced, such as dexamethasone [33], tocilizumab, interleukin-6 (IL-6) receptor-specific antibody [34, 35], Eculizumab, a complement 5 inhibitor [36], INF [37, 38], baricitinib, protein kinases inhibitors [39], and imatinib the Abl tyrosine kinase inhibitor (ATKI) [40]. Multiple COVID-19 vaccines have been developed and others are undergoing clinical validation. Despite improving disease morbidity, the vaccines failed to prevent SARS-CoV-2 infection [41, 42]. The drop in anti-SARS-CoV-2 neutralizing antibodies level explains the postvaccination reinfection [43]. Currently, there is no curative anti-SARS-CoV-2 treatment.

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3. Complementary and alternative medicine in COVID-19 infection

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, and emphysema [46, 47, 48, 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, 54, 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, 60, 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 7 days. 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, 86, 87, 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 hyper-inflammation 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].

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, 109, 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, 123, 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].

3.1.7 Ginger (the rhizome of Zingiber officinale)

Ginger has been widely used for thousand years due to its numerous benefits. It was recorded in Chinese, Roman and Arabic medical literature [140]. It is mentioned in Holy Quran as one of Heaven’s drinks [141]. Ginger contains many active ingredients, terpene and phenolic are mainly responsible for its pharmacological activities [142, 143]. Ginger has anti-inflammatory, antioxidative, immunomodulatory, antimicrobial, anti-fungal, anticancer, hepatoprotective, antidiabetic, cardiovascular protective, respiratory protective, anti-obesity, anti-nausea, and anti-emetic activities [144]. Ginger also exhibits a direct anti-viral potential [145, 146, 147]. A molecular docking study defined the inhibitory effect of 8-gingerol, 10-gingerol, 6-gingerol, and another class of the ginger’s ingredients on SARS-CoV-2-related papain-like protease (PLpro) such protease is vital for viral survival and replication [148, 149, 150]. In addition, 6-gingerol showed interaction with some SARS-CoV-2 proteins which are crucial for replication, such as protease, SARS-CoV3C-like molecule, and cathepsin K [151] 6-gingerol binds with S protein as well [152]. Another docking study reported the affinity of gingerol, geraniol, shogaol, zingiberene, zingiberenol, and zingerone to the SARS-CoV-2 MPro [153]. A clinical study demonstrated that consumption of Echinacea tablet with Zingiber officinalis improved the clinical symptoms in COVID-19 outpatients. There was an alleviation of cough, dyspnea, and muscle pain without recorded side effects [154]. Consumption of ginger with other herbs improved the disease outcomes in COVID-19 patients [155, 156, 157].

3.1.8 Saussurea costus (S. costus)

S. costus, is a perennial, aromatic plant that is native to the Himalayan region [158]. For centuries, S. costus was applied in folk medicine to treat numerous health disorders, mainly lung problems [159]. It is mentioned in Islamic literature. Prophet Muhammad (PBUH) said that “Treat with the Indian incense, for it has healing for seven diseases; it is to be sniffed by one having throat trouble and to be put into one side of the mouth of one suffering from pleurisy.” [124] S. costus has a lot of ingredients the most effective are terpenes, anthraquinones, alkaloids, flavonoids, costunolide, and dehydrocostus lactone [160]. These compounds have a variety of pharmacological effects: antifungal activity anthelmintic, antidiabetic, antitumor, antimicrobial, immunostimulant, antiulcer, anti-inflammatory, and antihepatotoxic [161, 162, 163, 164, 165, 166, 167]. Moreover, the anti-viral activity recommended the use of S. costus to treat many viruses [160]. Silico with a molecular docking study reported that dehidrocostus lactone showed better binding potential with SARS-CoV-2 S protein than other compounds of S.costus [168]. An animal experiment showed that S. costus with N. sativa and honey induced a significant elevation of Th2, Th17 along with a rise in humoral immunity markers (TGF-β, sIgA,, IL-4, B-def, and IgG) in rat treated group versus placebo [169].

3.2 Cupping therapy

Cupping therapy (Al-Hijamah) is an ancient part of CAM that was widely practiced in the world and mentioned in every culture [170, 171]. It is mentioned in the book of medicine of Sahih Al-Bukhari where Prophet Muhammad (PBUH) stated that “If there is any healing in your medicines, then it is in cupping, a gulp of honey or branding with fire (cauterization), (one of three) according to that suits the ailment, but I do not like to be (cauterized) branded with fire.” [124] Cupping therapy is a procedure where cups are placed on the skin and induce suction, hence, a negative pressure is created. This allows toxic substances to get out of the body [172]. There are a lot of types of cupping therapy, dry and wet cupping are the two main types [173]. Dry cupping is done without skin laceration, however, in wet cupping, the skin is scarified, so that blood is drawn into the cup [174]. Cupping therapy acts via many mechanisms, it elevates the level of endogenous opioids in the brain, hence, improves pain control with subsequent comfort and relaxation [175]. Other mechanism is to improve blood circulation and clear the blood from toxins substances [176]. This mechanism is mediated by the enhancement of microcirculation, angiogenesis, and capillary endothelial cell repair [172, 177]. Muscle relaxation and parasympathetic activity due to blood loss and vasodilation is other mechanisms [178]. A lot of studies reported the possible preventive and therapeutic advantages of cupping therapy in variable diseases, such as lung disorders, type 2 diabetes mellitus, autoimmune diseases, cardiac diseases, and chronic fatigue syndrome [179, 180, 181, 182, 183]. Cupping therapy is highly recommended in patients with COVID-19 infection for health improvement and to boost the sensation of well-being [184]. The Immunomodulation effect was recorded in 30 patients with rheumatoid arthritis when cupping therapy was combined with conventional therapy versus 20 patients who received conventional treatment only. NK-cell was significantly increased while soluble interleukin-2 receptor (SIL-2R) insignificantly lowered after combined treatment [181]. In a randomized controlled trial, cupping therapy increased the arterial O2 saturation when applied to smokers and enhanced breathing after 12 hours of application [185]. Cupping therapy and acupuncture helped in ameliorating the clinical severity in a case of COVID pneumonia and relieved the complications of respiratory disorders [186]. In a clinical study, warm cupping of the posterior thorax was applied with conventional treatments for 7 days in 8 patients who suffered from COVID-19 with acute respiratory destress syndrome (ARDS). Improvement of the symptoms severity scores was reported in all patients who were discharged without the need for mechanical ventilation [187].

3.3 Acupuncture

Acupuncture is a type of traditional Chinese medicine. It is commonly used in the treatment of respiratory diseases [188, 189]. Acupuncture is supposed to be an effective agent in treating the breathlessness of chronic obstructive pulmonary diseases (COPD) [190]. This encourages its utility to improve dyspnea and enhance the quality of life in COVID-19 patients [191]. Headache is a common symptom of COVID-19 infection. Acupuncture is widely used in pain and headache treatment [192, 193]. In China, it was added to COVID-19 patients’ routine regimens [194]. Acupuncture-induced analgesia through opioid peptides and dopamine receptors. Where acupuncture activates dopamine and β-endorphin, which in turn downregulates cytokine production via type 1 dopamine receptors, so inhibit systemic inflammation [195, 196, 197, 198]. This effect may help in the cytokine storm of COVID-19 infection. Despite having good potential for COVID-19 treatment, there is not enough high-quality evidence to support acupuncture [199].

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4. Conclusion

Based on the previous studies, complementary and alternative remedies are needed to potentiate the effect of standard therapy and prophylaxis in COVID-19 patients. This will alleviate the symptoms, boost immunity and induce the sensation of well-being, especially in patients who are not eligible for the vaccines.

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Acknowledgments

Gratitude and praise to God who sprouted man and plants from the earth to benefit each other.

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Written By

Sally Elnawasany

Submitted: 21 July 2022 Reviewed: 29 July 2022 Published: 20 September 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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