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A review on five medicinal considering the therapeutic potentials in the management of COVID-19.

Md. Fahad Jubayer1*, Md. Shahidullah Kayshar1, Md. Anisur Rahman Mazumder2, Syeda Sabrina Akter1

1Department of Food Engineering & Technology, Sylhet Agricultural University, Sylhet-3100, Bangladesh. 2Department of Food Technology and Rural Industries, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh.

*Corresponding author:

Md. Fahad Jubayer Assistant Professor, Department of Food Engineering & Technology Sylhet Agricultural University, Sylhet-3100, Bangladesh. Email: [email protected] Phone: +88-01876-529642.

Abstract: The spread of pandemic coronavirus disease-2019 has become a health emergency worldwide. Since the unprecedented outbreak, attention has been raised worldwide to develop and research for control options and treatments. Although several clinical trials are ongoing, no registered drugs or vaccines are available yet. As situation warrants for the exploration of a successful antiviral, there should be a search for the remedies in nature also. and their metabolites have long been used as a treatment option for various life-threatening diseases with minimal or no side effects. Thus this review aims to summarize previous outcomes concerning the role of medicinal plants in treating several life-threatening diseases. Above all, this work intends to find the constituents of five selected medicinal plants and their possible working mechanisms in the management of COVID-19. Constituents of the presented medicinal plants possess excellent pharmacological properties, including significant antiviral and antimicrobial potential. Based on the traditional uses, pharmacological properties, and previous studies, these medicinal plants mentioned in this review can be considered as a possible therapeutic option for the management and treatment of COVID-19. However, further extensive researches and trials are suggested to discover specific effects and dosage for this pathogenic outbreak.

Keywords: COVID-19; medicinal plants; black ; ; licorice; echinacea.

Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SARS-CoV, severe acute respiratory syndrome coronavirus; MERS- CoV, middle east respiratory syndrome coronavirus; 2019-nCoV, novel coronavirus; ARDS, acute respiratory distress syndrome; CVD, cardio vascular disease; HIV, human immunodeficiency viruses; NDV, Newcastle disease virus; HSV, herpes simplex virus; VSV, vesicular stomatitis viruses; HCV, virus; HRSV, human respiratory syncytial virus; IV, influenza virus; ACE2, angiotensin-converting enzyme 2 gene; RdRp, RNA-dependent RNA polymerase; HCQ, hydroxychloroquine; TQ, hhymoquinone; RA, rheumatoid arthritis; 1L-1β, interleukin 1 beta; TNFα, tumor necrosis factor alpha; α-LA, α-lipoic acid; GC, ; 18β-GA, 18β-glycyrrhetinic acid; LCA, licochalcone A; GLD, glabridin; HBsAg, hepatitis B antigen.

Introduction

Once identified in Wuhan, China, in December 2019, the global pandemic, as declared by the WHO, the novel coronavirus disease (COVID-19) has made its deadly mark in about all countries worldwide. The Chinese Centre for Disease Control and Prevention (CCDC) identified the contributory agent from throat swab samples on January 7, 2020 and designated it as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [1]. As of September 09, 2020, there are nearly 27 million confirmed cases in almost every country and territory with a burden of about 895K deaths [2].

Coronavirus is an enveloped single-stranded positive-sense RNA virus which belongs to the subfamily Coronavirane [3]. The first article related to 2019-nCoV revealed that the virus belongs to the beta-coronavirus group, imparting family line to bat coronavirus HKU9-1, like SARS coronavirus [4]. Other studies featured that SARS-CoV-2 genes share <80% nucleotide identity and 89.10% nucleotide similarities with SARS-CoV genes [5]. In spite of succession assorted variety, its spike protein collaborates firmly with the human ACE2 receptor [4]. The key target of infection is the lower respiratory tract [6]. The commencement of the disease was found with high fever, fatigue, dry cough, sore throat, nasal blockage, headache, runny nose, sore throat, vomiting, and diarrhea. Along with these mild symptoms, some have appeared with different fatal complications like organ failure, septic shock, severe pneumonia and Acute Respiratory Distress Syndrome (ARDS) [7]. Presently, the SARS-CoV-2 infection has become a public health threat because of its high transmission rate as well as the unusualness of infection movement around the world. At present, no effective and standard treatment or vaccine is available against COVID-19. However, the role of several antiviral agents, anti-inflammatory agents, antibiotics, and their controlled clinical trials has been reviewed to explore the competence against COVID-19. Among the treatments, the combination of lopinavir-ritonavir, remdesivir, favipiravir, hydroxychloroquine, ivermectin, doxycycline – has been recommended different times till date [8], [9], [10].

Nutritional interventions are important to boost up the host immune system against different infections or diseases. Previous investigations on nutritional interventions have also shown the efficacy against measles, influenza, SARS-CoV and MERS-CoV. Vitamin A supplementation can reduce the morbidity and mortality rate in diseases like measles, diarrheal, measles-related pneumonia, HIV and malaria. Vitamin C boosts up immune functions and shows the potentiality against SARS coronavirus, atypical pneumonia, and lower respiratory tract infections. Moreover, patients with diseases like diabetes, , CVD, and cancer may establish a resistance to SARS-CoV-2 with the appropriate intake of vitamin D and vitamin E [11]. On the other hand, the combination of zinc and pyrithione at a certain dosage inhibits the replication of SARS-CoV [12].

In the absence of registered treatment or vaccine for this novel coronavirus, it is vital to find alternative methods to control the spread of the coronavirus disease (COVID-19) as well as to prevent the replication of the same. In this circumstance, based on historical records and evidence, the introduction of natural products and their derivatives hopefully will effective against SARS-CoV-2. There are solid attestation in favor of medicinal plants being utilized for fortifying body immune functions and treating different diseases in prehistoric systems of Unani, Ayurvedic, and Chinese tradional medicine. Natural products and medicines have crucial role in drug discovery. The U.S. Food and Drug Administration have approved many drugs that are being prepared and derived from natural sources [13]. A good number of study indicated that natural products and their derivatives have significant antiviral activity and potential of inhibiting viral replication [14]. Moreover, during the outbreak of COVID-19, some Chinese was widely used as it considered enhancing host immunity against the infection. However, adequate research and evidence on the development of antiviral medications from natural products and their derivatives, is lacking. Ample researches and rigorous clinical trials should be conducted to assure the possible preventive effect of these medicinal plants and their constituents. In accordance with the foregoing discussion, this review aims to draw a current status of efficacy of five medicinal plants (black cumin, licorice, Echinacea, ginger, and ) and their metabolites as possible management option of COVID- 19. This review will also help the general people think of the benefits of the medicinal plants and tend them to include these kinds of plants in their daily lifestyle during this time.

Why medicinal -based approach?

Till date, there has been no breakthrough in antiviral vaccines and therapeutic drugs for the management of COVID-19. Alongside with containment strategies, ongoing treatments are primarily focused on symptomatic and respiratory support according to the diagnosis. Severe atypical pneumonia is the main cause observed for the death in this disease. The infected patients usually observed with symptoms of mild upper respiratory tract infection, which has similarities with the common cold attack. Prognosis refers, the most common symptoms of COVID-19 includes fever (88-98%), upper airway congestion, dry cough, fatigue, sore throat, , diarrhea, myalgia, and gastrointestinal disorders [7], [15]. Based on currently available information and clinical expertise, people of any age who have severe underlying medical conditions like diabetes, CVD, asthma etc. might be at higher risk from this disease [6]. In a cohort study, it was observed that, patient with hypertension (19.4%) and diabetes (10.9%) had greater comorbidity rate compared to other patients [16]. Previous experience of fighting the epidemic SARS-CoV and MERS-CoV, some treatment approaches against coronavirus have been practiced around the world following the most efficient research strategy “old drug, new use”. Currently, symptom-based treatments for SARS-CoV-2 infections are carrying out at different parts of the world. In ancient times, people used to search for drugs in nature. A significant amount of world populations rely on medicinal plants and for attaining their primary healthcare needs [17]. In this grave state, it is better for us to find alternatives by giving attention towards available medicinal plant around. The herbal treatment can be considered as a substitute for conventional medicines for more than a few reasons, including easy access and availability, minimum or no side effects, and economic. Indigenous knowledge about various kinds of medicinal plants often offers great insight into the way of drug development for an emerging disease. Moreover, an adaptive and powerful immune system is undoubtedly essential for the human body to defense the SARS-CoV-2 [3]. The use of these plants can be helpful to prevent the onset of this disease by strengthening the body’s immune system [18]. It is better to take preventive measures before the treatment and get diseased. Medicinal plants have curative potentials along with different complex chemical substances as secondary metabolites of different composition. Medicinal herbs and can positively be antimicrobial without being anti-life. Furthermore, these plants can be useful against viruses and fungal infections and support the ecosystem of human body. The immune system plays a great role in protecting the body from autoimmune disorders, cancers, and seasonal allergies as it is one of the best defense mechanisms for a human body. And for strengthening the immune system, there are no better options than the natural resources. Clinical trials and numerous scientific researches on the use and efficacy of herbal plants and spices are on the rise now-a-days. The intensive care and non-specific treatment to improve the symptoms of the patient are possibly the solitary options currently [19]. Maximizing the natural immunity of the body is crucially important as the host environment is supposed to be a governing factor for the attacking organism. Moreover, medicinal plants and their extracts have long been uses for the treatment of several viral and respiratory diseases. It is noticeable that, integrative Chinese- Western medicine (IM) treatment was started for all confirmed patients in Shanghai [20]. The first Chinese medicine (CM) oriented hospital started its function in Wuhan since February 2020 and the first recovery in Beijing came from the treatment with the IM [21]. During the outbreak of SARS, traditional Chinese medicine also helped the healthcare workers maintaining good mental and physical status with no infection [22]. In addition, plant-based, traditional, and home remedies can be used as a form of primary treatment. Several studies reported the inhibition effects of various medicinal plants and herbs extracts on the replication of a number of viruses including the SARS [23]. Some more researches spot the lights onto the antiviral potential of several plant extracts against those strains of viruses that are resistant to the conventional antiviral agents. This led us to think forward to explore the antiviral components of natural medicinal plants. Based on these facts, it can be said that, the approaches to the study of medicinal plants should also be addressed beside the other forms of drugs in order to fight or manage the currently untreatable, life-threatening diseases like COVID-19.

Medicinal plants and their therapeutic potentials in the management of COVID-19

Black cumin ( L.)

As a popular and well-known medicinal food, black cumin (Figure 1) has been used from ancient times as a form of anti-microbial treatment. Its and oil have been commonly used as a traditional remedy for the treatment of a variety of health conditions for more than 2000 years. Furthermore, the Prophet (PBUH) mentioned the name of black cumin as a treatment for all diseases except death [24]. It is also specified within the list of natural medication of 'Tibb-e-Nabavi', or "Medicine of the Prophet (Muhammad PBUH)" [25]. It was prescribed by the physicians of Egypt and Greek for the treatment of migraine, toothache, worms, nasal blockage, along with a milk production tonic for the breastfeeding women [26]. The seeds of N. sativa also have traditional uses in the Middle East and Southeast Asian countries [25] for the treatment of a number of diseases as shown in Table 1. Different pharmaceuticals and industries around the world manufacture black cumin supplements for human use.

Nigella sativa seeds and its active compounds (Figure 2) have been traditionally familiar to establish a significant inflammatory response by suppressing the chronic inflammation along with building healthy immune responses. N. sativa is suggested strongly for combating the coronavirus disease (COVID-19) based on recent computational findings and its therapeutic potentials against autophagy dysfunction, immune disturbance, CVD, viral and bacterial infections [27]. Thymoquinone (TQ) is the main bioactive compound obtained from black cumin volatile oil. It has a significant antioxidant, anti-histaminic, anti-inflammatory, anti-microbial, anticancer, and cardioprotective activities with low or no side effects [28]. TQ promotes autophagy in human body and autophagy is considered as a possible therapeutic way to the management of the coronavirus disease [29], [30]. People who have rheumatoid arthritis (RA) are more susceptible to infection compared to healthy people. According to some study, there is a possible link between RA and respiratory viral infections like parainfluenza or coronavirus [31]. Arthritis scores and pro-inflammatory cytokines levels (1L-1β and TNFα) were significantly controlled by TQ, as found in a study on adjuvant-induced arthritic rats [32]. Therefore, this capability of TQ could decrease the severity of arthritis. Black cumin has been proved effective in reducing high blood glucose level significantly. Combination of α-lipoic acid (α-LA) L- carnitine, and Nigella sativa functioned well in improving the carbohydrate metabolism in diabetic rats [33]. Thus, for diabetic patients, one of the vulnerable risk groups to COVID-19, black cumin may be a good option for regular intake. Oil of black cumin helps to improve insulin levels, hyperlipidemia, achieve pancreatic islet extent, and hepatic antioxidant enzymes with increased glycogen contents [34]. N. sativa was found helpful against numerous viruses namely, murine cytomegalovirus [35], avian influenza [36], HIV [37], hepatitis C [38], Newcastle disease virus (NDV) [39]. Viral infections can cause apoptosis that may lead to lymphocyte depletion in the host cell. Apoptosis caused due to viruses can be inhibited by antioxidants, along with the inhibition of the viral replication. Thus a linkage can be built between antiviral and antioxidant effects. N. sativa has been evaluated for its potent antioxidant activities of in- vivo and in-vitro studies [40]. Severe lung injury and upper respiratory tract infection was observed in patients suffering from coronavirus. And almost all patients of COVID-19 are suffering from pneumonia [16]. A couple of in vivo studies showed the protective effects of N. sativa and its oil on lung tissue damage [41], [42]. An anti-malarial drug named hydroxychloroquine (HCQ) was suggested previously as a treatment option for coronavirus through a number of recent studies [43], [44], although being told not so much fruitful now-a-days. HCQ is likely to ease the severe progression of coronavirus, inhibiting the cytokine storm by suppressing T cell activation [43]. This molecule was mentioned earlier as a potent inhibitor of most coronaviruses, including SARS-CoV-1 [44]. The current form of coronavirus bears about 80% nucleotide identity of SARS-CoV-1 [45]. Nigellidine and α-hederin are compounds that are found in Nigella sativa. These two elements may inhibit the ongoing COVID-19 providing better energy score compared to chloroquine, hydroxychloroquine, and favipiravir under clinical examinations [46]. The observed results of N. sativa in several in-vivo and in-vitro studies are shown in Table 1.

Figure 1. Medicinal plants: Black cumin (a) , (b) Seeds; Licorice (c) Plant, (d) ; Echinacea (e) Plant; Ginger (f) Plant, (g) Root; Costus (h) Plant, (i) Root.

Figure 2. Major constituents of Black cumin with chemical structures.

Licorice ( glabra)

The first known herbal and medicinal application of Licorice (Figure 1) was started about 2500 years ago in the Egyptian and Mesopotamian kingdom [47]. Accordingly, this indigenous plant was used traditionally for centuries in Arabian, Chinese, , and Indian cultures [47], [48]. Ancient Romans and Greeks used licorice as a form of drug. The Greeks procured this plant’s pharmacological application from the Scythians, a group of ancient tribes from southern Siberia [49]. Diseases like influenza, cough, liver damage, lung problems, and asthma are usually treated by licorice in oriental and folk medicine [48].

With the ability to inhibit or slowing the action of a variety of viruses, Licorice establishes itself as a broadly used antiviral containing more than 20 triterpenoids and 300 flavonoids [50]. It has a component named glycyrrhizin (GC) that is usually effective against the envelope viruses like SARS related coronavirus, hepatitis D, flaviviruses, retroviruses, influenza A, herpesviruses, togaviruses, etc. as well as eleven types of flavivirus (dengue, yellow fever, Japanese encephalitis) [51]. In a study, glycyrrhizin, a constituent of Licorice root, was found promising for the treatment of SARS [52] (Table 1). Moreover, two triterpenoids (GC and 18β-GA) of Licorice possess antiviral potential [50]. Glycyrrhizin inhibits the SARS virus in invading a target cell and reproduction of virus. Glycyrrhizin was found as the most effective antiviral against SARS among glycyrrhizin, 6-azauridine, pyrazofurin, ribavirin, and mycophenolic acid [53]. In another study, lycorine, an extract of Licorice, was suggested as anti-SARS-CoV medication for the treatment of SARS [54]. Several in-vivo and in-vitro studies showed the effect of GC against numerous viruses including SARS-CoV (Table 1). After a molecular docking, it can be seen that glycyrrhizin possess the potential binding to ACE2 (estimated ΔG (kcal/mol) – 9) [55]. Besides, compounds derived from Licorice such as glycyrrhizin (GC), glycyrrhetinic acid (GA), licoagroaurone, licochalcone A (LCA), licoagrone, licoagrodin, glabrol, glabridin (GLD) were evaluated in a number of studies for their inhibitory effect on diabetes mellitus [50], [56]. In China, after the outbreak of COVID-19, doctors from the State Administration of Traditional Chinese Medicine used herbal combinations to treat the affected patients. Among other herbs, Licorice was present in 6 grams. That treatment had a success rate of 90% [20]. Some active and major constituents with their chemical structures are shown in Figure 3.

Figure 3. Major constituents of Licorice with chemical structures.

Echinacea (Echinacea spp.)

Echinacea (Figure 1) is considered as one of the most vital immune stimulants and used for centuries in the Western herbal medicines. The Native Americans (Choctaw, Omahas, Comanches, Crows, Hidatsasused, and Cheyennes) to treat toothache, snakebites, sore throats, flu, cold, gum disease, and various infections by using this plant [57].

Having the potential of increasing the number of macrophages inside the body, Echinacea has been one of the supportive herbs for the immune system with an effective antiviral, antibacterial, and antiseptic action. It is commonly known as an immune stimulant. Usually, three of Echinacea (E. purpurea, E. angustifolia, and E. pallid) are used to make various herbal preparations [58]. E. purpurea Root extracts contained a somewhat powerful activity against herpes simplex virus (HSV), vesicular stomatitis viruses (VSV), and influenza virus (FV) [59]. Moreover, there are another three compounds, namely, caffeic acid, chicoric acid and echinacin that have significant antiviral activity [60]. Viruses, like coronavirus, influenza A and B, parainfluenza, some adenoviruses, respiratory syncytial viruses, neumoviruses, and bocaviruses are mainly responsible for human respiratory infections [61]. Current coronavirus disease (COVID-19) has a number of similar symptoms of common respiratory tract infection caused by specific viruses. These include sneezing or coughing, mucus membrane irritation, runny nose, sore throat, cough, fever, asthma, pneumonia, etc. Pro-inflammatory cytokines simulation is the reason behind these symptoms. Echinacea interferes with the cytokine release from viruses and helps to relieve the symptoms. Echinaforce, a hot drink prepared from extracts, was suggested as a prophylactic treatment for all CoVs, including recent occurring SARS-CoV-2 [62]. E. purpurea aerial parts are effective against the coronavirus, influenza, HSV 1 and HSV 2, and rhinoviruses [63], while the are antiviral against influenza and HSV 1. On the other hand, roots and aerial parts of E. angustifolia are beneficial for the treatment of influenza, HSV 1, and rhinoviruses [58]. Moreover, the polysaccharides present in Echinacea possess anti-hyaluronidase action, which inhibits the viruses to take over the body cells. There are numerous scientific literatures on in-vitro and in- vivo studies of the pharmacological activities of Echinacea species. Some of them are mentioned in Table 1. Also the major constituents are shown in Figure 4.

Figure 4. Major constituents of Echinacea with chemical structures.

Ginger (Zingiber officinale)

Ginger (Figure 1) is one of the broadly used, extensively cultivated, and savory herbs that have been used widely for centuries in Chinese, Arabian, and Tibb-Unani herbal medicine for the treatment of colds, asthma, vomiting, rheumatism, stroke, headache, and digestion problems [64]. It is mainly grown in Asia and tropical regions. The use of ginger as both and medication can be traced back to the old tradition of Arab, Chinese, Indian, Greece, and Roman [47].

The most common application of ginger in traditional medicine is to reduce cold and fever. Besides, the modern application of it includes the treatment of cancers, bone and vascular disorders, metabolic dysfunction, emesis, etc. There are nearly 400 types of constituents have been identified in ginger, including carbohydrates, volatile oils, lipids, oleo-resins, amino acids, vitamins, etc. [65]. Major constituents of this plant can be seen at Figure 5 with chemical structures. A computational study disclosed the multi-target binding ability of ginger compounds with ligands at the time of using a molecular docking system [66]. In the above mentioned treatment strategy of Yang et al., 2020, ginger was present in 9 grams in the formulation. When coming to antiviral effects of ginger, a number of studies found the use of ginger useful against HSV-1 [67], avian influenza virus [68], food borne viral contamination [69], and human respiratory syncytial virus (HRSV) [70]. But, it is good to mention that, the indication was given for the use of only the fresh , not the dried ones. Apart from these, ginger and its extracts have anti-bacterial, anti-fungal, anti-tumorigenic, anti-inflammatory, and anti- oxidative potentials also [71]. In a recent study, ginger has been declared as one of the promising drugs against SARS-CoV-2. Ginger also is suggested as a possible treatment option for its more substantial inhibition potential of COVID-19 protease [72].

Figure 5. Major constituents of Ginger with chemical structures.

Costus ( costus, Syn: Saussurea lappa)

Costus (Figure 1) is an ancient and well-identified medicinal plant of family that has also been used as a component of various medicines all over the world. In the Ayurveda and Unani medicine, it is used singly or combined with other drugs as a remedy for cholera, cough, asthma, skin diseases, piles, rheumatism, etc. In Prophetic medicine, costus is recommended as a specific treatment for pharyngitis, pleurisy, snakebite, and tonsillitis in infants [73]. In the Book of Medicine (Kitab Al‑Tibb), Sunan Abi Dawud, an authentic Hadith, Prophet (PBUH) suggested using the Indian aloeswood (costus) for the treatment of pleurisy, a lung disease [74].

Significant elements present here are sesquiterpene lactones (e.g. costunolide, dehydrocostus lactone). The dried root of this plant is being used in Unani medicine as a form of powder and decoration for the treatment of diseases, such as asthma, pain, dysentery, skin disease, neurological diseases, liver diseases, intestinal parasites, etc. [75]. S. costus is used as a herbal treatment of malaria in Yemen [76]. It has anti-cancer, antiviral, anti-arthritic, anti-inflammatory, anti-ulcer, anti-convulsing, and hepatoprotective properties as shown with clinical in-vivo and in-vitro evidence in Table 1. The root of costus is used to chew in traditional treatment of throat infection, and root powder is taken with hot water for the management of cold and cough. Costunolide and dehydrocostus lactone (extracted from S. lappa) inhibit the hepatoma Hep3Bcells in human, thus hinder the hepatitis B antigen (HBsAg) production. This plant has the potential to be a part of potent antiviral drugs [77]. Anti-inflammatory properties of a drug can be used to treat COVID-19. A decrease in the inflammatory cytokynins (TNF-α, IL-1β) would also be effective in the treatment. Costunolide has an inhibitory effect on IL-1β gene expression, while different sesquiterpene lactones are found to have anti-inflammatory effects [78]. The major constituents are shown in Figure 6.

Figure 6. Major constituents of Costus with chemical structures.

Table 1. General details and experimental studies conducted with Black cumin, Licorice, Echinacea, Ginger, and Costus.

Conclusion and perspective After the outbreak of highly pathogenic SARS-CoV and MERS-CoV, the world has faced another pandemic outbreak, known as COVID-19 which is followed by almost the similar lineage of the beta-coronavirus group. Because of the high transmission rate and unpredictable nature to trace, the COVID-19 has posed a severe public health threat all over the world. In the absence of specific treatments of proven efficacy, early detection and quarantine of infected ones with some supportive treatments is still now the minimal measure to prevent the outbreak. Although some antiviral drugs are thought to be effective because of their previous potentiality on the treatments of SARS-CoV and MERS-CoV, without a rigorous clinical trial, it can’t be applied. In this viewpoint, it is necessary to explore promising alternatives employing unconventional resources. In this review, we highlighted five potential ethnic medicinal plants which have a wide gamut of antimicrobial properties as well as pharmacological potentials, for the treatment of COVID-19. These plants and their derivatives can play a vital role by enhancing the host immune responses and preventing the virus replication, thus inhibits further infection. However, adequate researches and thorough clinical trials are necessary to find out accuracy in the fight against pathogenic viruses. These medicinal plants can create the new window for drug development against such pandemic or the COVID-19 in virtue of their natural origin, less or no side effects compared to synthetic drugs, and availability with low cost.

Declaration of competing interest

The authors declare that they have no conflict of interest

References

1. Sohrabi C, Alsafi Z, O’Neill N, Khan M, Kerwan A, Al-Jabir A, et al. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). International Journal of Surgery. 2020; 76: 71-6. https://doi.org/10.1016/j.ijsu.2020.02.034

2. World Health Organization. Weekly Epidemiological and Operational updates September 2020, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports

3. Li Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. Journal of Medical Virology. 2020;92(4):424-32. https://doi.org/10.1002/jmv.25685

4. Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Science China Life Sciences. 2020;63(3):457-60. https://doi.org/10.1007/s11427-020-1637-5 5. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265-9. https://doi.org/10.1038/s41586-020-2008-3

6. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020;395(10229):1054-62. https://doi.org/10.1016/S0140-6736(20)30566-3

7. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet. 2020;395(10223):507-13. https://doi.org/10.1016/S0140-6736(20)30211-7

8. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research. 2020;30(3):269-71. https://doi.org/10.1038/s41422-020-0282-0

9. Wang Y, Fan G, Salam A, Horby P, Hayden FG, Chen C, et al. Comparative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection. The Journal of Infectious Diseases. 2020;221(10):1688- 98. https://doi.org/10.1093/infdis/jiz656

10. Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. MedRxiv. 2020. https://doi.org/10.1101/2020.03.17.20037432

11. Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. The Lancet Oncology. 2020;21(3):335-7. https://doi.org/10.1016/S1470-2045(20)300966

12. Te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathogens. 2010;6(11):e1001176. https://doi.org/10.1371/journal.ppat.1001176

13. Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. Journal of Natural Products. 2007;70(3):461-77. https://doi.org/10.1021/np068054v 14. Lin LT, Hsu WC, Lin CC. Antiviral natural products and herbal medicines. Journal of Traditional and Complementary Medicine. 2014;4(1):24-35. https://doi.org/10.4103/2225- 4110.124335

15. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020;75:1730-41. https://doi.org/10.1111/all.14238

16. Wu C, Chen X, Cai Y, Zhou X, Xu S, Huang H, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Internal Medicine. 2020;180(7):934-43. https://doi:10.1001/jamainternmed.2020.0994

17. Srivastava AK. Significance of medicinal plants in human life. In: Synthesis of Medicinal Agents from Plants. 2018 (pp. 1-24). Elsevier. https://doi.org/10.1016/B978-0-08-102071- 5.00001-5

18. Fan Y, Zhang Y, Tariq A, Jiang X, Ahamd Z, Zhihao Z, et al. Food as medicine: a possible preventive measure against coronavirus disease (COVID-19). Phytotherapy Research. 2020. https://doi.org/10.1002/ptr.6770

19. Yang QX, Zhao TH, Sun CZ, Wu LM, Dai Q, Wang SD, et al. New thinking in the treatment of 2019 novel coronavirus pneumonia. Complementary Therapies in Clinical Practice. 2020;39:101131. https://doi: 10.1016/j.ctcp.2020.101131

20. Yang Y, Islam MS, Wang J, Li Y, Chen X. Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective. International Journal of Biological Sciences. 2020;16(10):1708-17. https://doi.org/10.7150/ijbs.45538

21. National Administration of Traditional Chinese Medicine (NATCM). Beijing’s first confirmed case of new coronavirus pneumonia cured by Symptomatic and Chinese medicine treatment. 2020. National Administration of Traditional Chinese Medicine, Beijing.

22. Lau JT, Leung PC, Wong EL, Fong C, Cheng KF, Zhang SC, et al. The use of an herbal formula by hospital care workers during the severe acute respiratory syndrome epidemic in Hong Kong to prevent severe acute respiratory syndrome transmission, relieve influenza-related symptoms, and improve quality of life: a prospective cohort study. Journal of Alternative & Complementary Medicine. 2005;11(1):49-55. https://doi.org/10.1089/acm.2005.11.49

23. Kotwal GJ, Kaczmarek JN, Leivers S, Ghebremariam YT, Kulkarni AP, Bauer G, et al. Anti- HIV, Anti-Poxvirus, and Anti-SARS Activity of a Nontoxic, Acidic Plant Extract from the Trifollium Species Secomet V/anti-Vac Suggests That It Contains a Novel Broad Spectrum Antiviral. Annals of the New York Academy of Sciences. 2005;1056(1):293.https://doi.org/10.1196/annals.1352.014

24. Duke JA. Handbook of medicinal herbs. CRC Press; 2002.

25. Sharma NK, Ahirwar D, Jhade D, Gupta S. Medicinal and phamacological potential of nigella sativa: a review. Ethnobotanical Review. 2009;13:946-55.

26. Goreja WG. Black : nature's miracle remedy. Karger Publishers. 2003.

27. Islam MN, Hossain KS, Sarker PP, Ferdous J, Hannan MA, Rahman MM, et al. Revisiting pharmacological potentials of Nigella sativa seed: a promising option for COVID-19 prevention and cure. OSF Preprints. 2020. https://doi.org/10.31219/osf.io/56pq9

28. Woo CC, Kumar AP, Sethi G, Tan KH. Thymoquinone: potential cure for inflammatory disorders and cancer. Biochemical Pharmacology. 2012;83(4):443-51. https://doi.org/10.1016/j.bcp.2011.09.029

29. Xiao J, Ke ZP, Shi Y, Zeng Q, Cao Z. The cardioprotective effect of thymoquinone on ischemia-reperfusion injury in isolated rat heart via regulation of apoptosis and autophagy. Journal of Cellular Biochemistry. 2018;119(9):7212-7. https://doi.org/10.1002/jcb.26878

30. Hannan MA, Rahman MA, Rahman MS, Sohag AA, Dash R, Hossain KS, et al. Intermittent fasting, a possible priming tool for host defense against SARS-CoV-2 infection: crosstalk among calorie restriction, autophagy and immune response. Immunol. Lett. 2020;226:38–45.

31. Joo YB, Lim YH, Kim KJ, Park KS, Park YJ. Respiratory viral infections and the risk of rheumatoid arthritis. Arthritis Research and Therapy. 2019;21(1):199. https://doi.org/10.1186/s13075-019-1977-9

32. Vaillancourt F, Silva P, Shi Q, Fahmi H, Fernandes JC, Benderdour M. Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis. Journal of Cellular Biochemistry. 2011;112(1):107-17. https://doi.org/10.1002/jcb.22884

33. Salama RH. Hypoglycemic effect of lipoic acid, carnitine and Nigella sativa in diabetic rat model. International Journal of Health Sciences. 2011;5(2):126.

34. Abdelrazek H, Kilany OE, Muhammad MA, Tag HM, Abdelazim AM. Black seed thymoquinone improved insulin secretion, hepatic glycogen storage, and oxidative stress in streptozotocin-induced diabetic male wistar rats. Oxidative Medicine and Cellular Longevity. 2018; 8104165. https://doi.org/10.1155/2018/8104165

35. Salem ML, Hossain MS. Protective effect of black seed oil from Nigella sativa against murine cytomegalovirus infection. International Journal of Immuno pharmacology. 2000;22(9):729-40. https://doi.org/10.1016/S0192-0561(00)00036-9

36. Umar S, Munir MT, Subhan S, Azam T, Nisa Q, Khan MI, et al. Protective and antiviral activities of Nigella sativa against avian influenza (H9N2) in turkeys. J. Saudi Soc. Agric. Sci. 2016. https://doi.org/10.1016/j.jssas.2016.09.004

37. Onifade AA, Jewell AP, Adedeji WA. Nigella sativa concoction induced sustained seroreversion in HIV patient. African Journal of Traditional, Complementary and Alternative Medicines. 2013;10(5):332-5. https://dx.doi.org/10.4314/ajtcam.v10i5.18

38. Oyero OG, Toyama M, Mitsuhiro N, Onifade AA, Hidaka A, Okamoto M, Baba M. Selective inhibition of hepatitis c virus replication by Alpha-zam, a Nigella sativa seed formulation. African Journal of Traditional, Complementary and Alternative Medicines. 2016;13(6):144-8. https://doi:10.21010/ajtcam.v13i6.18.

39. Khan AU, Tipu MY, Shafee M, Khan NU, Tariq MM, Kiani MR, et al. In-vivo antiviral effect of Nigella sativa extract against Newcastle Disease Virus in experimentally infected chicken embryonated eggs. Pakistan Veterinary Journal. 2018;38:434-7. https//doi:10.29261/pakvetj/2018.075

40. Yimer EM, Tuem KB, Karim A, Ur-Rehman N, Anwar F. Nigella sativa L. (black cumin): a promising natural remedy for wide range of illnesses. Evidence-Based Complementary and . 2019; 1528635. https://doi.org/10.1155/2019/1528635 41. Kanter M. Effects of Nigella sativa seed extract on ameliorating lung tissue damage in rats after experimental pulmonary aspirations. Acta Histochemica. 2009;111(5):393-403. https://doi.org/10.1016/j.acthis.2008.10.008

42. Tayman C, Cekmez F, Kafa IM, Canpolat FE, Cetinkaya M, Tonbul A, et al. Protective effects of Nigella sativa oil in hyperoxia-induced lung injury. Archivos de Bronconeumología (English Edition). 2013;49(1):15-21. https://doi.org/10.1016/j.arbr.2012.11.003

43. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. Journal of Antimicrobial Chemotherapy. 2020;75:1667-70. https://doi.org/10.1016/S0140-6736(20)30566-3

44. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?. International journal of Antimicrobial Agents. 2020:105938. https://doi.org/10.1016/j.ijantimicag.2020.105938

45. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD. Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. BioRxiv. 2020. https://doi.org/10.1101/2020.01.22.914952

46. Bouchentouf S, Missoum N. Identification of Compounds from Nigella Sativa as New Potential Inhibitors of 2019 Novel Coronasvirus (Covid-19): Molecular Docking Study. medRxiv. 2020. https//doi:10.26434/chemrxiv.12055716.v1

47. Coates PM, Paul MC, Blackman M, Blackman MR, Cragg GM, Levine M, et al. Encyclopedia of Dietary Supplements (Online). CRC press. 2004.

48. Bahmani M, Rafieian-Kopaei M, Jeloudari M, Eftekhari Z, Delfan B, Zargaran A, et al. A review of the health effects and uses of drugs of plant licorice (Glycyrrhiza glabra L.) in Iran. Asian Pacific Journal of Tropical Disease. 2014;4:847-9. https://doi.org/10.1016/S2222- 1808(14)60742-8

49. Fiore C, Eisenhut M, Ragazzi E, Zanchin G, Armanini D. A history of the therapeutic use of liquorice in Europe. Journal of Ethnopharmacology. 2005;99(3):317-24. https://doi.org/10.1016/j.jep.2005.04.015

50. Yang R, Wang LQ, Yuan BC, Liu Y. The pharmacological activities of licorice. Planta Medica. 2015;81(18):1654-69. https://doi.org/10.1055/s-0035-1557893 51. Buhner SH. Herbal Antivirals: Natural Remedies for Emerging & Resistant Viral Infections. Storey Publishing; 2013.

52. Hoever G, Baltina L, Michaelis M, Kondratenko R, Baltina L, Tolstikov GA, et al. Antiviral Activity of Glycyrrhizic Acid Derivatives against SARS− Coronavirus. Journal of Medicinal Chemistry. 2005;48(4):1256-9. https://doi.org/10.1021/jm0493008

53. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. The Lancet. 2003;361(9374):2045-6. https://doi.org/10.1016/S0140-6736(03)13615-X

54. Li SY, Chen C, Zhang HQ, Guo HY, Wang H, Wang L, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Research. 2005;67(1):18-23. https://doi.org/10.1016/j.antiviral.2005.02.007

55. Chen H, Du Q. Potential natural compounds for preventing SARS-CoV-2 (2019-nCoV) infection. Preprints. 2020. https://doi.org/10.1016/S0002-9343(01)01059-2

56. Wu F, Jin Z, Jin J. Hypoglycemic effects of glabridin, a polyphenolic flavonoid from licorice, in an animal model of diabetes mellitus. Molecular Medicine Reports. 2013;7(4):1278-82. https://doi.org/10.3892/mmr.2013.1330

57. Kindscher K, editor. Echinacea: Herbal medicine with a wild history. Springer; 2016.

58. Hudson J, Vimalanathan S. Echinacea—A source of potent antivirals for respiratory virus infections. Pharmaceuticals. 2011;4(7):1019-31. https://doi.org/10.3390/ph4071019

59. Binns SE, Hudson J, Merali S, Arnason JT. Antiviral activity of characterized extracts from Echinacea spp.(Heliantheae: Asteraceae) against herpes simplex virus (HSV-I). Planta Medica. 2002;68(09):780-3. https//doi:10.1055/s-2002-34397

60. Duke JA. The green pharmacy: New discoveries in herbal remedies for common diseases and conditions from the world's foremost authority on healing herbs. Rodale; 1997.

61. See H, Wark P. Innate immune response to viral infection of the lungs. Paediatric Respiratory Reviews. 2008;9(4):243-50. https://doi:10.1016/j.prrv.2008.04.001

62. Signer J, Jonsdottir HR, Albrich WC, Strasser M, Züst R, Ryter S, et al. In vitro antiviral activity of Echinaforce®, an Echinacea purpurea preparation, against common cold coronavirus 229E and highly pathogenic MERS-CoV and SARS-CoV. Virology. 2020. https://doi.org/10.21203/rs.2.24724/v2

63. Pleschka S, Stein M, Schoop R, Hudson JB. Anti-viral properties and mode of action of standardized Echinacea purpurea extract against highly pathogenic avian influenza virus (H5N1, H7N7) and swine-origin H1N1 (S-OIV). Virology Journal. 2009;6(1):1-9. https://doi.org/10.1186/1743-422X-6-197

64. Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food and Chemical Toxicology. 2008;46(2):409-20. https://doi.org/10.1016/j.fct.2007.09.085

65. Prasad S, Tyagi AK. Ginger and its constituents: role in prevention and treatment of gastrointestinal cancer. Gastroenterology Research and Practice. 2015; 142979. https://doi.org/10.1155/2015/142979

66. Azam F, Amer AM, Abulifa AR, Elzwawi MM. Ginger components as new leads for the design and development of novel multi-targeted anti-Alzheimer’s drugs: a computational investigation. Drug Design, Development and Therapy. 2014;8:2045-59. https://doi:10.2147/DDDT.S67778

67. Schnitzler P, Koch C, Reichling J. Susceptibility of drug-resistant clinical herpes simplex virus type 1 strains to essential oils of ginger, , hyssop, and sandalwood. Antimicrobial Agents and Chemotherapy. 2007;51(5):1859-62. https://doi.org/10.1128/AAC.00426-06

68. Ahmed I, Aslam A, Mustafa G, Masood S, Ali MA, Nawaz M. Anti-avian influenza virus H9N2 activity of aqueous extracts of Zingiber officinalis (Ginger) and Allium sativum () in chick embryos. Pak. J. Pharm. Sci. 2017;30(4):1341-4.

69. Aboubakr HA, Nauertz A, Luong NT, Agrawal S, El-Sohaimy SA, Youssef MM, et al. In vitro antiviral activity of and ginger aqueous extracts against feline calicivirus, a surrogate for human norovirus. Journal of Food Protection. 2016;79(6):1001-12. https://doi.org/10.4315/0362-028X.JFP-15-593.

70. San Chang J, Wang KC, Yeh CF, Shieh DE, Chiang LC. Fresh ginger (Zingiber officinale) has anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines. Journal of Ethnopharmacology. 2013;145(1):146-51. https://doi.org/10.1016/j.jep.2012.10.043 71. Chrubasik S, Pittler MH, Roufogalis BD. Zingiberis rhizoma: a comprehensive review on the ginger effect and efficacy profiles. Phytomedicine. 2005;12(9):684-701. https://doi:10.1016/j.phymed.2004.07.009

72. Goswami D, Kumar M, Ghosh SK, Das A. Natural Product Compounds in and Ginger are Potent SARS-CoV-2 Papain-like Protease Inhibitors. ChemRxiv. 2020. https://10.26434/chemrxiv.12071997.v1

73. Sanna AK, Al-Elyani RA, Dalia MD. Histological and ultrastructural studies on the effect of Costus Plant and Amphotericin B on male lung rats infected by Aspergillus niger. Life Science Journal-Acta Zhengzhou University Overseas Edition. 2012;9(4):5321-38.

74. El-Far AH, Shaheen HM, Alsenosy AW, El-Sayed YS, Al Jaouni SK, Mousa SA. Costus speciosus: Traditional Uses, Phytochemistry, and Therapeutic Potentials. Pharmacognosy Reviews. 2018;12(23).https://doi.org/10.4103/phrev.phrev_29_17

75. Ansari S. Ethnobotany and pharmacognosy of qust/kut (Saussurea lappa, cb clarke) with special reference of unani medicine. Pharmacognosy Reviews. 2019;13(26):71. https://doi.org:10.5530/phrev.2019.2.7

76. Al-Adhroey AH, Al-Abhar YM, Noman NM, Al-Mekhlafi HM. Ethnopharmacological survey of herbal remedies used for treating malaria in Yemen. Journal of Herbal Medicine. 2020:100332. https://doi.org/10.1016/j.hermed.2020.100332

77. Zahara K, Tabassum S, Sabir S, Arshad M, Qureshi R, Amjad MS, et al. A review of therapeutic potential of Saussurea lappa-An endangered plant from Himalaya. Asian Pacific Journal of Tropical Medicine. 2014;7:60-9. https://doi.org/10.1016/S1995-7645(14)60204-2

78. Henehan M, Montuno M, De Benedetto A. Doxycycline as an anti-inflammatory agent: updates in dermatology. Journal of the European Academy of Dermatology and Venereology. 2017;31(11):1800-8. https://doi.org/10.1111/jdv.14345

79. Barakat EM, El Wakeel LM, Hagag RS. Effects of Nigella sativa on outcome of hepatitis C in Egypt. World Journal of Gastroenterology. 2013;19(16):2529-36. https://doi.org/10.3748/wjg.v19.i16.2529

80. Okeola VO, Adaramoye OA, Nneji CM, Falade CO, Farombi EO, Ademowo OG. Antimalarial and antioxidant activities of methanolic extract of Nigella sativa seeds (black cumin) in mice infected with Plasmodium yoelli nigeriensis. Parasitology Research. 2011;108(6):1507-12. https://doi.org/10.1007/s00436-010-2204-4

81. Boskabady MH, Mohsenpoor N, Takaloo L. Antiasthmatic effect of Nigella sativa in airways of asthmatic patients. Phytomedicine. 2010;17(10):707-13. https//doi:10.1016/j.phymed.2010.01.002

82. Bamosa AO, Kaatabi H, Lebdaa FM, Elq AM, Al-Sultanb A. Effect of Nigella sativa seeds on the glycemic control of patients with type 2 diabetes mellitus. Indian J Physiol Pharmacol. 2010;54(4):344-54.

83. Matsumoto Y, Matsuura T, Aoyagi H, Matsuda M, Hmwe SS, Date T, et al. Antiviral activity of glycyrrhizin against hepatitis C virus in vitro. PloS One. 2013;8(7):e68992. https//doi:10.1371/journal.pone.0068992

84. Moisy D, Avilov SV, Jacob Y, Laoide BM, Ge X, Baudin F, et al. HMGB1 protein binds to influenza virus nucleoprotein and promotes viral replication. Journal of Virology. 2012;86(17):9122-33. https//doi.10.1128/JVI.00789-12

85. Sasaki H, Takei M, Kobayashi M, Pollard RB, Suzuki F. Effect of glycyrrhizin, an active component of licorice roots, on HIV replication in cultures of peripheral blood mononuclear cells from HIV-seropositive patients. Pathobiology. 2002;70(4):229-36. https://doi.org/10.1159/000069334

86. Michaelis M, Geiler J, Naczk P, Sithisarn P, Ogbomo H, Altenbrandt B, et al. Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages. Medical Microbiology and Immunology. 2010;199(4):291-7. https://doi.org/10.1007/s00430-010-0155-0

87. Hardy ME, Hendricks JM, Paulson JM, Faunce NR. 18 β-glycyrrhetinic acid inhibits rotavirus replication in culture. Virology Journal. 2012;9(1):1-7. https://doi.org/10.1186/1743-422X-9-96

88. Soufy H, Yassein S, Ahmed AR, Khodier MH, Kutkat MA, Nasr SM, et al. Antiviral and immune stimulant activities of glycyrrhizin against duck hepatitis virus. African Journal of Traditional, Complementary and Alternative Medicines. 2012;9(3):389-95. http://dx.doi.org/10.4314/ajtcam.v9i3.14 89. Sen S, Roy M, Chakraborti AS. Ameliorative effects of glycyrrhizin on streptozotocin-induced diabetes in rats. Journal of Pharmacy and Pharmacology. 2011;63(2):287-96. https://doi.org/10.1111/j.2042-7158.2010.01217.x

90. Rauš K, Pleschka S, Klein P, Schoop R, Fisher P. Effect of an Echinacea-based hot drink versus oseltamivir in influenza treatment: a randomized, double-blind, double-dummy, multicenter, noninferiority clinical trial. Current Therapeutic Research. 2015;77:66-72. https://doi.org/10.1016/j.curtheres.2015.04.001

91. Jawad M, Schoop R, Suter A, Klein P, Eccles R. Safety and efficacy profile of Echinacea purpurea to prevent common cold episodes: a randomized, double-blind, placebo-controlled trial. Evidence-Based Complementary and Alternative Medicine. 2012; 841315. https://doi.org/10.1155/2012/841315

92. Rininger JA, Kickner S, Chigurupati P, McLean A, Franck Z. Immunopharmacological activity of Echinacea preparations following simulated digestion on murine macrophages and human peripheral blood mononuclear cells. Journal of Leukocyte Biology. 2000;68(4):503-10. https://doi.org/10.1189/jlb.68.4.503

93. Cundell DR, Matrone MA, Ratajczak P, Pierce Jr JD. The effect of aerial parts of Echinacea on the circulating white cell levels and selected immune functions of the aging male Sprague– Dawley rat. International Immunopharmacology. 2003;3(7):1041-8. https://doi:10.1016/S1567- 5769(03)00114-0

94. Currier NL, Miller SC. Echinacea purpurea and melatonin augment natural-killer cells in leukemic mice and prolong life span. The Journal of Alternative and Complementary Medicine. 2001;7(3):241-51. https://doi.org/10.1089/107555301300328115

95. Fuhrman B, Rosenblat M, Hayek T, Coleman R, Aviram M. Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice. The Journal of Nutrition. 2000;130(5):1124-31. https://doi.org/10.1093/jn/130.5.1124

96. Jiang Y, Turgeon DK, Wright BD, Sidahmed E, Ruffin MT, Brenner DE, et al. Effect of ginger root on cyclooxygenase-1 and 15-hydroxyprostaglandin dehydrogenase expression in colonic mucosa of humans at normal and increased risk of colorectal cancer. European Journal of Cancer Prevention. 2013;22(5):455. https://doi:10.1097/CEJ.0b013e32835c829b 97. Shidfar F, Rajab A, Rahideh T, Khandouzi N, Hosseini S, Shidfar S. The effect of ginger (Zingiber officinale) on glycemic markers in patients with type 2 diabetes. Journal of Complementary and Integrative Medicine. 2015;12(2):165-70. https://doi.org/10.1515/jcim- 2014-0021

98. Jittiwat J, Wattanathorn J. Ginger pharmacopuncture improves cognitive impairment and oxidative stress following cerebral ischemia. Journal of Acupuncture and Meridian Studies. 2012;5(6):295-300. https://doi.org/10.1016/j.jams.2012.09.003

99. Rao KS, Babu GV, Ramnareddy YV. Acylated flavone from the roots of Saussurea lappa and their antifungal activity. Molecules. 2007;12(3):328-44. https://doi.org/10.3390/12030328

100. Chandur U, Shashidhar S, Chandrasekar SB, Bhanumathy M, Midhun T. Phytochemical evaluation and anti-arthritic activity of root of Saussurea lappa. Pharmacologia. 2011;2:265-9. https://doi:10.5567/pharmacologia.2011.265.267

101. Ansari S, Siddiqui MA, Malhotra S, Maaz M. Antiviral efficacy of qust (Saussurea lappa) and afsanteen (Artemisia absinthium) for chronic Hepatitis B: A prospective single-arm pilot clinical trial. Pharmacognosy Research. 2018;10(3):282. https://doi:10.4103/pr.pr_157_17

102. Hasson SS, Al-Balushi MS, Al-Busaidi J, Othman MS, Said EA, Habal O, et al. Evaluation of anti–resistant activity of Auklandia (Saussurea lappa) root against some human pathogens. Asian Pacific Journal of Tropical Biomedicine. 2013;3(7):557-62. https://doi.org/10.1016/S2221-1691(13)601136

103. Hung JY, Hsu YL, Ni WC, Tsai YM, Yang CJ, Kuo PL, et al. Oxidative and endoplasmic reticulum stress signaling are involved in dehydrocostuslactone-mediated apoptosis in human non-small cell lung cancer cells. Lung Cancer. 2010;68(3):355-65. https://doi.org/10.1016/j.lungcan.2009.07.017

104. Hsu YL, Wu LY, Kuo PL. Dehydrocostuslactone, a medicinal plant-derived sesquiterpene lactone, induces apoptosis coupled to endoplasmic reticulum stress in liver cancer cells. Journal of Pharmacology and Experimental Therapeutics. 2009;329(2):808-19. https://doi.org/10.1124/jpet.108.148395 105. Sun CM, Syu WJ, Don MJ, Lu JJ, Lee GH. Cytotoxic Sesquiterpene Lactones from the Root of Saussurea l appa. Journal of Natural Products. 2003;66(9):1175-80. https://doi.org/10.1021/np030147e

106. Hemamalini K, Vasireddy U, Nagarjun GA, Harinath K, Vamshi G, Vishnu E, et al. Anti- diarrhoeal activity of extracts Anogessius accuminata. Int J Pharm Res Dev. 2011;3(6):55- 7.

Figure Legends

Figure 1. Medicinal plants: Black cumin (a) Flower, (b) Seeds; Licorice (c) Plant, (d) Root; Echinacea (e) Plant; Ginger (f) Plant, (g) Root; Costus (h) Plant, (i) Root.

Figure 2. Major constituents of Black cumin with chemical structures.

Figure 3. Major constituents of Licorice with chemical structures.

Figure 4. Major constituents of Echinacea with chemical structures.

Figure 5. Major constituents of Ginger with chemical structures.

Figure 6. Major constituents of Costus with chemical structures.

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

FIGURE 1

Thymoquinone Thymohydroquinone Nigellidine

α-hederin Rutin Thymol

p-cymene

FIGURE 2

Glycyrrhizin Lycorine Glycyrrhetinic acid

Licoagroaurone Licochalcone A Asparagin

FIGURE 3

Undeca-2Z,4E- Dodeca-2E,4Z- Dodeca-2E-ene- Echinacoside diene- 8,10-diynoic diene-8,10 -diynoic 8,10-diynoic acid- (Phenylpropanoids) acid-isobutylamide acid-isobutylamide isobutylamide (Alkamides) (Alkamides) (Alkamides)

Verbascoside Humulene Xyloglucan (Phenylpropanoids) (volatile oils) (Polysaccharides)

Arabinogalactan Caftaric acid (Polysaccharides)

FIGURE 4

Gingerols Shogaols Curcumene

Zingiberene Camphene Bisabolene

FIGURE 5

Costunolide Dehydrocostus lactone Cynaropicrin

Betulinic acid Mokkolactone

FIGURE 6

Table legend

Table 1. General details and experimental studies conducted with Black cumin, Licorice, Echinacea, Ginger, and Costus.

Table 1

Common Scientific Traditional Traditional uses Parts used Observed effects Ref. name name names Black Nigella sativa Kalonji Hypertension, Seeds -Immunotherapeutic effects against Newcastle [39] cumin L. (Urdu), fever, flu, disease virus kalijira dyspepsia, -Reduce the pathogenic effect of avian [36] (Bengali), rheumatism, influenza in turkeys habat-ul- diabetes, asthma, -Significantly improved HCV viral load in [79] barakah cough, bronchitis, human subjects (Arab). headache, -Considerably reduced the risk of lung damage [42] paralyses, in rats influenza, skin -Antimalarial activity in Swiss albino mice [80] eruptions, -Protective effects against rheumatoid arthritis [32] vomiting, etc. -Reduced elevated blood glucose level in [33] diabetic rat model -Significant alleviation of symptoms and [81] occurrence of asthma in human patients -Reductions in fasting blood , positive [82] effects on insulin resistant syndrome -Positive effects on investigational lung injury [41] and inhibited inflammatory pulmonary responses in Wister rats -Effective antiviral against murine [35] cytomegalovirus Licorice Glycyrrhiza Yashtimadhu, Cough, cold, Roots -Inhibits HCV (in-vitro) [83] glabra Mulethi strength and (fresh and -Inhibits influenza virus (in-vitro) [84] (), endurance, chest dried), -Inhibit HIV (in-vitro) [85] Sweet root, and lung diseases, , -Inhibits H5N1 influenza (in-vitro) [86] Sweet wood bronchial asthma, . -Effective against rotavirus (in-vitro) [87] (English), arthritis, swelling, -Effective against duck hepatitis virus (in-vivo) [88] Shirin bayan heart diseases, etc. -Anti-diabetic effects in rats [89] (Persian), -Hypoglycemic effects in mice [56] Balik -Inhibits the replication of SARS-coronavirus [52] (Kurdis). (SARS-CoV) in-vitro

Echinacea Echinacea American Snakebites, septic Leaves, -Echinaforce (E. purpurea based hotdrink) [90] spp. cone flower, wounds, sore roots, improves influenza in patients purple cone throats, blood whole plant -Prevention of common cold episodes in [91] flower, black purifiers, flu and can also be human subjects sampson, colds, skin ulcers used -Inhibits the dissemination and replication of [63] snakeroot, and burns, including influenza virus (in vitro) scurvy root, toothaches, etc. the -Immunopharmacological activity (in vitro) [92] Indian head, rhizome -Antiviral activity against HSV-1 (in vitro) [59]

comb flower, -Improve the function of immune system in [93]

niggerhead, male Sprague–Dawley rats

black susans, -Increased life span in leukemic mice [94]

hedgehog.

Ginger Zingiber Adrak (India), Spice, nausea, Root, -Inhibit atherosclerosis development in mice [95] officinale Ada vomiting, cold, rhizome. -Reduction of basal COX-1 protein in high risk [96] (Bangladesh), joint aches, colorectal cancer patients Sheng gian headache, -Improvement of glycemic indices in type 2 [97] (Chinese), digestion, ear diabetic patients Singabera infections, etc -Improves cerebral ischemia in male wistar [98] (). rats -Proved antiviral effect on food borne viral [69] contamination (FCV) (in vitro) -Effective against HSV-1 (in-vitro) [67] -Possible potential against avian influenza [68] -Effectiveness against HRSV [70] Costus Saussurea Kuth (), Cholera, Tuber, -Showed antifungal activity in-vitro [99] costus, Kut (Gujrati), Pneumonia, cough root, leaves -Effective anti-arthritic function observed in [100] Syn: Kur (Bengali), with cold, arthritis, rats Saussurea Postkhai stomachache, -Antiviral effects against chronic hepatitis B in [101] lappa (Kashmiri), dysmenorrhea, human subjects Sepuddy scanty urination, -Effective against Klebsiella pneumonia (in- [102] (), piles, etc vitro) Kot -Anti-cancer elements for treating non-small [103] (Punjabi), cell lung cancer (in vitro) Kushta -Anti-cancer potential for liver cancer (in- [104] (Sanskrit), vitro) Kostum -Potential cytotoxic activity in human cells [105] (Tamil), -Anti-diarrheal effects in Wistar rats [106] Kustam (Telgu), Kushta (Marathi), Koshta ().