INTRODUCTION
Coronaviruses belong to the family of Coronaviridae, which include viruses that commonly cause respiratory tract diseases ranging from the common cold to severe conditions. It has Middle East respiratory syndrome-coronavirus (MERS-CoV) or severe acute respiratory syndrome-coronavirus (SARS- CoV) [1]. A new strain of the corona virus was identified in the city of China, named Wuhan, at the end of 2019 [2] and was initially named the 2019-novel Corona Virus (2019-nCoV) [3]. The International Committee on Taxonomy of Viruses (ICTV) named this novel coronavirus as “severe acute respiratory syndrome coronavirus 2” (SARS-CoV2) on February 11, 2020, by picking its name from the causative virus of the 2003 outbreak of severe acute respiratory syndrome (SARS). It is genetically similar to the SARS virus [4]. After that, the World Health Organizat-
ion (WHO) officially declared the disease name caused by this virus as COVID-19 (coronavirus disease-2019) [5]. After identifying the first case of the novel coronavirus in late December 2019 in China, it rapidly spread to other countries such as Germany, the USA, France, Iran, Spain, Italy, India, and now spread worldwide [6]. COVID-19 has over 1 million cases across the globe, almost 50,000 deaths are caused, and 203 countries are affected by this novel coronavirus decalred by WHO. Emergency Committee of WHO declared the SARS-CoV-2 a global pandemic on March 11, 2020 [7].
The period from exposure of the virus to the appearance of symptoms ranges from 2 to 14 days, but the average incubation period is 5 days [3]. Initial symptoms of COVID-19 are commonly non-specific such as dry cough, fever, and fatigue, etc. It may involve multiple systems such as the respiratory system causing sore throat, shortness of breath, cough, chest pain, hemoptysis and rhinorrhea, musculoskeletal causing muscle ache, gastrointestinal causing nausea, vomiting, diarrhea, and neurologic causing confusion and headache [8]. In severe cases, COVID-19 causes multiple organ failure and lead to death [9].
Currently, there is no specific vaccine or treatment available for COVID-19 [10]. Some studies have investigated anti-viral drugs, including protease inhibitors such as Ritonavir/Lopinavir, neuraminidase inhibitors, nucleoside analogs, Lamivudine, Tenofovir Disoproxil, Umifenovir, and Remdesivir for the treatment of patients of COVID-19 [11]. The results of these studies for therapeutic use are clinically not approved for the treatment of infected patients of COVID-19 [12]. Supportive therapies and preventive measures are implemented to avoid further complications of COVID-19 and prevent organ damage [13].
Symptomatic Comparison of SARS-CoV, MERS-CoV, and COVID-19
For the last two decades, the world has suffered from a few of the most devastating outbreaks of viral diseases. It includes the epidemics of coronaviruses like SARS-CoV that emerged in Guangdong, China, MERS-CoV emergence in Saudi Arabia, and newly emerged SARS-CoV-2 in Wuhan, China causing several causalities. HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1 are among the other viruses belonging to the same family causing outbreaks in different regions [14, 15]. The viruses are closely related to each other as several studies reported the sequence homology of SARS-CoV-2 with other viruses belonging to β-coronaviridae. The studies conducted by Wu et al. [16] and Zhou et al. [8] in 2020 reported the sequence homology of 79.5% between SARS-CoV-2 and SARS-CoV. However, Chan et al. (2020) reported the sequence homology of 89% and 82% with bat SARS-like CoVZXC21 and human SARS-CoV [17]. The previous epidemic of SARS-CoV and MERS-CoV reported being zoonotically originated from bats and transmitted to humans via intermediate hosts of civet cats and camel, respectively. For SARS-CoV-2, bats were considered as native hosts as the virus has 96% similarity with SARS-like coronaviruses, including bat- SL-CoVZX21 and bat-SL-CoVZX45 [18, 19]. The potential route of transmission from person to person is through inhalation of infectious aerosol. The potential of COVID-19 spreading is higher compared to other phylogenetically related viruses. This may be due to mutations like longer 8b segments, shorter 3b segments, absence of 8a, the difference in open reading frame 8 (ORF8), and open reading frame 10 (ORF10), and the difference in nsp2 and nsp3 proteins [20-23]. Besides these mutations, the changes in the nsp2 protein of SARS-CoV-2 lead to an increased potential to become more contagious than other related viruses [24].
After incubation of about 5-7 days, SARS-CoV leads to the onset of the disease typically associated with symptoms like fever, headache, myalgia, malaise, dyspnea, and dry cough, in which 25% of the patients develop watery diarrhea. In some severe cases, the disease progresses to severe pneumonia and respiratory distress [25-28]. A similar disease goes in the MERS-CoV infected individuals who may develop an asymptomatic or mild infection, including fever, chills, myalgia, and dyspnea, followed by a nonproductive cough. Abdominal pain, diarrhea, and vomiting are reported in 25% of infected individuals. The severity of the progression of the disease may result in acute renal failure along with respiratory distress and pneumonia [29, 30]. The case fatality rate in MERS-CoV infected individuals is 34.4% compared to SARS-CoV with a fatality rate of 9.6%, and SARS-CoV-2, with a mortality rate of >3.4% [31-33].
The mean incubation period of SARS-CoV-2 is 5.2 days and 14 days of median duration from onset of symptom to death, and the mortality rate is alarming in the patients with age more than 70 years as they have a median duration of 11.5 days from the initial onset of the symptoms to the death [34]. Human coronaviruses are mostly associated with the upper respiratory tract causing mild to moderate illness. Still, in some moderate to severe cases, the lower respiratory tract can be infected and result in severe complications [35]. The COVID-19 infection ranges from asymptomatic to mild and severe infection as similar to SARS-CoV and MERS-CoV. The symptoms include fever, myalgia, dry cough, fatigue, chest pain, anorexia, nausea, vomiting, dyspnea, arrhythmia, and diarrhea. Complications related to coronaviruses infection involve acute respiratory distress syndrome, multiple organ failure, various degrees of liver infection [36], testicular tissue damage [37], kidney infections, RNAemia, cardiac injury, and metabolic acidosis [38]. Moreover, the infected individual can be observed with ground-glass opacities and peripheral consolidation in the lungs. The bilateral finding seems to be higher in SARS-CoV-2 infected patients [39].
The symptomatic comparison of SARS-CoV, MERS-CoV, and SARS-CoV-2 is shown in Table 1. In COVID-19 disease, the viral load is higher compared to SARS-CoV and MERS-CoV infections, even in asymptomatic or mild infections [40]. The laboratory findings of these coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) are also similar, indicating the lymphopenia, thrombocytopenia, elevated LDH level, elevated cytokines level (IL-1, IL-2, IL-6, and IL-10 INFγ), and elevated C-reactive protein [30, 41-43].
| Disease | Emergence | Transmission | Incubation Period | Symptoms | Complications | Recovery Period |
Treatment | ||
|---|---|---|---|---|---|---|---|---|---|
| SARS-CoV | 2002, China | Human to Human via respiratory droplets, Inhalation of aerosol, Nosocomial transmission, Zoonotic transmission |
2-7 days post-exposure | Fever, dry cough, breathing difficulties, myalgia, diarrhea, and loss of appetite | Acute respiratory distress syndrome (ADRS), Severe pneumonia |
5-6 weeks | Oxygen therapy, Anti-viral drugs, Corticosteroids to reduce inflammation in the lungs |
||
| MERS-CoV | 2012, Saudi Arabia | Human to Human via respiratory droplets, Inhalation of aerosol, Nosocomial transmission, Zoonotic transmission |
5-6 days post-exposure | Fever, dry cough, nasal congestion, sore throat, chills, nausea, and vomiting | Acute renal failure, Pneumonia, Multiple organ failure ARDS, |
6-8 weeks | No proper treatment, Only symptoms are treated |
||
| SARS-CoV-2 | 2019, China | Human to Human via respiratory droplets, Inhalation of aerosol, Nosocomial transmission, Zoonotic transmission, Oral-fecal transmission |
2-14 days post-exposure | Fever, sore throat, myalgia, nasal congestion, shortness of breath, vomiting, diarrhea, and dry cough | Severe pneumonia, Septic shock, Pulmonary edema, ARDS and organ failure |
2-8 weeks | No vaccine and No treatment, Symptoms are treated, Breathing ventilator for oxygen therapy |
||
Medicinal Plants against Coronaviruses
Medicinal plants have potential therapeutic effects for different infectious diseases and have long been used to treat the diseases in the past. Medicinal plants can be used as a whole, as an extract of the plant or phytochemicals isolated from plants [44] and endophytes isolated to extract secondary metabolites that have therapeutic effects [45]. More than 60,000 plant species have been used for medicinal purposes worldwide, in which 3,000 species are traded internationally, and 28,000 species are well documented, with one-third are known to be cultivated commercially [46]. There is a wide range of medicinal plants and treatment applications based on the plants that have been practiced in the Indian subcontinent and China for a long time. Traditional medicinal practices in India use medicinal plants that directly include Unani, Homeopathy, Ayurveda, Naturopathy, and Siddha. AYUSH system of medicine focuses on the prophylactic treatment, dietary management, and simple traditional remedies for the treatment of symptoms by using medicinal plants [47]
Ni et al. [48] reported the case study for the treatment of COVID-19 using TCM called Shuanghuanglian. Shuanghuanglian (SHL) is a TCM that contains the extract from three medicinal plants, namely Forsythia, Scutellaria baicalensis, and Honeysuckle. It is usually used to treat the common cold with fever, cough, and sore throat. The case study reported the effectiveness of this medicine with no adverse side effects. Thus a clinical trial is needed to be used in the future for treating the COVID-19 patients.
Andrographis paniculata is a medicinal plant that has shown the therapeutic ability for viral respiratory infections in Ayurveda and other natural remedies-based treatment systems [49]. It was reported that Andrographis paniculata suppressed the increase in caspase-1, interleukin-1β, and NOD-like receptor protein involved in SARS-CoV's pathogenesis and more likely of SARS-CoV-2 infection [50]. The plants like Allium sativum [51] and Glycyrrhiza glabra [52] are known to target SARS-CoV replication; thus, they can be promising candidates against the COVID-19 causative agent SARS-CoV-2. Similarly, the herbal medicinal plant is called Clerodendrum inerme (L.) Gaertn has the potential to neutralize the viral infection by inactivating the virus, thus can be investigated as potential candidate for the drug that targets SARS-CoV-2 proteins translation [53]. Hyoscyamus niger, the medicinal plant, has inhibitory effects on the Ca2+ channel and has bronchodilation ability, thus targeting the Ca2+ channels of orf3a that trigger various downstream pathways after the infection of the virus [54].
Moreover, Sambucus ebulus is found to inhibit the activity of enveloped viruses and can be a potential target for treating COVID-19 individuals [55]. Some of the medicinal plants produce bioactive molecules like flavonoids that have anti-viral activities. The medicinal plants including Spinacia oleracea, Brassica oleracea, Anethum graveolens, Sauropus androgynous, Foeniculum vulgare, Allium cepa, and Oregano vulgare are reported to produce the secondary metabolite like Kaempferol and Quercetin that can be used as anti-viral agents [56, 57].
TCM system is also in practice to find its effectiveness in treating COVID-19 infections. These TCM use medicinal plants to extract the phytochemicals or secondary metabolites for the treatment of COVID-19. Some studies have reported that TCM plants can modulate T-cells to enhance the host defense system [58, 59]. Another Chinese herb, Liquorice root, contains an active compound called glycyrrhizin, which can potentially inhibit the replication of the SARS-CoV virus in clinical isolates [60]. Furthermore, the TCM extracts from Houttuynia cordata [61], a flavonoid extracted from seeds of litchi [62], beta-sitosterol extracted from the roots of Isatis indigotica [63], and Rhubarb extracts have shown the enzymatic activity against the SARS 3CLpro (3-chymotrypsin-like protease). The compound is important for replicating viral particles and can thus be a promising drug target for SARS-CoV-2 and other coronaviruses [64].
Western medicines in practice cannot effectively treat COVID-19 infected patients. The main strategy for treating the infectious individual of COVID-19 is supportive care, supplemented by a combination of anti-virals, broad-spectrum antibiotics, convalescent plasma therapy, and corticosteroids. Therefore, herbal medicines have become an important area of interest for preventing and treating COVID-19 [61].
Traditional Chinese Medicine (TCM) against Coronaviruses
TCM is a system of medical field based on principles of herbal pharmacology, theories, pathogenesis, symptoms, diagnosis, and treatment of disease. It differs from Western naturopathy and orthodox medicine. The application of TCM has evolved over millennia from knowledge gained through observation of clinical diseases and treatment. TCM has quickly expanded in recent years, and its users account for 3.2% of overall medicines [65].
There has been a long history of TCM, which played an important role in preventing and treating many epidemic diseases [66]. TCM has been used since 2003 to fight against several viral diseases such as SARS, MERS, H7N9, H1N1, and EBOV [67]. A considerable therapeutic effect was achieved by using TCM during the outbreak of SARS that occurred in 2003 [68].
Results of many clinical practices revealed that TCM plays a vital role in treating infection of COVID-19, which brings a new hope to control and prevent COVID-19 [66]. “New Coronavirus Pneumonia Diagnosis and Treatment Plan” also recommended TCM to treat symptoms caused by COVID-19 [69].
TCM Prescription for COVID 19
Many TCM have been described in the publications of medical institutions and local government [70]. The Chinese medicinal herbs used to treat COVID-19 patients mainly include Trichosanthes, Ephedra, Glycyrrhiza, Amomum, bitter almond, reed root, and gypsum. The main functions of these herbal medicines include toxicity clearance and heat removal from the lungs, improve immunity, and relieving cough [71]. The patent medicines used to treat COVID-19 patients mainly include the Suhuang Zhike capsule, Reduning injection, and Xuebijing [69].
The combined study of the Virology Institute in Wuhan, the Chinese Academy of Sciences, and Materia Medica institute in Shanghai reported that the oral liquid of Shuanghuanglian could inhibit COVID-19 [48]. Shuanghuanglian is composed of a Chinese skullcap, honeysuckle flowers, and forsythia. Previous studies reported that components such as forsythin, chlorogenic acid, and baicalin could inhibit many bacteria and viruses [72]. The mechanism of therapeutic effect might be achieved by decreasing the inflammatory response caused by bacteria and viruses in the body through these components [73]. Shuanghuanglian is effective for the treatment of cough, fever, and sore throat [74].
Based on the overall symptoms of pneumonia caused by COVID-19, TCM has suggested prescriptions that might be effective, such as qingfei touxie fuzheng recipe, sheganmahuang decoction, gancaoganjiang decoction, and qingfei paidu decoction (QPD), etc., [66]. QPD consists of Zingiberis Rhizoma Recens, Zingibere et Alumine, Asteris Radix et Rhizoma, Pinelliae Rhizoma Praepratum cum, Farfarae Flos, Scutellariae Radix, Belamcandae Rhizoma, Bupleuri Radix, Asari Radix et Rhizoma, Poria, Atractylodis Macrocephalae Rhizoma, Dioscoreae Rhizoma, Pogostemonis Herba, Ephedrae Herba, Citri Reticulatae Pericarpium, Glycyrrhizae, Aurantii Fructus Immaturus, Radix et Rhizoma Praeprata cum Melle, Polyporus, Armeniacae Semen Amarum, Alismatis Rhizoma, Cinnamomi Ramulus and Cinnamomi Ramulus. In China, QPD is promoted to be included in the general prescription plan for the diagnosis and treatment of COVID-19 [75]. The QPD effective rate to cure COVID-19 is more than 90%. This decoction is primarily specific for the treatment of lung diseases. It can act on various ribosomal proteins of COVID-19, as a result, block viral replication. It removes inflammation by regulating immune response and related pathways of cytokine action [76]. Molecular docking predicts that shionone, ergosterol, and patchouli alcohol found in the formula of QPD is highly effective against COVID-19, which can provide a molecular structure for the development of new drugs [66].
Treatment measures of COVID-19 patients revealed that early involvement of TCM plays a vital role in reducing the disease course, enhance the cure rate, delay the progression of the disease, and low the mortality rate. Moreover, TCM not only inhibits COVID-19, but it also reduces infection rate or block infection, inhibits inflammatory action, improves immune response, and promote body repairing. Furthermore, the control measures and prevention of COVID-19 show entirely the idea of “preventive treatment of disease” [77, 66].
TCM considers Qi as a fundamental constituent of the human body that maintains normal functioning. There are two types of Qi such as pathogenic Qi and healthy Qi. Pathogenic Qi is a substance that can harm body health, while healthy Qi can regulate the body's normal functioning [78].
TCM to Prevent COVID-19 Infection
The target for COVID-19 is the lungs. Therefore, TCM treatment's purpose is to protect the lungs. Yupingfeng San is a patent TCM, selected to prevent pathogenic Qi and to improve lung Qi. TCM effectively prescribes Yupingfeng San prevent pneumonia caused by the novel coronavirus, COVID-19 [79]. It is made of herbs such as 20g of Astragalus, 15g of Fangfeng, and 15g of Atractylodes. Astragalus decreases phlegm and enhances lungs Qi [78]. Fangfeng relieves pain, removes pathogenic Qi, and prevents dampness. Atractylodes improve absorption and digestion by enhancing spleen Qi. Yupingfeng San can enhance the immune response of the body [75]. These herbs are mixed and then boiled for about 15 minutes in 1000ml pure water to make a tincture of about 600ml. About 200ml of tincture is orally taken three times a day by dividing it into three doses [78].
TCM to Treat the Mild Infection
According to TCM theories, lung Qi is harmed by pathogenic Qi, due to which the lung is unable to work correctly. It results in moisture and heat in the lungs and some common symptoms of mild infection of COVID-19 such as cough, fever, sore throat, and fatigue [78]. The method is used to remove moisture and lung heat for treatment. Two types of TCM, such as Yinqiao san and Sangju yin, are prescribed for clinical treatment. These prescriptions function to relieve cough, expel phlegm, remove lung heat, and restore and regulate the normal function of the lungs [80]. The medicinal herbs used in making Yinqiao san include Bamboo leaves 6g, Nepeta 6g, licorice 3g, Chinese bellflower 6g, Mint 6g, Forsythia 15g, Honeysuckle 15g, light tempeh 5g, and Burdock 6g. Medicinal herbs in Sangju yin are Mint 6g, Mulberry leaves 15 g, Chinese bellflower 6g, Chrysanthemum 10g, Reed root 15g, Forsythia10g, Almond 9g, Licorice 3g. These herbs are mixed and then boiled for about 15 minutes in 1000ml pure water to make a tincture of about 600ml. About 200ml of tincture is orally taken three times a day by dividing it into three doses [78].
Yin Qiao San improves the immune response of the respiratory tract, and it may have anti-viral and anti-bacterial activity [81]. These two medicines can be prescribed to treat patients having a mild infection of SARS CoV-2 [78].
TCM to Treat Severe Infection
During severe cases of COVID-19, respiratory and multiple organ failures occur, resulting in death [6]. If the pathogenic Qi is powerful and patients of COVID-19 are not appropriately treated, then healthy Qi is severely destroyed due to which lungs are unable to work. As a result, a large amount of sputum is produced and causes difficulty in breathing [78]. Baihegujin tang and Maxingshigan tang are TCM that can remove pathogenic Qi, improve healthy Qi, expel sputum, and allow air to enter the lungs [82]. The medicinal herbs used in Baihegujin Tang are Beimu 6g, Chinese bellflower 6g, Licorice 3g, Xuanshen 10g, Angelica 15g, Lily 6g, Dihuang 15g, Ophiopogon 6g, White peony 6g, and Shudihuang 15g. The medicinal herbs used to prepare Maxinshigan Tang include Almond 10g, Ephedra 15g, Licorice 9g, and Plaster 20g. These herbs are mixed and then boiled for about 15 minutes in 1000ml pure water to make a tincture of about 600ml. About 200ml of tincture is orally taken three times a day by dividing it into three doses [78].
Baihegujin tang is mainly used to improve lung Qi. Maxinshigan tang removes phlegm and cures lung fever. The two prescriptions should be taken together in case of severe infection to remove pathogenic Qi and enhance the healthy Qi [82].
Wild Plants against COVID-19
There are about 60,000 species of plants used for medicinal applications all across the globe. The use of approximately 28,000 is well-documented [46]. Wild plants have been used for a long time in medicine to support health care. Medicines based on plants may have no or minor side effects and toxicity. Many wild plants are well-known for their anti-viral activities and are used in herbal treatment [83]. The most important medicinal plants are Ocimum tenuiflorum, Ocimum sanctum, Allium sativum, Allium cepa, Glycyrrhiza glabra, Curcuma longa, Daucus maritimus, Cinnamomum verum, and Piper nigrum, etc. Using these plants' aqueous extract and honey and lemon juice is effective for the treatment of common cold and cough [84-93].
With the current outbreak of COVID-19, the use of wild plants in the medicinal formulation of the different medical systems such as Ayurveda, Unani, and TCM has dramatically increased [94]. It is estimated that 30% of the industrial production of TCM is obtained from sources of wild plants [95]. Over 125 species of wild plants are used in the formulation of Chinese medicines. A wild plant such as Glycyrrhiza spp. (Liquorice) used in more than 11 Chinese medicine formulations. Some wild species are used in more than five medicine formulations: Pogostemon cablin, Forsythia suspensa, Atractylodes macroce phala, Armeniaca spp., Ephedra spp., cutellaria baicalensis, Magnolia officinalis, and Cibotium barometz, etc., [94].
The Licorice root (Glycyrrhiza glabra) has an efficient anti-viral activity [96]. This is a native plant of Europe and Asia and is known as weed. This plant possesses anti-viral activity against certain viruses such as HIV-1, respiratory syncytial virus, SARS coronavirus, herpes viruses, cytomegalovirus, hepatitis viruses, varicella-zoster, HIV, Influenza A virus, H5N1, H1N1, and rotavirus, etc., [97-99]. More than 20 triterpenoids and 300 flavonoids are found in this plant which possesses anti-viral activity [96]. This plant is used in Unani, Homeopathy, and Ayurveda medicines to control COVID-19 [100]. Liquorice root is also an essential ingredient in TCM. Its aqueous extract is mainly recommended to relieve symptoms of COVID-19 such as cough, reduce body temperature, improve pulmonary infiltration absorption, and reduce corticosteroids dosage and breathing difficulties [94].
The use of medicinal herbs to treat COVID-19 infection is the same for their help to treat SARS disease, the outbreak of which happened in 2002/2003 [101]. Some of the species of wild plants most commonly used for the treatment of SARS include Panax quinquenfolius, Angelica sinensis, Schisandra chinensis, Scutellaria baicalensis, Atractylodes macrocephala, and Glycyrrhiza uralensis [94].
AYUSH issues a statement, with the help of the ministry of India, “Ayurveda's immunity-boosting measures for self-care during COVID 19 crisis”, which recommended daily use of the formula of Chyavanprash containing a large number of ingredients of the wild plant [94]. Anastasiya Timoshyna, co-chairperson of a specialist group of the International Union for Conservation of Nature (IUCN) Medicinal Plant said, “Dependence of Mankind's on wild species of plants for well-being and necessary health care has never been more noticeable than the current pandemic of COVID-19” [102].
Many plant species used in medicines recommended for the treatment of COVID-19 are likely to be obtained from a wild source. The uses of these plant species provide remedies for the outbreak of COVID-19 and highlight the importance of herbal medicines, especially those from wild sources, to support health [94].
Indian Subcontinents Plants against COVID-19
Plants have been used for thousands of years in traditional systems of medicines [103, 104]. India has various agro-climatic zones and is abundant with flora of medicinal plants that have been used in the Indian medicine system for centuries to treat human diseases. India is familiar with its ethnomedicine and the use of traditional medicines [105]. The information of medicinal plants has been included in various traditional systems of medicines such as Ayurveda, Siddha, Unani, and Homeopathy, etc. India reported that traditional healers use 2500 species, and 100 plant species serve as regular medicine sources [106].
In various parts of India, there has been an increasing interest in the study and use of medicinal plants to treat different diseases, including viral diseases, during the last few decades. The extract of Indian medicinal plants such as Swertia chirata has potent anti-viral activity against the Herpes simplex virus [107]. The leaf extract of the mangrove plant of India, such as Avicennia marina has anti-viral activity against hepatitis viruses and HIV [108].
India is a center of the traditional system of alternative medicines. Therefore, it is obvious to find the solution from Indian medicinal plants to fight against COVID-19, among the sources. The following are Indian medicinal plants that have the potential to be used safely as part of therapeutic formulation for the prevention and management of COVID-19 [44].
Ashwagandha (Withania somnifera)
Ashwagandha (Withania somnifera) is a traditional Indian medicinal plant that has been used for more than 3,000 years due to its medicinal values [109]. The bioactive compounds found in this plant can prevent and treat several diseases such as impotence, arthritis, cancer, anxiety, amnesia, cardiovascular and neurodegenerative diseases, and many others [110]. The natural phytochemicals found in Ashwagandha might have potent activity against COVID-19. Receptor binding domain (RBD) found in the spike protein of COVID-19 engages the Angiotensin-converting enzyme 2 (ACE2) receptor of the host cell. Withanone, a phytochemical compound in W. somnifera, docks very well with the RBD-ACE2 complex binding surface and interferes with the binding of viral RBD to the host cell ACE2 receptor. Withanone decreases electrostatic binding interaction between ACE2 receptor and viral RBD; as a result, entry of COVID-19 is weakened or even blocked. In this way, Ashwagandha cures the infectivity of COVID-19 [111].
Harsinghar (Nyctanthes Arbortristis)
Harsinghar is one of the critical traditional plants in India, which has many medicinal values. The scientific name of Harsinghar is Nyctanthes arbor-tristis, and it belongs to the Oleaceae family. Commonly, it is also known as Night jasmine and Parijat [112]. It is an important source of many useful medicines against different diseases. It contains various phytochemicals that have been investigated to include significant pharmacological activities [113]. Phytochemicals of Harsinghar such as glycoside, flavonoid, oleanolic acid, tannic acid, benzoic acid, glucose, friedelin, lupeol, carotene, and essential oils have been reported. They all have anti-bacterial, anti-viral, anti-fungal, anti-malarial, anti-leishmaniasis, anti-inflammatory, anti-oxidant, anti-histaminic, hepato-protective, and antipyretic activities [114]. The n-butanol fractions, ethanolic extract as well as two pure compounds such as arbortristoside A and C extracted from Harsingar have high anti-viral activity against Semliki Forest Virus (SFV) and Encephalo Myocarditis Virus (EMCV) [115]. Lupeol(C25H26O4), astragalin (C21H20O11), and nictoflorin (C27H30O15) compound extracted from the Harsingar have been reported to possess activity against the main protease of COVID-19 and inhibit its replication. The anti-viral activity of Harsingar extract was found to be greater than hydroxychloroquine and an anti-malarial compound already studied to inhibit the main protease of COVID-19 [116].
Giloy (Tinospora Cordifolia)
Giloy (Tinospora cordifolia) is an Indian plant that is well known for possessing several medicinal properties. Giloy is an excellent stimulant of the immune system and has many antimicrobial properties [117]. The bioactive components found in Giloy have excellent immunomodulatory effects. This plant contains many phytochemicals such as choline, berberine, jatrorhizine, palmatine, palmarin, tinocordifolioside, tinosporol, tinosporin, tinosporic acid, tinosporon, tinosporon, tinosporal, tinosporic acid, tembeterine, tinosporaside, diterpenoid furano lactone, heptacosanol, chasmanthin, and columbin, etc. which have medicinal properties [118, 119]. It is widely used to treat various diseases such as asthma, urine disorder, rheumatoid arthritis, jaundice, dyspepsia, diabetes, excess mucus, cardiac debility, gout, inflammations, pyrexia, and spleenopathy, etc., [120]. Diterpenoid and tinosporin have been used against certain viruses such as the herpes simplex virus (HSV), all kinds of retroviruses, and many other viruses [121].
The natural phytochemicals found in Giloy can suppress the infectivity of COVID-19. In-silico models reported that tinocodiside, one of the Giloy phytochemicals, docks very efficiently with the RBD-ACE2 complex binding surface and interferes with the binding of viral RBD to the host cell ACE2 receptor. Giloy extract rich in tinocordiside is one of the options available to control the entry of COVID-19. The innate immunity could also be enhanced against infection of COVID-19 due to the immunomodulatory effects of Giloy [120].
Neem (Azadirachta indica)
Neem (Azadirachta indica) is a tree that belongs to the family Meliaceae and genus Azadirachta [122]. It is a native plant of the Indian Sub-continent and is also known as Indian lilac. Neem seeds, flowers, and leaves are well known for centuries in India due to their medicinal properties [123]. In Sanskrit, Neem is known as Sarva Roga Nivarini, which means Universal healer that cures all diseases [124].
More than 10 compounds are present in different parts of the Neem, such as its roots, bark, trunk, leaves, seeds, and flowers. The compounds found in Neem leaves include Nimocinol, Meliacinanhydride, Nimbin, Nimbandiol, Zafaral, Nimbolide, Nimocinol, Desacetylnimbin, Nimbinene, and Isomeldenin have been studied [125]. The extract of Neem leaves has antiseptic, anti-bacterial, anti-viral, and anti-fungal properties [126]. Neem leaves have been reported to be effective against several viral diseases such as chickenpox, smallpox, HIV, and Herpes virus, etc., [127, 128].
Ingestion of Crude Neem leaves or extracted powder of Neem leaves prevent replication of COVID-19 by targeting its main protease such as Mpro, which inhibits the virus. It also acts as an inhibitor of the host ACE-2 receptor for COVID-19. Furthermore, other compounds found in Neem leaves such as zinc, quercetin, vitamin A, B1, B2, B6, C, and E can also enhance immunity [124].
Tulsi (Ocimum sanctum)
In the Indian medicinal system, Tulsi (Ocimum sanctum) is known as “The Queen of Herbs” and “Mother Medicine of Nature” due to its spiritual and medicinal properties. Tulsi is rich in phytochemicals, which have high medicinal properties [129]. Hundreds of scientific researches on the Tulsi plant have shown its medicinal properties in-vitro human and animal experiments. Such studies reported a unique combination of Tulsi activities including Antimicrobial (such as anti-viral, anti-bacterial, anti-fungal, anti-malarial, antiprotozoal, and antihelmintic), anti-oxidant, anti-diabetic, antipyretic, anti-diarrheal, anti-inflammatory, anti-asthmatic, anti-allergic, anti-tussive, adaptogenic, cardio-protective, neuroprotective, hepato-protective, anti-stress and immunomodulatory actions [130].
Tulsi extracts are a good source of flavonoids and flavones. Based on the 2-phenyl-1-benzopyran-4-one backbone, flavones make the main class in the family of flavonoids. Naturally occurring flavones include 6-hydroxyflavone, scutellarein, luteolin, tangeritin, chrysin, wogonin, baicalein, and apigenin. Since the 1990s, flavones are known to have anti-viral properties when apigenin was used along with acyclovir against HSV-1 and HSV-2, which resulted in increased anti-viral effects [131].
Natural flavonoids also have anti-viral properties. Scutellarein and myricetin strongly inhibit the helicase enzyme of SARS-CoV by inhibiting the function of the ATPase enzyme. In-silico study using phytochemicals of Tulsi, RNA replicase of SARS-CoV was targeted. It showed that only a few phytochemicals found in Tulsi affect catalytic cleft of RNA replicase. Scutellarein, one of Tulsi phytochemicals, binds to RNA replicase with docking energy of -8.3 kcal/mol and disturbs Motif B used for polymerization. It is postulated that coronavirus replication could be inhibited by the phytochemicals of Tulsi based on these observations, to further control its spread and growth [120].
AYUSH Recommended Medicinal Plants or Extracts against COVID-19
AYUSH is an Indian medicine system implemented by the government for the treatment of various diseases. This system has five different approaches for treatment, such as Ayurveda, Yoga, Unani, Sidha, and Homeopathy, which being combined in a single term of AYUSH [132]. Among these treatment approaches, Ayurveda, Homeopathy, and Yoga are accepted worldwide and are known as an ancient system of medicine. This traditional system of medicine focuses on disease prevention through prophylactic interventions, lifestyle modification, dietary management to boost the immune system, and simple remedies for treatment based on the appearance of symptoms [133]. Based on the fact that no treatment is available against the COVID-19 in any medical system, the Indian government implemented the AYUSH system to improve respiratory health by boosting the immune system of citizens [134].
Fig. (1))
AYUSH recommended plants against COVID-19.
Ayurveda Medicines
Ayurveda is a traditional medicinal system of the Indian subcontinent which is increasingly gaining importance [135]. India is a rich source of medicinal plants due to various agro-climatic zones [136]. Ayurvedic medicines have a long history since the Vedic period preceding back to over 2000 years in the Indian subcontinent [137]. Ayurvedic medicines are used for a very long time to treat several viral diseases [138]. Conventional medicines are now replacing with ayurvedic medicines for many reasons, such as low cost, easy availability, and no or fewer side effects [139].
Ayurvedic medicines work to control infection of COVID-19. The historical background suggests that if Ayurveda medicinal system is scientifically studied, it may provide an alternate solution to control and prevent COVID-19 infection [140].
Ayurveda suggested several medicines in the current pandemic of COVID-19 to boost immunity and relieve symptoms of COVID-19 [141]. These include turmeric milk, Chyavanprash, and herbal tea. Herbal tea is made from black pepper, basil, dry ginger, cinnamon, and raisin. Black peppers are traditionally used to treat the flu and cold. Holy basil benefits to treat respiratory complications including asthma, allergic bronchitis, eosinophilic lung disease, cough, and liquify phlegm [142]. Ginger target cold-causing viruses due to the presence of chemicals known as sesquiterpenes. Cinnamon contains trans-cinnamaldehyde and cinnamaldehyde, which have anti-oxidant properties. Raisins are rich in energy and a good source of minerals, vitamins, and fibers, due to which they have several medicinal values. Due to these ingredients in Herbal tea, it is recommended to enhance immunity [133].
In Ayurveda, five ways are prescribed to consume medicinal plants and herbs by Panchvidh Kashyapam in Charak Samhita [143]. These include: i) Kwath (decoction), ii) Swaras (juicing), iii) Phant (an herb-infused concoction), iv) Kalka (in paste form), v) Hima (concoction induced by herb) [144]. A valuable Ayurvedic method to enrich active agents present in pharmacological herbs includes Kadha (decoction) preparation. Kadha is made of less juice or dry ingredients such as herbs and spices. During crises of COVID 19, Kadha is recommended by AYUSH to boost immunity and reduce inflammation (Fig. 1) [145]. Herbs commonly used in Kadha preparation include Haldi (Curcuma longa), Black pepper (Piper nigrum), Giloy (Tinospora cordiofolia), Ginger (Zingiber officinale), Ashwagandha (Withania somnifera), Cardamom (Elettaria cardamomum), Clove (Syzygium aromaticum), Tulsi (Ocimum sanctum) and lemon (Citrus limon) [146]. The active phytochemicals found in various herbs used in Kadha preparation were docked with various proteins of COVID-19 (include viral NSP polymerase, capsid, proteases, spike proteins), pro-inflammatory mediators (IRAK, PLA2, COX2, and NIK proteins) as well as host cell proteases and receptors (such as furin and Human receptor ACE2). The study predicted that phytochemicals possess a significant affinity for binding towards functional regions of host cell receptors, various inflammatory mediators, and viral proteins. Regular use of ayurvedic Kadha for consumption improves the host's immunity, helps prevent COVID-19 pathogenicity and infection, and reduces the severity of disease in infected individuals [144].
Ayurveda medicine system suggests a tablet known as Swasari Ras to treat respiratory tract disorders such as asthma, bronchitis, cough, excess mucous formation, and rhinitis. Swasari Ras is an herbal formulation that is used in India [147]. Swasari Ras consists of Lavanga, Akarkara, Pippali, Maricha, Ardraka, Rudanti, Karkatashringi, Dalchini, and Mulethi. Swasari Ras contains various metabolites of bioactive plants that produce anti-inflammatory actions in respiratory disorders. Swasari Ras also has mineral components of calcium such as Abhraka bhasma, Mukta shukti bhasma, Godanti bhasma, and Kapardak bhasma. These minerals are traditionally known for treating inflammation, cough, asthma, and other lung diseases. This tablet is helpful in treating respiratory symptoms caused by COVID-19 [120].
Unani Medicinal Plants for the Prevention and Management of COVID-19
The COVID-19 symptoms are almost similar to the symptoms of nazla-e-wabaiya as illustrated in Unani books as initial symptoms include cough, fever, malaise, etc., which may lead to diarrhea [148]. Unani medicines suggest the following management practices and preventive measures: Preventive measures: Precau-tionary measures of distancing, quarantine, and isolation must be followed [100]. The environment serves as a medium for spreading viruses, so special importance is given to the disinfection of the environment [149, 150]. Several disinfectants in the form of spray have been prescribed to fumigate, as sanitizers, and for applying on curtains. These mostly have aroma such as sandroos, loban, za'fran, vinegar, and rose water, etc., which can clear microbes [148]. Herbal disinfectants can provide a safer and cost-effective alternative to chemical drugs in the future [151]. Health care must be promoted during epidemics. Citrus fruits have immunomodulatory effects known by Unani physicians, so these fruits should be included in the diet. Take a healthy diet, avoid fish and meat, avoid starvation, and stay hydrated for promoting health [152]. Several drugs for the promotion of health may be advised, such as halela (Terminalia chebula), gul-e- banafsha (Viola odorata), and revand chini (Rheum australe). Gargling with a solution of arqe-gulab (Rosa damascena), rub-e-jauz (Juglans regia), rub-e-toot (Morus nigra), and sumaq (Rhus coriaria) may be advised as a prophylactic measure [148].
Suggested management: The nazla-e-wabaiya is managed with immunomodula-tory, anti-inflammatory, and antipyretic drugs described in the Al Asbab wa-Alamat. These Unani medicines include unnab (Rhamnaceae; Ziziphus jujube), khaksi (Brassicaceae: Sisymbrium adenophorum), sapistan (Boraginaceae: Cordia dichotoma G. Forst), and behidana decoction (Rosaceae; Cydonia oblonga). If diarrhea is associated, tabasheer (Poaceae; Bambusa bambos) and habb-ul aas (Myrtaceae; Myrtus communis) are also prescribed. Thirst can be relieved by giving tukhm e kahu sheera (seed paste of Compositae; Lactuca sativa L.). If pleurisy or pneumonia develops 1g of Aloe vera sap, 1g of C. sativus abd, 10g of qairooti aarad karsana are crushed and mixed and then slightly warmed to apply on the wall of the chest. After applying, the chest is covered with a bandage of cotton [148].
Qairooti is the polyherbal ointment in Unani medicine prescribed specially for chest diseases [153]. A paste is prepared by including the following ingredients in the formulation of Qairooti aarad karsana, Aarad e Hulba (Leguminosae; Gontsch and Trigonella adscendens, flour), Aarad e Karsana (Leguminosae; Pisum sativum L. flour) each of 60g, Aqarqarha (Compositae; Anacyclus pyrethrum L., root) of 18.g, Asl-us-Soos (Leguminosae; Glycyrrhiza glabra L., root), Kalonji (Ranunculaceae, Nigella sativa L., seeds) each of 24 g, an equal amount of beeswax and Roghan-e-Sosan (Iridaceae; Iris ensata Tunb, oil) for quantum satis. These Unani medicines are useful in relieving symptoms caused by COVID-19 [148].
Homeopathic Medicines for COVID-19: Currently, the SARS-2 patients require treatment of symptoms to cure, and hospital facilities are used to manage emergencies. The foundation of the medical system of homeopathy depends on the treatment of symptoms which plays an important role in tackling this worldwide challenge [153]. Several medicines of homeopathic are available for infection of COVID-19 patients. Pulsatilla, Calcarea carbonicum, Nitrum muriaticum, Arsenic album, Silicia, Nux vomica, Phosphorus, Lachesis, Sulphur, Hyper Sulphur, and some other homeopathic medicines are reviewed to treat COVID-19 symptoms [154]. While considering the COVID-19 symptoms of a patient, a homeopathic doctor can easily select the right choice of medicine for remedy. 'AYUSH', India's ministry recently suggested 'Arsenic albumin 30 homeopathic medicine as a prophylactic to avoid infection of COVID-19 [155] in which few have been shown in Fig. (1). This proposal is supported by the general secretary of LMHI (Liga Medicorum Homeopathica Internationalis) [154]. Dr. Vithoulkas pointed out that patients' access to the homeopathic physician is limited in this current outbreak [156]. Many other researchers have proved the effectiveness of homeopathic medicine for similar symptoms of respiratory tract infections and the treatment of mild pneumonia [157]. Some scholars demonstrated the prophylactic scope of homeopathic medicine and the management of flu symptoms [158]. In bronchioles of COVID-19 patients, proliferation tissues of fibero-granulation have been found by researchers; homeopathic medicines such as Arsenicum iodatum and Silicea have a role in resolving pulmonary fibrosis symptoms. In severe cases of COVID-19, many homeopathic medicines such as Lobelia inflata, Zingiber officinale, and Cassia sophera could be helpful along with management of the hospital. The Cassia sophera tincture made of leaves powder is useful in respiratory discomfort shown by aresearcher's group [154]. Lobelia has an antidyspnoetic effect that stimulates the respiratory system [159], and Zingiber officinale aqueous extract can be used as a chemotherapeutic agent for the treatment of infection of the respiratory tract. In the current outbreak of COVID-19 in Iran, a group of patients' were treated with homeopathic medicines [160]. Another study was done in Italy in which a group of patients probable and positive of COVID-19 was treated with homeopathic medicines [161]. Based on the results of these studies, homeopathic medicines are suggested for the prevention and treatment of COVID-19 infection [154].
Telemedicine and COVID-19
Since the emergence of the first case of the novel coronavirus, COVID-19, also known as SARS-CoV-2, in Wuhan city of China, new cases are rapidly emerging each day [162]. A sudden outbreak of the disease, quick spread of the virus, and the disease with unresolved nature rapidly overwhelmed the health care practice [163]. Attention was given to the new system of health care by understanding that the facilities of health care could be the cause of disease spread [164]. Therefore, telemedicine was focused on as a new health care model [165]. This method involves remote services relating to health, such as online education, advice, and monitoring, using a safe connection between patients and clinicians [166].
Types of Telemedicine
Telemedicine can be classified based on time, mode, persons engaged in communication, and communication purpose [167].
1-Communication Time
Asynchronous Telemedicine: Asynchronous telemedicine uses the technology of “store and forward” information related to health that may be medical data or questions in the form of audio, video clip or photo. They are sent to the health care provider, who responds later by giving a reasonable opinion for health [168]. Examples include email and other portals with electronic medical records [169].
Synchronous or Real-time Telemedicine: In this type of telemedicine, both health care providers and patients must be presented in real-time to communicate via a live video or audio telecommunication system [170]. For example, telephone or another live video or audio connection [171].
2- Communication mode
Text: Telemedicine communication based on chat, digital service for short messaging, other platforms for chat such as Google Hangout, WhatsApp, Facebook messenger, fax, and emails, etc., [172].
Audio: Audio applications, phone, voice by using the protocol of the internet [173].
Video: Zoom, Skype, Facetime, and Microsoft Team, etc., [174].
3-Persons engaged in teleconsultation
- Doctor to doctor
- Patient to doctor
- Caregiver to doctor
- Health care worker to doctor [167].
4-Consultation purpose
First consult: This type of telemedicine includes any patient who wants first-time consultation or any patient of follow-up who has not consulted for over six months. It may consist of follow-up patients who do not consult for the previous disease but desire to consult for another disease.
Follow-up consult: Follow-up consult includes a patient consulted to a health care provider within six months [167].
Telemedicine During the Previous Outbreak of Diseases
Telemedicine was appeared to be beneficial in the outbreaks of the diseases that occurred in the past, such as previous outbreaks of coronavirus including SARS-CoV and MERS-CoV. Other infectious diseases caused by Zika and Ebola viruses led to public health emergencies [14, 15, 175, 176]. In 2015, the first concept was published to implement telemedicine during the outbreaks of the disease [15, 177]. The framework included monitoring patients having contact cases by remote technology, tele-expertise, and teleconsultation for isolated and triage cases [162].
Telemedicine During the Pandemic of COVID-19
A new light is given to telemedicine during the pandemic of Covid-19, and the requirement for remote technologies has increased because of medical personnel's desire to stay disease-free and healthy [178]. In these situations, digital health provides an appropriate solution. Therefore, both WHO and CDC recommended monitoring patients by telemedicine to lower the risk of the virus spread that occurs by visiting patients to hospitals [179]. Telehealth is covering the gap among clinicians, people, and health care systems to enable everyone, particularly symptomatic patients to communicate with doctors and health care professionals through online digital channels while staying at home during this pandemic of COVID-19. It helps to reduce viral spread to the medical staff at the forefront and the mass population of people [180].
The American Medical Association (AMA) and the Academy of Family Physicians promote telemedicine services during the COVID-19 [181]. With the times, even companies that promote telemedicine are evolving. For example, companies such as EverlyWell and PlushCare plan to release testing kits of COVID-19 for the home that can smartly introduce their current services of remote consultation. Others such as HeyDoctor and Doctor on-demand offer free assessments of the risk of SARS-CoV-2 and then direct patients of high risk towards a phone or video consultation with a physician [182]. Telemedicine is affirmed to be at the front line in the coming times of medicine and assured to make modern health care more approachable instead of waiting in line for hours [183].
FUTURE PROSPECTIVE
Various factors influence the pandemic of COVID-19, which are needed to be evaluated in future work. There is a need to promote health literacy, a healthy lifestyle, and strong immunity through a balanced diet, physical activity, balanced micronutrients, nutraceuticals, and adequate sleep to survive COVID-19 or any other pandemic in the future [184].
Medicinal plants play an important role in the prevention and treatment of infectious diseases [185]. The use of herbal medicines must be recommended to boost immunity and fight against several problems related to health as medicines based on plants have no toxicity and side effects [186]. The proper combination of medicinal herbs in formulations of different medicinal systems and the appropriate dose for consumption is promoted and advised to prevent and treat COVID-19 and other viral diseases. The selection of a good combination of herbs against the current outbreak of COVID-19 may help health care providers to fight against any health-associated issues. During the recent outbreak of COVID-19, utilization of safer and convenient drug delivery options by using herbs such as mukhwas of herbal tonic, inhaler providing herbal immunity, proactive lozenges using herbs and patches of the herbal drug become an important area of interest. However, it requires proper care and knowledge. Patients should be properly educated about plants used in traditional medicines for their health benefits [187].
The development of vaccines is a highly effective method to reduce the burden of infectious diseases. Researchers are not trying to develop vaccines derived from plants to control the COVID-19 infection, which can be produced in high amounts with less cost. Patients readily accept carrier plants. Antigens derived from plants can be preserved for a long time and are stable [188]. At the San Diego University in California, nano-engineers are exploring a plant virus to develop a vaccine of COVID-19 that can be transported anywhere across the world without using refrigeration. This researcher group is using legume infecting virus, which is non-pathogenic to humans. They design the virus similar to the SARS-CoV-2 and then molecular signatures of COVID-19 will be placed on the virus surface to stimulate the immune system's response [189]. A green environment is needed to be conserved to store its resources keeping in view the health benefits of medicinal plants [187].
During the current outbreak of COVID-19, telemedicine using mobile apps or any other social media must be promoted to provide healthcare guidelines and prevent the spread of infectious diseases. Preventive measures, policies, and recommendations must be enforced and implemented by authorities [190].
Moreover, the new generation must be educated about science and technology to combat any such problem in the future. There must be specialized centers for research funded by all countries across the globe under the guidance of WHO. The most important centers for research are needed for insect-based diseases, viral diseases, bacterial diseases, etc. These research centers are necessary to combat any calamity in the world in the future [100].
CONCLUSION
The disease of COVID-19 first originated from the city of China, named Wuhan of Hubei Province, in December 2019. According to WHO, this viral disease has become pandemic by spreading to 203 counties, and the patients infected with SARS-CoV-2 present flu-like symptoms with breathing difficulties and high-grade fever. Although no treatment is still available for COVID-19, following preventive measures is the best option to prevent the spread of disease, and supportive therapy is provided. Medicinal plants used in formulations of various medicinal systems such as TCM, Ayurveda, Unani, Homeopathy may play an important role in the prevention and control of COVID-19. Telemedicine serves as a good source of providing healthcare guidelines and reduces the transmission of infectious diseases, mainly COVID-19, by close person-to-person contact. Proper management and preventive measures are important to combat this pandemic of COVID-19, and there is no need to be panic.