Sonali S Gadge
P R Patil Institute of Pharmacy, Talegaon (SP), Dist-Wardha (MS), India- 442202.
The COVID-19 has spread all over the world and there is no single drug or medicine for the prevention and the treatment of this deadly disease. One can get prevention from this disease by boosting the immune system. Persons with weak immune system e.g. children, elder patients or patients with preexisting diseases affect rapidly due to coronavirus. This novel coronavirus attacks mainly on the person immunity. For the centuries the herbal medicinal plants have many beneficial effects against deadly viruses. Herbal medicines provide a rich resource for new antiviral drug development. These natural agents interact with the life cycle of virus such as virus entry, replication, assembly and release. In this review, the importance, immunomodulator, antiviral and pharmacological activities of some medicinal plants, namely, Allium Sativum, Zingiber Officinalis, Cinnamomum zeylanicum, Curcuma longa, Ocimum sanctum, Glycyrrhiza glabra, Ginseng, Black pepper, Emblica officinalis, Withania somnifera, Tinospora cordifolia, Echinacea purpurea, Azadirachta indica, Piper betel, Eugenia caryophyllata, Cinchona calisaya, Nigella sativa, Cuminum cyminum are highlighted. These medicinal plants have many phytoconstituents like alkaloids, glycosides, terpenoids, flavonoids, lactones, polysaccharides, volatile oils, tannins, resins, etc which are helpful for boosting immunity and will help in the prevention and in the management of COVID-19. Several types of research attempted to use herbal medicines against COVID-19.
SARS-CoV-2 is a single-stranded RNA virus belonging to the family Coronaviridae. It is contagious, spread rapidly from one person to another. The virus has spread in almost all the countries of the world and has created a global threat to mankind. World Health Organization (WHO) on February 11, 2020, named the infection as COVID-19 as an acronym for ‘coronavirus disease-2019’ and on March 11, 2020, declared the outbreak a pandemic1. COVID-19 can affect all the people without discrimination, however, older, immune-compromised and people with health problems like diabetes, obesity, chronic respiratory illness and cardiovascular ailments are more susceptible.
The virus chiefly spread through droplet infection from an infected person to healthy one by coughing, sneezing or with infected hands when touched to eyes, nose or mouth. Coronaviruses are said to have glycoproteins composed of two subunits, S1 and S2 which form the viral surface and in fact guide the host receptors2. Strong immune response in the host against the virus, labelled as a cytokine storm, results in serious tissue damage. Interleukin-6 produced by leukocytes is considered to be the protagonist of this whole storm. The infection may begin with a dry cough, tiredness, headache, mild fever, and rarely diarrhea, sore throat, nasal congestion or running nose3,4. In severe cases, the patient may experience high-grade fever, pneumonia, breathlessness, and severe acute respiratory syndrome. A good percentage of people remain asymptomatic5. Diagnostic tests currently in use involve polymerase chain reaction, serological assay, and rapid antigen test. A chest X-ray or CT scan can be helpful for detecting pathological changes in the lungs. So far no specific treatment is available for novel coronavirus-2019 and the patients have to be managed only with symptomatic treatment. In the case of breathlessness oxygen therapy is recommended and in case of respiratory failure mechanical ventilation is needed while as septic shock requires hemodynamic support6. Various antivirals and antimicrobials used in different countries to curtail the disease include Lopinavir/Ritonavir (400/100mg 12 hourly), Chloroquine (500mg 12 hourly) and Hydoxychloroquine (200mg 12 hourly)7. Some suggest human IgG1 monoclonal antibody, commonly used in rheumatoid arthritis treatment. Moreover, social distancing, quarantine and isolation of suspected cases are the best tools for containing the disease. Maintenance of proper hygiene, washing hands frequently with soap or alcohol (> 70 %) based sanitizers, and use of masks at public places have the utmost importance. As of April 30, 2020, more than 33 lakh cases and about 234000 deaths have been reported throughout the globe. USA is the worst- hit country till date where more than 60,000 mortalities have been recorded, followed by Italy, Spain, France and the UK. The average mortality rate is about 3-4 per cent. In the current pandemic viral infection (COVID-19) it is clear that those with a weak immune system are highly susceptible to this infection and its worst outcomes8. Thus, immune-enhancing herbs may be helpful for the body to combat COVID-19 infection9. The traditional medicines include the use of herbs, nutrition and spices that are widely available and used in day to day life by the Asian population10.
The immune system helps to prevent death by producing antibodies by binding to the antigens of infectious agents. The immune system defends against bacterial infection through frequently interacting innate and adaptive mechanisms. The immune system estimates the amino acid sequence space of potential antibodies for identifying attacking pathogens. The adaptive immune system and two components of the innate immune system form the pervasive immune system. The innate system includes extrinsic defenses like serum proteins, nonspecific phagocytic leukocytes, mucous membranes and the skin11. This system is a primary to build into cells that are located on the front line of defense against bacterial invasions, including epithelial cells in the gut, lung, skin, periodontium, neutrophils and macrophages. The adaptive immune system takes a longer time to develop the response specifically. In fact, it provides a specific response against attacking organisms after evolvement. As reported in the literature, different immune function parameters are affected by viruses including immunoglobulin levels, antibody generation, and induction of immunological tolerance, graft-versus-host reaction, delayed-type skin reaction, graft rejection, lymphocyte transformation, and phagocytosis12.
Spices and Herbs have many Phytoconstituents that helps to boost immunity. Additionally, they have many medicinal properties. In India, traditional medicines are available widely and according to WHO, about 80% of the population all over the world use spices and condiments to prevent and manage different diseases and disorders13.
An ancient Indian text states that “aushadham ucchyathe sarvam”, which implicit that food is the absolute cure and healer. Ayurveda is a traditional Indian medicine system that stimulates several herbs, roots and spices to boost the immune system naturally12. In Ayurveda, spices and herbs are used to cure long-standing health conditions by eliminating metabolic conditions and commonly termed as ‘cleansers’. Traditionally, in Indian cuisine, herbs and spices are used in a dish according to their nutritional benefits and their ability to strengthen our immune system, which in turn, can protect us from ailments and infections. A strong immune system helps the body fight against flu, disease-causing viruses, as well as bacteria. People with weak immunity are more susceptible to fall sick and their symptoms for any disease are more severe as compared to others. That’s why they need for a strong immune system is extremely important because that will enable us to live a healthy life. According to the World Health Organization, around 80% of the world population uses herbal medicines for primary health care, particularly across South Asia and Europe. Research studies stated the herbs build the body’s immunity and have anti-inflammatory properties and have fewer side effects. This review discussed some important immunomodulatory herbs that can be used as immunity boosters14.
Currently, there is no specific treatment for COVID-19. Herbal medicines can be used as immunomodulators to fight against COVID-19 infection. The herbs contain various active constituents which have antiviral, antimicrobial, anti-inflammatory and immunostimulant properties. Thus it can be suspect that herbs can be used for preventing or treating COVID-19 infection15.
Allium Sativum- Lehsun (Garlic):
Allium sativum is belonging to the species in the onion genus, Allium. It includes the onion, shallot, leek, Chinese and chive onion16. Garlic is indigenous to Central Asia and Northern Iran over 6000 years ago and employed as a medicinal agent17. Garlic is one of the most important and common of all plants which are marked in the mankind history12. Garlic contains many active chemical constituents including alliin, allicin, ajoene, vinyldithin, S-allylcycsteine and diallyl sulphides which are having antioxidant, anti-inflammatory, immune-modulating, antibiotic, bacteriostatic, antifungal, antiviral, antihelminthic, antithrombic, hypotensive, hypoglycemic, and hypocholesterolemic properties18,19.
One of the most important constituent of garlic is allicin which attacks more than 23 kinds of bacteria, including salmonella, as well as 60 types of yeast and fungi, and also effective against all of 17 most dangerous fungi (Candela albicans), expels tapeworms and restores sensation in areas affected by leprosy.
When garlic is crushed or chewed, the compound turns into allicin which is the main active ingredient responsible for its taste and smell. Allicin is unstable and quickly converts to other sulphur-containing compounds which exhibit medicinal properties. These compounds boost the disease-fighting response of leukocytes in the body when they kill viruses, such as the viruses that cause the common cold or flu20. Aged garlic extract contains fructans (fructooligosaccharides) which selectively stimulate some beneficial bacteria in colon, modulating immune responses21. Various garlic preparations such as aqueous extract, aged garlic extract and garlic oil are sold in the market with distinct health benefits. The raw garlic as well as garlic preparations is effective.
The role of garlic in immuonutrition is immunostimulant and immunosuppressant. The consumption of garlic results in an improvement in haematological attributes, e.g., total leukocytes counts as well as homeostasis characteristics. Consumption of garlic increase the production and release of nitric oxide (NO) that is responsible for enhanced release of IFN-α in humans, beneficial against viral, or proliferative diseases. The overall improvement in the immune system could be attributed to the activation of specific responses and detoxification mechanisms. There are some possible routes of garlic for its immunomodulatory properties are a proliferation of lymphocytes; infiltration of macrophages and lymphocytes, macrophage phagocytosis and stimulating release of IL-2, TNF-α, and IFN-γ. Additionally, it enhances NK cell and lymphokine-activated killer cell activities and represents effective stimulation of the immune responses22.
Garlic inhibits the growth of cancerous cells. It has also been reported from the last decade that garlic and its preparations may possess anticancer activities against the skin, prostate, mammary carcinoma colon, lungs, gastric cancer, etc.23,24
Due to the unavailability of accurate drugs and vaccines, the global health authorities are working on the use of traditional medicine system against the contagious agents and thus, for curing the disease. Garlic is known for centuries related to its protecting capacity against diseases along with immune-boosting activities. It is effective against various viruses, bacteria and fungi hence it is well known for its antibacterial, antiviral and antifungal properties. The garlic possesses antioxidants properties with free radicals25. The garlic also possesses an antiviral property which may be useful in reducing the severity of colds, flu or COVID-19 infection. Hence, Garlic helps to boosts the immune response and in fighting against viruses and other diseases26.
An old folk tale states that: “Eat onions in March and garlic in May, then rest of the year, your doctor can play. Garlic in its natural form incorporated with a healthy diet is beneficial to health, prevents disease and will help prolong life.
Zingiber officinalis- Adrak (Ginger):
Zingiber officinalis is a famous spice for its dietary and medicinal properties in India and in other countries. Ginger has been used for the treatment of rheumatism, catarrh, nervous diseases, gingivitis, toothache, stroke, asthma, constipation and diabetes in Ayurvedic, Chinese and Tibb-Unani herbal medicines27. The medicinal, pharmacological and chemical properties of ginger have been considerably reviewed the evidence for its effectiveness as an -inflammatory agent antioxidant, anti-nausea compound, and anticancer agent. The protective effects of ginger against other disease conditions are also reviewed28. Many researchers have proved that whenever someone suffers from common cold or flu, Ginger Tea or Ginger extract is recommended to get relief from the symptoms. Ginger possesses many effective plant compounds and has excellent anti-viral properties and treating respiratory issues29. The pungent chief active constituent present in Ginger is Gingerol along with other sulphur-containing compounds (allicin, alliin, and ajoene25), zingiberine, sesquiterpenes, shogaol, gingerdione, hexahydrocurcumin, paradol and gingerenone A30 and enzymes (allinase, peroxidase, and myrosinase). The constituents present in Ginger increases the antioxidant activity i.e. superoxide dismutase and glutathione peroxidase in the body in combating the Viral Infections. Ginger prevents severe damage to the lungs ameliorates allergic asthma and inflammation31,32.
The aqueous extract of Ginger and Clove is very effective in the prevention of the contamination. To prevent the fresh vegetables from decontamination, the aqueous extracts of six raw food materials (fenugreek seeds, garlic and onion bulbs, flower buds of clove, ginger rhizomes, and jalapeno peppers) were tested against the foodborne infection33.
In comparison to the dried ginger, the fresh ginger is reported to inhibit human respiratory syncytial virus (HRSV)-induced plaque formation when taken in proper doses in both A549 (adeno carcinomic human alveolar) and HEp-2 (human laryngeal carcinoma) cell lines. Also, 300 μg/mL of fresh ginger is found to reduce the plaque counts to 19.7% (A549) and 27.0% (HEp-2) compared to the control group, respectively34.
Ginger is consumed in many cultures as immune boosters, and its anti-inflammatory potential has been highlighted in a number of scientific investigations. The mechanisms for its anti-inflammatory properties.
include inhibition of arachidonic acid-induced platelet aggregation and formation of thromboxane B, upregulation of histone H3 acetylation, and suppressed histone deacetylase (HDAC), inhibition of IL-1, TNF-α and IL-8, downregulation of inflammatory inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) gene expression through inactivation of Nuclear Factor Kappa B (NF-KB)35.
Cinnamomum zeylanicum- Dalchini (Cinnamon):
Cinnamon is reddish-brown bark with a good smell belongs to the family Lauraceae. It is said to be hot and most commonly used as a spice. It is used in the treatment of respiratory ailments like cough and asthma. It is also having phlegmagogue, cardiotonic and aphrodisiac, anti-inflammatory, antimicrobial and antioxidant actions. In addition to these, researchers have found that this herb is effective in diabetes, ischemic heart disease, hypertension, gastric cancer, Alzheimer’s disease, dyslipidemia. It can be used in the form of decoction or powder form with a dosage of 1-2 gm. The active chemical constituents present in cinnamon are cinnamaldehyde, cinnamic acid, cinnamate and essential oils like trans-cinnamaldehyde, eugenol, caryophyllene oxide, cinnamyl acetate, L-borneol, E-nerilidol, b-caryophyllene, α-cubebene, α-thugene, α-terpinol, and terpinolene. The extensive study revealed the antimicrobial activity of cinnamon. The cinnamon is proven to have antiviral activity against H7N3 influenza A virus36. Cinnamon along with other medicines is highly effective in acute and chronic human infections fungal, bacterial or viral37. Cinnamon derived compound, Procyanidin type A inhibits the entry of hepatitis C virus38. It was found that inhibits the TNF-α-induced inflammation through suppression of NF-κB activation. Cinnamaldehyde decreases the production of prostaglandins (PGEs) by decreasing IL-1β-induced COX-2 activity and lowering the hyper inflammation in a dose-dependent manner. Researchers showed the evidence that cinnamaldehyde is a potential anti-inflammatory bioactive compound and could be useful in mitigation of SARS-CoV-2 induced hyper inflammation in the lung39.
Curcuma longa-Turmeric (Haldi):
Curcuma longa is also called “Indian saffron”. Turmeric belongs to the ginger (Zingiberaceae) family and the Curcuma genus40,41. It is a rhizome which is yellow orange in color and well-known spice and has numerous medicinal benefits. Curcuma longa rhizome (turmeric), commonly used as spice and is well known for its medicinal value in the Indian traditional system of medicine. In the Unani medicinal system it is used as anti-inflammatory, phlegmagogue, analgesic, antipyretic, blood purifier, and has healing properties. The herb can be utilized in the form of decoction or powder with a dose of 1-3 gm40. Scientists have reported that it is having immunomodulating, antioxidant, anti-inflammatory, antimicrobial and anticancer activities. The main constituent of Curcuma longa is Curcumin (diferuloylmethane) which is responsible for the biological activity and gives yellow colour to turmeric. Curcumin is strongly effective in acute respiratory distress syndrome, COPD’s, pulmonary fibrosis and acute lung injury42. Turmeric suppresses TNF-α and inhibits NF-κB and acts as a potent anti-inflammatory agent43. Curcuma extract is effective against various pathogenic bacteria including Staphylococcus, Streptococcus Klebsella pneumoniae, Helicobacter pylori, Vibrio chlolera, Bacillus subtilis, etc. Turmeric also contains dihydrocurcumin, and hexahydrocurcumin. Some volatile constituents like α-phellandrene, cinol, borneol, zingiberine and different sesquiterpenes44. The herb of the turmeric acts against the viruses like H1N1, H6N1, respiratory syncytial virus, herpes simplex virus, parainfluenza virus type-3, coxsakievirus B3, Japanese encephalitis, hepatitis B virus, hepatitis C virus, human papillomavirus-16 and -1845,46. It has also been found to inhibit HIV-1 long terminal repeat-directed gene expression.
A new study suggested that an interplay between COVID-19 and the renin-angiotensin-aldosterone system (RAAS). A preclinical study demonstrated that an ACE inhibitor or angiotensin-receptor blocker (ARB) might increase ACE2 expression. In addition, another study indicated that the administration of RAAS inhibitor did not influence the ACE2 receptor47. It can be concluded that the results are inconsistent regarding the administration of the RAAS inhibitor since they may or may not increase the ACE2 receptor. Based on the data, there is a possibility that the administration of curcumin prevent COVID-19 may cause a highly susceptible individual to get infected with SARS CoV- 2 and eventually become worse48.
Ocimum sanctum Linn- Holy basil (Tulsi):
Tulsi is noted as “mother medicine of nature” and it shortens the course of all illness. Tulsi is also called holy basil. It is an indigenous plant to India and is highly renowned for its medicinal properties in Ayurvedic and Siddha medicinal system. Tulsi has immunomodulatory activity, antibacterial, antioxidant, anti‑inflammatory, anti-carcinogenic activity, anti-diabetic, antipyretic, and also analgesic property, anti-viral and anti-fungal activity. A decoction of the Tulsi leaves is beneficial for the treatment of respiratory disorders like asthma, bronchitis, influenza, and cough and cold49,50.
Tulsi leaves contain bright, yellow coloured and pleasant volatile oil (0.1% - 0.9%). The percentage of oil content of the drug varies depending upon the type, the place of cultivation and season of its collection. It contains approximately 70% eugenol, carvacrol (3%), and eugenol-methyl-ether (20%). It also contains caryophyllin. Tulsi seeds contain fixed oil with good drying properties.
The plant also contains glycosides, alkaloids, tannins, saponin, a considerable amount of vitamin C and traces of maleic, tartaric and citric acid.
In Ayurveda, Tulsi is denoted as “Elixir of life” for its healing activity and promising potential in curing different health diseases including bronchitis, rheumatism pyrexia, asthma, skin diseases, parasitic and microbial infections, gastric and hepatic disorders, etc.
Tulsi is used for curing pain, diarrhoea, cough and fever, which are common symptoms related to COVID-19, thus it can be used in controlling COVID-19. Tulsi is a well known herb to treat pneumonia51. The essential oils like Eugenol of Tulsi leaves produce anti-viral activity against different viruses namely, poliovirus type 3, herpes virus (HSV), hepatitis B virus etc52. Ethanolic extract of leaves of Tulsi plant in the concentration of 22.5mg/ml, inhibit polio type 3 virus replication. The extracted components of Tulsi like linalool and ursolic acid have shown broad- spectrum antiviral activity against DNA viruses like RNA virus and adenoviruses53.
Tulsi helps in the prevention and controlling of COVID-19. Social Science Research Network (SSRN, Elsevier) studied the binding affinity of seven photophilic compounds from Tulsi i.e., tulsinol A, B, C, D, E, F, G, and dihydrodieuginol B, with SARS CoV receptors. This study confirmed that the use of Tulsi extract against COVID-19 due to its recognized role in inhibiting replication of SARS-CoV with ACE II blocking properties54.
Glycyrrhiza glabra- (Liquorice) Mulethi, Yashtimadhu:
From the ancient time, Glycyrrhiza glabra is indicated for the symptoms of respiratory disease, namely, cough sore throat. Potential uses of Glycyrrhiza glabra for anti-tumour, anti-microbial, antiviral, anti-inflammatory, immune regulatory and several other activities that contribute to the recovery and protection of the nervous, alimentary, respiratory, endocrine, and cardiovascular systems55. Liquorice for medicinal purposes is used mostly in the form of decoction with a dosage of 3-7gm.
A number of active constituents have been isolated such as glycyrrhizin, glabridin, 18-beta-glycyrrhetinic acid, liquiritigenin, licochalcone A and licochalcone E, responsible for its broader activities56. The chief constituent of liquorice root is glycyrrhizin (glycyrrhizic acid or glycyrrhizinic acid) which is sweetened in taste. Glycyrrhizin is well known to have various immunomodulating and biological response-modifier activities. The phytoestrogens namely isoflaveneglabrene, isoflavaneglabridin and chalcones are also present in the liquorice root57.
The extract of Glycyrrhiza is found to be effective against hepatitis C virus, coxackievirus B3, H5N1 influenza A virus, H3N2 influenza virus, human respiratory syncytial virus, coxsackievirus A and enterovirus58,59.
The researchers investigated the antiviral properties of glycyrrhizic acid derivatives against SARS-CoV virus. They tested 15 Glycyrrhizin derivatives for their antiviral activity against SARS-CoV and reported that amides and conjugates of Glycyrrhizin with two amino acid residues and 30 free -COOH functional groups represent up to 70-fold increased activity against SARS-CoV60.
Ginseng is also known as “man-root”. It is a slow-growing root herb that has been used medicinally by practitioners of traditional Chinese medicine for more than 3000 years. Ginseng is indigenous to Asia and America and is very popular for its many beneficial medicinal products from years61. It has antimicrobial antioxidative, antidiabetic, anti-inflammatory, anti cardiovascular disease and anticancer properties. It helps to enhance the immunity, combating various cardiovascular diseases, neurological disorders and diabetes62.
Ginseng is treated as an adaptogen, a substance thought to enhance the body’s ability to resist physical and mental stress63. Traditional herbalists also consider it to be a “general tonic,” a substance that helps protect the body against disease, much as one would expect from an immunostimulant. Several species are commonly referred to as ginseng. The three species of ginseng are most commonly used are Asian or Korean ginseng (Panax ginseng), American ginseng (Panax quinquefolius), and Siberian ginseng, more properly called “eleuthero” (Eleutherococcus senticosus). The Panax species is considered as “true” ginseng64.
The main chemical constituents of ginseng are triterpenoid, protopanaxadiols, protopanaxatriols, steroidal saponins (ginsenoid, polysaccharides) and proteins which show strong activities against antibacterial or like other activity especially for microorganisms that cause respiratory infections in the human body. Furthermore, the antimicrobial activity of ginseng and their bioactive constituents was found to be effective against various bacteria (Escherichia coli, Helicobacter pylori, Staphyllococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes), fungi (Fusarium oxysporum) and yeast (Candida albicans) species61. It is also effective against different human viral infections such as rhinovirus, influenza virus, human immunodeficiency virus hepatitis virus, enterovirus, norovirus, human herpes virus, rotavirus and coxsackievirus respiratory syncytial virus65.
The research study stated that the ginseng was effective against viral infections such as H1N1 and decreased the formation of free radicals such as reactive oxygen species (ROS)66. The marketed formulations as Ginseng supplementation are widely available in the market, which helps to improve immunity and also used as anti-viral properties. The extract of the Ginseng can help to manage COVID -19 pandemic67.
Black pepper is used in many cuisines that hold a very useful among medicinal plants68. It is well known as ‘king of spices’ and widely used as a flavoring agent and taste enhancer of various dishes. It is rounded, small and black fruit of a plant somewhat bitter in taste and zesty in nature. It is said to be effective in fevers, asthma, breathlessness and other respiratory diseases. It is used for its anti-inflammatory, analgesic, phlegmagogue, anti-flatulent, anti-thyroid, anti-tumour, anti-bacterial, appetizer, anti-venom, aphrodisiac, neuroprotective, cardioprotective and health-boosting actions36,69. More than 600 phytochemicals including lignans, terpenes, alkaloids/amides, neolignans etc. are present in this plant. Various chemical constituents obtained from black pepper include piperine, piperamide, piperic acid, piperolein-B, piperlonguminine, pellitorine, piperitine, eugenol and kusonokinin in addition to some volatile oils70. Piperine shows a strong anti-inflammatory activity and thus can be repurposed for suppression of hyper inflammation induced during COVID-1939. Also, piperine is a potent antioxidant and protect against oxidative damage by neutralizing free radicals, ROS, and hydroxyl radicals71. Due to these properties, piperine can be used as a therapeutic compound to protect from the oxidative stress and hyper inflammation due to COVID-1939.
Emblica officinalis- Amla:
Emblica officinalis is also known as Phyllanthus emblica. It is one of the major constituents of many Ayurvedic tonics prescribed for recuperation, rejuvenation and vitality72. Amla is the richest source of vitamin C and sour in taste. It is widely used in common cold, fever, dyspepsia, hair growth, liver disorders etc. Amla fruits are rich in various minerals like phosphorus, iron and calcium. It also contains various chemical constituents like ellagic acid, gallic acid, norsesquiterpenoids, gearaniin, and prodelphinidins. It has different biological activities like immunomodulatory, antioxidant, anticancer, cytoprotective, analgesic, antimicrobial, antipyretic, antitussive and hepatoprotective effect73. Amla is well known for its anti-oxidant property as it balances pro-oxidant and anti-oxidant homeostatic phenomenon in the body. It also reduces the side effects induced by radiotherapy and chemotherapy72. Amla improves both cell-mediated and humoral immune response. It intensifies gamma –IFN, IL-2, and natural killer (NK) cell activity74. Amla shows extreme immune empowering property and thus it is believed to be effective against viral infections75.
Withania somnifera- Ashwagandha:
Ashwagandha is known as Indian winter cherry and Indian ginseng and belongs to the family Solanaceae. It is one of the most important herb in Ayurveda and used for improving good physical and mental health, immunomodulation, management of stress and combating infectious agents76. It is widely used as a nerve tonic, body tonic, aphrodisiac, anti-inflammatory, antiarthritic antivenom, antihypertensive and anti-tumour medicine. It is used as an immunomodulator and used as a dietary supplement in the form of churna77,78.
Ashwagandha consists of sterols, alkaloids, saponins, amino acids and polysaccharides. Alkaloids such as ashwagandhine, cuseohygrine, trpine, isopelletierine, anaferine etc. have been isolated from Ashwagandha. The multiple numbers of sterols are isolated from this herb which includes withaferins, withasomidienone, withasomniferin A, withanolides, and withanone. Sitoindisides (VII, VIII, IX and X) and withaferin A, have shown antidepressant properties79. Withaferin A, a constituent of ashwagandha have a high binding affinity towards neuraminidase and inhibit neuraminidase of H1N1 influenza virus potently80.
Researchers found that Ashwagandha increases the production of antibodies in the body. These antibodies engulf the toxins and excrete them in the form of mucus, sweat, faeces and urine81. It also increases the production of Nitric Oxide, which is responsible for the activation of macrophage actions of the immune system with the improved ability of ingestion of invader cells82. The extract of Ashwagandha when added with DPT (Diptheria, Pertussis and Tetanus) vaccine gives protective immune response against fatal outcomes of Diptheria and Pertussis toxins83. It is also reported that the SARS-Cov-2 directly attack on ACE 2 in the human body with the help of spike proteins. To respond it, the phytoconstituents present in the Ashwagandha have effects on binding of the virus in the human body. That is why; Ashwagandha could be the best choice among various medicinal plants to fight against COVID-19 as the roots have high antiviral activity67.
Tinospora cordifolia- Giloy:
Giloy or Guduchi or Amruta is a large climbing shrub belonging to the family Menispermaceae. It is found throughout India. Tinospora cordifolia has importance in traditional Ayurvedic medicine and used for the treatment of chronic diarrhoea, dysentery, cancer, jaundice, bone fracture, pain, asthma, skin disease, poisonous insect, snake bite and eye disorders84. It gives relief from chronic cough, breathlessness, tuberculosis, syphilis, gonorrhoea and leprosy in Unani medicine85. It also improves learning and memory power86. Giloy has many medicinal properties like anti-inflammatory, anti-osteoporotic, anti-arthritic, antioxidant, anti-allergic, antihyperglycemic, immunomodulatory, antipyretic, anti-infective, hepatoprotective, antileprotic, antifertility, antimutagenic, antiobesity, antineoplastic and radioprotective activity87. Different classes of chemical constituents are present in Giloy are lactones, alkaloids, glycosides, sesquiterpenoids, diterpenoids, steroids, phenolics, essential oils, polysaccharides, aliphatic compounds and flavonoids. The chief constituents are tinosporone, tinosporine, tinosporic acid, cordifolisides A to E, syringe, berberine and giloin88.
Giloy also contains high fibre content (15.8%), protein (4.5%-11.2%), carbohydrate (61.66%), and low fat (3.1%), high chromium (0.006%), potassium (0.845%), sufficient iron (0.28%) and sufficient calcium (0.131%). Nutritive value of T. cordifolia nutritive is 292.54 calories per 100 grams89. Researchers have found that methanolic extract of Giloy is found to have broad-spectrum antimicrobial effectiveness against various strains which are Staphylococcusaureus, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Shigella flexneri, Salmonella paratyphi, Salmonella typhimurium, Salmonella typhi, Enterobacter aerogene, Serratia marcesenses and Proteus vulgaris90.
1, 4-alpha-D-glucan which is one of the constituent of Tinospora cordifolia found to activate macrophages, NFκB translocation and cytokine production, and hence activates the immune system91. Favorable effects of Tinospora cordifolia was seen in HIV positive patients when it was used with conventional antiviral treatment92. Tinosporin is effective against HIV and other viral diseases as immunomodulatory and selective inhibition of the virus to target T helper cell.
Sanshamani Vati (also called Guduchi ghana vati) which is made from the aqueous extract of T. cordifolia can be administered as 500mg twice a day, 15 days with warm water as a preventive and prophylactic drug for COVID-1993 .
The combined herbal formulation of Giloy, six leaves of tulsi, one or two tablespoon of ginger juice and four to six seeds of black pepper receiving enormous popularity and found to be helpful for preventing COVID-19 disorder. This mixture is crushed or grind into a fine powder and use it as herbal tea or consume with honey. It can control fever, cough and support immunity94.
Echinacea purpurea- Coneflower:
The genus Echinacea (coneflower, family Asteraceae) is indigenous to North America. Echinacea preparations are commonly used as immunostimulants and prevent cold and other respiratory infections and conditions associated with respiratory discomfort. These preparations widely used as dietary supplements in Europe and the United States. In Germany, Echinacea containing products have the greatest popularity and approved for supportive treatment of respiratory and urinary infections95.
Preparations of Echinacea purpurea can be made in the form of tinctures, extracts and sprays. Echinacea purpurea preparations stimulate phagocytosis of neutrophils both in vitro and in vivo and activate cellular immunity. It contains chemical constituents like caffeic acids, polysaccharides, chicoric acid, alkylamides, essential oils, hydroxycinnamic acids, tannins, saponins, flavonoids, echinacin, echinacoside, echinolone, organic acids, resins and phenolcarboxylic acids96.
The extract of E. purpurea has antiviral activity against virus-induced diseases. It is effective against herpes simplex virus, influenza and rhinovirus. Depending on different studies, it can be concluded that E. purpurea can be used for the prevention and treatment of COVID-1948.
Azadirachta indica- Margosa (Neem):
Scientific name of neem is Azadirachta indica found everywhere in India. Every part of the neem tree such as leaves, root, fruit, bark, oil seeds and gum are useful and it is used to cure or control diseases arises from parasitic, bacterial, viral or any other causes97. Neem tree is used in the treatment of certain medical conditions such as hypertension, cancer, heart diseases and diabetes98.
It is known that compounds in neem extracts have antifungal, antibacterial, antimalarial, anti-hyperglycemic, immune-modulator, anti-carcinogenic, anti-inflammatory, anti-mutagenic, anti-oxidant anti-ulcer, antinephrotoxicity, wound healing effect, neuroprotective activity and anti-viral effects99,100. The neem tree effectively helps to purify the air. The main phytoconstituents present in neem are limonoids and terpenes.
The chief chemical constituents present in the neem tree are sodium nimbidate, catechin, gallic acid, nimbidin, nimbolide, gedunin, mahmoodin, margolone, isomargolone and polysaccharides which are responsible for their anti-inflammatory, antifungal, anti-bacterial and anti-inflammatory activities94.
Neem oil possesses antifungal, antimalarial and antipyretic activities. Neem oil contains Azadirachtin which have strong anti-feedant, insecticidal and antimalarial property101.
The neem extract have anti-viral effects against herpes virus, chickenpox, smallpox, polio virus, dengue virus, coxsackie B group virus and HIV virus102.
In urban areas, many people use the neem extract from leaves for bath to prevent infection against chicken pox which is caused due to varicella-zoster virus. Neem leaves in small amount taken orally to kill the harmful worms inside the body. It also helps for maintaining blood sugar level in body94. Research showed that the several molecules extracted from the neem extract showed inhibitory effect on protein of the SARS-CoV-2103.
Piper betel – Paan:
The scientific name of betel leaves is Piper betel L. belongs to the family Piperaceae. In ancient books of Ayurveda, the importance of Betel leaves has been described. In Chinese folk medicine, betel leaves are used for the treatment of various disorders and have detoxification, anti mutation and antioxidant properties. It has many vernacular names as in Sanskrit; it is known as Nagvelleri, Tamboolavalli or Tamboola, in Malayalam, it is called, Vetta or Vettila. It is a perennial climbing vine with semi-woody stem and short adventitious climbing roots. The leaves are glabrous with aromatic odour and pungent taste and extensively found in damp forests. In Hindu culture, betel leaves play an important role in various cultural, social, and religious occasions. The leaves are edible and have medicinal, religious and ceremonial value and consumed as a mouth freshener having a strong pungent and sweet taste with a strong aromatic flavor. The leaves vary from pungent taste too sweet in taste depending varieties of leaves, nutritional composition and chemical compounds104.
Traditionally betel leaves are used for healing the illnesses like headache, scanty or obstructed urination, and weakness of nerves, sore throat, respiratory disorders, constipation, and problem of breast milk secretion, wounds, inflammation and boils105.
The main constituents of Piper betel are Chavibetol acetate (15.5%) Chavibetol (53.1%). Other constituents are chavibetol methyl ester, allypyrocatechol, α-pinene, β-pinene, eugenol, safrole, α-limonene, 1,8-cineole. The chief chemical constituents of Piper betel are chevibitol, catechol, chavicol, charvacrol, allyl pyrocatechol, Vitamin A, B, C and essential oils having strong antioxidant and immunomodulatory activity against some bacterial and viral infections94,106.
Piper betel possesses many pharmacological activities like antimutagenic, anticancer, anti-inflammatory, anti-amoebic, antigiardial, anti-microbial, mosquito larvicidal, antiulcerogenic, immunomodulatory, antifungal, radioprotective and antileishmanial activity107.
Leaves contain essential oil, is used in respiratory catarrhs. Thus, it is used in the treatment of cough and easiness from the difficulty of breathing. Piper betel fruits with honey are an effective remedy for cough treatment108. Betel leaf extracts also have the antioxidant and anti-inflammatory characteristics, are capable of scrimmaging against influenza-like disease109.
Researchers also showed that betel leaf ingredients with commercially available influenza-specific antiviral showed a synergistic activity. Thus, it reduces the effective dose of antiviral drug and helps to reduce the cost of drug, pressure and development of resistant viral strains in the patient110.
Eugenia caryophyllata- Clove (Lavang):
The scientific name of clove is Eugenia caryophyllata L. Merr. & Perry (synonym: Syzygium aromaticum) belongs to the family Myrtaceae. It is used in the treatment of respiratory disorders, dental disorders, sore throats and headaches in traditional medicines in Australia and several Asian countries. Clove possesses anti-fungal, anti-microbial, anti-viral, anti-inflammatory, cytotoxic and anaesthetic properties. Clove also possesses anti-oxidant property and lipid peroxidation111. The clove plant is rich in protein, carbohydrates, vitamins (A, C, E and K), thiamin, riboflavin, folate, niacin, dietary fibres and minerals112.
The main chemical constituents of clove are eugenol (50-87%), eugenyl acetate, tanene, thymol and cariophyllene113. One study demonstrated that the ethanolic and aqueous extract of clove which is rich in eugenol have anti-oxidant activity111.
The clove oil contains many phenolic compounds like eugenol, eugenol acetate, α- humulene and β- caryophyllene. It was also reported that clove oil has strong anti-inflammatory activity. It is revealed that eugeniin, one of the phytoconstituent of clove have good antiviral activity against the herpes virus. It inhibits the virus DNA polymerase enzyme and prohibiting the DNA synthesis114.
The scientific name of Cinchona is Cinchona calisaya wedd belonging to family Rubiaceae. There are around 40 Genus of Cinchona tree. Cinchona ledgeriana and Cinchona officinalis are other species of Cinchona. Traditionally, Cinchona is used in the treatment of inflammation, fevers and other ailments. Cinchona is also used for influenza, leg cramps, common cold, etc.115 Many chemical compounds are derived from the Cinchona bark are chinoline derivatives such as quinine, cinchonine, cinchonidine, and quinidine. Quinine has strong antimalarial activity116. It shows other pharmacological activities like anti-arrhythmic, anti-parasitic, anti-protozoal, anti-spasmodic, cardiotonic and as a bitter digestive aid to stimulate digestive juices117.
Quinine is designated as an immunomodulatory agent, but it has been known for its immunostimulant and immunosuppressant activities against viral infections48.
Chloroquine is a synthetic derivative of quinine, known since 1934 for the treatment of malaria. Due to its properties and mechanism of action encouraged, it is used in the treatment of different diseases. Currently, chloroquine (CQ) and its hydroxyl-analogue hydroxychloroquine (HCQ) cannot be used as antimalarial drugs. They are effective in the treatment of rheumatoid arthritis. Because they are low in cost and toxicity, high tolerability and immunomodulatory properties, CQ and HCQ have been proposed for use against viral infections109.
When quinine increases the production of the IFN- α, it acts as an immunostimulator to inhibit viruses.
Otherwise, quinine inhibits the release of TNF-α secretion and shows immunosuppressant effect. These two different activities may have a beneficial effect on people who are infected with COVID-19 but routine consumption of this herbal medicine by healthy people for the prevention of COVID-19 is not recommended because it may cause various harmful events48.
Nigella sativa- Black cumin (Kalonji):
Nigella sativa or black cumin is also known as Kalonji, are seeds of a flowering plant belonging to family Ranunculaceae. It is bitter in taste118.
Black cumin is reported to cure a variety of ailments including rheumatism, jaundice, diabetes, conjunctivitis, anorexia, intrinsic haemorrhage, cough, asthma, bronchitis, fever, influenza, anorexia, hypertension, dysmenorrhoea, scorpion poisoning and snakebite119. Black cumin possesses many pharmacological activities such as antiviral, anti-tussive, anti-inflammatory, immunomodulatory, anti-coagulant, bronchodilatory, anti-histaminic, spasmolytic, diaphoretic, antineoplastic, carminative and potent analgesic activity119,120.
The important phytoconstituents present in black cumin are thymoquinone, dithymoquinone, α-pinene, p-cymene, thymohydroquinone, carvacol, pentacyclic triterpene, sesquiterpene, terpineol and saponins. Thymoquinone is the chief phytoconstituent present in black cumin which is responsible for most of its therapeutic properties121.
There are trace elements such as vitamins (Vitamin E, Thiamine, Niacin, Riboflavin, Folic acid, Pyridoxine,), and minerals (Phosphorus, Magnesium, Sodium, Potassium, Copper, Calcium, and Iron)122.
Black cumin shows antibacterial activity against staphylococcus aureus, Salmonella typhimurium, pseudoaeruginosa and H-pylori123.
Black cumin seed oil possesses antioxidant property and inhibits certain types of short-lived local tissue hormone which are responsible for inflammation. The antioxidants which are present in the oil help to slow the cartilage degeneration.
Nigella sativa seeds and oil possess antiviral properties against viruses like hepatitis C virus (HCV) and HIV124.
Researchers reported that the administration of Nigella sativa seed oil capsules in the dose of 450 mg, three times daily for 3 months to patients with Hepatitis C Virus (HCV) resulted in a significant decrease in viral load with increased Total Antioxidant Capacity (TCA) and improved laboratory biomarkers such as total protein, red blood cell, and platelet count, fasting blood glucose decreased and postprandial glucose in both diabetic and non-diabetic HCV patients125. It was also reported that patients with COVID-19 received Nigella sativa seeds (80 mg/Kg/day) with honey (1 gm/Kg/day), significantly improved the symptoms, viral clearance and mortality in COVID-19 patients. Thus, Nigella sativa seeds and honey can be used alone or with other treatment for the prevention of COVID-19126.
For the prevention of cold and cough, one can make a warm healthy tea mixture of crushed Black cumin seeds with pure honey and warm water.
Cuminum cyminum – Cumin (Jira):
The scientific name of cumin is Cuminum cyminum, belonging to the family Apaiaceae. It is referred to as Jira, Afedziiraa, Safedjiiraa, zeera in various parts of India. The name ‘Cumin’ derived from the Latin word ‘Cuminum’127.
Cumin seeds are oblong and yellow–grey. Since ancient times cumin seeds in whole as well as in ground forms are used in several cuisines of many different food cultures. In India, cumin seeds have been used since ancient times as a traditional ingredient of numerous dishes including kormas and soups and also form an ingredient of several other spice blends128.
The flavor of the seeds is due to the presence of the flavor component cumin aldehyde. Traditionally, cumin seeds are used as carminative, eupeptic, antispasmodic, astringent and used in the treatment of diarrhea, dyspepsia, mild digestive disorders, flatulence, morning sickness, colic, dyspeptic headache and bloating, and promote the combination of other herbs and to improve liver function129.
Nutritionally cumin seeds contain proteins, fats, carbohydrates, soluble dietary fibres, vitamins (thiamine, riboflavin and niacin) and moisture127.
The seeds contain major phytoconstituents are cuminaldehyde, limonene, α- and β-pinene, 1, 8-cineole, o- and p-cymene, α- and γ-terpinene, safranal and linalool, alkaloids, anthraquinone glycosides, flavonoids, resin, saponins, coumarin, tannin and steroids129.
The seeds have also been used in bronchopulmonary disorders and as a cough remedy and as an analgesic. The mixture of seeds, alcohol and castor oil has been used for the treatment of scabies120.
The cumin seeds possess multiple medicinal properties namely, antidiabetic, neuroprotective, cardioprotective, chemoprotective, anti-inflammatory, immunomodulatory, anti-oxidant, digestive stimulant, dyspepsia, anti-microbial and osteoprotective130. Cumin seeds’ oil shows anti-inflammatory activity in lipopolysaccharides-stimulated RAW cells by inhibiting NF-κB and mitogen-activated protein kinase131.
In a recent study, it was found that oral treatment with cumin showed immunomodulatory activity in normal and immune-suppressed species by the stimulation of T cells (CD4 and CD8) with TH1 cytokines132.
FUTURE PERSPECTIVE AND CONCLUSION:
Due to the COVID-19, there is a need to discover new medicines for the prevention and cure of the deadly disease. There are a number of medicines of synthetic origin which are used to boost the immune system but there are a number of side effects and their cost is high. Thus, one can use Ayurvedic formulations and medicinal plants to boost immune system without any side effects. There are several medicinal plants that have been used for centuries for the treatment of various diseases in Ayurveda. They are considered as potential clinical agents against viral diseases due to their immunomodulatory and anti-viral properties. Many clinical trials are ongoing on these herbal medicinal plants for the prevention and treatment of COVID-19. The formulations derived from these herbal plants composed of a number of phytoconstituents such as terpenoids, sesquiterpenoids, alkaloids, flavonoids, tannins, resins, phenols, polyphenols, polysaccharides, saponins, proteins, lipids and peptides that possess various functions against viral invasion, penetration, replication, expression, assembly and release.
Many scientists all over the world are continuously working to develop a suitable antidote for this virus. In recent years, the use of medicinal plants is gaining more acceptances due to their versatility, safety, and cost-effectiveness. Many herbal medicinal plants show immunomodulatory, antiviral, anti-inflammatory and antioxidant properties, it may be considered for the treatment of COVID-19. There is a need to carry out standard clinical trials for scientifically prove its efficacy. The Council of Scientific and Industrial Research (CSIR) along with the AYUSH ministry work collaboratively on four Ayurvedic formulations for validation against COVID-19. The herbs which are mentioned in this review are used as immunomodulators and help to fight against the virus. Additionally, these herbs possess anti-inflammatory, antiviral, antioxidant, antimicrobial, anticarcinogenic, antiulcer and antinephrotoxicity activities in different studies. This herbal medicinal therapy can be used as primary and adjuvant therapy for the prevention and cure from the deadly coronavirus.
The author is thankful to P R Patil Institute of Pharmacy for continuous guidance and support.
CONFLICT OF INTEREST:
The author has no conflict of interest.
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Received on 21.02.2021 Modified on 08.03.2021
Accepted on 16.03.2021 ©AandV Publications All right reserved