key: cord-0913677-fr6k5c7v
authors: Singh, Rahul Soloman; Singh, Ashutosh; Kaur, Harpinder; Batra, Gitika; Sarma, Phulen; Kaur, Hardeep; Bhattacharyya, Anusuya; Sharma, Amit Raj; Kumar, Subodh; Upadhyay, Sujata; Tiwari, Vinod; Avti, Pramod; Prakash, Ajay; Medhi, Bikash
title: Promising traditional Indian medicinal plants for the management of novel Coronavirus disease: A systematic review
date: 2021-06-16
journal: Phytother Res
DOI: 10.1002/ptr.7150
sha: 73aaac2c1c1b2c1d7b53a3d21a789a81495caf24
doc_id: 913677
cord_uid: fr6k5c7v

Traditional Indian medical practices (Ayurveda, Siddha, Unani, and homeopathy) are a vast reservoir of knowledge about medicinal plants. The promising pharmacological properties of these plants have paved the way for developing therapy against novel Coronavirus (CoV) infection. The current review will summarize published works of literature on the effects of traditional Indian medicinal plants against acute respiratory infection (COVID‐19, SARS, Influenza, and Respiratory syncytial virus infection) and registered clinical trials of traditional Indian herbal medicines in COVID‐19. The current study aims to comprehensively evaluate the data of traditional Indian medicinal plants to warrant their use in COVID‐19 management. PubMed, Embase, and Cochrane databases were searched along with different clinical trial databases. A total of 22 relevant traditional Indian medicinal plants (35 relevant studies) were included in the current study having potential antiviral properties against virus‐induced respiratory illness along with promising immunomodulatory and thrombolytic properties. Further, 36 randomized and nonrandomized registered clinical trials were also included that were aimed at evaluating the efficacy of herbal plants or their formulations in COVID‐19 management. The antiviral, immunomodulatory, and thrombolytic activities of the traditional Indian medicinal plants laid down a strong rationale for their use in developing therapies against SARS‐CoV‐2 infection. The study identified some important potential traditional Indian medicinal herbs such as Ocimum tenuiflorum, Tinospora cordifolia, Achyranthes bidentata, Cinnamomum cassia, Cydonia oblonga, Embelin ribes, Justicia adhatoda, Momordica charantia, Withania somnifera, Zingiber officinale, Camphor, and Kabusura kudineer, which could be used in therapeutic strategies against SARS‐CoV‐2 infection.

Infections caused by viruses pose a great challenge due to their wide spectrum of clinical presentations (Zou et al., 2020) . Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes coronavirus disease reported to affect more than 8 million people worldwide and has shown significantly high morbidity and mortality rates within a very short period (WHO, Situation Report-150, 2020) . The critical cases of coronaviruses (CoV) are linked to severe acute respiratory infection (SARI), aberrant immune response (L. Chen et al., 2020; Z. Xu et al., 2020) , and thrombosis (Connors & Levy, 2020; Helms et al., 2020) . At present, there is no drug therapy available for this disease. The research is currently focused on three strategies, first to test broad-spectrum antiviral drugs, second in silico screening, and finally repurposing of drugs .

Apart from these strategies, alternate medicines, for instance, traditional Indian medicines can be explored to find effective drug therapy against the current pandemic. There is a dearth of suitable therapeutic strategies for COVID-19; therefore, it is imperative to peruse all the available options. Traditional Indian medicinal practices, for instance, Ayurveda, Siddha, Unani, and Homeopathy are some of the oldest practices that emerged in the first two centuries (common (Arora et al., 2011) .

Influenza, CoV, and Respiratory syncytial viruses (RSV) all belong to the category of SARI and imposed a great burden on our healthcare (Boncristiani, Criado, & Arruda, 2009 ). These viruses affect both upper and lower respiratory tracts. The complications in these diseases range from fever to pneumonia with high morbidity and mortality (V. C. Cheng, Tang, Wu, Chu, & Yuen, 2004; Thompson & Zambon, 2009 ).

The study aimed to review the efficacy of traditional Indian medicinal plants in these viral-induced respiratory illnesses SARS, RSV, and Influenza) . Further, the study also reviewed the registered clinical trials of traditional Indian herbal medicines and their formulations against COVID-19.

In novel coronavirus, the positive single-stranded RNA of length 30 kb is encircled in a nucleocapsid (N protein) . An important protein present on the virus called spike protein S is a final determinant of its entry into the cell (de Wit, van Doremalen, Falzarano, & Munster, 2016) leading to dysregulation of multiple pathways (Figure 1 ).

RSV is a single-stranded, negative-sense RNA virus whose receptors included toll-like receptor-4 (TLR-4), heparan sulfate proteoglycans (HSPGs), and CX3 chemokine receptor 1 (CX3CR1), which are present at the cell surface. These receptors bind with viral RSV glycoprotein and restrain the virus to the surface of the cell.

Nucleolin cell surface proteins help in the virus entry by activating the fusion of host and virus-cell membranes. Furthermore, the virus hijacks the cellular machinery for its replication. RNA-dependent replication cycle plays an important role in RSV multiplication (Griffiths, Drews, & Marchant, 2017; Ye & Wang, 2018) .

The influenza virus is a single-stranded RNA virus (Rossman & Lamb, 2011) encoding 11 proteins (Blackburne, Hay, & Goldstein, 2008; Tumpey et al., 2007) . The hemagglutinin (HA) protein of the virus complexes binds to the sialic acid residues present on the alveolar epithelium of the target cell to carry out the endocytosis process. The entry of the virus into the lysosome triggers the acidification that activates the matrix protein-2 viral channel resulting in membrane fusion leading to the detachment of the ribonucleoprotein core of the virus. The ribonucleoprotein is then transported to the nucleus for viral replication (Herold, Becker, Ridge, & Budinger, 2015; Rust, Lakadamyali, Zhang, & Zhuang, 2004) .

COVID-19, influenza, and RSV viruses exhibit a broad range of respiratory illnesses from asymptomatic to severe disease and death.

The transmission factors for these viruses are common such as droplets, aerosols, and fomites ( Figure 2 ) (Killingley & Nguyen-Van-Tam, 2013 ; Thompson & Zambon, 2009 

The eligibility of the studies was assessed independently in an unblinded standardized manner. Disagreements between reviewers were resolved by consensus. A total of 1,877 studies were searched using the mentioned criteria out of which 71 studies were scrutinized for the study (Figure 3 ).

(2) Proteolytic cleavage at SARS-CoV S protein at S2 position; (3) Membrane fusion followed by endocytosis; (4) Viral genome released; (5) Polyprotein and Structural protein released; (6) Viral replication takes place, Nucleocapsid formed from genomic RNA and nucleocapsid protein and ultimately ERGIC generate viral particle; (7) Double-layer vesicles contain viral particle formed; (8) Vesicles fuse with plasma membrane and release virus; (9) Viral peptide presentation to antigen-presenting cells and antigen-presenting cells present antigen to T-cells (CD4+ and CD8+); Acacia arabica is also known as gum arabic tree. It has many medicinal roles in Ayurveda and is used in the management of several health diseases, for instance, asthma, inflammation, cough, flu (Singh, Satapathy, & Prasad, 2020) , Peste des petits ruminants (PPR) virus , and goatpox virus . Ghoke et al. (2018) 

Achyranthes bidentata is commonly known as ox knee and is indigenous to the hilly districts of India, China, and Japan. It is widely used as antiarrhythmic, laxative, ecbolic, antihypertensive, antiviral, antispasmodic, anticoagulant, and antitumor (Devi et al., 2007) .

Achyranthes bidentata was found to be effective in bronchitis, which is a type of bronchial tube inflammation caused by certain viruses like coronaviruses, influenza, rhinovirus, and adenovirus (Peiris et al., 2003) . The root extract was found to be effective in bronchitis, cough, asthma, pneumonia, and fever (Singh et al., 2014) .

The sulfated Achyranthes bidentata polysaccharide (ABPS) has a potent antiviral activity. The potency of ABPS was evaluated against porcine reproductive and respiratory syndrome virus (PRRSV) strain that is, (VR2332) in MARC-145 (African green monkey kidney-derived cells) cells. The sulfated form showed antiviral activity even at lower concentrations when compared to nonmodified ABPS in MARC-145 cells (C. Liu et al., 2013) .

The immunomodulatory effect of Achyranthes bidentata polysaccharide (ABP) was evaluated in underdeveloped piglets. The study illustrated increased lymphocyte proliferation, serum IgG (Immunoglobulin type G), IgM, IgA, IL-2 (Interleukin type-2), and IFN-γ (Interferon-gamma) levels. Moreover, it also increased the production of peripheral T-cells and splenic lymphocytes (Q. Chen, Liu, & He, 2009) . Table 2 presents traditional Indian medicinal plants with immunomodulatory properties.

Achyranthes bidentata polypeptide k (ABPPk) has a potential thrombolytic activity. It can prevent oxidative damage of brain endothelial cells caused by ischemia and also leads to NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and plasminogen activator inhibitor-1 activation. ABPPk inhibited the neutrophils, basophils, and eosinophils infiltration along with the activation of various MMP-2/-9 (matrix metalloproteinases) in the ischemic penumbra and alleviated neurological functions (Q. Cheng et al., 2019) . Table 3 Neuraminidase (NA) is an enzyme that hydrolyses sialic acid residue of viruses and receptors of the host. It also helps in virus movement and plays an important role in escaping viruses from the host cell after replication. Aloin inhibited the NA, which further leads to immune suppression, and inhibition of virus replication. Aloin increased the immunity along with an increased hemagglutininspecific T-cell response to the infection (C. T. Huang et al., 2019) . Aloe vera aqueous gel extract from leaves showed a significant immunomodulatory effect by increasing the cell viability of infected macrophages (Farahnejad et al., 2011). 3.1.4 | Andrographis paniculata (Burm.f.) Nees (Acanthaceae) Generally called Kariyat, Andrographis paniculata is a herb that is harvested annually and has a common occurrence throughout India (Rajagopal, Kumar, Deevi, Satyanarayana, & Rajagopalan, 2003) . Sornpet et al. (2017) studied the crude extract of Andrographis paniculata in Influenza A virus subtype H5N1 (H5N1) strain using MDCK cells. The study observed a significant decrease in the virus titer in the treatment group. Enmozhi et al. (2020) observed andrographolide (an Andrographis paniculata extract) fitted with the inhibitor site of one of the proteases that play a central role in the -SARS-CoV-2 virus that is, main protease (Mpro). In silico studies highlighted Andrographolide scored high in the docking study. The docking affinity of the compound was found to be significantly higher than the synthetic compounds like disulfiram, tideglusib, and a combination of lopinavir, oseltamivir, and ritonavir. The in silico study of andrographolide showed significantly high druggability, permeability, solubility, and target accuracy.

Andrographis paniculata has also been observed to inhibit increased levels of NOD-like receptor protein-3 (NLRP3), caspase-1, and interleukin-1β molecules involved in SARS-CoV mechanism (Y. T. Liu, Chen, et al., 2020; Z. Liu, Xiao, et al., 2020) .

The hot water extract of Andrographis paniculata illustrated significant immunomodulatory activity through its multitarget efficacy in esophageal cancer management (Yue et al., 2019) . HN-02 (a mixture of different Andrographis paniculata extract) ameliorated cyclophosphamide-induced immune suppression and stimulated the humoral and cell-mediated immunity (Naik & Hule, 2009 (2), TXB(2), decreased in serum cholesterol Thomson et al., 2002 Abbreviations: ABPPk, Achyranthes bidentata polypeptide k; MMP-2/9, Matrix metalloproteinase-2/9; TNF-α, Tumor necrosis factor alpha; PGE (2) Cydonia oblonga, commonly known as Quince, mainly found in sub-Himalayan regions is effective against diabetes, inflammation, cancer, and ailments related to the heart and brain (R. Sharma, Joshi, & Rana, 2011) .

Phenolic extract of Quince fruit significantly decreased the influenza viral titer (hemagglutinin =27) when compared to the control group (HA = 210). One of the components of phenolic extract that is, procyanidins was found to have strong antiviral activity and prevent infection in the throat (Hamauzu et al., 2005) . During inflammation, TNF-α converting enzyme cleaves the transmembrane protein that is, TNF-α to release it in the extracellular space. Embelia Ribes was found to reduce the secretion of TNF-α thereby act as an antiinflammatory and immunomodulatory agent (Dhanjal et al., 2014) .

Adenosine diphosphate and thrombin-induced platelet aggregation were significantly reduced by ethanol extract of Embelin ribes and moreover, it also inhibited malondialdehyde production in platelets.

Arteriovenous shunt and stasis-induced thrombosis were significantly reduced by embelin in rats (Jagtap et al., 2012) .

3.1.10 | Glycyrrhiza glabra L. (Leguminosae)

Glycyrrhiza glabra, locally known as "liquorice" and "mulaithi," is found mainly in the Punjab and Sub-Himalayan regions of India (Shibata, 2000) . This herb is employed abundantly in traditional Indian medicine as antiinflammatory and antiviral agents (Damle, 2014) . 

Ocimum tenuiflorum is widely distributed in India and its medicinal roles have been mentioned in Indian Ayurveda (Wealth of India, 1991) . There are different parts of Ocimum tenuiflorum used for the treatment of several ailments like asthma, bronchitis, cough, cold,

and digestive disorders (Ghosh, 1995 ).

An in silico study concluded the potential role of Ocimum tenuiflorum extracts in inhibition of ACE-2 (angiotensin-converting enzyme À2)

receptor of SARS-CoV-2 (Varshney, Varshney, & Nath, 2020) . 

Tinospora cordifolia, generally called heart-leaved moonseed, is a shrub that mainly grows in higher altitudes of India. It is found to be effica- Kumar, Kumar, & Mishra, 2010 ).

An in silico study concluded four natural compounds (Berberine,

showed high binding affinity toward four important targets of SARS-CoV-2 that are responsible for attachment (6VSb, 6M0J) and replication (6M71, 6Y84). The reported efficacy of the natural compounds is either equivalent or superior to some of the important antiviral drugs such as Favipiravir, Lopinavir, and Remdesivir (Sagar & Kumar, 2020) .

(1,4)-alpha-D-glucan (alpha-DG) drug was extracted from Tinospora cordifolia and its antiviral efficacy was evaluated in the lungs of E. coli endotoxin-stimulated juvenile rats. Quantification of protein using enzyme-linked immunosorbent assay (ELISA) showed a decline in pro-inflammatory and antiinflammatory cytokines in a drug-treated group when compared to endotoxemia (Velazquez et al., 2009 ).

G1-4A a polysaccharide of Tinospora cordifolia effectively activated macrophages via TLR4-MyD88 dependent pathway and plays an important role in innate immunity (Gupta et al., 2017) .

Tinospora cordifolia aqueous extract efficiently ameliorated cyclophosphamide-induced immunosuppression in a rodent model (Alrumaihi et al., 2019) .

Further, as a herbal formulation, Tinospora cordifolia prevented platelet aggregation, increased the production of lipoprotein lipase enzyme, and delayed plasma calcification. This process resulted in inhibition of atherogenicity (Mary et al., 2003) .

Viscum album belongs to the family Viscaceae and it has various therapeutic roles as a traditional Indian medicinal plant in many diseases like asthma, vertigo, lumbago, and hypertension (Duke, 1987; Zarkovic, Zarkovic, Grainca, Kissel, & Jurin, 1997) .

Different extracts of Viscum album, for instance, distilled water, chloroform, ethanol, acetone, and petroleum ether were examined for antiviral potential against human parainfluenza virus type 2 (HPIV-2) growths in Vero cells. The study observed that out of five extracts, the aqueous extract was the most potent selective inhibitor followed by chloroform extract (Karagöz et al., 2003) .

The peptide of the Viscum album at 2 micrograms/ml enhanced the NK-cell activity in animals. It also induced antibody cellular cytotoxicity and increased the antibody titer in peptide-treated animals (Kuttan & Kuttan, 1992) . Children who were exposed to radioactive fallout when treated with Viscum album resulted in the regulation of immune indices in the controlled range (Chernyshov et al., 2000) .

Withania somnifera (Ashwagandha) has several medicinal roles like antiinflammatory, antioxidant, and immunomodulatory (Malik et al., 2007; Mishra, Singh, & Dagenais, 2000) .

It has an active component Withaferin A (WA) that acts as an antiviral agent. Withaferin A decreased activity of NA in H1N1 influenza.

The docking and molecular dynamics simulation studies found that Withaferin A has a high binding affinity toward NA and showed several important molecular relationships with the residues that are important in the course of simulations (Cai et al., 2015) .

Withania somnifera extract and Withaferin A significantly decreased the toxicity mediated by zinc oxide nanoparticles under in vivo conditions. The extracts also restored TLR6 and phagocytic activities (J. Kumar et al., 2019) . Administration of Withania somnifera extract in mice increased the number of plaque-forming cells, circulation of antibody titer in mice spleen, and phagocytosis activity of macrophages (Davis & Kuttan, 2000) .

As a thrombolytic agent, Withaferin A increased bleeding time and inhibited aggregation of platelets, the formation of thrombus, and fibrin polymerization (Ku & Bae, 2014) .

Woodfordia fruticosa is found throughout the region of India, East

Asia, and some parts of Africa. The flower of the plant has a medicinal role in diseases like menorrhagia, stomach troubles, and liver diseases (Das et al., 2007) .

Gallic acid was prepared from the flower of Woodfordia fruticosa and evaluated for its antiviral potential against human rhinoviruses that the ginger aqueous extract significantly exhibited antiviral activity against H9N2 (Rasool et al., 2017) .

Administration of ginger essential oil orally for a week induced humoral immunity (with sheep red blood cells) in immunosuppressed mice (Carrasco et al., 2009) . Jafarzadeh et al. (2014) showed that the administration of extract of ginger in the experimental mice model of autoimmune encephalomyelitis decreased the IL-27 and IL-33 expression and also modulated the disease severity.

Zingiber officinale has thrombolytic activity. In one of the studies, the use of 500 mg/kg of the ginger extract significantly decreased the serum level of prostaglandin-E(2) and platelet thromboxane-B(2) levels.

The higher doses of the ginger extract significantly decreased the serum cholesterol level (Thomson et al., 2002) .

One of the studies depicted that silver nano-particles of Piper longum fruit extract has potential antibacterial activity and cytotoxicity activity against MCF-7 (breast cancer cell lines) cell lines (Reddy, Vali, Rani, & Rani, 2014) while Tinospora cordifolia has promising antiviral, immunomodulatory, and thrombolytic properties (Alrumaihi et al., 2019; Gupta et al., 2017; Mary et al., 2003; Velazquez et al., 2009 ).

ZingiVir H tablets showed a significant role against respiratory infec- 

Dabur Chyawanprash is a formulation of herbals that are broadly used as a dietary supplement in India. The popularity of herbal remedies is now extended after the occurrence of COVID-19. It has been used for health benefits from ancient times for boosting the immunity of the body. Dabur Chyawanprash is a composition of more than 40 herbs that are clinically tested and found to enhance two times immunity from common routine infections (Phelamei, 2020) . 

Samshamani Vati is recommended for the treatment of fever and anemia at a dose of 500 mg twice a day (Maurya, Kumar, Bhatt, & Saxena, 2020 

Administration of AYUSH-64 for 1 week showed significant improvement in symptoms of Influenza. The study did not report any adverse drug reaction (Gundeti et al., 2020) .

In silico study of 74 compounds depicted that Kaba Sura

Kudineer Chooranam (KSKC) has the potency to inhibit the main protease of COVID-19 (Lakshmanan, Moulishankar, & Suresh, 2020) .

3.2.10 | Vitamin C Vitamin C can be beneficial in the management of viral diseases due to its proven antiviral and immunomodulatory activities (Righi et al., 2020) . 

In silico study depicted that camphor has a good affinity for the protease of COVID-19 and ACE-2 receptor (Omar, Bouziane, Bouslama, & Djemel, 2020) .

Ayush kwath is an Ayurvedic formulation consisting of four medicinal plants (Ocimum sanctum Linn., Cinnamomum zeylanicum Breyn.,

Zingiber officinale Rosc., and Piper nigrum Linn.). The formulation has important antiviral, thrombolytic, antiinflammatory, and immunomodulatory activities. Therefore, it has been recommended by the Government of India as an immune booster against COVID-19 (Gautam, Gautam, Chhetri, & Bhattarai, 2020) .

Arsenic Alba-30 is an important Unani medicine, known for its biological and antioxidant activities. It acts at the subcellular and cellular levels by regulating certain genes that are involved in the enzymatic activity to prevent oxidative damage and genotoxic effects induced by arsenic trioxide (Kundu, Mitra, & Bukhsh, 2000) .

"Joshanda" (decoction) means boiling and "Andah" means prepared by; therefore, it means prepared by boiling. The preparations were used predominantly for influenza, common cold, cough, fever, and respiratory ailments (I. Ahmad, Shamsi, & Shadab, 2020) . (Deodhar & Deodhar, 2020) . Crotalus horridus from rattlesnake venom may be able to inhibit the replication of HIV (P., 2015).

Neolamarckia cadamba is used predominantly in Indian traditional medicine for cough, fever, gastrointestinal ailments, and skin diseases (Umachigi et al., 2007) .

AOIM-Z tablet is manufactured by Solumiks Herbaceuticals and has antioxidant and immunomodulatory properties. It enhances the host defense and is used against respiratory tract infections (Aoim-Z tablets, 2020).

Ayurvedic kadha consists of basil, cinnamon, black pepper, dry ginger, and raisins are effective as an immune booster (Ministry of AYUSH, 2020). Tang, and Baihegujin Tang (Z. .

Correspondingly, the Indian subcontinent is a huge repository of medicinal herbs that have been in use to counteract numerous virusrelated infections of the respiratory tract for ages. There is an unmet need for antiviral agents against COVID-19 that must be effective, safe, and cost-effective (Mitjà & Clotet, 2020) .

The current review puts light on some of the important traditional Indian medicinal herbs that can be a potential antiviral agent against SARS-CoV-2. For instance, in silico studies revealed the potential role of extracts of Andrographis paniculata, Camphor, Ocimum tenuiflorum, and Kabusura kudineer in inhibition of COVID-19. Andrographolide (Andrographis paniculata) fitted well with Mpro of SARS-CoV-2 with high druggability and permeability (Enmozhi et al., 2020) that has a vital role in posttranslational modification of replicase protein in SARS-CoV-2 (Peele et al., 2020) . Another important drug target is the ACE-2 receptor that is the entry gate for SARS-CoV-2 and SARS-CoV.

The inhibition of this receptor can prevent the orchestrated multiple organ damage induced by these coronaviruses (Li, Tang, Li, & Liu, 2020) . In silico studies concluded that Camphor (Omar , 2020) , Ocimum tenuiflorum extract (Varshney et al., 2020) , and Kabusura kudineer (Lakshmanan et al., 2020) bind with the ACE-2 receptor of the coronaviruses that supports their promising role in drug development for COVID-19. The four natural compounds of Tinospora cordifolia are found to bind with the important proteins of -SARS-CoV-2 (Sagar & Kumar, 2020) .

Glycyrrhiza glabra inhibited the cellular pathways of SARS-CoV and prevented its adsorption, penetration, and replication. The findings strongly suggest the use of this herb for the treatment of SARS-CoV-2 infection (Cinatl et al., 2003) .

Apart from these medicinal herbs, which were evaluated against (Rajbhandari et al., 2009) and Cinnamon silver (Ag) nanoparticles showed antiviral activity against influenza with a significant safety profile (Fatima et al., 2016) . In RSV infection, silver nanoparticles of Curcuma longa decreased the viral load (X. X. Yang et al., 2016) and also the viral titer in influenza by inhibiting PI3K signaling pathway (Richart et al., 2018) . Cydonia oblonga and Embelia ribes significantly lowered the viral load of different types of Influenza virus under in vitro conditions (Hamauzu et al., 2005; Hossan et al., 2018) . Hypericum perforatum inhibited IFNγ and chemotactic protein in influenza (N. Huang et al., 2013) while Jatropha curcas inhibited the absorption of H1N1 .

Justicia adhatoda, Momordica charantia, Psoralea corylifolia, Syzygium cumini, Withania somnifera, and Zingiber officinale inhibited the virus titer of different types of Influenza viruses (Cai et al., 2015; Chavan & Chowdhary, 2014; Pongthanapisith et al., 2013; Rasool et al., 2017; Shoji et al., 2015; Sood et al., 2012) . Viscum album significantly reduced the replication of HPIV2 virus under in vitro conditions (Karagöz et al., 2003) . Though these traditional Indian medicinal plants have not been evaluated against SARS-CoV-2, they provide compelling evidence to assess their efficacy against the virus.

The severity of the novel coronavirus infection is associated with high expression of IFN-γ-induced protein-10, macrophage inflammatory protein 1α, monocyte chemo-attractant protein-1, granulocytecolony stimulating factor, TNF-α, IL-2R, IL-6, and interstitial mononuclear inflammatory infiltrates (L. Chen et al., 2020; Z. Xu et al., 2020) . The traditional Indian medicinal plants have a promising immunomodulatory activity, for instance, Achyranthes bidentata increased the lymphocyte proliferation and release of certain cytokines (Q. Chen et al., 2009) while Andographis paniculata and Aloe Vera can activate the humoral and innate immunity on exposure to viral infections (C. T. Huang et al., 2019; Naik & Hule, 2009) . Bergenia ciliata and Cinnamomum Cassia affect the lymphocyte growth and functions (Koh et al., 1998; Tumova & Vokurkov a, 2018) , whereas Curcuma longa increased the PBMC proliferation (Sornpet et al., 2017) . Hypericum perforatum alters the production of cytokines (N. Huang et al., 2013) while Jatropha curcus was found to activate antibody secretion and lymphocyte activation against the Newcastle disease virus (Abd-Alla et al., 2009) . Justicia adhatoda can activate delayed-type hypersensitivity (Vinothapooshan & Sundar, 2011) while Momordica charantia ameliorated the cyclophosphamide-induced immunosuppression in rats (Deng et al., 2014) . Ocimum tenuiflorum can affect the neutrophil and lymphocyte population (Mukherjee et al., 2005) , whereas Psoralea corylifolia induced the NK-cell activity and antibodies-dependent cytotoxicity in cancer cells (Latha et al., 2000) . Tinospora cordifolia activated the innate immune response via TLR4-MY88 axis (Gupta et al., 2017) and ameliorated cyclophosphamide-induced immunosuppression in rats (Alrumaihi et al., 2019) . Viscum album regulated immune indices in radioactive exposed children (Chernyshov et al., 2000) while Withania somnifera has a beneficial role in humoral immunity (Davis & Kuttan, 2000) . Woodfordia fruticosa is useful in immunocompromised conditions (Shah & Juvekar, 2010) , and Zingiber officinale induced humoral immunity in immunosuppressed mice (Carrasco et al., 2009 ). These medicinal plants exhibit significant immunomodulatory activity that could be beneficial in ameliorating the cytokine storm induced by the SARS-CoV-2 virus.

Also, the severity of the disease is associated with a high prevalence of clinically relevant thrombosis in COVID-19 patients. Numerous COVID-19 patients develop ARDS that results in life-threatening thrombotic complications (Connors & Levy, 2020; Helms et al., 2020) .

The traditional medicinal plants showed significant thrombolytic activity, which is attributed to the decreased thromboxane B2 (TXB2), serum level of prostaglandin-E(2), factor Xa, and increased level of 6-keto-prostaglandin F1α (6-keto-PGF1α) that improved blood circulation and reduced weight of thrombus. For instance, Achyranthes bidentata can activate plasminogen activator inhibitor-1 in brain ischemia (Q. Cheng et al., 2019) while Cinnamomum cassia inhibited arachidonic acid and thromboxane A2-induced platelet aggregation (Kim et al., 2010) . Cydonia oblonga dose-dependently reduced venous and arterial thrombus along with decreased thromboxane B2 (TXB2) and increased level of 6-keto-prostaglandin F1α (6-keto-PGF1α) (Zhou et al., 2014) . Embelin ribes inhibited malondialdehyde production in platelets and also reduced arteriovenous shunt and stasis induced thrombosis in rats (Jagtap et al., 2012) . Justicia adhatoda, Momordica charantia, Tinospora cordifolia, and Withania somnifera exhibit significant thrombolytic activity (Ku & Bae, 2014; Manjappa et al., 2015; Mary et al., 2003; Shahriar, 2013) . Zingiber officinale significantly decreased the serum level of prostaglandin-E(2) and platelet thromboxane-B(2) levels (Thomson et al., 2002) . can be used as an add-on therapy.

6. Further, the clinical trials have undertaken some of the potential Indian herbs and formulas against COVID-19. There is an urgent need for prospective cohort studies to further determine the potential of these traditional Indian medicines. Since there is the availability of the population sample of COVID-19, a sequence of prospective studies with well-designed studies should start producing authentic proof for this herbal prevention of COVID-19 or related respiratory infectious diseases shortly.

The authors declare no conflict of interest. 

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Rahul Soloman Singh https://orcid.org/0000-0002-3532-0018

Ajay Prakash https://orcid.org/0000-0002-3487-8482

Bikash Medhi https://orcid.org/0000-0002-4017-641X

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Antiviral activity against infectious bronchitis virus and bioactive components of Hypericum perforatum L

Vitro antitumor activity and synthesis of the key intermediate of bakuchiol

Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese Journal of tuberculosis and respiratory diseases

Achyranthes bidentata polysaccharide enhances immune response in weaned piglets

Anti-tumor effects of bakuchiol, an analogue of resveratrol, on human lung adenocarcinoma A549 cell line

Achyranthes bidentata polypeptide k improves long-term neurological outcomes through reducing downstream microvascular thrombosis in experimental ischemic stroke

Medical treatment of viral pneumonia including SARS in immunocompetent adult

Immunomodulatory and clinical effects of Viscum album (Iscador M and Iscador P) in children with recurrent respiratory infections as a result of the chernobyl nuclear accident

Anti-human rhinovirus activity of gallic acid possessing antioxidant capacity

Aloe vera and its components inhibit influenza A virus-induced autophagy and replication

03)13615-x Clinical trial of Ayurvedic Medicine Zingivir-H tablet starts on COVID-19 patients. (2020). Medical Dialogues

A Pilot study to estimate the effectiveness of Ayurvedic intervention in COVID-19 positive cases

A prospective non-randomised open label controlled interventional study on the effect of Siddha intervention as a prophylactic measure among high risk population (Health Care Workers/ Containment Zone population) exposed to COVID 19

-c). A Prospective, Open label observational clinical study to evaluate the efficacy and safety of MyVir tablets to improve immunity in quarantine patients of COVID-19

A prospective, single centre, randomized open labelled comparative clinical study to evaluate the effectiveness of Siddha medicine, Kabasura kudineer and vitamin c-zinc supplementation in the management of asymptomatic COVID 19 patients

Clinical Trials Registry-India. (n.d.-f). A Randomized, Open Label, Parallel Efficacy, Active Control, Exploratory Clinical Trial to Evaluate Efficacy and Safety of an Ayurvedic Formulation (AYUSH 64) as Adjunct Treatment to Standard of Care for the management of Mild to Moderate COVID-19 Patients

Single Arm Clinical Trial to ascertain the effect of Homoeopathic Medicines in arresting the pathogenesis of disease in asymptomatic Corona virus and suspected Corona virus Patients

Clinical Trials Registry-India. (n.d.-i). Clinical evaluation of Dabur Chyawanprash (DCP) as a preventive remedy in pandemic of COVID-19 -An Open label, Multi centric, Randomized, Comparative, Prospective, Interventional Community based Clinical Study on Healthy individuals

Clinical Trials Registry-India. (n.d.-l). Effect of an Ayurvedic Formulation as add-on to standard of care in COVID-19 positive patients in a tertiary hospital

Effectiveness of Arsenicum Album 30c in Prevention of Covid-19 in Individuals Residing in Hot Spots of Red Zones-A Multicentric, Randomised, Cluster Level

Effectiveness of Arsenicum Album 30c In Prevention Of Covid-19 In Individuals Residing In Hot spots Of Red Zones In Delhi-A Prospective Cohort Study

Efficacy Of Homoeopathic Prophylactic Intervention On Covid-19 Pandemic-A Double Blind Randomised Controlled Trial

Evaluation of Clinical Efficacy of AOIM -Z Tablets for Prevention of COVID -19 Pandemic in High Risk Healthy Police Personnel -Single Arm, Open Labelled, Prospective Exploratory Interventional Clinical Study

Evaluation of Efficacy and Safety of Ayurveda Intervention (Ayush-64) add-on therapy for patients with COVID-19 infection (Stage I)-A Randomized controlled clinical trial

Evaluation of Efficacy and Safety of Ayurveda Intervention (Ayush À64) in the management of COVID-19 infection (Asymptomatic &Mild to Moderate symptoms)-An open label single arm prospective clinical trial

Evaluation of protective potential of an Ayurvedic Rasayan (Chyawanprash) in the prevention of COVID-19 among Health Care Personnel -An open label, prospective Randomized controlled parallel group study. Identifier CTRI/2020/05/025275

Impact of Ayurvedic intervention (Guduchighanvati) in prevention of COVID-19 infection in containment areas of Himachal Pradesh-A community based study

Clinical Trials Registry-India. (n.d.-aa). Observational Study of Ashwagandha tablet intake as a preventive measure in pandemic of -COVID-19 -An open label, Randomized, Controlled, Prospective, Interventional, Community-based Clinical study on healthy subjects

Clinical Trials Registry-India. (n.d.-ac). Observational Study of Yashtimadhu tablet intake as a preventive measure in pandemic of COVID-19 -An open label, Randomized, Controlled, Prospective, interventional, Community-based Cclinicalstudy on healthy subjects

Randomized controlled Single blinded prospective multi-centre clinical trial to investigate the safety and efficacy of ZingiVir-H as an adjuvant therapy in hospitalized adults diagnosed with coronavirus disease

Ayurveda as Prophylaxis for Suspected COVID-19 Patients. Identifier NCT04395976

Ayurveda Self-Management for Flu Like Symptoms During the Covid-19 Outbreak. Identifier NCT04345549

Ayurveda for Flu Like Illness During Covid-19 Outbreak. Identifier NCT04351542

Protecting Health Care Workers During the COVID-19 Outbreak. Identifier NCT04387643

COVID-19 and its implications for thrombosis and anticoagulation

Situation Report -150

Potential anti-HIV activity of Jatropha curcas Linn. Leaf extracts

Glycyrrhiza glabra (Liquorice)-a potent medicinal herb

Woodfordia fruticosa: Traditional uses and recent findings

Immunomodulatory activity of Withania somnifera

Specificity and effector functions of human RSV-Specific IgG from bovine milk

Immunomodulatory activity and partial characterisation of polysaccharides from Momordica charantia

Utility of homeopathic medication 'Antimonium Tartaricum' in the treatment of COVID-19 syndrome

Antibacterial, in vitro lipid per oxidation and phytochemical observation on Achyranthes bidentata Blume

Current Insights into the novel Coronavirus disease 2019 (COVID-19) and its homoeopathic management

Embelin inhibits TNF-α converting enzyme and cancer cell metastasis: Molecular dynamics and experimental evidence

A review on Justicia adhatoda: A potential source of natural medicine

CRC Handbook of Medicinal Herbs

Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: An in silico approach

Immunomodulatory effects of Aloe vera and its fractions on response of macrophages against Candida albicans

In vitro antiviral activity of Cinnamomum cassia and its nanoparticles against H7N3 Influenza A virus

Immunity Against COVID-19: Potential Role of Ayush Kwath

Evaluation of antiviral activity of Ocimum sanctum and Acacia arabica leaves extracts against H9N2 virus using embryonated chicken egg model

Tulasi (NO Labiatae

Computer-guided approach to access the anti-influenza activity of licorice constituents

Respiratory Syncytial virus: Infection, detection, and new options for prevention and treatment

Pharmacological actions and potential uses of Momordica charantia: A review

AYUSH 64, a polyherbal ayurvedic formulation in Influenza like Illness: Results of a pilot study

Activation of murine macrophages by G1-4A, a polysaccharide from Tinospora cordifolia, in TLR4/MyD88 dependent manner

Phenolic profile, antioxidant property, and anti-influenza viral activity of Chinese quince (Pseudocydonia sinensis Schneid.), quince (Cydonia oblonga Mill.), and apple (Malus domestica Mill.) fruits

High risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study

Influenza virus-induced lung injury: Pathogenesis and implications for treatment

Antiviral activity of Embelia ribes Burm. f. against influenza virus in vitro

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Effect of aloin on viral neuraminidase and hemagglutinin-specific T cell immunity in acute influenza

The immuno-regulatory impact of orally-administered Hypericum perforatum extract on Balb/C mice inoculated with H1n1 influenza A virus

In vitro antiallergic effects of aqueous fermented preparations from Citrus and Cydonia fruits

Review on the role of Zn2+ ions in viral pathogenesis and the effect of Zn2+ ions for host cell-virus growth inhibition

Ginger extracts influence the expression of IL-27 and IL-33 in the central nervous system in experimental autoimmune encephalomyelitis and ameliorates the clinical symptoms of disease

Antiplatelet and antithrombotic activity of ethanol extract of Embelia ribes

Discovery of glycyrrhetinic acid as an orally active, direct inhibitor of blood coagulation factor xa

Antiviral potency of mistletoe (Viscum album ssp. album) extracts against human parainfluenza virus type 2 in Vero cells

Inhibitory effect of hot-water extract of quince (Cydonia oblonga) on immunoglobulin E-dependent late-phase immune reactions of mast cells

TIRYAQ E ARBA: A classical Unani formulation to boost immunity

Thrombolytic potential of Ocimum sanctum L., Curcuma longa L., Azadirachta indica L. and Anacardium occidentale L

Routes of influenza transmission. Influenza and Other Respiratory Viruses

Platelet anti-aggregation activities of compounds from Cinnamomum cassia

Comparative antimicrobial potential of Tribhuvana-Mishrana and its ingredients against clinical bacteria

Cinnamaldehyde inhibits lymphocyte proliferation and modulates T-cell differentiation

Antiplatelet, anticoagulant, and profibrinolytic activities of withaferin A

Exploration of immunomodulatory and protective effect of Withania somnifera on trace metal oxide (zinc oxide nanoparticles) induced toxicity in Balb/c mice

Anti-inflammatory and analgesic activity of Indian Hypericum perforatum L

Efficacy of a potentized homoeopathic drug (Arsenicum-album-30) in reducing cytotoxic effects produced by arsenic trioxide in mice: III. Enzymatic changes and recovery of tissue damage in liver

Immunomodulatory activity of a peptide isolated from Viscum album extract (NSC 635 089)

Screening of Kabasura Kudineer Chooranam against COVID-19 through targeting of main protease and RNA-dependent RNA polymerase of SARS-Cov-2 by molecular docking studies

Immunomodulatory and antitumour properties of Psoralea corylifolia seeds

Searching therapeutic strategy of new coronavirus pneumonia from angiotensin-converting enzyme 2: The target of COVID-19 and SARS-CoV

Synthesis and structure-activity relationship studies of water-soluble β-cyclodextrin-glycyrrhetinic acid conjugates as potential antiinfluenza virus agents

Sulfated modification can enhance antiviral activities of Achyranthes bidentata polysaccharide against porcine reproductive and respiratory syndrome virus (PRRSV) in vitro

A diterpenoid, 14-Deoxy-11, 12-didehydroandrographolide, in Andrographis paniculata reduces steatohepatitis and liver injury in mice fed a high-fat and high-cholesterol diet

Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2

A standardized root extract of Withania somnifera and its major constituent withanolide-A elicit humoral and cellmediated immune responses by up regulation of Th1-dominant polarization in BALB/c mice

Momordica charantia seed extract exhibits strong anticoagulant effect by specifically interfering in intrinsic pathway of blood coagulation and dissolves fibrin clot

Evaluation of pharmacognostical parameters and Hepatoprotective activity in Bryonia alba Linn

Antiatherogenic effect of Caps HT2, a herbal Ayurvedic medicine formulation

Therapeutic Development and Drugs for the Treatment of COVID-19

Evaluation of immunomodulatory activity of Glycyrhiza glabra L roots in combination with zing

Evaluation of immunomodulatory potential of Ocimum sanctum seed oil and its possible mechanism of action

Status of Embelia ribes Burm f.(Vidanga), an important medicinal species of commerce from northern Western Ghats of India. Current Science

Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): A review

Use of antiviral drugs to reduce COVID-19 transmission. The Lancet

Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement

Immunotherapeutic potential of Ocimum sanctum (L) in bovine subclinical mastitis

Evaluation of immunomodulatory activity of an extract of andrographolides from Andographis paniculata

National Health Commission of the People's Republic of China

Antibacterial activities and antioxidant capacity of Aloe vera

In-silico identification of potent inhibitors of COVID-19 main protease (Mpro) and angiotensin converting enzyme 2 (ACE2) from natural products: Quercetin, hispidulin, and cirsimaritin exhibited better potential inhibition than hydroxy-chloroquine against COVID-19 main protease active site and ACE2

Homeopathic medicine from snake venom can arrest spread of HIV, claim researchers. DNA India

Medico-botanical study of Yercaud hills in the eastern Ghats of Tamil Nadu

Evaluation of Jatropha curcas Linn. leaf extracts for its cytotoxicity and potential to inhibit hemagglutinin protein of influenza virus

Molecular docking and dynamic simulations for antiviral compounds against SARS-CoV-2: A computational study

Coronavirus as a possible cause of severe acute respiratory syndrome

Can Chyawanprash help prevent or cure coronavirus infection? Benefits and uses of Ayurvedic medicine

A dermocosmetic containing bakuchiol, Ginkgo biloba extract and mannitol improves the efficacy of adapalene in patients with acne vulgaris: Result from a controlled randomized trial

Antiviral protein of momordica charantia L. inhibits different subtypes of Influenza A. Evidence-based Complementary and Alternative Medicine: Ecam

Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata

Antiviral activity of some plants used in Nepalese traditional medicine

Genetic diversity analysis of Tinospora cordifolia germplasm collected from northwestern Himalayan region of India

Anti-avian influenza virus H9N2 activity of aqueous extracts of Zingiber officinalis (Ginger) and Allium sativum (Garlic) in chick embryos

The role of zinc in antiviral immunity

Evaluation of antioxidant, antibacterial and cytotoxic effects of green synthesized silver nanoparticles by Piper longum fruit

Synergic effect of curcumin and its structural analogue (Monoacetylcurcumin) on anti-influenza virus infection

Effects of vitamin C on oxidative stress, inflammation, muscle soreness, and strength following acute exercise: Meta-analyses of randomized clinical trials

Influenza virus assembly and budding

Assembly of endocytic machinery around individual influenza viruses during viral entry

Efficacy of natural compounds from Tinospora cordifolia against SARS-CoV-2 protease, surface glycoprotein and RNA polymerase

Bergenia ciliata extract prevents ethylene glycol induced histopathological changes in the kidney

Pharmacologic treatments for Coronavirus disease 2019 (COVID-19): A review

In vitro and in vivo immunostimulatory activity of Woodfordia fruticosa flowers on non-specific immunity

Phytochemical screenings and thrombolytic activity of the leaf extracts of Adhatoda vasica

Nutritional composition and processed products of quince

Immunomodulatory active compounds from Tinospora cordifolia

A drug over the millennia: Pharmacognosy, chemistry, and pharmacology of licorice

Bakuchiol is a phenolic isoprenoid with novel enantiomer-selective anti-influenza A virus activity involving Nrf2 activation

Charaka Saṁhit a

Survey on traditional uses of medicinal plants of Bageshwar Valley (Kumaun Himalaya) of Uttarakhand

Development, characterization and evaluation of microparticles containing Acacia arabica

Zinc and respiratory tract infections: Perspectives for COVID-19 (Review)

Antiviral activity of crude extracts of Eugenia jambolana Lam. against highly pathogenic avian influenza (H5N1) virus

Antiviral activity of five Asian medicinal pant crude extracts against highly pathogenic H5N1 avian influenza virus

Effect of zinc salts on respiratory syncytial virus replication

Version 1.1

Influenza, respiratory syncytial virus and SARS

The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent

Immunostimulant activity of Bergenia Extracts

A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission

Antimicrobial, wound healing and antioxidant activities of Anthocephalus cadamba

Tinospora cordifolia (Willd.) Hook. f. and Thoms. (Guduchi) -validation of the Ayurvedic pharmacology through experimental and clinical studies

Molecular Modeling of Isolated Phytochemicals from Ocimum sanctum Towards Exploring Potential Inhibitors of SARS Coronavirus Main Protease and Papain-Like Protease to Treat COVID-19

Immunological response to (1,4)-alpha-Dglucan in the lung and spleen of endotoxin-stimulated juvenile rats

Anti-ulcer activity of Adhatoda vasica leaves against gastric ulcer in rats

Immunomodulatory activity of andrographolide on macrophage activation and specific antibody response

New Delhi, CSIR. Publication and information directorate

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Therapeutic efficacy of Hypericum perforatum L. extract for mice infected with an influenza A virus

Traditional Chinese Medicine treatment of COVID-19

The effect of dietary bovine colostrum on respiratory syncytial virus infection and immune responses following the infection in the mouse

Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet

Curcumin modified silver nanoparticles for highly efficient inhibition of respiratory syncytial virus infection

Laboratory epidemiology of respiratory viruses in a large children's hospital: A STROBE-compliant article

Immunostimulatory activities of polysaccharide extract isolated from Curcuma longa

Evaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longa

Multiple modulatory activities of Andrographis paniculata on immune responses and xenograft growth in esophageal cancer preclinical models

The Viscum album preparation Isorel inhibits the growth of melanoma B16F10 by influencing the tumour-host relationship. Anti-Cancer Drugs

Effects of Cydonia oblonga Miller extracts on blood hemostasis, coagulation and fibrinolysis in mice, and experimental thrombosis in rats

SARS-CoV-2 viral load in upper respiratory specimens of infected patients

Promising traditional Indian medicinal plants for the management of novel Coronavirus disease: A systematic review