Exploring the Efficacy of Traditional Herbs in Combating COVID-19: A
Comprehensive Review

Anil      Sao; Tulsidas      Nimbekar; Garla      Venkateswarlu; Mohit      Mishra; Aditya      Kate; Meenakshi   Kanwar   Chauhan; Chandrashekhar   Mahadeo   Chakole
Abstract

Background: The entire world witnessed the COVID-19 pandemic outbreak. It has become deadly everywhere across the globe. COVID-19 mortality varies across age groups and has been linked to an individual's innate immunity. In contrast, it was more lethal in immunocompromised people. The spread of viruses is slowed by both passive immunity and vaccine-aided acquired immunity. However, vaccine-induced immunity is transient, and there is no assurance that vaccinemediated antibodies will be effective against all future virus mutants. As a result, natural immunity boosters have become essential supplements that must be used nowadays to stay immunized against such infections. In Ayurvedic medicine, traditional Indian spices have been used for a long time to boost the immune system and fight off different diseases.
Objective: This review aims to disseminate information about traditional natural medicine in repurposing as an immunity booster and for antiviral effects in COVID-19.
Methods: Using published articles from recent years, the in silico docking study, survey-based study, and in vitro and preclinical research work on selected traditional herbs for their anti-inflammatory, immunomodulating, and antiviral properties are summarized. Withania somnifera, Piper nigrum, Emblica officinalis, Andrographis paniculate, Glycyrrhiza glabra, Ocimum sanctum, Piper longum, and Curcuma longa are some of the most commonly used natural spices studied extensively and hence selected in this review.
Results: This context summarizes selected plants showing immunomodulatory and antiviral effects in experimental animals, simulation, and clinical studies.
Conclusion: By virtue of antiviral potential, the chosen herbs could be used for repurposing in COVID-19 management after thorough clinical investigations.
Graphical Abstract

[1]
Cucinotta D, Vanelli M. WHO declares COVID-19 a pandemic. Acta Biomed  2020; 91(1): 157-60.
 [PMID: 32191675]

[2]
Statement for healthcare professionals: How COVID-19 vaccines are regulated for safety and effectiveness (Revised March 2022). [https://www.who.int/news/item/17-05-2022-statement-for-healthcare-professionals-how-covid-19-vaccines-are-regulated-for-safety-and-effectiveness]

[3]
Coronavirus disease (COVID-19): Herd immunity, lockdowns and COVID-19.  [https://www.who.int/news-room/questions-and-answers/item/herd-immunity-lockdowns-and-covid-19]

[4]
Dube T, Ghosh A, Mishra J, Kompella UB, Panda JJ. Repurposed drugs, molecular vaccines, immune-modulators, and nanotherapeutics to treat and prevent COVID-19 associated with SARS-CoV-2, a deadly nanovector. Adv Ther  2021; 4(2): 2000172.
 [http://dx.doi.org/10.1002/adtp.202000172] [PMID: 33173808]

[5]
Sajna KV, Kamat S. Antibodies at work in the time of severe acute respiratory syndrome coronavirus 2. Cytotherapy  2021; 23(2): 101-10.
 [http://dx.doi.org/10.1016/j.jcyt.2020.08.009] [PMID: 32988772]

[6]
Kandimalla R, Chakraborty P, Vallamkondu J, et al. Counting on COVID-19 vaccine: Insights into the current strategies, progress and future challenges. Biomedicines  2021; 9(11): 1740.
 [http://dx.doi.org/10.3390/biomedicines9111740] [PMID: 34829969]

[7]
Sanjuán R, Domingo-Calap P. Mechanisms of viral mutation. Cell Mol Life Sci  2016; 73(23): 4433-48.
 [http://dx.doi.org/10.1007/s00018-016-2299-6] [PMID: 27392606]

[8]
Islam MT, Quispe C, Herrera-Bravo J, et al. Possible mutation pathways in SARS-CoV-2. Farmacia  2021; 69(6): 1001-17.
 [http://dx.doi.org/10.31925/farmacia.2021.6.1]

[9]
Das S, Samanta S, Banerjee J, et al. Is Omicron the end of pandemic or start of a new innings? Travel Med Infect Dis  2022; 48: 102332.
 [http://dx.doi.org/10.1016/j.tmaid.2022.102332] [PMID: 35472451]

[10]
Cascella M, Rajnik M, Aleem A, et al. Features, evaluation, and treatment of coronavirus (COVID-19) StatPearls. Treasure Island, FL: StatPearls Publishing 2022.

[11]
Enhancing response to Omicron SARS-CoV-2 variant:Technical brief and priority actions for Member States. Headquarters, Geneva, Switzerland: World Health Organization HQ 2021.

[12]
COVID-19, Vaccines, and the Immune System: Emerging Research from NCI’s SeroNet.  Available from: [https://www.cancer.gov/news-events/cancer-currents-blog/2021/covid-19-antibodies-nci-seronet]

[13]
Gruell H, Vanshylla K, Tober-Lau P, et al. mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant. Nat Med  2022; 28(3): 477-80.
 [http://dx.doi.org/10.1038/s41591-021-01676-0] [PMID: 35046572]

[14]
Calder PC. Nutrition, immunity and COVID-19. BMJ Nutr Prev Health  2020; 3(1): 74-92.
 [http://dx.doi.org/10.1136/bmjnph-2020-000085] [PMID: 33230497]

[15]
Sen S, Chakraborty R. Revival, modernization and integration of Indian traditional herbal medicine in clinical practice: Importance, challenges and future. J Tradit Complement Med  2017; 7(2): 234-44.
 [http://dx.doi.org/10.1016/j.jtcme.2016.05.006] [PMID: 28417092]

[16]
Elujoba AA, Odeleye OM, Ogunyemi CM. Traditional medicine development for medical and dental primary health care delivery system in Africa. Afr J Tradit Complement Altern Med  2005; 2(1): 46-61.

[17]
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect  2020; 80(6): 607-13.
 [http://dx.doi.org/10.1016/j.jinf.2020.03.037] [PMID: 32283152]

[18]
Tagde P, Tagde S, Tagde P, et al. Nutraceuticals and herbs in reducing the risk and improving the treatment of COVID-19 by targeting SARS-CoV-2. Biomedicines  2021; 9(9): 1266.
 [http://dx.doi.org/10.3390/biomedicines9091266] [PMID: 34572452]

[19]
Khuntia BK, Sharma V, Wadhawan M, et al. Antiviral potential of Indian medicinal plants against influenza and SARS-CoV: A systematic review. Nat Prod Commun  2022; 17(3): 1934578X221086988.

[20]
Paudyal V, Sun S, Hussain R, Abutaleb MH, Hedima EW. Complementary and alternative medicines use in COVID-19: A global perspective on practice, policy and research. Res Social Adm Pharm  2022; 18(3): 2524-8.
 [http://dx.doi.org/10.1016/j.sapharm.2021.05.004] [PMID: 33992585]

[21]
Alam S, Sarker MMR, Afrin S, et al. Traditional herbal medicines, bioactive metabolites, and plant products against COVID-19: update on clinical trials and mechanism of actions. Front Pharmacol  2021; 12: 671498.
 [http://dx.doi.org/10.3389/fphar.2021.671498] [PMID: 34122096]

[22]
Berretta AA, Silveira MAD, Cóndor Capcha JM, De Jong D. Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease. Biomed Pharmacother  2020; 131: 110622.
 [http://dx.doi.org/10.1016/j.biopha.2020.110622] [PMID: 32890967]

[23]
Abiri R, Abdul-Hamid H, Sytar O, et al. A brief overview of potential treatments for viral diseases using natural plant compounds: The case of SARS-CoV. Molecules  2021; 26(13): 3868.
 [http://dx.doi.org/10.3390/molecules26133868] [PMID: 34202844]

[24]
Halder M, Bose R, Jha S. The Potential Role of Medicinal Plants, Traditional Herbal Medicines, and Formulations to Overcome SARS-CoV-2 Induced Health Crisis. In: InMedicinal Plants: Biodiversity, Biotechnology and Conservation.  Singapore: Springer Nature Singapore 2023; pp. 465-524.

[25]
Demeke CA, Woldeyohanins AE, Kifle ZD. Herbal medicine use for the management of COVID-19: A review article. Metabolism Open  2021; 12: 100141.
 [http://dx.doi.org/10.1016/j.metop.2021.100141] [PMID: 34693242]

[26]
Ren W, Liang P, Ma Y, et al. Research progress of traditional Chinese medicine against COVID-19. Biomed Pharmacother  2021; 137: 111310.
 [http://dx.doi.org/10.1016/j.biopha.2021.111310] [PMID: 33761591]

[27]
Chu L, Huang F, Zhang M, Huang B, Wang Y. Current status of traditional Chinese medicine for the treatment of COVID-19 in China. Chin Med  2021; 16(1): 63.
 [http://dx.doi.org/10.1186/s13020-021-00461-y] [PMID: 34315521]

[28]
Sen IK, Chakraborty I, Mandal AK, Bhanja SK, Patra S, Maity P. A review on antiviral and immunomodulatory polysaccharides from Indian medicinal plants, which may be beneficial to COVID-19 infected patients. Int J Biol Macromol  2021; 181: 462-70.
 [http://dx.doi.org/10.1016/j.ijbiomac.2021.03.162] [PMID: 33794238]

[29]
Asif M, Saleem M, Saadullah M, Yaseen HS, Al Zarzour R. COVID-19 and therapy with essential oils having antiviral, anti-inflammatory, and immunomodulatory properties. Inflammopharmacology  2020; 28(5): 1153-61.
 [http://dx.doi.org/10.1007/s10787-020-00744-0] [PMID: 32803479]

[30]
Singh N, Bhalla M, De Jager P, Gilca M. An overview on ashwagandha: a Rasayana (rejuvenator) of Ayurveda. Afr J Tradit Complement Altern Med  2011; 8(5S) (Suppl.): 208-13.
 [http://dx.doi.org/10.4314/ajtcam.v8i5S.9] [PMID: 22754076]

[31]
Mandlik Ingawale DS, Namdeo AG. Pharmacological evaluation of Ashwagandha highlighting its healthcare claims, safety, and toxicity aspects. J Diet Suppl  2021; 18(2): 183-226.
 [http://dx.doi.org/10.1080/19390211.2020.1741484] [PMID: 32242751]

[32]
Shree P, Mishra P, Selvaraj C, et al. Targeting COVID-19 (SARS-CoV-2) main protease through active phytochemicals of ayurvedic medicinal plants – Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi) – a molecular docking study. J Biomol Struct Dyn  2022; 40(1): 190-203.
 [http://dx.doi.org/10.1080/07391102.2020.1810778] [PMID: 32851919]

[33]
Chikhale RV, Gurav SS, Patil RB, et al. Sars-cov-2 host entry and replication inhibitors from Indian ginseng: an in-silico approach. J Biomol Struct Dyn  2021; 39(12): 4510-21.
 [http://dx.doi.org/10.1080/07391102.2020.1778539] [PMID: 32568012]

[34]
Singh G, Chudasama K. Efficacy of ashvagandha (WITHANIA SOMNIFERA) on immunity of krisha (underweight). JAPS  2015; 2(3)

[35]
Straughn AR, Kakar SS, Withaferin A. Withaferin A: a potential therapeutic agent against COVID-19 infection. J Ovarian Res  2020; 13(1): 79.
 [http://dx.doi.org/10.1186/s13048-020-00684-x] [PMID: 32684166]

[36]
Butt MS, Pasha I, Sultan MT, Randhawa MA, Saeed F, Ahmed W. Black pepper and health claims: a comprehensive treatise. Crit Rev Food Sci Nutr  2013; 53(9): 875-86.
 [http://dx.doi.org/10.1080/10408398.2011.571799] [PMID: 23768180]

[37]
Purohit P. Potential medicinal plants for COVID-19. Faslnamah-i Giyahan-i Daruyi  2021; 9: 30-4.

[38]
Gautam S, Gautam A, Chhetri S, Bhattarai U. Immunity against COVID-19: Potential role of Ayush Kwath. J Ayurveda Integr Med  2022; 13(1): 100350.
 [http://dx.doi.org/10.1016/j.jaim.2020.08.003] [PMID: 32837101]

[39]
Rehman A, Mehmood MH, Haneef M, et al. Potential of black pepper as a functional food for treatment of airways disorders. J Funct Foods  2015; 19: 126-40.
 [http://dx.doi.org/10.1016/j.jff.2015.09.006]

[40]
Dhargawe N, Mahakalkar S, Mohod B, Raj JP. Evaluation of Analgesic, Anti-Inflammatory, and Antipyretic Activity of Piperine: An Experimental Study. Pharmacognosy Res  2021; 12(2)

[41]
Roshdy WH, Rashed HA, Kandeil A, et al. EGYVIR: An immunomodulatory herbal extract with potent antiviral activity against SARS-CoV-2. PLoS One  2020; 15(11): e0241739.
 [http://dx.doi.org/10.1371/journal.pone.0241739] [PMID: 33206688]

[42]
Davella R, Gurrapu S, Mamidala E. Phenolic compounds as promising drug candidates against COVID-19 - an integrated molecular docking and dynamics simulation study. Mater Today Proc  2022; 51: 522-7.
 [http://dx.doi.org/10.1016/j.matpr.2021.05.595] [PMID: 34094885]

[43]
Singh R, Singh N, Saini BS, Rao H. In vitro antioxidant activity of pet ether extract of black pepper. Indian J Pharmacol  2008; 40(4): 147-51.
 [http://dx.doi.org/10.4103/0253-7613.43160] [PMID: 20040947]

[44]
Khanna K, Kohli SK, Kaur R, et al. Herbal immune-boosters: Substantial warriors of pandemic COVID-19 battle. Phytomedicine  2021; 85: 153361.
 [http://dx.doi.org/10.1016/j.phymed.2020.153361] [PMID: 33485605]

[45]
Umashanker M, Shruti S. Traditional Indian herbal medicine used as antipyretic, antiulcer, anti-diabetic and anticancer: A review. IJRPC  2011; 1(4): 1152-9.

[46]
Bhagat M. Indian gooseberry (Emblica officinalis): Pharmacognosy review. In: Utilization and management of medicinal plants.   2014; 2: pp. 471-87.

[47]
Lim TK. Phyllanthus emblica InEdible Medicinal And Non-Medicinal Plants.  Dordrecht: Springer 2012; pp. 258-96.
 [http://dx.doi.org/10.1007/978-94-007-4053-2_37]

[48]
Zhang H, Dellsperger KC, Zhang C. The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update. Basic Res Cardiol  2012; 107(1): 237.
 [http://dx.doi.org/10.1007/s00395-011-0237-1] [PMID: 22189563]

[49]
Tarwadi K, Agte V. Antioxidant and micronutrient potential of common fruits available in the Indian subcontinent. Int J Food Sci Nutr  2007; 58(5): 341-9.
 [http://dx.doi.org/10.1080/09637480701243905] [PMID: 17558726]

[50]
Dharmananda S. Emblic Myrobalans: AMLA Key Herb of Ayurvedic Medicine. ITM 2003.

[51]
Bhattacharya A, Chatterjee A, Ghosal S, Bhattacharya SK. Antioxidant activity of active tannoid principles of Emblica officinalis (amla). Indian J Exp Biol  1999; 377: 676-80.

[52]
Habib-ur-Rehman , Yasin KA, Choudhary MA, et al. Studies on the chemical constituents of Phyllanthus emblica. Nat Prod Res  2007; 21(9): 775-81.
 [http://dx.doi.org/10.1080/14786410601124664] [PMID: 17763100]

[53]
Ghoshal S, Tripathi VK, Chauhan S. Active constituents of Emblica officinalis. Part I, the Chemistry and antioxidative effects of two hydrolyzable tannins, emblicanin A and B. Indian J Chem  1996; 35: 941-8.

[54]
Murugesan S, Kottekad S, Crasta I, et al. Targeting COVID-19 (SARS-CoV-2) main protease through active phytocompounds of ayurvedic medicinal plants – Emblica officinalis (Amla), Phyllanthus niruri Linn. (Bhumi Amla) and Tinospora cordifolia (Giloy) – A molecular docking and simulation study. Comput Biol Med  2021; 136: 104683.
 [http://dx.doi.org/10.1016/j.compbiomed.2021.104683] [PMID: 34329860]

[55]
Mohamed TS, Refahy LA, Romeih MH, Hamed MM, Ahmed HO, El-Hashash MA. Chromatographic Isolation and Characterization of Certain Bioactive Chemical Ingredients of Phyllanthus emblica Extracts and Assessment of Their Potentials as Antiviral and Anticancer Agents. Egypt J Chem  2022; 65(1): 179-92.

[56]
Varnasseri M, Siahpoosh A, Hoseinynejad K, et al. The effects of add-on therapy of Phyllanthus emblica (Amla) on laboratory confirmed COVID-19 Cases: A randomized, double-blind, controlled trial. Complement Ther Med  2022; 65: 102808.
 [http://dx.doi.org/10.1016/j.ctim.2022.102808] [PMID: 35093510]

[57]
Srivastav AK, Gupta SK, Kumar U. Computational studies towards identification of lead herbal compounds of medicinal importance for development of nutraceutical against COVID-19. Theoretical and Computational Chemistry 2020.
 [http://dx.doi.org/10.26434/chemrxiv.12581819.v1]

[58]
Pandey K, Lokhande KB, Swamy KV, Nagar S, Dake M. In silico exploration of phytoconstituents from Phyllanthus emblica and Aegle marmelos as potential therapeutics against SARS-CoV-2 RdRp. Bioinform Biol Insights  2021; 15.
 [http://dx.doi.org/10.1177/11779322211027403] [PMID: 34248355]

[59]
Chikhale RV, Sinha SK, Khanal P, et al. Computational and network pharmacology studies of Phyllanthus emblica to tackle SARS-CoV-2. Phytomedicine Plus  2021; 1(3): 100095.
 [http://dx.doi.org/10.1016/j.phyplu.2021.100095] [PMID: 35399824]

[60]
Gupta A, Chaphalkar SR. Flow cytometric analysis of immunoadjuvant activity of Emblica officinalis on human whole blood. World J Pharm Res  2015; 4(2): 1063-71.

[61]
Kaleem QM, Akhtar M, Awais MM, et al. Studies on Emblica officinalis derived tannins for their immunostimulatory and protective activities against coccidiosis in industrial broiler chickens. ScientificWorldJournal  2014; 2014: 1-10.
 [http://dx.doi.org/10.1155/2014/378473] [PMID: 24578631]

[62]
Kaur G, Sachdeva H, Kaur J. In vivo evaluation of the antileishmanial activity of two immunomodulatory plants, Emblica officinalis and Azadirachta indica in Balb/c mice. IJAHM  2013; 3: 1066-79.

[63]
Nath A, Raghunatha P, Joshi SR. Diversity and biological activities of endophytic fungi of Emblica officinalis, an ethnomedicinal plant of India. Mycobiology  2012; 40(1): 8-13.
 [http://dx.doi.org/10.5941/MYCO.2012.40.1.008] [PMID: 22783128]

[64]
Liu X, Zhao M, Wu K, et al. Immunomodulatory and anticancer activities of phenolics from emblica fruit (Phyllanthus emblica L.). Food Chem  2012; 131(2): 685-90.
 [http://dx.doi.org/10.1016/j.foodchem.2011.09.063]

[65]
Alamgir M, Uddin SJ. Recent advances on the ethnomedicinal plants as immunomodulatory agents. In: Ethnomedicine: a source of complementary therapeutics.   2010; 37: p. (661)2.

[66]
Suja RS, Nair AM, Sujith S, Preethy J, Deepa AK. Evaluation of immunomodulatory potential of Emblica officinalis fruit pulp extract in mice. Indian J Anim Res  2009; 43(2): 103-6.

[67]
Sai Ram M, Neetu D, Yogesh B, et al. Cyto-protective and immunomodulating properties of Amla (Emblica officinalis) on lymphocytes: an in-vitro study. J Ethnopharmacol  2002; 81(1): 5-10.
 [http://dx.doi.org/10.1016/S0378-8741(01)00421-4] [PMID: 12020921]

[68]
Mitra SK, Gupta M, Sarma DNK. Immunomodulatory effect of IM-133. Phytother Res  1999; 13(4): 341-3.
 [http://dx.doi.org/10.1002/(SICI)1099-1573(199906)13:4<341::AID-PTR410>3.0.CO;2-6] [PMID: 10404544]

[69]
Halim B, Syahputra RA, Adenin I, et al. Determination of Phytochemical Constituent, Antioxidant Activity, Total Phenol and Total Flavonoid of Extract Ethanol Phyllanthus emblica Fruit. Pharmacogn J  2022; 14(1): 63-7.
 [http://dx.doi.org/10.5530/pj.2022.14.9]

[70]
Verma H, Negi MS, Mahapatra BS, Shukla A, Paul J. Evaluation of an emerging medicinal crop Kalmegh [Andrographis paniculata (Burm. F.) Wall. Ex. Nees] for commercial cultivation and pharmaceutical & industrial uses: A review. J Pharmacogn Phytochem  2019; 8(4): 835-48.

[71]
Sainhi H, Sirohiya RA. A Review Article on Phytochemicals New Line of Treatment of Sars COVID-19. IOSR-JPBS  2020; 15(3): 36-46.

[72]
Sa-ngiamsuntorn K, Suksatu A, Pewkliang Y, et al. Anti-SARS-CoV-2 activity of Andrographis paniculata extract and its major component Andrographolide in human lung epithelial cells and cytotoxicity evaluation in major organ cell representatives. J Nat Prod  2021; 84(4): 1261-70.
 [http://dx.doi.org/10.1021/acs.jnatprod.0c01324] [PMID: 33844528]

[73]
Banerjee S, Kar A, Mukherjee PK, Haldar PK, Sharma N, Katiyar CK. Immunoprotective potential of Ayurvedic herb Kalmegh (Andrographis paniculata) against respiratory viral infections – LC–MS/MS and network pharmacology analysis. Phytochem Anal  2021; 32(4): 629-39.
 [http://dx.doi.org/10.1002/pca.3011] [PMID: 33167083]

[74]
Rajagopal K, Varakumar P, Baliwada A, Byran G. Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): An in silico approach. Future J Pharm Sci  2020; 6(1): 1-0.

[75]
Maity GN, Maity P, Dasgupta A, Acharya K, Dalai S, Mondal S. Structural and antioxidant studies of a new arabinoxylan from green stem Andrographis paniculata (Kalmegh). Carbohydr Polym  2019; 212: 297-303.
 [http://dx.doi.org/10.1016/j.carbpol.2019.02.051] [PMID: 30832860]

[76]
Abraham J, Florentine S. Licorice (Glycyrrhiza glabra) Extracts-Suitable Pharmacological Interventions for COVID-19? A Review. Plants  2021; 10(12): 2600.
 [http://dx.doi.org/10.3390/plants10122600] [PMID: 34961070]

[77]
Sharma D, Namdeo P, Singh P. Phytochemistry and Pharmacological Studies of Glycyrrhiza glabra: A Medicinal Plant Review. Int J Pharm Sci Rev Res  2021; 67(1): 187-94.
 [http://dx.doi.org/10.47583/ijpsrr.2021.v67i01.030]

[78]
Ashfaq UA, Masoud MS, Nawaz Z, Riazuddin S. Glycyrrhizin as antiviral agent against Hepatitis C Virus. J Transl Med  2011; 9(1): 112.
 [http://dx.doi.org/10.1186/1479-5876-9-112] [PMID: 21762538]

[79]
Hoever G, Baltina L, Michaelis M, et al. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J Med Chem  2005; 48(4): 1256-9.
 [http://dx.doi.org/10.1021/jm0493008] [PMID: 15715493]

[80]
Srivastava V, Yadav A, Sarkar P. Molecular docking and ADMET study of bioactive compounds of Glycyrrhiza glabra against main protease of SARS-CoV2. Mater Today Proc 2020.
 [PMID: 33078096]

[81]
Bailly C, Vergoten G. Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome? Pharmacol Ther  2020; 214: 107618.
 [http://dx.doi.org/10.1016/j.pharmthera.2020.107618] [PMID: 32592716]

[82]
van de Sand L, Bormann M, Alt M, et al. Glycyrrhizin effectively inhibits SARS-CoV-2 replication by inhibiting the viral main protease. Viruses  2021; 13(4): 609.
 [http://dx.doi.org/10.3390/v13040609] [PMID: 33918301]

[83]
Chrzanowski J, Chrzanowska A, Graboń W. Glycyrrhizin: An old weapon against a novel coronavirus. Phytother Res  2021; 35(2): 629-36.
 [http://dx.doi.org/10.1002/ptr.6852] [PMID: 32902005]

[84]
Zhao Z, Xiao Y, Xu L, et al. Glycyrrhizic acid nanoparticles as antiviral and anti-inflammatory agents for COVID-19 treatment. ACS Appl Mater Interfaces  2021; 13(18): 20995-1006.
 [http://dx.doi.org/10.1021/acsami.1c02755] [PMID: 33930273]

[85]
Patwardhan B, Warude D, Pushpangadan P, Bhatt N. Ayurveda and traditional Chinese medicine: a comparative overview. Evid Based Complement Alternat Med  2005; 2(4): 465-73.
 [http://dx.doi.org/10.1093/ecam/neh140] [PMID: 16322803]

[86]
Kumar R, Saha P, Lokare P, Datta K, Selvakumar P, Chourasia A. A Systemic Review of Ocimum sanctum (Tulsi): Morphological Characteristics, Phytoconstituents and Therapeutic Applications. International Journal for Research in Applied Sciences and Biotechnology  2022; 9(2): 221-6.
 [http://dx.doi.org/10.31033/ijrasb.9.2.15]

[87]
Kulkarni KV, Adavirao BV. A review on: Indian traditional shrub Tulsi (Ocimum sanctum): the unique medicinal plant. Journal of Medicinal Plants Studies  2018; 6(2): 106-10.

[88]
Naquvi KJ, Dohare SL, Shuaib M, Ahmad MI. Chemical composition of volatile oil of Ocimum sanctum Linn. Int J Biol Adv Res  2012; 3(2): 129-31.
 [http://dx.doi.org/10.7439/ijbar.v3i2.290]

[89]
Singh S, Taneja M, Majumdar DK. Biological activities of Ocimum sanctum L. fixed oil--an overview. Indian J Exp Biol  2007; 455: 403-12.

[90]
Jeba CR, Vaidyanathan R, Rameshkumar G. Immunomodulatory activity of aqueous extract of Ocimum sanctum in rat. Int J Pharm Biomed Res  2011; 2(1): 33-8.

[91]
Mondal S, Mirdha BR, Mahapatra SC. The science behind sacredness of Tulsi (Ocimum sanctum Linn.). Indian J Physiol Pharmacol  2009; 53(4): 291-306.
 [PMID: 20509321]

[92]
Kar P, Kumar V, Vellingiri B, et al. Anisotine and amarogentin as promising inhibitory candidates against SARS-CoV-2 proteins: a computational investigation. J Biomol Struct Dyn  2022; 40(10): 4532-42.
 [http://dx.doi.org/10.1080/07391102.2020.1860133] [PMID: 33305988]

[93]
Mohapatra PK, Chopdar KS, Dash GC, Mohanty AK, Raval MK. In silico screening and covalent binding of phytochemicals of Ocimum sanctum against SARS-CoV-2 (COVID 19) main protease. J Biomol Struct Dyn  2023; 41(2): 435-44.
 [PMID: 34821198]

[94]
Muthumanickam S, Kamaladevi A, Boomi P, Gowrishankar S, Pandian SK. Indian ethnomedicinal phytochemicals as promising inhibitors of RNA-binding domain of SARS-CoV-2 nucleocapsid phosphoprotein: an in silico study. Front Mol Biosci  2021; 8: 637329.
 [http://dx.doi.org/10.3389/fmolb.2021.637329] [PMID: 34277698]

[95]
Umashankar V, Deshpande SH, Hegde HV, Singh I, Chattopadhyay D. Phytochemical moieties from Indian traditional medicine for targeting dual hotspots on SARS-CoV-2 spike protein: an integrative in silico approach. Front Med (Lausanne)  2021; 8: 672629.
 [http://dx.doi.org/10.3389/fmed.2021.672629] [PMID: 34026798]

[96]
Sharma L. Immunomodulatory effect and supportive role of traditional herbs, spices and nutrients in management of COVID-19. Preprints  2020; 2020090026.
 [http://dx.doi.org/10.20944/preprints202009.0026.v1]

[97]
Chiang LC, Ng LT, Cheng PW, Chiang W, Lin CC. Antiviral activities of extracts and selected pure constituents of Ocimum basilicum. Clin Exp Pharmacol Physiol  2005; 32(10): 811-6.
 [http://dx.doi.org/10.1111/j.1440-1681.2005.04270.x] [PMID: 16173941]

[98]
Jindal D, Rani V. In silico Studies of Phytoconstituents from Piper longum and Ocimum sanctum as ACE2 and TMRSS2 Inhibitors: Strategies to Combat COVID-19. Appl Biochem Biotechnol  2023; 195(4): 2618-35.
 [PMID: 35157239]

[99]
Pant H, Kumar V, Giri B, et al. Potential roles of phytochemicals in combating severe acute respiratory syndrome Coronavirus infection. Plant Sci Today  2022; 9(2): 427-37.
 [http://dx.doi.org/10.14719/pst.1525]

[100]
Mediratta PK, Sharma KK, Singh S. Evaluation of immunomodulatory potential of Ocimum sanctum seed oil and its possible mechanism of action. J Ethnopharmacol  2002; 80(1): 15-20.
 [http://dx.doi.org/10.1016/S0378-8741(01)00373-7] [PMID: 11891082]

[101]
Mukherjee R, Dash PK, Ram GC. Immunotherapeutic potential of Ocimum sanctum (L) in bovine subclinical mastitis. Res Vet Sci  2005; 79(1): 37-43.
 [http://dx.doi.org/10.1016/j.rvsc.2004.11.001] [PMID: 15894022]

[102]
Mediratta PK, Dewan V, Bhattacharya SK, Gupta VS, Maiti PC, Sen P. Effect of Ocimum sanctum Linn. on humoral immune responses. Indian J Med Res  1988; 87: 384-6.
 [PMID: 3169894]

[103]
Ghoke SS, Sood R, Kumar N, et al. Evaluation of antiviral activity of Ocimum sanctum and Acacia arabica leaves extracts against H9N2 virus using embryonated chicken egg model. BMC Complement Altern Med  2018; 18(1): 174.
 [http://dx.doi.org/10.1186/s12906-018-2238-1] [PMID: 29866088]

[104]
Bano N, Ahmed A, Tanveer M, Khan GM, Ansari MT. Pharmacological evaluation of Ocimum sanctum. J Bioequivalence Bioavailab  2017; 9(3): 387-92.

[105]
Vaghasiya J, Datani M, Nandkumar K, Malaviya S, Jivani N. Comparative evaluation of alcoholic and aqueous extracts of Ocimum sanctum for immunomodulatory activity. Int J Pharm Biol Res  2010; 1(1): 25e9.

[106]
Venkatachalam VV, Rajinikanth B. Immunomodulatory activity of aqueous leaf extract of Ocimum sanctum Inrecent advancements in system modelling applications.  India: Springer 2013; pp. 425-32.

[107]
Patil U. Studies on antiviral activity of tulsi (Ocimum sanctum) crude extracts on selected viruses of veterinary importance. Int J Ayurveda Pharma Res 2018.

[108]
Jayati BA, Kumar A, Goel A, Gupta S, Rahal A. In vitro antiviral potential of Ocimum sanctum leaves extract against New Castle Disease Virus of poultry. Int J Microbiol Immunol Res  2013; 2(7): 51.

[109]
Ling AP, Khoo BF, Seah CH, et al. Inhibitory activities of methanol extracts of Andrographis paniculata and Ocimum sanctum against dengue-1 virus. 

[110]
Bhatia AK, Kumar A, Goel A, Rahal A. Immunomodulatory activity of hot aqueous extract of Ocimum sanctum leaves. Indian Journal of Comparative Microbiology. Immunol Infect Dis  2013; 34(1): 33-7.

[111]
Zaveri M, Khandhar A, Patel S, Patel A. Chemistry and pharmacology of Piper longum L. Int J Pharm Sci Rev Res  2010; 5(1): 67-76.

[112]
Kirtikar KR, Basu BD. Indian Medicinal Plants, 2 nd Edn.  Allahabad: Lalit Mohan Basu Publications 1933; pp. 2131-3.

[113]
Kumar S, Kamboj J. Suman, Sharma S. Overview for various aspects of the health benefits of Piper longum linn. fruit. J Acupunct Meridian Stud  2011; 4(2): 134-40.
 [http://dx.doi.org/10.1016/S2005-2901(11)60020-4] [PMID: 21704957]

[114]
Lee SA, Hong SS, Han XH, et al. Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity. Chem Pharm Bull (Tokyo)  2005; 53(7): 832-5.
 [http://dx.doi.org/10.1248/cpb.53.832] [PMID: 15997146]

[115]
Kirtikar KR, Basu Indian Medicinal Plants BD. Orients longman.  Mumbai, India 1980; pp. 21-8.

[116]
Rastogi RP, Malhotra BN. Compendium of Indian Medicinal Plants CDRI, Luckhnow and New Delhi.  India: Nisc 1993; pp. 504-857.

[117]
Tiwari RC, Clegg LX, Zou Z. Efficient interval estimation for age-adjusted cancer rates. Stat Methods Med Res  2006; 15(6): 547-69.
 [http://dx.doi.org/10.1177/0962280206070621] [PMID: 17260923]

[118]
Yadav V, Krishnan A, Vohora D. A systematic review on Piper longum L.: Bridging traditional knowledge and pharmacological evidence for future translational research. J Ethnopharmacol  2020; 247: 112255.
 [http://dx.doi.org/10.1016/j.jep.2019.112255] [PMID: 31568819]

[119]
Choudhary P, Chakdar H, Singh D, et al. Computational studies reveal piperine, the predominant oleoresin of black pepper (Piper nigrum) as a potential inhibitor of SARS-CoV-2 (COVID-19). Curr Sci  2020; 119(8): 1333-42.
 [http://dx.doi.org/10.18520/cs/v119/i8/1333-1342]

[120]
Pandey P, Singhal D, Khan F, Arif M. An in silico screening on Piper nigrum, Syzygium aromaticum and Zingiber officinale roscoe derived compounds against SARS-CoV-2: A drug repurposing approach. Biointerface Res Appl Chem  2020; 11(4): 11122-34.
 [http://dx.doi.org/10.33263/BRIAC114.1112211134]

[121]
Nag A, Chowdhury RR. Piperine, an alkaloid of black pepper seeds can effectively inhibit the antiviral enzymes of Dengue and Ebola viruses, an in silico molecular docking study. Virusdisease  2020; 31(3): 308-15.
 [http://dx.doi.org/10.1007/s13337-020-00619-6] [PMID: 32904842]

[122]
De Jesus M, Gaza J, Junio HA, Nellas R. Molecular Docking of Secondary Metabolites from Psidium guajava L and Piper nigrum L to COVID-19 Associated Receptors ACE2, Spike Protein RBD, and TMPRSS2. Theoretical and Computational Chemistry 2020.

[123]
Mahfouz AY, Daigham GE, Radwan AM, Mohamed AA. Eco-friendly and superficial approach for synthesis of silver nanoparticles using aqueous extract of Nigella sativa and Piper nigrum L seeds for evaluation of their antibacterial, antiviral, and anticancer activities a focus study on its impact on seed germination and seedling growth of Vicia faba and Zea mays. Egyptian Pharmaceutical Journal  2020; 19(4): 401.
 [http://dx.doi.org/10.4103/epj.epj_48_20]

[124]
Devikanniga D, Ramu A, Haldorai A. Efficient diagnosis of liver disease using support vector machine optimized with crows search algorithm. EAI Endorsed Transactions on Energy Web  2020; 7(29): e10.

[125]
Anandakumar H, Umamaheswari K. Supervised machine learning techniques in cognitive radio networks during cooperative spectrum handovers. Cluster Comput  2017; 20(2): 1505-15.
 [http://dx.doi.org/10.1007/s10586-017-0798-3]

[126]
Saetang J, Tedasen A, Sangkhathat S, et al. The attenuation effect of low piperine Piper nigrum extract on doxorubicin-induced toxicity of blood chemical and immunological properties in mammary tumour rats. Pharm Biol  2022; 60(1): 96-107.
 [http://dx.doi.org/10.1080/13880209.2021.2018470] [PMID: 34962450]

[127]
Priya NC, Kumari PS. Antiviral activities and cytotoxicity assay of seed extracts of Piper longum and Piper nigrum on human cell lines. Int J Pharm Sci Rev Res  2017; 44(1): 197-202.

[128]
Mair CE, Liu R, Atanasov AG, Schmidtke M, Dirsch VM, Rollinger JM. Antiviral and antiproliferative in vitro activities of piperamides from black pepper. Planta Medica  2016; 82(S01): P807.

[129]
Doshi G, Une H, Shanbhag P. Rasayans and non-rasayans herbs: Future immunodrug - Targets. Pharmacogn Rev  2013; 7(14): 92-6.
 [http://dx.doi.org/10.4103/0973-7847.120506] [PMID: 24347916]

[130]
Khushbu C, Roshni S, Anar P, Carol M, Mayuree P. Phytochemical and therapeutic potential of Piper longum Linn a review. Int J Res Ayurveda Pharm  2011; 2(1): 157-61.

[131]
Virmani M, Kapoor S, Garg SL, Virmani N. In vitro antiviral activity of plant extracts against infectious bursal disease virus. Journal of Immunology and Immunopathology  2009; 11(1): 48-52.

[132]
Majdalawieh AF, Carr RI. In vitro investigation of the potential immunomodulatory and anti-cancer activities of black pepper (Piper nigrum) and cardamom (Elettaria cardamomum). J Med Food  2010; 13(2): 371-81.
 [http://dx.doi.org/10.1089/jmf.2009.1131] [PMID: 20210607]

[133]
Sunila ES, Kuttan G. Immunomodulatory and antitumor activity of Piper longum Linn. and piperine. J Ethnopharmacol  2004; 90(2-3): 339-46.
 [http://dx.doi.org/10.1016/j.jep.2003.10.016] [PMID: 15013199]

[134]
Tripathi DM, Gupta N, Lakshmi V, Saxena KC, Agrawal AK. Antigiardial and immunostimulatory effect of Piper longum on giardiasis due to Giardia lamblia. Phytother Res  1999; 13(7): 561-5.
 [http://dx.doi.org/10.1002/(SICI)1099-1573(199911)13:7<561::AID-PTR479>3.0.CO;2-W] [PMID: 10548746]

[135]
Thimmulappa RK, Mudnakudu-Nagaraju KK, Shivamallu C, et al. Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19. Heliyon  2021; 7(2): e06350.
 [http://dx.doi.org/10.1016/j.heliyon.2021.e06350] [PMID: 33655086]

[136]
Boroumand N, Samarghandian S, Hashemy SI. Immunomodulatory, anti-inflammatory, and antioxidant effects of curcumin. Journal of Herbmed Pharmacology  2018; 7(4): 211-9.
 [http://dx.doi.org/10.15171/jhp.2018.33]

[137]
Guijarro-Real C, Plazas M, Rodríguez-Burruezo A, Prohens J, Fita A. Potential in vitro inhibition of selected plant extracts against SARS-CoV-2 chymotripsin-like protease (3CLPro) activity. Foods  2021; 10(7): 1503.
 [http://dx.doi.org/10.3390/foods10071503] [PMID: 34209659]

[138]
Babaei F, Nassiri-Asl M, Hosseinzadeh H. Curcumin (a constituent of turmeric): New treatment option against COVID-19. Food Sci Nutr  2020; 8(10): 5215-27.
 [http://dx.doi.org/10.1002/fsn3.1858] [PMID: 33133525]

[139]
Pawar KS, Mastud RN, Pawar SK, et al. Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: a randomized clinical trial. Front Pharmacol  2021; 12: 669362.
 [http://dx.doi.org/10.3389/fphar.2021.669362] [PMID: 34122090]

[140]
Gomathi M, Padmapriya S, Balachandar V. Drug studies on Rett syndrome: from bench to bedside. J Autism Dev Disord  2020; 50(8): 2740-64.
 [http://dx.doi.org/10.1007/s10803-020-04381-y] [PMID: 32016693]

[141]
Süntar I. Importance of ethnopharmacological studies in drug discovery: role of medicinal plants. Phytochem Rev  2020; 19(5): 1199-209.
 [http://dx.doi.org/10.1007/s11101-019-09629-9]

[142]
Abdizadeh R, Hadizadeh F, Abdizadeh T. In silico analysis and identification of antiviral coumarin derivatives against 3-chymotrypsin-like main protease of the novel coronavirus SARS-CoV-2. Mol Divers  2022; 26(2): 1053-76.
 [http://dx.doi.org/10.1007/s11030-021-10230-6] [PMID: 34213728]

[143]
Dominguez H, Muñoz MJ, Eds. Water extraction of bioactive compounds: from plants to drug development. Elsevier 2017.

[144]
Dominguez H, Muñoz MJ, Eds. Water extraction of bioactive compounds: from plants to drug development. Elsevier 2017.

[145]
Research guidelines for evaluating the safety and efficacy of herbal medicines. WHO Regional Office for the Western Pacific 1993.

[146]
Moghadamtousi S, Nikzad S, Kadir H, Abubakar S, Zandi K. Potential antiviral agents from marine fungi: An overview. Mar Drugs  2015; 13(7): 4520-38.
 [http://dx.doi.org/10.3390/md13074520] [PMID: 26204947]
Cite As
Coronaviruses

Exploring the Efficacy of Traditional Herbs in Combating COVID-19: A Comprehensive Review

Abstract

Graphical Abstract
