Role of medicinal plants in inhibiting SARS-CoV-2 and in the management of post-COVID-19 complications.

BACKGROUND: The worldwide corona virus disease outbreak, generally known as COVID-19 pandemic outbreak resulted in a major health crisis globally. The morbidity and transmission modality of COVID-19 appear more severe and uncontrollable. The respiratory failure and following cardiovascular complications are the main pathophysiology of this deadly disease. Several therapeutic strategies are put forward for the development of safe and effective treatment against SARS-CoV-2 virus from the pharmacological view point but till date there are no specific treatment regimen developed for this viral infection.
PURPOSE: The present review emphasizes the role of herbs and herbs-derived secondary metabolites in inhibiting SARS-CoV-2 virus and also for the management of post-COVID-19 related complications. This approach will foster and ensure the safeguards of using medicinal plant resources to support the healthcare system. Plant-derived phytochemicals have already been reported to prevent the viral infection and to overcome the post-COVID complications like parkinsonism, kidney and heart failure, liver and lungs injury and mental problems. In this review, we explored mechanistic approaches of herbal medicines and their phytocomponenets as antiviral and post-COVID complications by modulating the immunological and inflammatory states. STUDY
DESIGN: Studies related to diagnosis and treatment guidelines issued for COVID-19 by different traditional system of medicine were included. The information was gathered from pharmacological or non-pharmacological interventions approaches. The gathered information sorted based on therapeutic application of herbs and their components against SARSCoV-2 and COVID-19 related complications.
METHODS: A systemic search of published literature was conducted from 2003 to 2021 using different literature database like Google Scholar, PubMed, Science Direct, Scopus and Web of Science to emphasize relevant articles on medicinal plants against SARS-CoV-2 viral infection and Post-COVID related complications.
RESULTS: Collected published literature from 2003 onwards yielded with total 625 articles, from more than 18 countries. Among these 625 articles, more than 95 medicinal plants and 25 active phytomolecules belong to 48 plant families. Reports on the therapeutic activity of the medicinal plants belong to the Lamiaceae family (11 reports), which was found to be maximum reported from 4 different countries including India, China, Australia, and Morocco. Other reports on the medicinal plant of Asteraceae (7 reports), Fabaceae (8 reports), Piperaceae (3 reports), Zingiberaceae (3 reports), Ranunculaceae (3 reports), Meliaceae (4 reports) were found, which can be explored for the development of safe and efficacious products targeting COVID-19.
CONCLUSION: Keeping in mind that the natural alternatives are in the priority for the management and prevention of the COVID-19, the present review may help to develop an alternative approach for the management of COVID-19 viral infection and post-COVID complications from a mechanistic point of view.

Introduction

In 2002-2003, a surveillance definition was established following the outbreak of SARS-CoV-2. At the end of December 2019, a pneumonia patient with unidentified etiology was found positive for pan-β-coronavirus which has the closest resemblance to another coronavirus, Bat CoV-RaTG13 (Zhou et al., 2020). This new virus was termed SARS-CoV-2, and the disease it causes was termed coronavirus disease 2019 (COVID-19). Whole genome sequencing analysis of clinical SARS-CoV-2 isolates from COVID-19 patients revealed a total of 104 different viral strains as of yet (Hu et al., 2021). It generally is transmitted during close unprotected contact with infected persons via virus-loaded droplets and aerosoles. Due to its novel nature, there is no immune defence present in host. Globally 178,202,610 confirmed cases of COVID-19 were reported to the World Health Organization (WHO) including 3,865,738 deaths as of June 21, 2021 (Anonymus 2021, WHO coronavirus disease COVID-19 Dashboard 2021).

The symptoms of COVID-19 are non-specific and can be asymptomatic to severe pneumonia characterized by fever, coughing, shortness of breathing and also death. Headache, fatigue, anosmia, sore throat, increased sputum production, rhinorrhea, anorexia, dyspnea, pleurisy, skin sensitivity, hemoptysis, myalgias, and diarrhea can be developed as COVID-19 symptoms (Anaya et al., 2021; Rehman et al., 2021). On a mean incubation period of 5-6 days after infection, an infected person may develop pathological symptoms such as mild respiratory complications with fever. Many case reports showed that the mortality rate increases with age, people over 80 years of age having highest mortality rate and people over 60 years of age with other disorders including diabetes, hypertension, chronic respiratory disease, cardiovascular disease, and cancer. The case fatality rate (CFR) is also higher among males compared to female individuals at any age (Anonymous, 2020a; Lee et al., 2021; Report of the WHO-China Joint Mission on Coronavirus Disease 2019).

With the outbreak of COVID-19, the uses of medicinal plant and their product or traditional herbal preparation increased dramatically around the world (Peng et al., 2020). Based on preliminary clinical reports, FDA approved chloroquine sulfate and hydroxychloroquine sulfate as first-line treatment (Gao et al., 2020; Gautret et al., 2020; Naserghandi et al., 2020). Unfortunately, these conventional drugs are not as effective against COVID-19 infection as expected (Cao et al., 2020; Ferner and Aronson, 2020).

Antiviral drugs such as favipiravir, remdesivir and kaletra (lopinavir and ritonavir combination drug) have also been put forward to improve the condition of COVID-19 patients (Guo, 2020; Mifsud et al., 2019; Sheahan et al., 2020). Drug Controller General of India approved 2-deoxy-D-glucose (2-DG) for emergency use as add-on therapy in moderate to severe coronavirus patients (Balkrishna et al., 2020a; Verma et al., 2020). However, the outcome of large randomized clinical trials was not very encouraging (Tu et al., 2020). The most common preventive and effective approach to combat the COVID-19 pandemic is the use of vaccines (Khodadadi et al., 2020). Approximately, 78 vaccine candidates have already been developed worldwide and are at different stages of clinical evaluation (Liu et al., 2020; Thanh Le et al., 2020). Up to now, several vaccine candidates are approved through Emergency Use Authorization (EUA) including the Pfizer/BioNTech Comirnaty vaccine (BNT162b2), the Oxford–AstraZeneca COVID-19 vaccine (AZD1222) sold under brand name Covishield, the Moderna (mRNA 1273) vaccine by the American Pharmaceutical and Biotechnology Company, CoronaVac by a Chinese company named Sinovac Biotech. Sinopharm in collaboration with the Wuhan Institute of Virology and Beijing Institute of Biological Products developed inactivated Chinese Corona Virus (CVC) vaccine and BBIBP‑CorV, EpiVacCorona by a Russian company named Federal Budgetary Research Institution State Research Center of Virology and Biotechnology, China. Covaxin (BBV152) was developed by Bharat Biotech in collaboration with the Indian Council of Medical Research (ICMR) and National Institute of Virology (NIV). Sputnik V is a viral vector COVID-19 vaccine developed by the Russian Gamaleya Research Institute of Epidemiology and Microbiology (Logunov et al., 2021; Mishra and Tripathi, 2021). Still there are many vaccine candidates under clinical investigation. JNJ‑78436735 formerly known as Ad26.COV2.S was developed by Johnson & Johnson, CanSino Biologics developed a recombinant vaccine called Ad5‑nCoV and NVX‑CoV2373 was developed by Novavax (Kashte et al., 2021).

Methodology

Specific information on the topic was collected from the literature available from search engines such as Google Scholar, PubMed, Science Direct, Scopus, and Web of Science for retrieving published data (from 2003 to 2021) using different combination of keywords i.e., COVID-19/SARS-CoV-2, diagnosis/treatment guideline issued for COVID-19, cytokine storm, immunomodulation/anti-inflammatory/antiviral, post-COVID complications etc. The inclusion criteria limited to full text articles on pharmacological or therapeutic approaches for COVID-19 based on in-vivo, in-vitro, and in-silico and clinical trial reports on herbal drugs. News reports, editorial, peer review articles were also retrieved to and recent updates were included. The collected literature was electronically checked for duplicates using EndNote software. On the contrary, the exclusion criteria for the collected literature include, predatory journals source, non-english language.

Guidelines from different traditional system of medicine to combat COVID-19

The World Health Organization (WHO) welcomes initiatives to develop COVID-19 therapies, including drug repositioning and traditional medicines. In many countries, traditional medicine has a long history and plays an important role in healthcare. Nowadays, WHO in collaboration with several research institutions is working on the medicinal plant-based products used in traditional medicinal systems, in order to explore their scientific and clinical potential for the treatment and management of COVID-19. In many countries, WHO provided support to perform clinical COVID-19 trials for traditional medicinal products (Anonymous 2020b), WHO, Africa CDC push for COVID-19 traditional medicine research in Africa). The disease is almost controlled in China (Salzberger et al., 2020), but still widespread in Europe, USA, India, Brazil and other countries, which have emerged as new epicentres of COVID-19 (Grasselli et al., 2020). TCM is playing an important role to control the death rate. Along with TCM, Ayurveda might also help to manage COVID-19 (Sawarkar and Sawarkar, 2020; Patwardhan et al., 2020). However, there is not much solid evidence yet to prove this hypothesis. One may critically ask, why is the outbreak not under control in India, if Ayurveda would really help. The same is true for all other traditional medicines worldwide in a similar manner. Currently the data from www.clinicaltrials.gov and http://www.chictr.org.cn include 46 plant-derived phytomolecules and 64 traditional Chinese medicinal preparations are under clinical investigations targeting both management and prevention of COVID-19 viral infection (Jin et al., 2020). But still, it requires reliable and high-quality clinical evidence due to small sample size and long time line (Luo et al., 2020; Nile and Kai, 2021; Pang et al., 2020; Wang et al., 2021; Wei et al., 2020; Xu et al., 2020; Zhu et al., 2020). Randomized clinical trials, which reach international visibility and recognition concerning this issue, are urgently required to answer this question. The Ministry of AYUSH has come up with several preventive measures against COVID-19 infection. These preventive measures are published officially as Guidelines for Practitioners in Naturopathy, Siddha, Homeopathy, Unani, Ayurveda, Yoga and for Public Health and Health care Practitioners for COVID-19 (AYUSH Guidelines for COVID-19 2020)AYUSH Guidelines for COVID-19) (Interdisciplinary committee for integration of ayurveda and yoga interventions in the 'National clinical management protocol: COVID-19′ 2020). The Unani system of medicine may offer potential candidates for controlling the disease burden. The textbooks of Unani medicine focused explicitly on air-borne respiratory infections. In Unani medicine, epidemics and pandemics were described with the common term waba, which means diseases affecting a large geographical area. Most of the Unani herbal drugs are cheap, easy to administer and easily available. As an example, vinegar is recommended made from Saccharum officinarum L., Rosa damascena Herrm., Tamarindus indica L., Rheum austral D. Don, Viola odorata L., Terminalia chebula Retz., Cassia fistula L. and Punica granatum L. (Nikhat and Fazil, 2020).

Ayurveda can prevent the disease progression by regulating the immune-inflammation state in COVID-19 patients. The Ministry of AYUSH, India, recommended different preventive measures to improve the quality of life of individual patients. Daily practice of Yoga, Dhyana, and Pranayaam practices may help to withstand psychological perturbations in COVID-19 patients (Tillu et al., 2020). The use of spices such as Curcuma longa L., Cuminum cyminum L., Coriandrum sativum L., and Allium sativum L. is recommended for daily use. Consuming herbal decoctions of Ocimum sanctum L., Piper nigrum L., Zingiber officinale Roscoe, Cinnamomum verum J. Presl, Vitis vinifera L. are also recommended as teas to improve the immunity in COVID-19 patients. Taking Emblica officinalis Gaertn., Tinospora cordifolia (Willd.) Miers and Tribulus terrestris L. in equal ratio with honey suggested having benefits in post-COVID related complications. Daily consumption of ashwagandha (Withania somnifera (L.) Dunal) also having benefits in prophylactic care. An ayurvedic herbo-mineral preparation known as Chyawanprasha is also recommended due to its immunoboosting properties and in the management of post-COVID related complications. Patients with sore throat and cough are advised as steam inhalation with Mentha arvensis L. or Trachyspermum ammi L. with Syzigium aromaticum L. powder (Gupta et al., 2021a; Gupta et al., 2021b).

Based on the traditional and scientific evidence, the Ministry of AYUSH recommended the consumption of a poly-herbal decoction (Kadha) containing five different herbs namely, Tulsi (Ocimum tenuiflorum L.), Dalchini (C. verum), Kalimirch (P. nigrum), Shunthi (Z. officinale) and Munakka (V. vinifera) for boosting immunity. The network pharmacology analysis data of this immunomodulatory formulation showed to modulate several signaling pathways involved in the regulation of immunity in biological systems such as HIF-1, Estrogen, Rap1, p53, PI3K-Akt, Toll-like receptor, MAPK, cAMP, Ras, Wnt, Adipocytokine, NOD-like receptor, Chemokine, NF-κB, IL-17, TNF, Sphingolipid, and cGMP-PKG. Along with Kadha, it is also recommended to take raisins (dried Munakka) and golden milk (C. longa powder in hot milk) as a prophylactic against COVID-19 to boost immunity in the subjects with compromised immunity (Khanal et al., 2020; Schuster et al., 2017).

Global perspective of herbs and herbal formulae from different traditional systems of medicine to inhibit SARS-CoV-2 virus

Soon after the outbreak of COVID-19, the National Health Commission of the People's Republic of China announced a combination of TCM and commercial medicines to treat COVID-19 patients (Lin and Li, 2020). After the global spread of COVID-19, rushes for traditional herbal medications against COVID-19 have been reported in different parts of the world (Ang et al., 2020; Benarba and Pandiella, 2020; Mani et al., 2020; Mukherjee, 2019; Paudyal et al., 2021).

The exploration of herbs and herbal preparations used in traditional medicine, followed by bioassay-guided isolation of lead compounds from medicinal herbs, represent an attractive approach in combat this pandemic (Tahir et al., 2020). In several African countries, home remedies are used as alternative healthcare remedies to manage COVID-19. Natural spices and leaves of medicinal plants having the antioxidant and anti-inflammatory properties were reported to be effective (Orisakwe et al., 2020).

Many natural products have broad-spectrum antiviral activity, may inhibit multiple steps in viral infection and replication and have been used in the treatment of SARS, MERS, influenza, and dengue virus. Fig. 1 represents the chemical structures of the bioactive phytomolecules to be useful for the management of COVID-19 related complications. Moreover, they have been reported as immunomodulators, inhibiting inflammatory effect concerned for the significant morbidity and mortality of COVID-19 infection (Khan and Al-Balushi, 2021; McKee et al., 2020) (Table 1, Table 2, Table 3) . Medicinal plants that showed to be effective in the management of post-COVID related complications have been tabulated in Table 4 . Fig. 2 represents the probable inhibition mechanism of medicinal plants/products against SARS-CoV-2 viral replication. However, the phytochemicals could be toxic at certain levels, and hence in vitro and in vivo researches are needed to evaluate the safe and therapeutic levels for each natural compound before human clinical studies can be conducted (Mani et al., 2020). Infusino et al., (2020) focuses the possible role of supplements, probiotics, and nutraceuticals in reducing the risk of SARS-CoV-2 infection or mitigating the symptoms of COVID-19 in their study.

Fig. 1

Chemical structure of the compounds found to be active against COVID-19 virus.

Table 1

. Herbs found to be effective against COVID-19 through in-vivo/ in-vitro analysis

Plant Family	Plant name	Antiviral	Anti-inflammatory	Immunomodulation	References
In-vitro/in-vivo assays
Acanthaceae	Andrographispaniculata (Burm.f.) Nees	Binding potential with active residues of ACE2 that mediate host viral interface	Andrographolide reduces the levels of inflammatory cytokines TNFα, IL-12, IL-1β, IL-6, IL-18 in LPS/ IL-4-activated murine macrophages	Andrographolide significantly stimulate the immune response, regulate the production of NK cells andcytokines and stimulate the production of cytotoxic T-lymphocytes	Lu et al., 2019; Wang et al., 2010; Varma et al., 2011; (Zou et al., 2016)Dhanasekaran and Pradeep, 2020
Amaryllidaceae	Allium sativum L.	Aqueous bulb extracts and essential oils restrained viral protease enzyme by inhibiting amino acid synthesis	Allicin inhibit of TNF-inducedsecretion of IL-1β, CXCL8 and IP10	Crushed garlic extract increase the production of IFNγ and expansion of CD4+ T-cells	Mohammadi and Shaghaghi, 2020; Lang et al., 2004;Arreola et al., 2015
Anacardiaceae	Rhus chinensis Mill.	Ethanol extract of gall having the inhibitiory activity of SARS-CoV virus into host cell and prevented virus replicationTetra-O-galloyl-β-d-glucose showed to inhibit SARS CoV	Aqueous extract inhibits the production of inflammatory cytokine IL-6 in-vivo	Aqueous extract inhibits IL-10 expression and act as immunomodulator	Yi et al., 2004; Djakpo and Yao, 2010; Sun et al., 2018b
Asteraceae	Echinacea purpureaL.	Herb and roots ethanol extract act against some viruses with a membrane through direct virucidal activity	Unpurified fresh pressed juice mediated the increased release of various cytokines, including IL-1, IL-10,and TNF-α by macrophages	Crude polysaccharides act as immunostimulator	Sharma et al., 2009; Burger et al., 1997
Brassicaceae	Isatis indigotica Fortune ex Lindl.	Methanol root extract exhibited antiviral activity against Japanese encephalitis virus. An arabinogalactan isolated from the root showed antiviral activity against H1N1 influenza vaccine or hepatitis B surface antigen	Tryptanthrin was found to have anti-inflammatory activity. Topical administration of extracts significantly inhibited the ear oedema and paw oedema induced by carrageenan	Polysaccharides fraction promoted humoral immune response of the body and produces immune effect on KM and Balb/c mice respectively	b;(Chang et al., 2012) Shan et al., 2015; Chen et al., 2021; Ho and Chang, 2002; Hamburger, 2002
Caesalpinaceae	Cassia tora L.	Ethanol seed extract inhibits 3CL protease and SARS CoV replication. The anti-viral activity measured by cell-based on Vero E6 cells	Ethanol seed extract induces expression of phosphorylated cAMP response		Islam et al., 2020; Wen et al., 2011
Calophyllaceae	Calophyllum blancoi Planch.	Blancoxanthone and pyranojacareubin from the root exhibited antiviral activity against HCoV 229E virus	Extracts from leaves and roots showed anti-inflammatory and anti-nociceptive activity in mice model		Shen et al., 2005; Filho et al., 2009
Celastraceae	Tripterygium regelii Sprague	Triptofordin C-2 showed antiviral activity against HSV-1, HCMV, measles virus and influenza A virus	Dichioromethane and ethyl acetate fractions of herbs induced IL-8 in LPS-activated rat macrophages	Tripterygiumine I and tripterygiumine Q isolated from root extract exhibited immunosuppressive activity against human peripheral mononuclear cells	Hayashi et al., 1996; Lee et al., 1995; Lv et al., 2019
Cibotiaceae	Cibotium barometz (L.) J. Sm.	Methanol and ethanol extract of dried rhizome inhibit viral replication, levels of spike protein and SARS-CoV 3CL protease activity	The methanol extract of rhizome suppressed NO and IL-6 and also decreased iNOS and COX-2 expression		Wen et al., 2011; Wu and Yang. 2009
Compositae	Chrysanthemum indicum L.	The herb found to inhibitory SARS CoV-2 virus	Flower and bud ethanol extract reduced TNF-α, IL-6 and IL-1β production	Inflorescence or bud ethanol extract significantly increased delayed-type hypersensitivity reaction, enhanced antibody generation by splenic cells and IgG and IgM levels	Kwong et al., 2020; Lee et al., 2009; Cheng et al., 2005
Dryopteridaceae	Dryopteris crassi rhizoma Nakai	It clear heat and detoxify, removes lung hotness and having potent against SARS CoV-2	Ethanol root extract diminishes the production of NO and PGE2, down regulate the iNO synthase, COX-2, and TNF-a mRNA expression and also decrease the level of IL-6	Bioactive compound of isolated from rhizome extract exhibit immunomodulatory activity by replicating IL-1β, TNF-α	Yang et al., 2020; Yang et al., 2013; Cheng et al., 2016
Fabaceae	Mucuna pruriens (L.) DC.	Peptide fraction has been reported in the treatment of to liver cancer, HCV, and high activities of protecting DNA damages	Essential oil from leaf and flavonoids from seed powder showed anti-inflammatory	The bean extract showed immunomodulatory activity by modulating TNF-α, IL-6, IFN-l, IL-1b, iNOS and IL-2 level in the CNS and also enhanced the activity of the transcription factor NF-kB	Taghizadeh et al., 2021; Avoseh et al., 2020; Javed et al., 2011; Mallurwar et al., 2006; Rai et al., 2017
	Glycyrrhiza glabra L.	Glycyrrhizin (i) was shown to inhibit SARS-coronavirus (SARS-CoV) replication	Glycyrrhizic acid, liquiritin and liquiritigenin inhibited iNOS, COX-2, TNF-α, IL-1β and IL-6. The root extract also inhibited the expression levels of TNF-α, IL-1β and IL-6	Glycyrrhizin enhanced proliferation of allogenic T cells along with the production of IFN-γ and IL-10 and reduced IL-4 production	Cinatl et al., 2003; Hoever et al., 2005; Fiore et al., 2008; Bordbar et al., 2012
Gentianacee	Gentiana scabra Bunge	n-hexane extract of rhizome inhibited SARS-CoV replication in cell-based cytopathogenic effect	Chloroform and methanol extract of rhizomes and roots inhibit production of IL-6 and NO	Polysaccharide fraction the aqueous root extract increased lymphocyte proliferation	Yang et al., 2010; Wen et al., 2011; Wang et al., 2014; He et al., 2015
Lamiaceae	Hyptis atrorubens Poit.	Methyl rosmarinates inhibited 3CLpro of SARS-CoV-2 virus	Suaveolol and methyl suaveolate isolated from the methanol leaf extract showed anti-inflammatory activity in croton oil ear edema model		Qamar et al., 2020; Grassi et al., 2006
	Salvia miltiorrhizaBunge	Ethyl acetate and water extract of root showed antiviral activity against enterovirus 71by interrupting viral RNA synthesis and viral entry	The polysaccharides extract inhibited mRNA transcriptions of TNF-α, IL-6, iNOS, and COX-2 and protein expressions of NF-κB, p-p65, and p-IκBa in LPS stimulated RAW264.7 cells	Polysaccharides extract enhanced expression of  IL-4, IL-6,and IFN-γ	Liu et al., 2013; Chen et al., 2017; Han et al., 2018; Wu et al., 2007
	Salvia officinalis L.	Essential oils from fruits was found to be active against SARS-CoV and HSV-1 replication	Flavonoids isolated from fresh leaves and flowers reduce inflammation in the mouse carrageenan model. It's major constituent caffeic acid decrease the IL-6 level	The polysaccharide fractions showed immunomodulatory activity	Loizzo et al., 2008; Ghorbani and Esmaeilizadeh, 2017; Capek et al., 2003
	Scutellaria baicalensis Georgi	Baicalein (iv) inhibits 3CLpro, PLpro activity, RdRp and SARS-CoV-2 replication.Chrysin (v) inhibited PLproChrysin-7-O-β-glucuronide, Cosmosiin inhibited 3CLPro	The root aqueous extract inhibited the production of NO, IL-3, IL-6, IL-10, IL-12p40, IL-17, IP-10	Baicalin suppresses TNF-α, IL-6 and IL-12p70 secretion and expressions of CD80, CD86 and MHC II	Liu et al., 2021; Wu et al., 2020; Yoon et al., 2009; Lin et al., 2017(Chen et al., 2018)
	Scutellaria barbata D. Don	Flavon rich extract and aqueous root inhibit parainfluenza-virus-type-1 infection and respiratory syncytial virus	In lipopolysaccharides stimulated RAW264.7 cells the ethanol and ethyl acetate root extracts inhibit the production of iNO, PGE2, IL-6, and IL-1β	In Lewis-bearing C57BL/6 mice model aqueous root extract decreased levels of IL-17, IL-10, FOXP3, TGF-β1, RORγt, and IL-6 and increasing the levels of IL-2 and IFN-γ	Liu et al., 2018; Guo et al., 2009; Gong et al., 2015; Shang et al., 2010(Chen et al., 2020)
Lauraceae	Cinnamomumzeylanicum L.	Butanol extract of bark inhibited SARS CoV virus	Methanol bark extract showed anti-inflammatory activity in in-vivo animal models	Polyphenolic fractions of bark extract stimulate lymphocytes proliferation, immunoglobulin production and IL-1β production. The oil and bark extract having immunosuppressive potential	Zhuang et al., 2009; Kubo et al., 1996; Balekar et al., 2014
	Laurus nobilis L.	Essential oils inhibited SARS-CoV and HSV-1 replication in vitro	Hydro-alcoholic extracts of leaves and seeds showed anti-inflammatory activity in mice	Essential oils of leaves shows immune stimulatory activity by decrease in the hematocrites: HCT, hemoglobin (HGB) and increase the level of white blood cells	Loizzo et al., 2008; Esra et al., 2007
Leguminosae	Psoralea corylifolia L.	Ethanol seed extract inhibit SARS virus replication acting on papain‐like protease (PLpro)	Bakuchiol inhibited the expression of iNOS in RAW 264.7 macrophages cells	Ethanol seed extract having immunostimulant activity and increases cell mediated and humoral immune responses	Mohamed et al., 2017; Pae et al., 2001; Kim et al., 2014
Lessoniaceae	Ecklonia cava	Phlorotannins from ethanol extract exhibited antiviral property against porcine epidemic diarrhea virus, influenza A viral strains (H1N1 and H9N2)	In LPS stimulated RAW 264.7 cells ethanol extract of reduced NO, PGE2 level and downregulated TNF-α, IL-1β, and IL-6 gene expressions	In an in-vivo model the enzymatic extract having immunomodulatory effect by enhancing the mRNA expression and production IL-4 and IL-1. It also reduced TNF-α and IFN-γ level	Kwon et al., 2013Cho et al., 2019Kim et al., 2019Ahn et al., 2008
Loranthaceae	Taxillus chinensis (DC.)	Stem and leaf hexane extract inhibit viral replication in SARS-CoV-infected Vero E6 cells	Aqueous stem extract inhibits the production of NO and TNF-α and possesses anti-inflammatory activity	Polysaccharide fraction enhanced TNF-α and NO production	Zhang et al., 2013; Wen et al., 2011; Wen et al., 2011; Ding et al., 2013
Meliaceae	Azadirachta indica A. Juss	Nimboloid (terpenoid lactone) is effective in regulating the ARDS, is a key pathological feature of COVID-19	Quercetin (i) from leaf methanol extract showed anti-inflammatory activity by the inhibition of TNF-α	Flowers aqueous stimulated both specific and non-specific immune responses, humoral and cell mediated responseNimbin (constituent of neem oil) exhibited immunomodulatory activity by potentiate phagocytic activity, antigen-presenting ability of macrophages and enhances IL-1, IFN-Γ, and TNF-α production	Shetty et al., 2020; Schumacher et al., 2011; Shah et al., 2009; Das, 2021
	Toona sinensis (Juss.) M.Roem.	The leaf aqueous extract inhibit cellular entry of SARS CoV virus	The aqueous leaf extract suppresses NF-κB pathway and also reduce IL-6 production in LPS-treated RAW264.7 cells	Aqueous leaf extract promotes immune responses	Wang and Liu, 2014; Peng et al., 2019;(Lim et al., 2020) Yang et al., 2017
Moraceae	Broussonetia papyrifera (L.) L'Her. ex Vent	Polyphenols from ethanol root extract markedly inhibited 3CL and PL CoV proteases. The isolated compounds exerted significant SARS-CoV PLpro inhibitory activity through noncompetitive inhibition	Broussochalcone A inhibits iNOS, by suppression of IkBα phosphorylation, IkBa degradation, NF-kB activation and iNOS expression. Flavonoid rich fraction inhibit the production of TNF-α and IL-6	The plant root ethanol extract reduced IgE-dependent passive cutaneous anaphylaxis	Park et al., 2017;(Ryu et al., 2019) Wang et al., 2012
Myrtaceae	Syzygium aromaticum (L.) Merr.	Higher binding affinity with viral and host macromolecular targets and other human proinflammatory mediators, SARSCoV-2 main proteases, spike, human ACE2 and furin proteins	Eugenol prevent increase in IL-4, IL-5 and the down regulation of proinflammatory cytokines IL-6 and TNFα	Eugenol found immunomodulatory activity	Maurya and Sharma, 2020; Bachiega et al., 2012; Barboza et al., 2018; Pramod et al., 2010; Dibazar et al., 2015
Paulowniaceae	Paulownia tomentosa Steud.	Apigenin from methanol flower extract suppressed Enterovirus 71 replication by targeting the transacting factors	Stem bark methanol extract reduced the production of IL-6 and TNF- α in LPS-stimulated RAW264.7 cells	The flower polysaccharides extracts enhanced lymphocyte proliferation, serum antibody titer and serum IFN-γ concentrations	Ji et al., 2015; Jo and Kim, 2019; Lee et al., 2018; Yang et al., 2019
Piperaceae	Piper nigrum L.	Higher binding affinity with viral and host macromolecular targetsand other human proinflammatory mediators, SARSCoV-2 main proteases, spike, human ACE2 and furin proteins	Piperine inhibits the production of pro-inflammatory cytokines IL-1β, IL-6, IL-10and TNFα by inhibiting NF-κB activation	It act as immunomodulator	Maurya and Sharma, 2020; Dzoyem et al., 2017;Gorgani et al., 2017
Ranunculaceae	Cimicifuga racemosa (L.) Nutt.	Rhizome methanol extract inhibit corona virus replication.Cimicifugin (iii) showed antiviral effect against human Respiratory Syncytial Virus (RSV)	Root ethanol extract inhibited IL-6, IL-23 and TNF-α mRNA expression	The triterpenoid saponins possesses immunosuppressive	Kim et al., 2008; Guo et al., 2017; Li and Yu, 2006
Rutaceae	Phellodendron chinense C.K.Schneid	The methanol plant extract inhibit coronavirus specific porcine epidemic diarrhea virus	Methanol extract reduces release of TNF-α and IL-1β from microglia.In LPS-induced in-vivo model it decreases MCP-1and IL-6 in serum. It also inhibited nitric oxide synthase (iNOS), activated nuclear factor (NF)-κB and phosphorylated IκBα, and attenuated phosphorylation of mitogen-activated protein kinases (MAPKs; ERK 1/2, p38 and JNK) in-vivo	Polysaccharides from aqueous extract stimulate humoral immunity, macrophages and NK cells	Kim et al., 2008; Sun et al., 2019;
	Toddalia asiatica (L.) Lam.	5,6-Dihydronitidine inhibit 3CLpro	Methylene chloride and Methanol (1:1) root extract reduces carrageenin-induced acute inflammation paw oedema	Ethanol root extract showed immunomodulatory activity by inhibiting Proinflammatory cytokines	Gyebi et al., 2021; Kariuki et al., 2013; Martel et al., 2017
Theaceae	Camellia sinensis (L.) Kuntze	Hydrolysable tannins from leaf ethanol extract having antiviral property against influenza A by blocked the viral replication and RNA-dependent RNA polymerase	In RAW 264.7 cells the ethanol leaf extract decreased the levels of NO, COX-2, IL-6, IL-1b, and TNF-α	In immunocompromised rats aqueous leaf extract increased the level of IL-17A, IL-8, and HBD-2	Rahayu et al., 2018; Chattopadhyay et al., 2012; Gomes et al., 2014; Novilla et al., 2017; Mahmood et al., 2016
Urtiaceae	Urtica dioica L.	Lectin inhibitSARS-CoV infection by targeting early stages of the replication cycle or penetration and neutralizes the virus infectivity	Hydro alcoholic extract of aerial part decreased IL-6 and High Sensitive C-Reactive Protein (hs-CRP).	Flavonoid fraction and flavonoid glycosides from methanol extract of aerial part showed immunostimulatory activity	Day et al., 2009; Semalty et al., 2017; Akbay et al., 2003
Zingiberaceae	Curcuma longa L.	A combination of vitamin C, curcumin and glycyrrhizic acid exhibited COVID-19 Mpro inhibitions.Cucrcumin inhibited human respiratory syncytial virus replication and budding	Curcuminoids prevent leukotriene's, prostaglandins, interferon-inducible protein, TNF, IL-12 and IL-6	Aqueous extract increased NO, IL‑2, IL‑6, IL‑10, IL‑12, IFN-γ, TNF-α	Chen et al., 2020; Ashraf, 2018; Chandrasekaran et al., 2013
	Zingiber Officinale Roscoe	6-gingerol binds at active sites of R7Y COVID-19, mainprotease essential for replicationand reproduction of SARS-Cov-2	6-gingerol inhibits the production of proinflammatorycytokines IL-1β, IL-12, TNFα	6-gingerol possess immunomodulatory properties	Rathinavel et al., 2020; Tripathi et al., 2007; Sharifi-Rad et al., 2017
Zygophyllaceae	Tribulus terrestris L.	Methanol fruit extracts showed in vivo antiviral potential on newcastle disease virus Haemagglutination titer in vivo vero cell line culture. The extract exhibited enormous anti Newcastle disease virus effect in vero cell line	Tribulusamide D isolated from the hydroalcoholic extract of T. terrestris exhibited anti-inflammatory effect on lipopolysaccharide stimulated RAW 264.7 macrophages. The phytomolecule inhibited the production of LPS induced nitric oxide and prostaglandin E2, by reducing the expression of inducible nitric oxide synthase and cyclooxygenase 2 expression	Saponins isolated from the aqueous fruit extract exhbited increasing phagocytosis, stimulation of nonspecific immune response in a dose-dependent manner. Alcoholic extract of the whole plant having the effect to increase in humoral antibody titre and delayed type hypersensitivity response in a dose-dependent manner that indicating increased immune response	Tilwari et al., 2011.Lee et al., 2017.Malik et al., 2018

Table 2

: Herbs derived secondary metabolites found to be effective against COVID-19 through molecular docking analysis.

Plant Family	Plant name	Antiviral	Anti-inflammatory	Immunomodulation	References
Molecular docking study
Apocynaceae	Nerium oleander L.	Digitoxigenine (ix) and Calarene (x) interact with Coronavirus spike protein.	The flower aqueous extract inhibited NO production and ERK phosphorylation.Oleandrin blocked TNF-α induced activation of NF-kB.	Stimulate the cell-mediated and the humoral mediated immune systems, specifically stimulates T and B lymphocytes.	Aanouz et al., 2021; Atay Balkan et al., 2018; Manna et al., 2000;
Acantahaceae	Andrographis paniculata (Burm. f.) Wall. ex Nees	Andrographolide (xxvi) inhibthe main protease of SARS-COV-2 (Mpro) through in silico studies	Andrographolide significantly reduced production of IL-1β, IL-6, CXCL-1, MCP-1	Andrographolide was reported to stimulate an innate immune response in in-vivo model. Ethanol extract induced phagocytic activity and peritoneal macrophages and Increases lymphocytes cell proliferation	Enmozhi et al., 2021Shen et al., 2002; Puri et al., 1993;(Banerjee et al., 2021) Churiyah et al., 2015
Amaranthaceae	Amaranthus tricolor L.	Amaranthin (xxiv) may inhibit SARS-CoV-2 3CLpro activity and hence virus replication	The hydroalcohol extract of leaves showed anti-inflammatory activity in in-vivo model		Ul-Qamar et al., 2020; Bihani et al., 2013; Srivastava, 2017
Amaryllidaceae	Allium sativum L.	Allyl disulfide, allyl trisulfide, allyl (E)-1-propenyl disulfide, allyl methyl trisulfide, diallyl tetrasulfide, 1,2-dithiole, allyl (Z)-1-propenyl disulfide, 2-vinyl-4H-1,3-dithiine, 3-vinyl-1,2-dithiacyclohex-4-ene, carvone, trisulfide, 2-propenyl propyl, methyl allyl disulfide, diacetonalcohol, trisulfide, (1E)-1-propenyl 2-propenyl, allyl sulfide, 1-propenyl methyl disulfide, trisulfide, (1Z)-1-propenyl 2-propenyl showed inhibition of the ACE2 proteinAllicin (xxv) may act as potential inhibitors of the COVID-19 Mpro	DMSO extract of Garlic powder reduced NF-κB, IL-1β, IL-6, TNF-α and diallydisulfide also significantly reduced IL-1β and TNF-α	Aqueous extract of Garlic powder increases the nucleolar activity and lymphocyte proliferation	Thuy et al., 2020; Khaerunnisa et al., 2020; Keiss et al., 2003; Zamani et al., 2011
Apiaceae	Angelica keiskei (Miq.) Koidz.	Nine alkylated chalcones and four coumarins exhibited 3CLpro and PLpro inhibitory activity in a dose dependent manner	The n-hexane bark extract down regulate NF-κB-dependent gene products. Compounds present in the plant showed potent inhibition of IL-6 production in TNF-α-stimulated MG-63 cell.	Xanthoangelol B, xanthoangelol C, and xanthoangelol E are immunological stimulators.*Selinidin suppress LTC4 synthesis and TNF-α production	Islam et al., 2021; Caesar and Cech, 2016; Kil et al., 2017
Asteraceae	Aster tataricus L.	The phytomolecules may inhibit 3CLpro or viral entry through binding with spike protein	Ethanol root extract decreased IL-1β, IL-6 and TNF-α level.		Zhang et al., 2020d;Rho et al., 2020
Asteraceae	Erigeron breviscapus (Vaniot) Hand.-Mazz.	The phytomolecules may inhibit 3CLpro or viral entry through binding with spike protein	Scutellarin reduced IL-18, and IL-1β. Breviscapine down-regulated IL-6 In-vivo		Zhang et al., 2020d;Zhu et al., 2018
Betulaceae	Alnus japonica (Thunb.) Steud.	Diarylheptanoids (Hirsutenone) inhibited replication of SARS-CoV PLpro by inhibiting Papain like protease.	Ethanol bark extract inhibit NO and COX-2 production. Triterpenoid present in the plant inhibit IL-1β and IL-6 levels induced by LPS in macrophage cells.	Ethanolic extract of leaves and barks of A. japonica possesses immunomodulatory activity	Demeke et al., 2021; Choi et al., 2011; Kim et al., 2005
Brassicaceae	Isatis indigotica Fortune	Indigo, sinigrin, aloe emodin (xxiii) and hesperetin blocked the cleavage processing of the 3CLpro	Root methanol extract inhibited TNF-α, IL-1 or IL-6 production	The root aqueous extract with DNA vaccine has adjuvant effect on the immune response against foot-and-mouth-disease-virus	Liang et al., 2020;Meng et al., 2017; Lin et al., 2005;Chen et al., 2012
Celastraceae	Tripterygium regelii Sprague & Takeda	Quinone-methide triterpenes celastrol, pristimerin, tingenone, iguesterin and dihydrocelastrol showed potent inhibitory activities against SARS-CoV 3CLpro			(Ryu et al., 2010)b
Euphorbiaceae	Phyllanthus emblica L.	Phyllaemblicin B (xiv) andphyllaemblinol showed binding affinity to Helicase (Nsp13).Phyllaemblicin G7 showed binding affinity to Spike protein, ACE2 proteinPhyllaemblinol exhibited binding affinity to 3CLpro.Phyllaemblicin B found to inhibit RNA-dependent RNA polymerase	The aqueous fruit extract suppress COX-2, iNOS, IL-16, IL-6 and reduced TNF-α, IL-1β	The aqueous fruit extract enhance NK cell activity and antibody dependent cellular cytotoxicity	Yin et al., 2021; Wu et al., 2020; ; (Wang et al., 2017)Suresh and Vasudevan, 1994
Legumes	Phaseolus vulgaris L.	3,5,7,3′,4′,5′-hexahydroxy flavanone-3-O-beta-D-glucopyranoside have potential anti- SARS-CoV-2 property.Quercetin-3-glucuronide-7-glucoside, Quercetin 3-vicianoside, Schaftoside, Chrysoeriol 8-C-glucoside, Isosakuranetin 7-O-neohesperidoside, Delphinidin 3-O-glucoside, Petunidin 3-O-glucoside found to bind with Mpro and ACE2 receptors.	The navy bean or black bean flour-containing diet significantly reduced IL-1β, TNFα, IFNγ, IL-17A, and IL-9.	The lectin crude extract has immunomodulatory effect	Ul-Qamar et al., 2020; Joshi et al., 2020; Chaki and Bhattacharjee, 2016
Magnoliaceae	Magnolia officinalis Rehder & EHWilson	Magnolol (xvi) showed potential PLpro inhibition.	Honokiol and magnolol inhibit PGD2, PGE2, leukotriene C4, LTB4, and thromboxane B2. Bark extracts inhibit the production of IL-6 in HGF-1 cells.	polyphenol rich aqueous extract from bark reduced serum NO, IL-6 and TNF-α, inhibiting pneumonia, decreasing lung viral titers and sensitizing IVA-induced apoptosis	Wu et al., 2020; Lin et al., 2007; Wu et al., 2011
Menispermaceae	Tinospora cordifolia (Willd.) Miers	Berberine (xxi), isocolumbin, magnoflorine (xxii) and tinocordiside interfere with the viral attachment and replication due to binding efficacy against surface glycoprotein and receptor binding domain and main protease	Chloroform stem extract prevented IL-6, IL-1β and PGE2	Aqueous and methanolic stem extract stimulate production of IFN-γ, TNF-α, and IL-1βCordifolioside A and syringin possess immunomodulatory activity	Alsuhaibani and Khan, 2017; Sagar and Kumar, 2020; Vellingiri et al., 2020; Sharma et al., 2012; Philip et al., 2018
Myricaceae	Myrica cerifera L.	Myricitrin (xi) showed good interaction potential with SARS-CoV-2 3CLpro receptor.	Myricanone down-regule the NF-κB		Ul-Qamar et al., 2020; Paul et al., 2013;
Oleaceae	Olea Europaea L.	Luteolin-7-glucoside (xii) and Oleuropein (xiii) appeared to have potential to act as COVID-19 Mpro inhibitors.	Oleuropein inhibit IL-1β production and down regulated iNOS, COX-2, NFKB, and JNK, and IL-6 and IL-1β	The hydroalcohol leaf extract reduced IL-1β, IL-6, IL-8,TNF-α and iNOS expression	Khaerunnisa et al., 2020; Nediani et al., 2019; Vezza et al., 2017
Oxalidaceae	Averrhoa bilimbi Linn.	It possesses potential inhibition of Main Protease (Mpro) by Molecular docking study	The methanol fruit extract decreased IL-1b, IL-6, TNF-a levels	Methanol fruit extracts significantly inhibited the CD18/11a expression	Khaerunnisa et al., 2020; Harun et al., 2015
Piperaceae	Piper longum L.	Piperolactam A (xv) interacts with Mpro and ACE2 enzyme.	Dichloromethane fraction suppress IL-1β, IL-6, and TNF-α.Fruits inhibited the release of cytokines, eosinophil infiltration in lungs.	Piperine having anti-apoptotic and restorative ability against splenic B and T cell population and IL-2 and gamma-Interferon release	Wang et al., 2017; Joshi et al., 2020; Pathak and Khandelwal, 2007;
Ranunculaceae	Nigella sativa L.	Nigellidine (vii) and α- Hederin (viii) showed to inhibit 3clpro/Mpro COVID-19 and 3clpro/Mpro SARS-coronavirus in an in-silico study.	The fixed oil and thymoquinone both found to down-regulate COX, 5-LO, 5-HETE and suppresses IL-6, TNFα, and NO production	The aqueous seed extract improves both cellular immunity and humoral immunity by stimulating CD4+	Salim and Noureddine, 2020; (Majdalawieh and Fayyad, 2015
Solanaceae	Withania somnifera (L.) Dunal	Withanone (xviii) block or weaken COVID-19 entry and its subsequent infectivitySteroidal lactones and quercetin potentially inhibited SARS COV PLpro and 3CLpro	Aqueous root extract inhibited IL -8, IL‑6, TNF‑α, IL‑1β and IL‑12	A herbo mineral formulation containing aswagandha significantly increased the CD4+ and CD8+.	Balkrishna et al., 2020b; Gupta and Singh, 2014; Chandra et al., 2012; Sikandan et al., 2018; Davis and Kuttan, 2000; Gupta et al., 2006; Trivedi et al., 2017; Das et al., 2021
Taxaceae	Torreya nucifera (L.) Siebold & Zucc.	Biflavone (xix), amentoflavone (xx) showed 3CLpro inhibitory effect	The leaves reduced secretion of IL-1β, IL-6, NO and PGE2		Ryu et al., 2010a;(Yoon et al., 2009)
Theaceae	Camellia sinensis (L.) Kuntze	Theaflavin-3’-gallate, Theaflavin-3,3’-digallate and tannic acid are effective against 3CLProIsolated Theaflavin from leaves of C. sinensis exhibited inhibitory activity against SARS-COV-2 virus through binding to RNA dependent RNA polymerase	Ethanol leaf extract and epigallocatechin gallate suppressed the production of NO, COX-2, IL-6, IL-1β, and TNF-α	Hot water extract of leaves significantly increased blood leucocyte, lymphocyte count, peritoneal macrophages, spleen and thymic lymphocytes count, lung macrophages count	Chen et al., 2005; Novilla et al., 2017; Gomes et al., 2014; Sharangi, 2009; Islam et al., 2021
Zingiberaceae	Zingiber officinale Roscoe	6-gingerol (xvii) showed interaction with viral proteases, RNA binding protein, Spike proteinHot water extracts of fresh rhizomes inhibited viral attachment of human respiratory syncytial virus (HRSV)	Rhizome supplement reduced TNF-α, IL-6 level.	Ginger essential oil recovered the humoral immune response	Chang et al., 2013; Rathinavel et al., 2020; Maged et al., 2013; Penna et al., 2003; Carrasco et al., 2010
Zygophyllaceae	Tribulus terrestris L.	Cinnamic amides and ferulic acid showed inhibitory activity against PLpro.	Tribulusamide D inhibited the production of iNOS, PGE2 and reduced the expression of IL-6, IL-10 and TNF- α	Seed aqueous and ethanol extracts increases IL-6 level	Song et al., 2014; Wu et al., 1999; Lee et al., 2017; Abdelrazek et al., 2018

Table 3

. SARS-CoV-2 inhibition potential of herbs from traditional formulation through evidence based approaches

Plant Family	Plant name	Antiviral	Anti-inflammatory	Immunomodulation	References
Herbs used in traditional formulation
Fabaceae	Astragalus propinquus Schischkin	Used as an ingredient in Yu Ping Feng San for the treatment of SARS-CoV infection	Isoliquiritigenin and liquiritigenin inhibited IL-6 and IL-12 productionsPolysaccharide-enriched fraction suppressed IL-1β, IL-6 expression and TNF-α level in LPS-induced macrophages	Aqueous root extract enhances IL-1α and IL-12 expressionThe plant extract capable of diminishing the levels of TNF-α and IL-1β, and P-selectin and ICAM-1	Lee et al., 2003; Gong et al., 2018; Li et al., 2014
	Glycyrrhiza uralensis Fisch.	Used as an ingredient in Lian Hua Qing Wen Capsule used for the Treatment of SARS-CoV infection.	Isoliquiritigenin, iso-liquiritin, and liquiritigenin decreased the mRNA levels of TNF-α and IL-6	Polysaccharides from hydroalcohol root extract activate CD4+ and CD8+ immune cells population and increased production of IL-2, IL-6, IL-7 levels and decreased TNFα levels	Yang et al., 2020; Tanaka et al., 2008; Tanemoto et al., 2015; Ayeka et al., 2017
Labiateae	Schizonepeta tenuifolia (Benth.) Briq.	Used as an ingredient in yin qiao san used as an anti-SARS-CoV drug	The ethanol extract of the aerial part significantly decreased COX-2, PGE2 and NO production by inhibiting the production of TNF- α, IL-1β, IL-6	Aqueous extract of the aerial part suppressed IFN-α, TNF-y, IL-4, IL-6 and IL-10	Lin et al., 2018; ; (Wang et al., 2011)Byun, 2014(Chen et al., 2017); Yang et al., 2020
Lamiaceae	Mentha haplocalyx Briq.	Used as an ingredient Lian Hua Qing Wen Capsule for the Treatment of SARS-CoV infection	Phenolic fraction and linarin from ethanol extract of aerial part decreased NO, TNF-α, IL-1β, and IL-6 production and suppress mRNA expression levels of iNOS, TNF-α, IL-1β, and IL-6	The ethanol extract of aerial part inhibited Ig- E, IL-4 and IL-5 production	Yang et al., 2020; Lee et al., 2011; Zhang et al., 2015; Chen et al., 2017
Moraceae	Morus alba L.	Used as ingredient for the formulation, Shashen Maidong Tang and Xie Bai San, for treating recovery stage patients with COVID-19In an in-silico study morusin (vi) was identified as potential M protease inhibitors	The aqueous and ethanol root bark extract suppressed the expression of TNF-α, c-Fos, p-p38, and pNF-κB p65. Restored iNOS, COX-2, IL-10, and IL-1β expressionKuwanon G significantly decreased the levels of IgE and IL-4, IL-5, and IL-13 in the sera and BAL fluids	Polysaccharidesfrom aqueous root bark extract increased lymphocyte proliferation and decreased antibody production from B cells	Kwong et al., 2020; Yan et al., 2020; Zhang et al., 2020; Bayazid et al., 2020; Kavitha and Geetha, 2018; Kim et al., 2000
Rosaceae	Armeniaca sibirica (L.) Lam.	Aqueous seed extract used as an ingredient in Lian Hua Qing Wen Capsule used for the Treatment of SARS-CoV infection	The methanol seed extract able to suppress PGE2 and NO production		Erdogan-Orhan and Kartal, 2011; Yang et al., 2020; Chang et al., 2005

Table 4

. Medicinal plants to be useful for the management of post-COVID complications

Family Name	Plant Name	Mechanism of Action	Disease orientation	Reference
Acanthaceae	Andrographis paniculata (Burm.f.) Nees	Andrographolide improved cell apoptosis, collagen deposition and epithelial-mesenchymal transition in HK-2 cell line. It also improved renal tubular cell apoptosis, tubulointerstitial fibrosis, epithelial-mesenchymal transition, NLRP3 inflammasome activation and mitochondrial dysfunction in high glucose treated rats	Kidney complications	(Liu et al., 2021)
		Hydroalcohol extract improved lung injury condition by enriching the inflammatory response, NF-κB p65 protein expression and nuclear translocation, and phosphorylation of IκBα in male Wistar rats	Lung related complications	Yao et al., 2021
		Water extract of whole plant improved myocardial inflammation pathway, reduced the chances of cardiac hypertrophy and myocardial apoptosis in high fat diet obsessed mice	Cardiac complications	Hsieh et al., 2016
		Andrographolide improved GSK-3β activity, β-catenin and NeuroD1 levels in-vivo. Thus, it can be used to improve depression like behaviours	Mental Problem	Varela-Nallar et al., 2015
		Hydroalcohol extract of aerial parts restored glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, alkaline phosphatase, superoxide dismutase, glutathione peroxidase and lipid peroxides level in paracetamol treated rat liver	Liver related problem	Nagalekshmi et al., 2011
		Androgrpholide reported to protect mesencephalic neurons by reducing dopaminergic neurodegenaration in-vitro and also inhibited in-vivo microglial inhibition, ROS and pro-inflammatory cytokine production in lipopolysaccharide treated rats	Parkinsonism	Wang et al., 2004
Amaranthaceae	Amaranthus tricolor L.	Leave extracts with organic solvents (methanol, petroleum ether, dichloromethane) improved gene expression of the pro-inflammatory cytokines, TNF-α, IL-1 and IL-6 in AGEs-induced oxidative stress and neuroinflammation associated with the risk of brain aging and developing Parkinson's disease	Parkinsonism	Amornrit and Santiyanont, 2015
		Ethanol leaves extract improved serum GOT, GPT, GGT, ALP, bilirubin, and MDA level in CCl4 treated rats	Liver related problem	Al-Dosari, 2010
Amaryllidaceae	Allium sativum L.	Allicin isolated from bulbs improved acute lung injury and inflammation, oxidative stress, apoptosis condition in lipopolysaccharide treated neonatal rats and as a traditional medicine in Peru it used to treat cough, cold and sore throat	Lung related complications	Villena-Tajeda et al., 2021Wang et al., 2018
		Diallyl trisulfide improved liver injury by reducing the serum aspartate transaminase, alanine aminotransferase levels, sterol regulatory element binding protein and cell apoptosis in ethanol treated rat	Liver related problem	Chen et al., 2016
		Ethanol extract of bulb improved renal failure by restoring antioxidant and serum biomarker levels in cisplatin treated rats	Kidney complications	Anusuya et al., 2013
Anacardiaceae	Rhus chinensis Mill.	Aqueous extract of fruit pulp reduced calcium oxalate crystal formation, aggregation and crystal density in in-vitro calcium oxalate crystallization	Kidney complications	Heirangkhongjam and Ngaseppam, 2021
		Dammarane-type triterpenoids isolated from the root extract prevented heart failure in zebra fish by enhancing heart dilatation, venous congestion, cardiac output, blood flow velocity and heart rate	Cardiac complications	Ye et al., 2020
		Phenolic compound of fruit extract improved serum lipid level, steatosis and liver damage in high-fat and ethanol treated rat model	Liver related problem	Wu et al., 2019
Apiaceae	Angelica keiskei (Miq.) Koidz.	Ethanol extract of aerial parts its active principle, 4-hydroxyderricin improved myosin heavy chain degradation by suppressing expressions of MAFbx, MuRF-1 and myostatin	Cardiac complications	Kweon et al., 2019
		Ethanol extract of aerial parts improved apoptosis via intrinsic and extrinsic pathways against AAP treated hepatotoxicity	Liver related problem	Choi et al., 2017
		Xanthoangelol isolated from the hydroalcohol extract of aerial parts (1) inhibited monoamine oxidase and dopamine β-hydroxylase in rats	Mental problem	Kim et al., 2013
Asteraceae	Echinacea purpurea L. Moench	A double blind, placebo-controlled study (clinical study) decreased anxiety conditions	Mental problem	Haller et al., 2019
		Hydroalcohol extract of aerial part decreased serum AST, BUN, total and direct bilirubin content and improved histopatholgical changes of kidney tissue by early fibrosis and proliferation	Kidney complications	Rezaie et al., 2013
		Alk-8/9 isolated from the root showed good hepatoprotective activity against acute fulminant hepatitis condition in-vivo by increasing the expression of heme oxygenase (HO)-1 protein lipopolysaccharide/ D-galactosamine treated mice	Liver related problem	Hou et al., 2011
	Erigeron breviscapus (Vaniot) Hand.-Mazz	Scutellarin showed potent hepatoprotective effects by improving CYP2E1 and IκBα/NF-κB signaling pathways in carbon tetrachloride treated mice	Liver related problem	Miao et al., 2021
		Scutellarin improved lung damage due to its antioxidant, antinflammatory and antiapoptotic effects in a bilateral hind limb ischemia–reperfusion rat model	Lung related complications	Ibrahim et al., 2019
		Scutellarin improved renal function by reducing serum creatinine, blood urea nitrogen, urine total protein and microglobulin content	Kidney complications	Wu et al., 2018
		Ethanol whole plant extract, ethyl acetate and aqueous fraction potently and noncompetitively inhibited GABA transaminase and succinic semialdehyde dehydrogenase enzymes in in-vitro assay due to the presence of flavonoids	Parkinsonism	Tao et al., 2008
Brassicaceae	Isatis indigotica Fortune ex Lindl.	Erucic acid isolated from the ethanol extract improved lung injured condition by reducing CD8+ cytotoxic T lymphocyte, pro-apoptotic, hyperactivity signalling pathways and the immune inflammation	Lung related complications	Liang et al., 2020
Caesalpinaceae	Cassia tora L.	Hydroalcohol seed extract improved anxiolytic and antidepressant condition in Swiss mice model by reducing the locomotor activity and convulsion	Mental Problem	Shrivastava et al., 2020
		Seed extract improved renal reperfusion injury in rats by reducing blood urea nitrogen and serum creatinine level and increasing the catalase, superoxide dismutase, glutathione peroxidase, antioxidant, and nitric oxide expression	Kidney complications	(Park et al., 2019)
		Traditionally the leaves and seeds possess cardiotonic and cardioprotective activity	Cardiac complications	Awasthi et al., 2015
		The plant exhibited improved lung metastasis condition in BALB/c mice bearing 26-M3.1 colon carcinoma cell tumours	Lung related complications	Zhao et al., 2013
		Ethanol seed extract reduced plasma lipid levels, hepatic lipid accumulation and improved hepatic histological lesions by enhancing the phosphorylation of AMP-activated protein kinase enzyme in high fat diet treated rat	Liver related problem	Tzeng et al., 2013
		Petroleum ether, methanol and ethyl acetate extract improved in oxotremorine treated mice	Parkinsonism	Suryawanshi et al., 2009
Celastraceae	Tripterygium regelii Sprague	Methanol extract of leaves may prevent Parkinson's disease by increasing Bax, tyrosine hydroxylase, caspase-3, caspase-9 level, brain-derived neurotrophic factor and by decreasing Bcl-2 in SH-SY5Y cells	Parkinsonism	Choi et al., 2010
Cibotiaceae	Cibotium barometz (L.) J. Sm.	Hemiterpene glycosides isolated from hydroalcohol extract of rhizome showed hepatoprotective activity against acetaminophen induced HepG2 cell death	Liver related problem	Xie et al., 2017
Compositae	Chrysanthemum indicum L.	Ethanol flower extract showed cardio-protective activity by inhibiting atherosclerosis and decreased serum lipid level in high fat diet treated rats	Cardiac complications	Sravanthi and Shakir, 2017
		Ethanol extract improved p53 expression in porcine kidney cell line and also improved histopathological alterations and apoptosis in cisplatin treated rats	Kidney complications	Kim et al., 2015
		Aqueous flower extract showed hepatoprotective activity by decreasing glutamic oxaloacetic transaminase and pyruvic transaminase level in hepatocellular carcinoma cells	Liver related problem	Jeong et al., 2013
		Aqueous extract of flowers improved anxiolytic activity in mice mediated by the GABAA receptor and the 5-HT1A receptor	Mental Problem	Hong et al., 2012
		Methanol extract possessed protective effect against cytotoxicity in Parkinson's disease induced cell model by inhibiting cell loss, IκB-α degradation, NF-κB p65 and production of reactive oxygen species and prostaglandin E (2) expression	Parkinsonism	Kim et al., 2011
Dryopteridaceae	Dryopteris crassirhizoma Nakai	Ethanol extract improved in-vivo allergic asthma condition and airway inflammation by inhibiting the activation of NF-κB signalling	Lung related complications	Piao et al., 2020
Euphorbiaceae	Phyllanthus emblica L.	Ethanol fruit extract suppressed neuroinflammation in Microglia and promoted neurite outgrowth in Neuro2a cells	Parkinsonism	Phochantachinda et al., 2021
		Aqueous fruit extract improved endothelial function, decreasing reflection index, and malondialdehyde level and increased nitric oxide, glutathione activity in a randomised, double blind, placebo controlled clinical study	Cardiac complications	Usharani et al., 2019
		Aqueous fruit extract prevented precancerous lung lesions through regulating the IL-1β/miR-i101/Lin28B signaling pathway in benzopyran treated mice	Lung related complications	Wang et al., 2017
		Aqueous fruit extract improved in-vivo high fat diet (HFD)-induced dyslipidaemia, hepatosteatosis, and oxidative stress and significantly reduce body weight, enhance the antioxidant enzyme activities, and improve steatosis through elevating adiponectin in adipocytes and PPAR-α in the liver	Liver related problem	Huang et al., 2017
		Ethanol fruit extract improved SOD, CAT, GSH-Px, GSR, GSH, GST and TBARS level and decreased AChE activity in brain tissue homogenates	Mental Problem	Uddin et al., 2016
		Aqueous fruit extract improved malondialdehyde level, total antioxidant capacity, superoxide dismutase and catalase activity in contrast induced kidney injured rat	Kidney complications	Tasanarong et al., 2014
Fabaceae	Astragalus propinquus Schischkin	Astragaloside IV (AS-IV) inhibited apoptosis and inflammation via activating the JAK2/STAT3 signalling pathway	Parkinsonism	Xu et al., 2021
		Aqueous extract of the plant inhibited TNF-α and IL-6 production and down regulated the protein and mRNA expression of toll-like receptors 4, IL-1 receptor-associated kinase-1 and NF-κB/p65 in lipopolysaccharide treated rats	Lung related complications	Qin et al., 2018
		The plant prevented Ca2+ current remodelling in heart failure by down regulating CaMKII	Cardiac complications	Li et al., 2017
		The renal protective effects mediated through suppression of transforming growth factor beta expression and enhance nitric oxide production in Patients on Peritoneal Dialysis	Kidney complications	Lui et al., 2015
		Aqueous extract suppressed tyrosine hydroxylase and acetylcholine transferase expression in the brain of repeated stress treated depressed rats	Mental Problem	Park et al., 2009
	Glycyrrhiza glabra L.	Methanol extract exhibited protective action against pulmonary fibrosis lung of rats. The extract decreased hydroxyproline level in pulmonary tissue	Lung related complications	Fekri et al., 2021
		Glycyrrhizin reduced thrombin-fibrinogen clotting time, thrombin-induced platelet aggregation and improved plasma recalcification duration	Cardiac complications	Hasan et al., 2021
		Glycyrrhizin isolated from the aqueous root extract possessed anti-depressant activity in mice model	Mental Problem	Hasan et al., 2021
		A clinical study suggested oral administration of root syrup prepared with sugar, citric acid and gelling agent showed good symptomatic relief from Parkinson's disease	Parkinsonism	Petramfar et al., 2020
		Glycyrrhizic acid, liquiritin and liquiritigenin isolated from fermented root extract showed hepatoprotective activity in alcohol treated mice by decreasing lipid accumulation and increasing the hepatic glutathione level	Liver related problem	Jung et al., 2016
		Glycyrrhetinic acid isolated from the plant reduced the serum potassium concentration and hyperkalemia in hemodialysis patient	Kidney complications	Ferrari, 2009
	Glycyrrhiza uralensis Fisch.	Gancaonin N improved inflammatory response by inactivating the MAPK and NF-κB signaling pathways in acute pneumonia induced in-vitro model	Lung related complications	Ko et al., 2021
		Isoliquiritigenin exhibit protective effect on dopaminergic cell under oxidative stress conditions by regulating the apoptotic process	Parkinsonism	Hwang and Chun, 2012
		Liquiritin isolated from aqueous extract of root improved superoxide dismutase activity and plasma malondialdehyde level in chronic variable stress treated depressed rats	Mental Problem	Zhao et al., 2008
	Mucuna pruriens (L.) DC.	Aqueous seed extract improved protection of kidney by decreasing serum ALT and other kidney enzyme levels in arsenic treated rats	Kidney complications	Concessao et al., 2020
		Hydralcohol extract of leaves improved serum ALT, AST, ALP, and bilirubin levels in isoniazid-rifampicin treated rats	Liver related problem	Obogwu et al., 2014
		Hydroalcohol seed extract improved anti-depressant activity by reducing immobility time and showed potent activity against chronic unpredictable mild stress in rats	Mental problem	Rana and Galani, 2014
		Seed powder can improve long term management of Parkinson's disease and provide symptomatic relieve from PD	Parkinsonism	Katzenschlager et al., 2004
Gentianaceae	Gentiana scabra Bunge	Polyphenolic compounds isolated from aqueous extract exhibited hepatoprotective activity in CCl4 induced mice model by reducing oxidative stress and liver injury	Liver related problem	Ko et al., 2011
		Gentiacaulein isolated from the plant possessed antidepressant activity by inhibiting Monoamine oxidase	Mental problem	Yang et al., 2010
Labiateae	Schizonepeta tenuifolia (Benth.) Briq.	Hydroalcohol extract inhibited pro-inflammatory cytokines and oxidative stress, and activated the Nrf2-HO-1 axis in lipopolysaccharide treated mice	Lung related complications	Lee et al., 2021
Lamiaceae	Mentha haplocalyx Briq.	In TCM system Lian Hua Qing Wen Capsule containing the plant along with some other plant clear heat and relaxes lung	Lung related complications	Yang et al., 2020
	Salvia miltiorrhiza Bunge	Aqueous extract of the plant improved lung injured condition by inhibiting the production of TNF-α, IL-6 and the protein and mRNA expression of toll-like receptors 4, nuclear factor-ΚB, IL-1 receptor-associated kinase-1	Lung related complications	Qin et al., 2018(Chen et al., 2017)
		Essential oil from the aerial parts showed improved anxiolytic condition by increasing the intracellular Cl- concentration in in-vitro cell culture and also improved the anxiolytic effect and social interaction in in-vivo model	Mental Problem	Liu et al., 2015
		Cryptotanshinone isolated showed prevention of TNF-α, GalN/LPS-induced apoptosis, caspase-3, -8, -9 and cytochrome c activation. It also prevented the JNK, ERK and p38 phosphorylation and pro-inflammatory cytokine production in d-galactosamine (GalN)/lipopolysaccharide (LPS) treated mice	Liver related problem	Jin et al., 2014
		Intraperitoneal injection of aqueous root extract improved kidney iron, blood urea nitrogen, malondialdehyde and creatinine level	Kidney complications	Guan et al., 2013
		Salvanolic acid B from the aqueous extract of aerial part improved caspase-3 activity, and cytochrome C translocation from mitochondria to the cytosol. It also decreased the extracellular signal-regulated kinase activation and activated 6-hydroxydopamine-suppressed protein kinase C	Parkinsonism	Tian et al., 2008
	Salvia officinalis L.	Leaves extract showed hepatoprotective activity in oestrogen deficient ovariectomized rats by altered plasma transaminases and lipid profile activities of liver	Liver related problem	Koubaa-Ghobrel et al., 2020a
		Essential oils improved liver biochemical marker, cholesterol, body weight and renal dysfunction in high fat diet treated rat	Kidney complications	Koubaa-Ghobrel et al., 2020b
		Essential oils potentially reduced aspartate transaminase, alanine transaminase, γ‐glutamyltranspeptidase and lactate dehydrogenase activities and total cholesterol, triglycerides, total lipids, and low‐density lipoprotein cholesterol level in high fat diet induced mice	Cardiac complications	Koubaa-Ghobrel et al., 2020b
		Leave infusion inhibited lung fibrosis in rats and normalized lipid peroxidation, superoxide dismutase and catalase activities	Lung related complications	Bahri et al., 2020
		In a clinical study the ethanol extract of dried leave improved anxiety, alertness, calmness and contentedness on the Bond–Lader mood scales	Mental problem	Kennedy et al., 2005
	Scutellaria barbata D. Don	Wogonin (flavonoid) exhibited protective effect against atherosclerosis and restenosis by suppressing the proliferation of vascular smooth muscle cell and inhibited MMP-9 secretion	Cardiac complication	Chen et al., 2020
		Pre-treatment of aqueous root extract improved in-vivo renal dysfunction by reducing the pro-inflammatory cytokine level, tubular injury and toxic effects in cisplatin treated mice	Kidney complications	Lee et al., 2010
		Wogonin isolated from the ethanol root extract showed anxiolytic activity in in-vivo elevated plus maze test	Mental problem	Hui et al., 2002
Lauraceae	Cinnamomum zeylanicum L.	Bark extract increased latency period and possessed anxiolytic activity in in-vivo models	Mental Problem	Jain and Gupta, 2019
		Aqueous bark extract improved serum alanine aminotransferase, aspartate aminotransferase, creatinine, urea level in-vivo and reduced histological alterations in acetaminophen treated mice	Kidney complications	Hussain et al., 2019
		Aqueous bark extract showed hepatoprotective activity against acetaminophen treated hepatotoxicity by decreasing the serum alanine aminotransferase, aspartate aminotransferase, creatinine, urea levels and histological alterations in liver	Liver related problem	Hussain et al., 2019
		Bark extract inhibited catalepsy in Parkinson's disease induced mice model	Parkinsonism	Moazedi and Parham, 2018
		Methanol bark extract showed cardio-protective activity by controlling blood pressure and inhibiting angiotensin-converting enzyme in Sheep tissues	Cardiac complications	Ranjini et al., 2016
		Methanol bark extract improved lung condition by inhibiting angiotensin-converting enzyme in Sheep tissues	Lung related complications	Ranjini et al., 2016
	Laurus nobilis L.	Ethanol extract of leaves reduced the level of liver biomarkers including pro-inflammatory cytokine production, NLRP3 inflammasome activation, interleukin‐1β secretion and caspase‐1 activation in an in-vivo acute lung infection model	Lung related complications	Lee et al., 2018
		Ethanol leaf extract reduced liver biomarkers level such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ -glutamiltransferase, bilirubin, urea, albumin, glucose, cholesterol, triacylglycerides in CCl4 induced hepatotoxicity in-vivo model	Liver related problem	Gasparyan et al., 2015
		Spirafolide isolated from the methanol leave extract improved dopaminergic toxic condition by increasing cell survival rate and decreasing intracellular ROS levels	Parkinsonism	Ham et al., 2010
Leguminosae	Psoralea corylifolia L.	Corylin isolated from the whole plant extract reduced LPS-induced pro-inflammatory IL-6 and TNF-α production in human bronchial epithelial cells and in mice. It also inhibited the mitogen-activated protein kinase phosphorylation	Lung related complications	Chen et al., 2021
		D3, 2-hydroxybakuchiol (BU) isolated from the hydroalcohol seed extract inhibited dopamine uptake in dopamine transporter transfected Chinese hamster ovary cells and blocked dopamine reuptake	Parkinsonism	Zhao et al., 2009
		Psoralidin from the seed extract improved 5-HT, 5-hydroxyindoleacetic acid and dopamine secretion in mice brain and also improved the stress condition by improving the release of adrenal corticotropin hormone, corticosterone and serum corticotropin-releasing factor	Mental Problem	Yi et al., 2008
		Bakuchiol, bakuchicin and psoralen isolated from the aqueous seed extract showed protective effect against tacrine treated cytotoxicity in Hep G2 cells	Liver related problem	Cho et al., 2001
Lessoniaceae	Ecklonia cava	Dieckol isolated from the hydroalcohol extract improved calcium Signaling, PI3K/AKT/eNOS Pathway and vasodilation in in-vitro endothelial cell and in-vivo zebrafish models	Cardiac complications	Lu et al., 2021
		Ethanol extract improved cognitive function in-vivo by reducing the production of Aβ and tau-hyperphosphorylation	Mental problem	Park et al., 2019
		Dieckol-rich phlorotannins from the aqueous extract showed potent hepatoprotective activity by decreasing the liver enzymes and the histopathological changes in ethanol treated mice	Liver related problem	Kang et al., 2012
		Phlorotannins, triphlorethol-A, phloroglucinol, eckstolono, eckol and dieckol isolated from the ethanol extract of the plant showed potent ACE inhibition	Lung related complications	Wijesinghe et al., 2011
Loranthaceae	Taxillus chinensis (DC.)	The plant found to protect the liver function by improving glucose metabolism, lipid and anti-hepatic injury and cell apoptosis in diabetic induced rat	Liver related problem	Ping et al., 2019
		Plant extract present in the Chinese herbal formulation Tian-ma-gouteng-yin improved headache, dizziness, vertigo, tinnitus, blurred vision and a sensation of heat rushing towards the head	Mental Problem	Chang et al., 2016
Magnoliaceae	Magnolia officinalis Rehder & E.H.Wilson	Magnolia extract improved kidney inflammation and oxidative stress by increasing PGC-1α-mediated various antioxidative protein expressions in high fat diet treated mice	Kidney complications	Cui et al., 2013
		Magnolol improved dopamine transporter and tyrosine hydroxylase protein levels in the striatum	Parkinsonism	Muroyama et al., 2012
		Magnolol improved the number of total cells, neutrophils, macrophages in the bronchoalveolar lavage fluid and down-regulated TNF-α, IL-1β and IL-6 levels. It also inhibited the phosphorylation of IκB-α, NF-κB p65 and expression of TLR4 lipopolysaccharide treated mice	Lung related complications	Yunhe et al., 2012
		Aqueous bark extract improved hippocampal ACH release and central serotonergic activity in rat and human model	Mental Problem	Nakazawa et al., 2003
Meliaceae	Azadirachta indica A.Juss.	Ethyl acetate fraction of bark improved sedative and anxiolytic effect on adult zebrafish through serotonergic and GABAergic systems due to its phenolic and flavonoid content	Mental Problem	Silva et al., 2020
		Bark extract decreased rotational behavior condition and improved glutathione peroxidase, iNOS activity in 6-hydroxydopamine treated rat model	Parkinsonism	Xiang et al., 2018
		Aqueous leaves extract showed protective effects against cigarette smoke, lipopolysaccharide induced pulmonary inflammation and improved infiltration of neutrophils and macrophages in bronchoalveolar lavage fluid	Lung related complications	Lee et al., 2017
		Aqueous leaves extract improved renal injury in Plasmodium berghei treated renal injured mice	Kidney complications	Somsak et al., 2015
		Aqueous leaf extract exhibited potent cardioprotective effect in isolated perfused frog and rabbit heart	Cardiac complications	Khosla et al., 2002
		Aqueous leave extract reduced serum aspartate aminotransferase, alanine aminotransferase and gamma glutamyl transpeptidase levels in paracetamol treated rat	Liver related problem	Bhanwra et al., 2000
	Toona sinensis (Juss.)M. Roem.	Polyphenols present in seed extract inhibited Parkinson's disease by reducing neuroinflammation and inhibiting p38MAPK signaling pathway in rat model	Parkinsonism	Zhuang et al., 2019
		n-butanol seed extract showed anti-diabetic potential in rat model by reducing the blood glucose, urinary albumin, renal index, oxidative stress index, serum creatinine, urea, nitrogen levels and increasing the TGF-b1, collagen IV, and CTGF level	Kidney complications	Li et al., 2016
		Leaves extract showed hepatoprotective activity by reducing liver fibrosis, TGFbeta1 and collagen in thioacetamide treated rat	Liver related problem	Fan et al., 2007
Menispermaceae	Tinospora cordifolia (Willd.) Miers	Ethanol extract of aerial parts protected dopaminergic neurons and reduced iron accumulation in brain	Parkinsonism	Kosaraju et al., 2014
		Ethanol extract of stem improved COX-2, iNOS, ICAM-1, pro-inflammatory cytokines levels in asthma induced mice	Lung related complications	Tiwari et al., 2014
		Consumption of stem extract modulates changes in kidney chondroitin sulphate or dermatan sulphate in diabetes induced animal model	Kidney complications	Joladarashi et al., 2012
		Aqueous extract of stem and leaves improved superoxide dismutase, catalase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and acid phosphatase level	Liver related problem	Sharma and Pandey, 2010
Moraceae	Broussonetia papyrifera (L.) L'Her. ex Vent	Root bark extract showed hepatoprotective effect by prevention of hepatic steatosis in high fat diet treated mice	Liver related problem	Lee et al., 2021
		Traditionally the fruit extract used to treat various ailments related to heart	Cardiac complications	Zhang et al., 2020c
		The plant along with L. japonica reduced in-vivo septic inflammation and TNF-α, IFN-g, IL-1b levels and also inhibited cell recruitment in bronchoalveolar lavage fluid	Lung related complications	Ko et al., 2013
		Chloroform extract of twigs possessed improved Parkinson's condition in mushroom tyrosinase	Parkinsonism	Zheng et al., 2008
	Morus alba L.	Ethanol extract of root bark prevented endothelial dysfunction in rat aorta	Cardiac complications	Panth et al., 2018
		Root bark extract improved depression like behaviour condition in high fat diet treated rats and also reduced brain-derived neurotrophic factor expression and extracellular signal-regulated kinase phosphorylation	Mental Problem	Ye et al., 2017
		Flavonoid fraction from leaves showed potent nephroprotective activity by reducing the blood urea nitrogen and creatinine concentration induced in cisplatin treated rats	Kidney complications	Nematbakhsh et al., 2013
		Ethanol extract of root barks inhibited production of pro inflammatory cytokines IL-6, TNF-α, infiltration of inflammatory cells in lung epithelial cells and NO production in lung macrophages	Lung related complications	Lim et al., 2013
		Hydroalcohol fruit extract protected dopaminergic neurons in in-vitro cells. In-vivo treatment of the extract protected brain from bradykinesia dopaminergic neuronal damage	Parkinsonism	Kim et al., 2010
		Alcohol and water extract of leaves improved serum glutamate pyruvate transaminase, glutamate oxaloacetate transaminase, alanine phosphatase and bilirubin and histological changes in carbon tetrachloride treated rats	Liver related problem	Hogade et al., 2010
Myricaceae	Myrica cerifera L.	Myricetin increased glutathione, monoamine oxidase, glutathione-S-transferase, protein carbonyl content and lipid peroxidation	Parkinsonism	Ara et al., 2017
Myrtaceae	Syzygium aromaticum (L.) Merr. & L.M.Perry	Hydroalcohol extract of buds improved acute kidney injury by ameliorating necrosis, degeneration, dilatation and flattening in rats	Kidney complications	Nasri et al., 2020
		Essential oil isolated from the buds showed potent in-vivo anticonvulsant activity by improving the threshold of clonic seizures in chemical treated rats	Parkinsonism	Avanthi et al., 2015
		Essential oil from the buds reduced anxiety, depression and locomotor hyperactivity in in-vivo model	Mental Problem	Adli et al., 2014
		Aqueous flower bud extract of the plant improved in-vivo hepatic injury, liver serum biochemical parameters and oxidative stress in thioacetamide treated rat	Liver related problem	Prasad et al., 2010
Oleaceae	Olea Europaea L.	Leaf extract decreased IL-6, IL-8 and TNFα in hypertensive patients	Kidney complications	Javadi et al., 2019
		Oleuropein and hydroxytyrosol decreased NF-κB and TNF-α expression by p38 signaling pathway in bisphenol A-treated rats	Liver related problem	Mahmoudi et al., 2018
		Olive oil reduced behavioral deficits via altering 5-HT and DA metabolism level in in-vivo models on Wistar rats	Mental problem	Parveen et al., 2013
Paulowniaceae	Paulownia tomentosa Steud.	Chloroform fruit extract and ursolic acid showed potent hepatoprotective activity against hepatocarcinogenesis on MCF-7 and HepG2 cell line and restored various biochemical parameters	Liver related problem	Ali et al., 2019
		Methanol extract of stem bark reduced the production of pro-inflammatory cytokine IL-6, TNF-α in LPS-stimulated RAW 264.7 macrophages. It also reduced in-vivo neutrophils, macrophages, nitric oxide and inducible nitric oxide synthase levels, inflammatory cells infiltration and monocyte chemoattractant protein-1 in lipopolysaccharide treated mice	Lung related complications	Lee et al., 2018
Piperaceae	Piper longum L.	Piperine improved plasma concentrations of creatinine, urea-nitrogen, expression of pro-inflammatory factors, oxidative stress and renal histopathological injuries in ischemia-reperfusion rat	Kidney complications	Mohammadi et al., 2019
		Piperine potentially reduced activation of microglia and blocked release of proinflammatory cytokines thus, protected dopaminergic neurons damage	Parkinsonism	He et al., 2016
		Methanol extract of fruits inhibited monoamine oxidase activity and increased monoamine neurotransmitters levels in β-amyloid treated rat	Mental Problem	Hritcu et al., 2015
		Alcohol fruit extract inhibited bronchospasm and blocked the release of histamine in in-vitro guinea-pig ileum preparation and histamine treated guinea-pig	Lung related complications	Kaushik et al., 2012
		Piperine showed negative inotropic and negative chronotropic effect by blocking the action of adrenalin in isolated frog heart	Cardiac complications	Lokhande et al., 2006
		Piperine improved glutathione and peroxide level in the liver cell in tert-butyl hydroperoxide and carbon tetrachloride treated mice	Liver related problem	Koul and Kapil, 1993
	Piper nigrum L.	Essential oil from fruits showed anxiolytic and antidepressant activity and improved behavioural changes in depressed mice model	Mental Problem	Ghosh et al., 2021
		Ethanol extract of seed showed nephroprotective activity by improving serum biochemical parameter and histopathological changes in para-amino salicylic acid treated rats	Kidney complications	Gaikwad and Zodape, 2019
		Piperine improved in-vivo cardiac injury and cardiac function including myocardial oxidative stress, apoptosis and inflammation in doxorubicin treated mice	Cardiac complications	Yan et al., 2019
		Ethanol extract of the seed showed hepatoprotective activity in para-amino salicylic acid and ethinoamide treated rat liver and restored the biochemical changes	Liver related problem	Zodape and Gaikwad, 2019
		Alkaloids from seed hydroalcohol extract increased total movement time, distance, dopaminergic neuron level, and glutathione and superoxide dismutase activity	Parkinsonism	Bi et al., 2015
Ranunculaceae	Cimicifuga racemosa (L.) Nutt.	Consumption of the plant decreased systolic and diastolic blood pressure and inhibited arterial hypertension in perimenopausal women	Cardiac complications	Gorach, 2018
	Nigella sativa L.	Thymoquinone induced a significant positive baseline inotropic effect in the rat heart	Cardiac complications	Asoom and Al-Hariri, 2019
		Quercetin-3-O-α-L rhamnopyranoside, quercetin-7-O-β-D gluco pyranoside, tauroside E, and sapindoside B isolated from hydroalcohol extract of seeds improved antidepressant condition by inhibiting the uptake of norepinephrine, serotonin, and dopamine in mice	Mental Problem	Elkhayat et al., 2016
		Thymoquinone afford neuroprotection against 6-OHDA neurotoxicity in neurodegenerative disorders	Parkinsonism	Sedaghat et al., 2014
		Thymoquinone decreased serum creatinine, blood urea nitrogen, thiobarbituric acid reactive substances, total nitrate/nitrite level and increased glutathione, glutathione peroxidase, catalase and ATP levels in kidney tissues in gentamicin treated rats	Kidney complications	Sayed-Ahmed and Nagi, 2007
		Nigellon improved airway obstruction and blocked the release of histamine	Lung related complications	Gilani et al., 2004
		Thymoquinone improved ratio of helper to suppressor T cells, natural killer cell activity and production of IL-3 in isolated rat hepatocytes	Liver related problem	Daba and Abdel-Rahman, 1998
Rosaceae	Armeniaca sibirica (L.) Lam.	Hydroalcohol leaf extract improved sGOT, sGPT, sALP, TBARS, GGT, LDH TP, Albumin and sB levels in paracetamol treated rats	Liver related problem	Raj et al., 2016
		Ethanol extract significantly increased catalase, superoxide dismutase, and glutathione levels in methotrexate treated rats	Kidney complications	Vardi et al., 2013
Rutaceae	Phellodendron cortex	Alkaloids derived from the plant improved mental depression condition, noradrenaline, dopamine and monoamine oxidase-A levels and provide protection against Alzheimer's disease	Mental Problem	Kong et al., 2019
		Quercetin reduced the symptoms of heart failure and improved coronary heart disease condition	Cardiac complications	Sun et al., 2019
		Berberine isolated from n-butyl alcohol extract showed bronchodilation effect by inhibiting high K+- and acetylcholine-induced precontraction of airway smooth muscle in tracheal rings and lung slices	Lung related complications	Jiang et al., 2016
	Toddalia asiatica (L.) Lam.	Plant extract inhibited calcium influx, controlled blood pressure of anesthetized rats and relaxed the contractile smooth muscle	Cardiac complications	Zeng et al., 2021
Solanaceae	Withania somnifera (L.) Dunal	Aqueous root extract showed hepatoprotective activity by the antioxidant activity in CCl4 treated rats	Liver related problem	Sharma et al., 2021
		Withaferin A improved lung inflammation by blocking NF-κB and nuclear factor erythroid2 related factor 2 signalling pathway	Lung related complications	Logie and Vanden Berghe, 2020
		Root extract increased dopamine, 3,4-dihydroxy-phenylacetic acid, homovanillic acid, lipid peroxidation marker level in the corpus striatum	Parkinsonism	Raja Sankar et al., 2009
		Root extract exhibited nephroprotective effect by improving antioxidant activity in gentamicin treated animal	Kidney complications	Jeyanthi and Subramanian, 2009
Taxaceae	Torreya nucifera (L.) Siebold & Zucc.	Arctigenin, traxillagenin, and 49-demethyltraxillagenin improved hepatocytes condition by maintaining the GSH level CCl4 treated rats	Liver related problem	Kim et al., 2003
Theaceae	Camellia sinensis (L.) Kuntze	In repeated stress induced rats model the hydroalcohol leaf extract elevated depression condition, improve immobility condition, oestrogen level and glucose metabolism in brain	Mental Problem	Ye et al., 2019
		Pre-treatment of aqueous leave extract significantly reduced oxidative damage, urea, uric acid and creatinine level and showed good antioxidant effect in nicotine treated rats	Kidney complications	Saad et al., 2019
		Leaves and its major phytoconstituents such as, catechin, epicatechin and epigallocatechin gallate improved Parkinson's disease condition in in-vivo model	Parkinsonism	Pinto et al., 2015
		Aqueous leaf extract showed reduction of enzyme and non-enzyme levels of liver tissues and lipid peroxidation in CCl4 treated rat	Liver related problem	Hy and Ira, 2015
		Consumption of the plant effectively could manage cardiovascular risk factors	Cardiac complications	Deka and Vita, 2011
		Extract of the plant increased NO, TNF-α level, reduced the degree of injury and infiltration of neutrophil tissues in carrageenan-treated mice	Lung related complications	Paola et al., 2005
Urtiaceae	Urtica dioica L.	Hydroalcohol leave extract improved anti-depressant and anxiolytic condition in-vivo study.	Mental Problem	Patel et al., 2018
		Hydroalcohol extract improved motor function, mito-oxidative defense alteration in Parkinson's disease induced rat model	Parkinsonism	Bisht et al., 2017
		Aqueous extract inhibited eosinophilia, leucocytes, lymphocytes levels and lipid peroxidation in BALF in asthmatic rats	Lung related complications	Zemmouri et al., 2017
		Ethanol extract improved nephrotoxic condition by decreasing serum creatinine and blood urea nitrogen level in nephrotoxic rabbit model	Kidney complications	Salih, 2015
		Essential oil from the plant showed hepatoprotective activity in biliary obstruction induced rat model by reducing α-smooth muscle actin, cytokeratin-positive ductular proliferation and terminal deoxynucleotidyl transferase dUTP nick end labelling activity	Liver related problem	Oguz et al., 2013
		Aqueous plant extract showed cardioprotective in isolated Langendorff perfused rat heart by decreasing heart rate and increasing left ventricular pressure	Cardiac complications	Legssyer et al., 2002
Zingiberaceae	Curcuma longa L.	Curcumin showed hepatoprotective activity against alcohol induced liver disease by preventing apoptosis and inhibition of NF-κB in in-vivo models	Liver related problem	Farzaei et al., 2018
		Curcumin improved anti-immobility action in forced swim test and also enhanced the anti-immobility effect of monoamine oxidase inhibitors such as tranylcypromine, selegiline	Mental Problem	Kulkarni and Dhar, 2010
		Curcumin improved loss of dopaminergic neurons in Parkinson's disease induced rat model	Parkinsonism	Aggarwal and Harikumar, 2009
		Curcumin improved renal ischemia reperfusion injury and antioxidant gene expression in in-vivo model	Kidney complications	Aggarwal and Harikumar, 2009
		Curcumin protected rats from adriamycin-induced myocardial toxicity and inhibited the development of atherosclerosis in apoE/LDLR-double knockout mice	Cardiac complications	Aggarwal and Harikumar, 2009
		Curcumin inhibited in-vitro allergen-induced lymphocyte, proliferation and production of IL-2, IL-5, GM-CSF, IL-4 model and also reduced airway constriction	Lung related complications	Aggarwal and Harikumar, 2009
	Zingiber officinale Roscoe	Hydroalcohol extract of rhizome showed potent anxiolytic activity in mice models	Mental Problem	Kumar et al., 2020
		Ethanol extract of rhizome improved renal dysfunction, kidney tissue damage and oxidative damage by increasing serum creatinine, urea level and decreasing the creatinine clearance and reabsorption of urine albumin. It also decreased total antioxidant status and DNA content in cadmium treated rats	Kidney complications	Gabr et al., 2019
		Pre-treatment with aqueous ethanol extract of rhizome decreased cardiac enzyme troponin, creatine kinase, lactate dehydrogenase, alanine transaminase and aspartate transaminase activity thus improved myocardial injury in isoproterenol treated rats	Cardiac complications	Amran et al., 2015
		6-shogaol isolated from rhizome showed improved Parkinson's disease condition in rat mesencephalic cell culture. In-vivo treatment of 6-shogaol inhibited bradykinesia and restored MPTP-induced changes in motor coordination	Parkinsonism	Park et al., 2013
		Ethanol extract of rhizome showed protective hepatotoxic activity against thioacetamide-treated rat and Hep-G2 cells	Liver related problem	Bardi et al., 2013
Zygophyllaceae	Tribulus terrestris L.	Methanol extract of the fruit improved muscular strength, catatonia, locomotor functions and also restored the levels of CAT, SOD, GSH, and GPx. It also reduced the mRNA expression and IL-1β, α -synuclein, TNF-α, and AChE production	Parkinsonism	Saleem et al., 2020
		Oral administration of the hydroalcohol extract of root improved renal injury in mercuric chloride treated rats and decreased the accumulation of mercury in kidney tissue	Kidney complications	Yadav et al., 2019
		Whole plant methanol extract exerted potent activity against cardiac ischemia by improving various cardiac biomarker levels like serum creatinine kinase, serum lactate dehydrogenase, serum glutamic oxaloacetic transaminase, serum creatinine kinase, myocardial B fraction, serum glutamic pyruvic transaminase in both in-vitro and in-vivo models	Cardiac complications	Reshma et al., 2019
		Terrestrosin D isolated from the plant reduced in-vivo inflammatory cell infiltration, macrophages number, neutrophils, lymphocytes and percentage of macrophages in the monocyte-macrophage system. It also reduced the production of TNF-α and pro-inflammatory cytokine IL-6, IL-8, TGF-β1, PDGF-AB	Lung related complications	Qiu et al., 2019
		Saponins extracted showed significant antidepressant activity and increased the cortisol and corticotropin-releasing factor levels in stress induced rats	Mental Problem	Wang et al., 2013
		Hydroethanol extract of the plant showed potent hepatotoxic activity in acetaminophen treated rat	Liver related problem	Kavitha et al., 2011

Fig. 2

Probable inhibition mechanism of medicinal plants/product against SARS CoV-2 viral replication.

In this Review, the importance of medicinal herbs from different traditional medicine systems together with herbs-derived secondary metabolites are summarized based on the mechanistic point of view for post-COVID related complications.

Herbal formulae from different traditional systems of medicine

During the first outbreak of SARS in China (2002-2003), TCM showed a great potency in reducing the fatality rate (Yang et al., 2021; Chen and Nakamura, 2004; Yang et al., 2020). After the outbreak of COVID-19, several TCM formulations have been frequently prescribed, e.g., Lianhua Qingwen capsule, Yu Ping Feng San decoction, Guizhi-and-Mahuang decoction, Shuang-Huang-Lian, Sang Ju Yin and Yu Ping Feng San, Dang Gui Long Hui pill, Shufeng Jiedu capsule, Qingfei Paidu decoction, Huashi Baidu decoction, Huoxiang Zhengqi, Jinhua Qinggan granules, Xuebijing injection, Reduning injection, Tanreqing injection, Shufeng Jiedu capsule, Xuanfei Baidu decoction, Shenmai injection and Ma Xin Gan Shi Tang etc (Table 2). These herbal formulations have significant antiviral, anti-inflammatory and immunomodulatory activity to combat COVID-19 (Chan et al., 2018; Ding et al., 2017; Du et al., 2014; Fu et al., 2018; Gao et al., 2014; Huang et al., 2020; ;(Liu et al., 2015) Liu, 2020; Poon et al., 2006; Runfeng et al., 2020; Yang et al., 2020).

Based on recent updates, several herbs and isolated phytomolecules were found to inhibit the SARS-CoV-2 viral infection through different mechanisms (Table 3). Through the binding between SARS-CoV-2 spike protein and Angiotensin-converting enzyme 2 (ACE-2) receptor of the host is the major reason of viral entry into the cells of the nasal and bronchial epithelium. SARS-CoV-2 virus ingestion, replication can easily be inhibited by inhibiting human ACE-2 receptor (Galani and Andreakos, 2021). Weng et al., (2019) showed that the phenol-rich extract of Sambucus formosana Nakai inhibited viral replication of human coronavirus NL63. Triterpenoids and flavonoid glycosides isolated from the ethanolic extract of Euphorbia neriifolia L. exhibited antiviral activity against human coronavirus. The molecular docking study of isolated 3β-friedelanol showed that the friedelane skeleton could be a potential scaffold for developing new anti-HCoV-229E drugs (Chang et al., 2012). In another study, the methanol extract of Strobilanthes cusia (Nees) Kuntze blocked the cytopathic effect of HCoV-NL63-infected cells (Tsai et al., 2020). Mechanism based inhibition of medicinal plants/products through regulation of cytokine storm in SARS CoV-2 infection has been represented in Fig. 3 Figure 3 .

Fig. 3

Mechanism based inhibition of medicinal plants/product through regulation of cytokine storm in SARS CoV-2 infection.

The Ministry of AYUSH in collaboration with the CSIR started clinical trials of four ayurvedic herbs with immunoboosting properties to alleviate the symptoms caused by SARS-CoV-2. These are W. somnifera, T. cordifolia, Glycyrrhiza glabra L. and Piper longum L. with AYUSH-64. This polyherbal formulation is used against malaria-related fever (Vishamjvara), inflammation and joint pains (Gundeti et al., 2020). Based on a clinical trial on patients with bronchial asthma, the polyherbal formulation DCBT4567-Astha-15 reduced clinical symptoms such as dyspnoea, wheezing, cough, expectoration, disability, and sleep disturbances (Murali et al., 2006). This formulation is under clinical investigation to be used against COVID-19.

Role of natural products in the management of post-COVID complications

Parkinsonism

SARS-CoV-2 has been detected in the brain and it has been also isolated from the cerebrospinal fluid of affected patients (Papa et al., 2020). The dynamic pro-inflammatory state of COVID-19 accompanies abnormal accumulation of α-synuclein in nerve fibres, neurons and glial cells, which leads to increased oxidative stress and causes neuro-inflammation (Stefanis, 2012; Achbani et al., 2020) and Parkinson's disease symptoms. During viral infections, α-synuclein participates in the innate immune response and acts as inhibitor of viral RNA and growth in neurons (Chana-Cuevas et al., 2020; McCann et al., 2014).

Bacopa monnieri (L.) Wettst. reduced dopaminergic neurodegeneration by decreasing α-synuclein aggregation and might, thus, be used as a potent anti-parkinsonian agent (Jadiya et al., 2011). Cinnamomum zeylanicum Blume bark and Centella asiatica (L.) Urb. leaves extract inhibit α-synuclein aggregation, stabilized and disintegrate the oligomers and fibrils (Berrocal et al., 2014; Khotimah et al., 2015; Shaltiel-Karyo et al., 2012). The flower petals of Carthamus tinctorius L. improved the behavioral dysfunction in a Parkinson's induced rat model by inhibiting α-synuclein aggregation and astrogliosis (Ren et al., 2016). The stigma of Crocus sativus L. inhibited the fibril dissociation and α-synuclein aggregation (Inoue et al., 2018). Crocin-1, crocin-2, and crocetin present in the extract were the major components responsible for the anti-Parkinson's effect. Leaves of Corema album (L.) D.Don ex Steud. promoted the formation of non-toxic α-synuclein species in vitro and inhibited its toxicity and aggregation in cells, by promoting the autophagic flux and reducing oxidative stress (Macedo et al., 2015). Geum urbanum L. inhibited α-synuclein fibrillation in a concentration-dependent way and partly disintegrated α-synuclein fibrils (Lobbens et al., 2016). The root of Panax ginseng C.A.Mey. prevented dopaminergic loss by attenuating α-synuclein aggregation, microgliosis and apoptosis (Van Kampen et al., 2003). The root of Scutellaria pinnatifida A.Ham. also attenuated α-synuclein aggregation (Sashourpour et al., 2017). Trichosanthes kirilowii Maxim., Prunus japonica Thunb., Perillae Ramulus, Pogostemon cablin (Blanco) Benth. and Cuscuta chinensis Lam. displayed detoxification effects on α- synuclein-induced damage in a yeast model of Parkinson's disease (Fu et al., 2014; Sohn et al., 2012). The alkaloid acetylcorynoline from Corydalis bungeana Turcz. reduced α-synuclein aggregation leading to decreased lipid peroxidation which also maintained efficient cellular signaling (Follmer, 2020). Curcuminoids prevented neuroinflammation by reducing pro-inflammatory cytokine levels (Ojha et al., 2012). Medicinal plants that showed to be effective for the mangement of post-COVID complications have been represented in Table 4.

Olfactory dysfunctions are very common among COVID-19 patients. A considerable portion of patients experienced with the loss of smell and taste, while one third additionally suffered from rhinitis. Hyposmia is a common non-motor symptom of early stages of Parkinson's disease (Bocksberger et al., 2020; Xiao et al., 2014). Hyposmia without nasal dysfunction and rhinorrhea was also documented (Giacomelli et al., 2020; Lechien et al., 2020; Lovato and Filippis, 2020).

Mental problems

SARS-CoV-2 can appear as being both neuro-invasive and neuro-virulent. One in every three patients recovering from COVID-19 suffers from neuropsychological problems ranging from headache, dizziness, memory disorder, seizures, depression and lingering loss of smell or taste to mood disorders and deeper cognitive impairment. Those patients with insomnia feature stress, anxiety, depressive symptoms, denial, anger, mental breakdown, and those with pre-existing mental illness experience worsening of their conditions (Anaya et al., 2021; Czeisler et al., 2020; Roy et al., 2021; Schäfer et al., 2020). The demyelination syndrome troubles COVID-19 patients, in which the protective coating of nerve cells is attacked by the immune system. This is an autoimmune disease causing weakness, numbness, tingling, spurring psychosis and also hallucinations (Coony, 2020).

COVID-19 patients are challenged by severe stressors, including fear of death from life-threatening illness, pain from medical interventions, endotracheal intubation, limited ability to communicate, and the feeling to loose control (Kaseda and Levine, 2020). The Chicago medical center reported that more than 40% of COVID-19 patients exhibited neurologic manifestations and more than 30% of those had impaired cognition. Sometimes, the neurological manifestations can be calamitous and can even lead to death.

Implementation of Indian herbs and herbal formulations such as Brahmi (B. monnieri), Shankhpushpi (Convolvulus prostratus Forssk.), Giloy (T. cordifolia), Malkangni (Celastrus paniculatus Willd.), Tulsi (O. tenuiflorum), Ashwagandha (W. somnifera) etc. can help managing psychological post-COVID conditions. Bacoside from B. monnieri induced an antioxidant environment in brain, and its neuroprotective activity was attributed to the regulation of mRNA translation and surface expression of AMPA, NMDA and GABA neuroreceptors in the brain. Acorus calamus L. is another plant, which is used as nerve tonic, tranquilizer, sedative etc. by reducing AChE levels and interaction with GABA receptors. It showed antidepressant properties by induction of α1, α2 and 5-HT1A receptors. Flowers of Convolvulus pluricaulis Choisy showed anxiolytic activity and are also used as brain tonic in mental aberration and neurosis. The plant possesses strong antioxidant activity towards brain cells. It also inhibited AChE and 5-LOX, which are involved in neurodegenerative disorders. The seed oil of C. paniculatus exhibited significant antidepressant-like effects by interaction with dopamine D2 receptors, serotonergic and GABAB receptors. It also inhibited MAO-A and caused reduction in plasma corticosterone levels (Joshi and Pandya, 2020).

TCM plants including Lily bulb, Rehmannia, Anemarrhenae and Ganmai Dazao decoctions were incorporated to treat depression. G. Dazao decoction was used to treat hysteria, whose symptoms were sadness, crying, mood disorders, and abnormal behaviour. It is composed of G. glabra, Triticum aestivum L. and Ziziphus jujuba Mill. According to the TCM theory, this decoction nourishes Yin of heart and calms mind (Ma et al., 2020). G. Dazao decoction combined with Lily bulb and Rhizoma Anemarrhena decoction is also used to treat depression, which effectively reduced the depression symptoms of patients and improved their sleep status. This modified G. Dazao decoction is clinically efficient and safe in the treatment of perimenopausal patients with severe depression, because of the regulation of monoamines and aminoacid neurotransmitters, regulation of immune inflammation, and also the reduction of the level of inflammatory factors (Li and Gao, 2014).

Suanzaoren decoction, Huang lian E jiao secoction, Zhizi Chi decoction were also incorporated in the drug treasure trove to treat the anxiety of internal heat and Yin deficiency syndrome. Suanzaoren decoction is made from Ziziphus spinosa Hu, liquorice root, R. Anemarrhena, Poria cocos (Schw.) and Chuanxiong Rhizoma. Huang lian E jiao decoction is composed of Coptidis Rhizoma, Scutellariae Radix, Paeoniae Radix Alba, Colla Corii Asini and fresh egg yolk. The anti-anxiety properties of the Suanzaoren decoction was related to an increased NO concentration in the blood and the decrease of IL-1β and TNF-α level in serum (Wang and Xie, 2004; Liu, 2018). In another study, the combination of Suanzaoren decoction and Zhizi Chi decoction was significantly improved anxiety-related insomnia (Liu et al., 2014). The anti-anxiety activity of Suanzaoren decoction and Huanglian E jiao decoction was related to elevated γ-GABA levels (Zhao, 2012). Lily bulb, Rehmannia decoction and Guilu Erxian decoction were useful against post-traumatic stress disorder (PTSD; internal heat and Yin deficiency syndrome) by regulating synaptic plasticity, anti-apoptosis, anti-inflammation and reducing fear memory (Li et al., 2020).

Kidney failure

The CDC reported that of the adults hospitalized for COVID-19 with underlying conditions in USA, 74.8% had chronic renal disease, but patients with chronic renal disease consisted of only 3% of the total cases (Abbott, 2020). A recent clinical study with 701 patients from a hospital in Wuhan found that 5.1% of patients admitted for COVID-19 developed acute kidney injury (Cheng et al., 2020). During the infection, the virus circulated in the blood to reach the kidney and caused damage to renal resident cells, which was manifested by proteinuria, hematuria, and elevated levels of blood urea nitrogen, serum creatinine, uric acid as well as D-dimer (Cheng et al., 2020; Henry and Lippi, 2020; Li et al., 2020). The mortality rate of COVID-19 patients with AKI was significantly higher (5.3 times higher in acute kidney injury than 1.5 times in chronic illnesses) (Alberici et al., 2020; Su et al., 2020; Xu et al., 2020). The main binding site for SARS-CoV-2 is the ACE2 protein, which is expressed in the kidney much more than the lungs (Serfozo et al., 2020; Ye et al., 2006). Targeting of ACE2 by SARS-CoV-2 results in angiotensin dysregulation, innate and adaptive immune pathway activation, and hyper-coagulation to result in organ injury and AKI associated with COVID-19. SARS-CoV-2 might cause tubular damage through infiltrating renal parenchyma by an exaggerated and often uncontrolled surge of plasma pro-inflammatory factors (IL2, IL7, IL- 10, GSCF, IP-10, MCP-1, MIP1A and TNF-α) known as ‘‘cytokine storm’’ (Wen et al., 2020). Inflammatory cells such as CD68+ macrophages, CD4+ T cells, and CD56+ natural killer cells can be present in tubulointerstitium of affected patients. The hyper-activation of these immune cells may eventually promote fibrosis, induce epithelial cell apoptosis, and cause microvasculature change. Moreover, C5b-9 complex expression and disposition on tubular cells causes renal interstitial damage (Diao et al., 2021; Rodríguez et al., 2018; Saffarzadeh et al., 2012).

Thirty-eight patients with moderate chronic renal failure were treated with 1 g Rheum palmatum L. (Chinese rhubarb) root extract per day, which led to significant decreases in serum BUN and creatinine level (Sanada, 1996). Tincture of lespedeza (Lespedeza capitata Michx.) showed beneficial effect in patients with acute and chronic renal failure (Yarnell and Abascal, 2007). The effect may be due to the compound proanthocyanidins present in the plant extract showing angiotensin-converting enzyme (ACE) inhibition effects (Wagner and Elbl, 1992). A study showed that Urtica dioica L. seed might be an effective herbal treatment for renal failure patients, as it lowers the serum creatinine levels and also reduces the symptoms (Treasure, 2003). Roots of Andrographis paniculata (Burm.f.) Nees significantly reduced blood proteinemia and uremia (Rao, 2006). Rheum officinale Baill. combined with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and and Chinese patented medicine Rheum (CPM-Rheum) might be used to improve the condition of impaired renal function (Yang et al., 2018).

Heart failure

Some patients having problems related to heart even exhibited signs related to mild to severe heart damage in post-COVID infection due to an overactive immune response with abnormal heart rhythms, heart muscle disease and also heart failure in severe cases of myocarditis (Sharma, 2020). A report of the University of Frankfurt in Germany showed that more than 78% patients exhibited cardiac issue and 60% patients, who had COVID-19, exhibited cardiac inflammation (Puntmann et al., 2020). In severe cases, elevated troponin levels in the blood were seen in infected patients. Multi-drug therapy may cause serious cardiovascular complications due to drug-drug interactions. The antiviral drug remdesivir reduced blood pressure and caused unusual heart rhythm (Citroner, 2020; Healthline.com; https://www.healthline.com/health-news/how-covid-19-may-damage-your-heart).

The ACE2 receptor plays an important role in regulating blood vessel dilation and blood pressure. The anti-hypertensive therapy could raise the number of ACE2 receptors expressed on cells, generating more molecular gates for SARS-CoV-2 to enter (Pesheva, 2020). In Ayurveda, Rasayana acts as antioxidant, anti-stress, anti-inflammatory drug and improves the cardiac health of patients (Rastogi et al., 2020). Cucurmin from C. longa blocked cytokine release, specifically IL-1, IL-6, pro-inflammatory cytokines and TNF-α possesses anti-inflammatory activity in COVID-19 patients (Khanna et al., 2021). Naringin, naringenin and hesperidin present in Citrus sp. inhibited the expression of pro-inflammatory cytokines in macrophages, restrained cytokines via inhibiting HMGB1 expression and obstructed binding affinity of the ACE 2 receptor to the coronavirus (Cheng et al., 2020). G. glabra root also exhibited anti-inflammatory properties, which induces interferon production in the body and prevents heart disease. Cannabis sativa L. shows anti-inflammatory actions by modulation of expression of ACE2 and the serine protease TMPRSS2, which is a pre-requisite for SARS-CoV-2 invasion into host cells. Triterpenoids and flavonoids in Glycyrrhizae radix is used as anti-inflammatory and cardioprotective drug. Aconiti lateralis radix praeparata was widely used to treat heart failure in COVID-19 patients (Ang et al., 2020). For cardiovascular and circulatory disorders, Salvia miltiorrhiza Bunge and T. terrestris can be used in infected and recovered patients (Benarba and Pandiella, 2020). Uncaria tomentosa (Willd. ex Schult.) DC. exhibited immunostimulating and cardiovascular protective activity. Uncaria rhynchophylla (Miq.) Miq. ex Havil. possesses anti-inflammatory and antioxidant effects by inhibition of the TLR4/NF-kB/NLRP3 pathway in murine alveolar macrophages (Firenzuoli et al., 2020). P. longum contains phenanthrenes, phenylpropanoic acids, diarylheptanoids, piperidines, oxanes showing cardioprotective activity. T. cordifolia is well known for its cardiotonic activity and is used to treat heart diseases (First Report and Reccomendation, 2020, ayush.gov.in).

Liver injury

Some studies reported higher serum pro-inflammatory cytokine and chemokine levels in infected patients with abnormal liver function (Duan et al., 2003; Feng et al., 2020; Zhang et al., 2020; Li et al., 2020). Hepatic cells can be directly infected due to the ACE2 expression in the liver, bile duct cells and cholangiocytes, which may explain dysregulated liver function in COVID-19 patients (Chai et al., 2020; Hamming et al., 2004). Liver biopsies in infected patients showed a significant increase in mitotic cells and ballooned hepatocytes, causing apoptosis of liver cells (Chau et al., 2004). The SARS-CoV-specific protein 7a affects the liver tissue by inducing apoptosis via a caspase-dependent pathway (Tan et al., 2004).

Besides, application of high-dose antibiotics along with hepatotoxic antiviral drugs and steroids led to liver abnormalities and liver injury in 76% of COVID-19 patients (Ali, 2020), as documented by elevated serum levels of ALT, AST, GGT, and TB (Cai et al., 2020; Guan et al., 2020; Zhang et al., 2020b Zhao et al., 2020). Pre-existing liver disease among COVID-19 patients showing comorbidities such as hypertension (68%) and diabetes (48%) increased the risk of mortality (Singh and Khan, 2020; Zhang et al., 2020a).

T. cordifolia (leaf, stem and root), Momordica charantia L. (fruit), M. arvensis (leaves), Lawsonia inermis L. (leaves), E. officinalis, Eclipta alba (L.) Hassk. (leaves), Clitoria ternatea L. (leaves), Cassia angustifolia M. Vahl (leaves), Argemone mexicana L. (leaves), Abrus precatorius L. (seeds) normalized elevated levels of AST, ALT, ALP and bilirubin in vivo (Battua and Kumara, 2009; Beedimani and shetkar, 2015; Bhuvaneswari et al., 2014; Kavitha and Geetha, 2018; Kowti et al., 2013; Mohamed et al., 2017; Nithianantham et al., 2011; Shanmugasundaram et al., 2010; Sourabié et al., 2012; Zahra et al., 2012). The fruits of Solanum xanthocarpum Schrad. & H. Wendl. normalized the serum parameters (SGOT, SGPT, ALP, TB) better than Juniperus communis L. fruit in paracetamol- and azithromycin-induced liver toxicity in rats (Singh et al., 2015).

Lung injury

The heterogeneity of the clinical COVID-19 presentation has prompted the conceptualization of novel paradigms to individualize clinical management of COVID-19 (Gattinoni et al., 2020). The Berlin Criteria define the acute respiratory distress syndrome (ARDS) by acute hypoxaemic respiratory failure following an acute event (such as viral respiratory infection) that presents as bilateral pulmonary infiltrates on lung imaging in the absence of a purely cardiogenic or hydrostatic etiology (Definition Task Force et al., 2012). Nevertheless, a recent cohort study reported that 85% ICU patients with COVID-19 meet the Berlin Criteria definition of ARDS and that is a well-established supportive intervention for ARDS, such as low tidal volumes and prone ventilation, resulted in significant improvement in oxygenation and lung compliance (Ziehr et al., 2020). Mortality attributable to SARS-CoV-2 infection occurs mainly through the development of viral pneumonia-induced ARDS.

The virus could cause lung parenchymal injury resulting in pneumonitis barring interstitial lung and/or alveolar inflammation features. Also, the virus could directly bind to the ACE-2 receptors facilitating endothelial dysfunction. The deregulated inflammatory response of cells (e.g., polymorphonuclear neutrophils, macrophages, vascular endothelial cells and alveolar epithelial cells) activated the production of pro-inflammatory factors (e.g., TNF-α, IL-1, IL-9 and IL-8), inflammatory mediators (e.g., elastin, cathepsins, collagenases and gelatinases, cytokines, chemokines) and other inflammatory transmitters, which cause damage to the alveolar epithelial cells. The associated cytokine release syndrome could exacerbate both lung parenchymal and microvascular inflammation, promoting refractory forms of ARDS with associated hypercoagulable states and microthrombosis (Klok et al., 2020; Tang et al., 2020; Zhang et al., 2020c). Several signal transduction pathways such as NF-κB, mitogen-activated protein kinase (MAPK), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3), toll like receptors (TLRs), adrenergic receptors and JAK/STAT signaling pathways are involved in this inflammatory process (Chang et al., 2018; Li et al., 2019; Sun et al., 2018a). Hence, it can be stated that the COVID-19-associated cytokine release syndrome may be the catalyst of two parallel inflammatory pathways: one promoting parenchymal lung injury and another one facilitating thromboembolic phenomena, resulting in a “dual-hit” lung injury (Fraissé et al., 2020; Hékimian et al., 2021; Menter et al., 2020). Another cause is lung edema and lung dilatation due excess production of reactive oxygen species (ROS), which cause damage to the cell membrane by unsaturated fatty acids (Fu et al., 2017; Imai et al., 2008). Several plant-derived phytomolecules were reported to be effective in acute lung infection through modulation of NF-κB, MAPK and Nrf2 signaling pathways owing to their anti-inflammatory and anti-oxidant activities (He et al., 2021).

Discussion

Traditionally used Indian medicinal herbs/herbal preparations are promising candidates for the treatment and management of various illnesses through rejuvenating human wealth (Gomathi et al., 2020; Mukherjee et al., 2017). Ayurveda and Siddha practices are still widely used among the Indian population for maintaining human well-being (Mukherjee et al., 2019). By identifying certain phytocompounds, it is possible to effectively characterize medicinal herbs that could help to alleviate the SARS-CoV-2 viral infection. Hence, by repurposing Indian medicinal plants, more innovative treatment options can be penned down to defeat this viral pandemic and post-COVID related complications (Balachandar et al., 2020). In this review, we systematically summarized and analyzed the pharmacological importance of herbs and herbs-derived secondary metabolites which may be effective against COVID-19 related infections and by the traditional practice recommended by all available guidelines.

Several therapeutic strategies were put forward for the development of treatments against COVID-19 from the pharmacological point of view such as antivirals (e.g., ribavirin, sofosbuvir, lopinavir/ritonavir, remidesivir, favipiravir etc.) (Clercq, 2007) and antimalarials (hydroxychloroquine) (De Clercq, 2009), anti-inflammatory drugs (e.g., baricitinib) (Stebbing et al., 2020), and monoclonal antibodies (Zheng and Song, 2020). In China, three patent herbal drugs, Lianhuaqingwen capsules and Jinhuaqinggan granules for mild conditions and Xuebijing (injectable) for severe conditions were approved to treat COVID-19 symptoms. These herbal formulations can effectively relieve symptoms, such as fever, cough, and fatigue, and reduce the probability of patients developing severe conditions (A report by National Health Commission of Chinese). Glycyrrhizin from liquorice root is the most frequently used Chinese herb, which inhibited the replication of clinical isolates of the SARS virus (Cinatl et al., 2003). T. cordifolia aqueous extract twice a day for 15 days can be effective against chronic fever, provided by AYUSH, Government of India as therapeutic approach against COVID-19 (Vellingiri et al., 2020). AYUSH also suggested that the extract of Eupatorium perfoliatum L. may be helpful to treat COVID-19-related respiratory symptoms (Vellingiri et al., 2020). After the acute phase of COVID-19, majority of the patients developed persistent and prolonged clinically significant physical and mental adverse outcomes affecting the quality of life. It was observed that such adverse outcomes were not confined; rather it is recognized as a multi-organ disease and increased risk of indolent death (Oronsky et al., 2021). The reviewed data shows that A. paniculata, Cassia tora L., Phyllanthus emblica L., G. glabra, Azadirachta indica A.Juss., Morus alba L., P. longum, Nigella sativa L., Camellia sinensis (L.) Kuntze, U. dioica, C. longa, T. terrestris, Chrysanthemum indicum Thunb., Astragalus propinquus Schischkin, S. miltiorrhiza, Salvia officinalis L., C. zeylanicum, P. nigrum, Z. officinale, Mucuna pruriens (L.) DC., Psoralea corylifolia L., Ecklonia cava, T. cordifolia, Syzygium aromaticum (L.) Merr. & L.M.Perry, W. somnifera were found to have enriched biological benefits due to their varied secondary metabolites. This may provide a more rational phytotherapeutic choice to improve the general well-being effectively by counteracting the biological complications caused by for patients affected with COVID-19.

Conclusion and perspectives

As a matter of fact, the pandemic is far from over. There are more questions than answers about diagnosis, treatments, and, what we need most, effective cures and aftercare. This review may serve as reference in traditional herbal medicine for COVID-19 treatment. The present review compiled pharmacological information of more than 50 herbal medicines, which potentially combat the viral infection and post-COVID complications through different mechanisms. Most information is rather based on some in-vitro and in-silico investigations and anecdotal clinical data. The basic molecular mechanisms are also unexplored yet.

It should be noted that there is still no convincing clinical evidence on the activity of most herbal products. Unlike modern medicines, herbs are often claimed to be non-toxic, due to their natural origin and long-term use as traditional medicines. However, numerous difficulties can be occurred due to the adulteration, substitution, contamination, misidentification, intrinsic toxicity, drug-herb interactions and lack of standardization. For that reasons, pre-clinical evaluation of therapeutic effectiveness is a great concern for the further development of safe and effective herbal treatments. As the COVID-19 pandemic continues, substantial progress has been made in pathogen monitoring, identifying sources, basic etiology, and clinical treatment. Herbs from traditional system of medicine may be useful in alleviating the disease symptoms but it requires more research works to unravel their therapeutic potential. The integration of traditional medicine into conventional treatment may be an alternative approach for the treatment of COVID-19 in the future. However, the global situation is very serious, and numerous questions remain unanswered. It will take combined efforts of traditional and western medical systems worldwide to ultimately extinguish this pandemic.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.