A Comprehensive Review and Perspective of Herbal Medicines in the Treatment of COVID-19

Background: An emergent COVID-19 outbreak originated in Wuhan City, in December 2019. The COVID-19 contamination has swiftly unfold from Wuhan to maximum different provinces and different 24 countries. WHO declared a public health emergency of global concern over this worldwide COVID-19 outbreak on 30 January 2020. Manifold research has been intensely initiated for immunization and drug development for COVID-19 till date no specific vaccine or approved drugs are accessible for COVID-19. Alternatively, therapy consists of supportive care and non-specific anti-viral, anti-malarial, and antibiotics are being testedas drugs for COVID-19. Review Article Moin et al.; JPRI, 33(26A): 70-95, 2021; Article no.JPRI.67662 71 Though, novel approaches could play a crucial role to combat mortality rate and patient recovery in the treatment of COVID-19. Objective: To reveal the epidemiology, pathophysiology, and comparison of promising synthetic and natural drug targets to avert and cure of COVID-19. Method: This article sets a brief understanding of the viral characteristics, its life cycle, infection to humans, and the pathophysiology of the disease. It also throws light on the currently used synthetic medicines. we have reviewed the effect of natural products to prevent or treat COVID-19 infection. Their mechanisms of action have been elaborately discussed. literature research was undertaken using PubMed, Google Scholar, Scopus, and WHO website. The different herbal products (extracts) and their moieties which are promising as anti-SARS-CoV-2 by direct inhibition of the virus replication or entry has also been discussed. Results and Conclusion: In conclusion we have highlighted that natural therapeutics either alone or in combinationcould be used as alternative medicines to treat/prevent COVID-19 infection. Moreover, their structures may offer clues for the development of anti-SARS-CoV-2 drugs.The integration of nanocarriers for effectively delivering the conventional as well as the herbal drugs becomes a key point for their efficacy and safety.


INTRODUCTION
Coronavirus (CoVs) is a protein covered single-stranded RNA virus that is zoonotic and majorly targets the human respiratory system causing symptoms ranging from high body temperature, cold, cough, exhaustion, chills and breathing problems. The examination of the chest X-ray of the lungs of the infected person showed diffused infiltration with gridding shadow [1]. Previous out breaks of coronavirus included the Severe Acute Respiratory Syndrome (SARS)-CoV and Middle East Respiratory Syndrome (MERS)-CoV. In the latter half of December 2019, a cluster of patients reported pneumonia caused by an unidentified organism of animal origin in Wuhan city, China [2,3]. Based on the initial reports and estimated reproduction number range (1.4-6.4) the predicted onset potential CoVs was much higher than SARS-CoVs [4].World Health Organization (WHO) named CoVs as COVID-19 on 11 th February 2020.
WHO and a medical journal Lancet hosted by Johns Hopkins University [5], reported 2,006,523 infected cases with 1,28,886 confirmed deaths as of 15 th April 2020. At the same time,617,628 confirmed cases were reported from the United States (US) alone with 26,977 deaths. Besides, COVID-19 was found infecting population spread across 179 countries globally.Ten countries have shown confirmed cases>10,000 and while 32 nations have reported 1000-10,000 confirmed cases/million people. On 27 th March the US surpassed China in terms of infected cases count [6].
Despite the progress in the field of drug development and immunization, COVID-19 lacks preventive vaccines and effective drug therapies due to the viral escape mutants. There is a need for the identification of effective anti-viral drugs and natural compounds for the preventing and curing of COVID-19. Also, clinical practice suggests Chinese herbal medicine as an alternative therapy [7]. Medicinal plants are now receiving more consideration than ever as they have the perspective of providing huge profits to society or undeniably to all mankind, particularly in the track of medicine. By decreasing the deadliness and the adverse influences of drugs at the same time, herbal treatment aids in increasing the calming value and biodiversity [8,9].
For the development of novel formulations, herbal medicines were not considered due to the absence of scientific explanation and handling complications. Scientific needs of herbal medicines such as pharmacokinetics, mechanism of action, dose, dosage form,etc. can be solved by modern phytopharmaceutical research and can be incorporated in novel drug delivery systems such as solid dispersions, solid lipid nanoparticles, nanoparticles, liposomes, micro-emulsions, etc. With enhanced efficacy, herbal drugs can be applied in an improved procedure by integrating them into contemporary dosage systems. By designing novel drug delivery systems, this can be achieved for herbal constituents [10,11].
This review aims to present the pathogenesis, risk factors, transmission, life cycle and diagnosis of COVID-19, current treatment reports of synthetic drugs, traditional herbal medicine for the cure of COVID-19, identification of anti-COVID-19 moieties from herbal medicine, clinical trials of herbal medicine and possible dosage forms to target the disease.

SEARCH METHODOLOGY AND SELECTION CRITERIA
The identification of articles was accomplished using a systematic search in the PubMed (National Library of Medicine), MEDLINE (International Literature on Health Sciences), SciELO (Scientific Electronic Library Online), Lilacs (Latin American and Caribbean Literature on Health Sciences),PubMed, LitCovid, COVID-Evidence, Clinical Trials, and Science Direct. The relevant search strategy and keywords (such as "Novel coronavirus" or "COVID-19" or "SARS-CoV-2") were used to collect information on the novel coronavirus. Additional keywords (such as "natural products and COVID-19" or "Role of ACE-2 in SARS-CoV-2" or "COVID-19 and chinese medicines") were used to collect all useful information for this review. The search was carried out systematically for the screening of the related content as shown in Fig. 1. Initially, a total of 351 publications were retrieved from different databases and 82 articles were deleted due to duplication. The remaining articles have been carefully reviewed in order to determine the eligibility and methods used. 141 articles were referred for the present review work.

UNDERSTANDING PATHOGENESIS, RISK FACTORS AND DIAGNOSIS OF COVID-19
It was reported that COVID-19 is an acute respiratoryinfection, but the severity is characterized by substantial alveolar damage and a progressive respiratory failure with a case fatality rate of 4.65% (Fig. 1). The pathological features greatly resembled SARS and MERS upon obtaining the biopsy samples of the major end organs. Both lungs exhibited bilateral diffused alveolar damage accompaniedby cellular fibromyxoid discharge, the formation of hyaline membrane, and desquamation of pneumocytes which indicated acute respiratory distress syndrome (ARDS). Also, inflammatory infiltrates dominated by the lymphocytes were present in the interstitium. Various cellular pathological transformations were visible in the intra-alveolar spaces characterized by symplasm, the cytoplasm was granular withprominent nucleoli.

Fig. 1. Search methodology and selection criteria
Liver biopsy indicated moderate infiltration of liver cells with fat associated with disturbed metabolism, signifying liver damage or injury which may be drug-induced or due to infection. Apart from the inflammatory infiltrates in the interstitium there was no major damage to the heart tissue. Upon analyzing the peripheral blood through cytometric analysis CD4 and CD8 T-cells count decreased with associated hyperactivity which wasindicted by increased amounts of HLA-DR (CD4 3.47%) and CD38 (CD8 39.4%). Also, CD8 T-cells were discovered to accommodate cytotoxic granules in high concentrations where the cells were 64.2% granulysin positive, 31.6% perforin positive, and 30.5% double positive with granulysin and perforin. Furthermore, proinflammatory CCR6+ Th17 was enhanced in CD4 T-cells which was due to the overactivity of T-cells causing severe immune injury to the patient. Patients also demonstrated lymphopenia in common which may be a major factor in the severity of the disease and mortality rate [12].
The higher Multisystem Organ Failure (MSOF) numberand d-dimer greater than 1 μg/mL increased the risk of mortality. A uni-variable analysis in the hospital setup demonstrated that the mortality was higher in a patient with heart disease and diabetes mellitus. Other factors such as elevated levels of procalcitonin, prothrombin time, creatinine, high sensitive cardiac troponin (hscTn) 1, d-dimer, IL-6, lactate dehydrogenase, serum ferritin and Alanine transaminase (ALT), conditions such as lymphocytopenia, Age and leucocytosis also enhanced the mortality rate [15].
COVID-19 RNA detection method involves sampling from the respiratory tract or the throat swab and analysis by quantitative fluorescence polymerase chain reaction method (PCR). Other methods include the detection of the positive nucleic acid of COVID-19 by real-time PCR (RT-PCR) method by analyzing the sputum, throat swabs, and secretions of the respiratory tract. Also,the detection of flu antigens A, B, H7N type leads to early detection but has enhanced falsenegative rate. New sequencing and electron microscopy techniques are deficient due to the lack of specific nucleic acid detection technology [16].

TRANSMISSION AND LIFE CYCLE OF COVID-19
Research to find out the possible host reservoir or intermediate carriers for the probable infection was recognized as two species of snakes that could be the reservoir. However, to date no concluding evidence has been found other than birds and mammals [17,18]. COVID-19 viral genomic sequence analysis showed 88% similarity with earlier coronaviruses whose origin was a bat, that was responsible for severe acute respiratory syndromes (SARS) [19,20] indicating that mammals being the likely link between virus and humans. Reports also indicated that personto-person spread is the most probable route for spreading COVID-19 infection. This is because it was observed among people who did not have any exposure to the wet animal market in Wuhan yet suffered from the infection [21,22]. Infection from Person-to-person spreads by direct contact or through droplets generated on coughing or sneezing from an infected subject or through fecal contamination (Fig. 2). A limited study was conducted on infected women howoever delivering babies through cesarean; the test confirmed no transmission from mother to child. However, no study was done to confirm for transmission occurring during vaginal birth.

CURRENT TREATMENT USING SYNTHETIC DRUGS
The current worldwide pandemic brought about by the SARS-CoV-2 just dispensed unconquerable harm human lives and worldwide economy.
COVID-19 infected patient is isolated followed by the administration of various antiviral and antibiotic regimens. No specific vaccines or antiviral drugs are treating this infection. The current treatment being adopted is broad spectrum antiviral therapy that includes nucleoside analogs and HIV-protease inhibitors 19 infected patient is isolated followed by the administration of various antiviral and antibiotic regimens. No specific vaccines or antiviral drugs are treating this infection. The current treatment being adopted is broadthat includes protease inhibitors that could assuage virus infection until the specific antiviral becomes available treatment protocolincluded 75 patients who were administrated existing antiviral drugs that included twice a day oral therapy of 500 mg lopinavir, 75 mg oseltamivir, 500 mg ritonavir along with intravenous administration of 0.

KNOWLEDGE FROM SARS: PHARMA-COLOGICAL ARBITRATIONS
The take home message from pervasiveness of SARS and MERS can be used to develop certain medicines for SARS-CoV-2 pollution [53]. As of late antiviral drugs like oseltamivir, peramivir, zanamivir, ganciclovir, acyclovir and ribavirin are not proposed for COVI-19 treatment [54,55]. Also, major corticosteroid treatment, for instance, methylprednisolone isn't recognized as a treatment decision for SARS-CoV-2 infected patients [56]. In such a circumstance, similiarity of SARS-CoV and MERS disease to SARS-CoV-2 infection, a comprehension into the treatment decisions for SARS and MERS could drive us to gain knowledge on pharmaceutical agents with anti SARS-CoV-2 [57].

PARADIGM SHIFT IN THETREATMENT OF COVID-19 BY TRADITIONAL HERBAL MEDICINE
Traditional Herbal Medicine (THM), is an ancient system of medicine that includes the Chinese system of medicine (CSM), the Indian system of medicine-Ayurveda, a Korean system of medicine-Kampo, Unani andhomeopathic system of medicine. (Table 1) [58]. In many practices, they may have certain short comings, but they are still an appreciable source of medicinal information. Lau et al, stated that, throughout the SARS outbreak, 1063 volunteers covering 926 hospital workers and 37 laboratory technicians employed in high-risk environments were on this herbal formulation-Sang Ju Yin plus Yu Ping Feng San and interestingly, in comparison to 0.4% of infection among the control group, nobody was infected. Moreover, the evidence stated that Sang Ju Yin plus Yu PingFeng San could potentially alter T cells to augment host protection capability [59,60]. But Liu and his colleagues established other sets of literature data suggesting no advantage of adjuvant treatment with herbal medicines observed in terms of mortality [61]. Owing to these outcomes, systematic clinical trials employing potential THM for the treatment of COVID-19 should be essentially conducted.

COVID-19 Management through Clinical Trials of Herbal Medicines
Herbal traditional medicines have been utilized in China since the outbreak of the COVID-19 episode. Without a doubt, these customary medications showed promising results in 90% of the 214 patients treated [70]. Comparative promising outcomes were accounted for in Zhejiang Province -China. Chinese customary meds known as ShuFengJie Du and Lianhuaqingwen have been prescribed because of their showed adequacy against previous influenza A (H1N1) or SARS-CoV-1. A gathering of specialists from the Zhongnan Hospital of Wuhan University remembered the utilization of conventional prescriptions for the rules for the treatment and anticipation of COVID-19. A few strategies utilizing restorative plants were suggested for the counteraction of COVID-19. Additionally, to treat the sickness, the specialists suggested the utilization of various natural blends as indicated by the illness stage [71]. CSM is greatly appreciated by China in its fight to overcome and eliminate SARS-CoV-2. For instance, the Health Commission of china has authenticated in 26 capitals that, CSM must be employed along with allopathic drugs in the treatment. China's National Health Commission on February 17, 2020, recounted 60,107 confirmed cases (85% of confirmed cases) were treated with CSM [72]. According to another clinical trial report on 1 st March 2020, they were a total of 303 uncompleted clinical trials trying to assess the effectiveness and safety of

IDENTIFICATION OF ANTI-COVID-19 MOIETIES FROM HERBAL MEDICINE
Herbal medicines employed in CSM can be exploited as potential drug candidates for COVID-19 therapy. In the last few decades research is been done to identify therapeutic moieties having activity against various viruses and in particular the corona family. Additionally, the phytoconstituents responsible for the activity in the herbs were also studied ( Table 3). Similarity in SARS-CoV and SARS-CoV-2, prompt us to study the potential use of natural herbs that have a positive therapeutic effect on SARS-CoV for their potential effects on SARS-CoV-2.The 3-chymotrypsin-like protease (3CLpro) is very much important for viral replication which indicates itself as a potential drug target for the drug development for SARS-CoV and SARS-CoV-2.   (Fig. 6) The coronavirus encodes more than proteins, some of which are essential entry and replication. Among these most well-studied are papain-like (PLpro), 3C-like protease (3CLpro) protein. theseproteins make attractive drug development.
The entrance of the SARS-CoV-2 the host cells happens because of CoV-2 spike protein binding to receptors By utilizing phylogenetic examination site of ACE 2 structure, various example, feline, pigeon, and anticipated to be transmitters for [104]. Hoffmann et al. exhibited that receptor is utilized by SARS-CoV human cells [105].
Studies have indicated that TMPRSS2 may be a promising alternative against CoV-2. TMPRSS2 is a transmembrane protease that separates both ACE2 protein. Ortega et al. [106] approaches suggested association changes in SARS-CoV-2 Spike

COMPOUND ACE 2-
than a dozen of essential to viral these proteins, the like protease (3CLpro) and spike attractive targets for genome into of the SARSreceptors [103]. examination and basic animals, for sheep were SARS-CoV-2 that the ACE2 CoV-2 to enter TMPRSS2 inhibitors against SARStransmembrane serine ACE2 and the S used silico association between protein and ACE2 receptor. They displayed SARS-CoV-2 spike protein towards in comparison to that of the Bat-CoV ACE2. This assessment concluded ACE2 receptor may be the key "connect" by SARS-CoV-2 to contaminate people. al. [107] confirmed that not withstanding that SARS-CoV and SARS-CoV-2 glycoprotein had 72% of essential SARS-CoV-2 RBD indicated correspondence with ACE2. ACE2 thought to alter RBD restricting block SARS-CoV-2 disease. Additionally, et al. [108] found that the SARS demonstrated a higher affection SARS-CoV. Adedeji et al. [109] early blocking of SARS-CoV with ACE2 was one of the segments used by SARS has been showed up in three assessments on COVID-19 that and diabetes mellitus triggers the COVID-19 infection, inspite of utilizing inhibitors. ACE2 inhibitors, angiotensin receptor blockers, and ibuprofen upregulation which legitimizes the utilize as well as distinguish elective blockers. Along these lines, therapeutic could be considered as alternative exhibit anti SARS-CoV-2.  Appropriately, Myricetin and scutellarein were recommended to be promising alternative for anti SARS drugs (Fig. 7) [110].

Supression of TMPRSS2 by Natural Products
Recently, Hoffmann et al. [105] reported that SARS-CoV-2 could also utilize TMPRSS2 for binding to S protein. TMPRSS2 is a transmembrane serine protease that cleaves both ACE2 and the S protein. After the association between the S spike protein (SARS-CoV-2) and the ACE2 (host cell), the complex is severed by the TMPRSS2 to encourage viral passage [111]. Matsuyama et al. [112] found that a significant TMPRSS2 articulation in cells makes them vulnerable to SARS-CoV-2.
Researchers have reported that the use of TMPRSS2 inhibitors could be a treatment altenative against SARS-CoV-2.
Since SARS-CoV-2 viral entry is dependent ACE2 receptor, the latter should be attached to the TMPRSS, alternatives to suppress the TMPRSS2 expression in human cells could represent a promising therapeutic or preventive approach [113]. It has been demonstrated that kaempferol had the option to inactivate TMPRSS2 articulation by 49.14 and 79.48% at 5 and 15 μM, (Da et al., 2019). Moreover, sulforaphane (an isothiocyanate) was found to inhibit TMPRSS2 articulation via translocation of the Nrf2 (atomic factor (erythroid-inferred 2)-like 2) [114]. Mamouni et al. (2018) found that flavonoids including luteolin, quercetin, and kaempferol inhibited TMPRSS2 articulation (Fig.  8). In spite of positive and synergisitc effects attributed to the three flavonoids, at low concentrations, the efficacy and safety of these compounds in COVID-19 patients is still unclear [115].

Natural Products Targeting the Papain-Like Proteinase (Plpro)
PLpro is one of the nonstructural proteins within the SARS-CoV-2 genome. Also, PLpro has been discovered to be an antagonist of the host's natural protection.PLpro was shown to focus on the interferon creation by obstructing the IRF3 phosphorylation, dimerization, and atomic movement and NF-κBsignalling pathways (by forestalling IκBα debasement) [116]. These impacts were appeared to happen in Toll-like receptor 3 and retinoic acid-inducible gene 1 pathways. Studies shown that SARS-CoVPLpro represses the TLR7 pathway by means of inactivation of TRAF3/6-TBK1-IRF3/NF-κB/AP1 signalling pathways (Fig. 9) [117].

NATURAL PRODUCTS TARGETING THE CHYMOTRYPSIN-LIKE PROTEASE [3CL(PRO)]
3CL(pro) forms a part of 16 nonstructural proteins of the SARS-CoV-2. 3CL(pro) is considered a potential therapeutic target for anti-COVID-19 drugs [122] as it contributes towards SARS-CoV-2 replication process. Some of the natural compounds also exhibited anti 3CL(PRO) effect (Fig. 10).

Inhibitory Potential of Alkylated Chalcones as anti SARS-CoV-3CL(pro)
Inhibitory potential toward of alkylated chalcones and coumarins extracted from Angelica keiskei (Miq.) Koidz was explored utilizing a fluorescence resonance energy transfer (FRET) method. Except for coumarins, alkylated chalcones showed promising inhibitory impacts in a dose dependent pattern. IC50 ran from 11.4 ± 1.4 to 129.8 ± 10.3 µM. Also, xanthoangelol E ( Figure 5) was discovered to be the most powerful SARS-CoV-3CL(pro) inhibitor. Motor investigations demonstrated that both alkylated chalcones were serious inhibitors. Since xanthoangelol E was additionally found to hinder SARS-CoV-PLpro it could be a promising competitor in the remedial methodology against COVID-19 [123].

Inhibitory potential of Phlorotannins From Ecklonia cava (Algae)as anti SARS-CoV-3CL(pro)
From ethanolic concentrate from earthy colored Alga Ecklonia cava nine phlorotannins were isolated by Park et al. [124]. These phlorotannins were investigated for their inhibitory impacts towards SARS-CoV-3CL(pro) via without cell based assay. Eight phlorotannins (triphloretolAn, eckol, dioxinodehydroeckol, 2-phloroeckol, 7phloroeckol, fucodiphloroethol G, dieckol, and phlorofucofuroeckol A) were demonstrated to be serious inhibitors of SARS-CoV-3CL(pro) in a dose dependent manner. IC50 went from 2.7 ± 0.6 (dieckol) to 164.7 ± 10.8 µM (triphloretol A). Besides, six phlorotannins (dioxinodehydroeckol, 2-phloroeckol, 7-phloroeckol, fucodiphloroethol G, dieckol, and phlorofucofuroeckol A) brought about a critical micromolar dose dependent portion inhibition of SARS-CoV-3CL(pro) ciscleavage action. It was further supported by Molecular docking studies which showcased that diekcol had the most reduced restricting vitality (11.51 kcal/mol) towards SARS-CoV-3CL(pro). Diekcol was appeared to frame solid H bonds to the reactant dyad (Cys145 and His41). The bioavailability of phlorotannins with respect to their utilization is as yet a considerable constraint to approve their convenience. [125]. Also, their configuration with assorted variety of basic linkages and the distinctive auxiliary and conformational isomers for a similar sub-atomic weight, and the absence of clear connection between their structure and bioactivity might be another restriction to their clinical use [55].

Inhibitory potential of Tanshinones From Salvia miltiorrhiza Bunge as anti SARS-CoV-3CL(pro)
The inhibitory capability of Salvia miltiorrhiza Bunge towards SARS-CoV-3CL(pro) was evaluated by Park O. K. et al. (2012). It was concluded that ethanolic extricate Salvia miltiorrhiza Bunge (30 µg/ml) could cause 60% hindrance of SARS-CoV-3CL(pro). Moreover, they exhibited that six tanshinones of the plant (lipophilic portion) caused hindrance of SARS-CoV-3CL(pro) in a percentage though not in a time dependent manner. IC50 was assessed at 14.4-89.1 µM. Dihydrotanshinone I showed the most significant inhibitory impact with an IC50 of 14.4 ± 0.7 µM. With respect to the dynamic system of SARS-CoV-3CL(pro) hindrance, Salvia miltiorrhiza Bunge tanshinones were discovered to be noncompetitive inhibitors [126].

POSSIBLE DOSAGE FORMS TO TARGET COVID-19
The action of herbal medicines relies on the complete utility of the variability of dynamic components, as all the elements offer synergists action and therefore improve the healing rate [128]. Every function plays an essential role which is related to each other that possesses the insoluble character which is resulting in lesser bioavailability and increases systematic approval necessitating repetitive administration or higher dose, which lets the drug be a minor candidate for the use of treatment [129]. Nano-dosage forms (Polymeric Nanoparticles) are developed in Phyto-formulation research that includes Liposome, Solid Liquid Nanoparticles (SLNs), Proliposomes which have several advantages for herbal drugs that are the improvement of bioavailability and solubility, improvement of pharmacological action, safeguarding from venomousness, improving tissue macrophages dissemination, improvement of constancy, increased physical-chemical stability there preventing easy degradation and sustained delivery, etc. [130]. For improving the activity and overpowering issues that are connected with plant medicines, Nano drug delivery systems (NDDSs) of natural drugs have a great potential in future drug therapy. In the traditional medicine system, integration of the nano-carries as an NDDS that is essential to conflict more chronic diseases such as cancer, asthma, diabetes, and so on [131].

FUTURE PERSPECTIVES AND CONCLUSION
Globally, numerous herbal medicines of Indian, China, Western and Arabic origin are marketed. These medicines with unique insights carry the experience of thousands of years in preventing, controlling the prevalence of wide-ranging diseases, and enhancing the immunity of the body. The crucial key in COVID-19 treatment is early intervention to curtail disease progression, shorten the course of the disease and improve the cure rate thereby decreasing the overall mortality rate using herbal medicine. The main reason behind the effectiveness of these herbal medicines is not only to prevent the virus growth but also to regulate and enhance one's immune system of the body that alters the various inflammatory responses there by promoting the early repair of the body. More in-depth research needs to be done on CSM that have definite curative effects to understand their mechanism of action for enhanced effective utilization in the treatment of the disease. Recently, some studies have been conducted on these aspects of herbal medications against COVID-19 [132][133][134][135].
The herbal drugs have several drawbacks such as poor bioavailability, instability, low solubility, low oral absorption, and unpredictable toxicity. Growth of herbal therapies in several institutes that have been carried out at basic and clinical trial levels. Further research should be directed for developing the concept of herbal nanoparticles for COVID-19 delivery in suitable animal models for studying the entire viral life cycle.

CONSENT
It's not applicable.

ETHICAL APPROVAL
It's not applicable.