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Scientific production on medicinal plants and their efficacy against Covid-19: A review and scientometric analysis based on VOSviewer

Historically, numerous plants have been used to alleviate various diseases, particularly viral diseases (bronchitis, influenza virus and dengue virus). This review evaluated their therapeutic potential against Covid-19 and mapped the 10 most studied plants during the pandemic. The standardized protocol for systematic reviews (PRISMA-P) was developed in this study. All studies involving medicinal plants and their potential against Covid-19 infection were also considered. Two specific search fields “traditional medicine and Covid-19” and “medicinal plants and Covid-19” with appearance in the title, abstract and keywords were used to search for information. Only papers (review and original) published between 2020 and October 2021 were included. Short communications, letters to the editor, books and book chapters were excluded. A total of 24,046 articles were recorded among the four databases and an increase of 69% in publications for the 2021 search date, a higher percentage compared to the previous year (31%). China was the country with the highest production with 28% (2725 papers). The analysis of variance showed that the number of studies of Nigella sativa L. (1.62 ± 0.21; p = 0.02), Glycyrrhiza glabra L. (1.50 ± 0.32; p = 0.03), Zingiber officinale Roscoe (1.51 ± 0.32; p = 0.03) were statistically significant with respect to the other species. This is probably because these species show compounds with high antiviral spectrum. Despite the pharmacological potential found in medicinal plants, more large-scale clinical trials are still needed to demonstrate the efficacy of phytocompounds against viral diseases.


Introduction
The new SARS-Cov-2 (severe acute respiratory syndrome) appeared in December 2019 in Wuhan (China), where cases of pneumonia linked to this new strain were reported. Subsequently, cases increased rapidly throughout much of China [1,2]. The first 41 patients infected with the new strain were confirmed by laboratory testing in early January 2020 in Wuhan. Of the patients, 30 were men and 11 were women with different comorbidities including hypertension, diabetes and cardiovascular problems [1]. The number of cases spread to regions worldwide, leading the World Health Organization (WHO) to declare the disease a pandemic in mid-March 2020 [3]. By the end of May 2020, there was an increase in cases by more than 5 million and 350,000 confirmed deaths [4]. With this concern, the race against time began in search of efficient treatments to stop or at least mitigate the ravages that quickly emerged as a result of the new outbreak [3,5]. Among the main therapies treatments commonly used are ivermectin, hydroxychloroquine and azithromycin [3,[6][7][8]. However, hydroxychloroquine strategies did not have the desired impact, which was also challended and not recommended by WHO [9]. Another global therapeutic strategy has been the use of plants to manage the impacts of nCoV2019 [10,11]. According to the International Union for Conservation of Nature (IUCN) there are at least 50,000 to 80,000 plant species with medicinal purposes worldwide [12] and it has been estimated that 80% of the world's population relies on the use of medicinal plants as the sole resource for health management in their territories [13,14]. Additionally, its evolution in part is due to socio-cultural dynamics and phytochemical properties [15][16][17]. However, the traditional knowledge represented by the general public (eg. Indigenous and Afro-descendants) with reference to the health care faced a significant decrease throughout the world mainly due to the negative factor suggesting the destruction of environment, misinterpretation and the invasion of territories by outsiders [18][19][20]. This is mainly due to the lack of inconclusive policies that often recognizes and protects cultural heritage [21,22] Nevertheless, there is an important gap that needs to be filled up based on the evidence, where local communities are not recognized as owners of important scientific knowledge [23].
In this sense, the medicinal potential shown by some plant species has boosted the growth of research aimed at exploring new medicines against potentially fatal respiratory diseases. Nigella sativa L., Zingiber officinale Roscoe, Glycyrrhiza glabra L. and Allium sativum L. are on the list of plants with enormous promising potential to combat major diseases including Covid-19 [24][25][26][27]. Studies have reported on the use of plants in the management of important diseases such as HIV [28], Dengue [29], influenza (H1N1) [30], Covid-19 [31], among others. Some species such as Rosmarinus officinalis (L.) Scheid, Salvia leucantha Cav and A. sativum have been used for arthritis problems, diabetes and viral infections respectively [32,33]. In addition, the presence of medically important bioactive compounds such as sesquiterpenes in Z. officinale and lepicatechin in Calotropis procera (Aiton) W.T. Aiton have been reported [34,35]. Despite the plausible potential found in traditional medicine, many countries do not consider this alternative to face public health situations in their territories. A specific case of lack of empathy has been observed in Europe and North America where governments in these regions have been silent on the idea of empowering traditional medicine in the midst of the health crisis caused by Covid-19 [36]. In Europe, for example, the traditional evidence base has been greatly weakened and underestimated. Some plants (e.g. Lythrum salicaria L.) that used to be considered an effective and potent natural remedy have lost their popularity [37]. Furthermore, the lack of credible potential found in traditional medicines, North American and European Governments in the midst of the health emergency chose to remain silent to formulate treatment based on medicinal plants. In the meantime, health authorities in China, India and South Korea quickly issued guidelines to identify traditional medicine to mitigate the impacts of COVID-19. The main aspect from these two regions (Europe and North America) is likely due to the discrepancy in culture, history, and philosophical views of medical care and medication, and discordant policies and standards in the regulation and legalization of traditional practices [36]. Lack of political will from others has prevented traditional medicine from acquiring the status it should have within policy agenda's globally [36].
This review article is aimed to evaluate the scientific production related to traditional medicine and Covid-19 and to identify the top 10 plant species and their main potential phytoconstituents responsible for counteracting the impacts of SARS-Cov-2.

Materials and methods
An exhaustive search for information was carried out in four databases, PubMed, ScienceDirect, Scopus and JSTOR. Two specific search fields: 1) "traditional medicine and Covid-19" and 2) "medicinal plants and  were used for the search with appearance in the title, abstract and keywords. Short communications, letters to the editor, books and book chapters were excluded. Dissertations and conference proceedings were also excluded. These exclusions were done as they did not report on the medicinal plants used to combat the respiratory diseases. After filtering the information, the database files and metadata were downloaded in the following formats (scopus.ris and scopus.bib). For this study, only review articles and originals published between 2020 and october 2021 were included.

Information eligibility criteria
We included articles that reported on phytocompounds responsible for the inhibitory action of Covid-19, so we ensured that the medicinal plants reported in the studies were exclusively for human use. We also included studies that documented guidelines and on the use of medicinal plants to counteract the effects of Covid-19 in infected patients. Articles that did not report on the aforementioned aspects were excluded. The screening process is shown in Fig. 1.

Data analysis
Two types of analysis were performed: co-occurrence and coauthorship. Keywords and authors were the two main default units of analysis for the particular type of study. For co-authorship analysis a maximum number of 25 authors per document, a minimum of 11 publications per author for a total of 50 authors visualized in the network map within a set of 10,199 data and for co-occurrence a maximum occurrence of 148 for 40 keywords in a set of 16,699 data were defined. This threshold is defined with the purpose of generating graphical outputs that are not very saturated with information and easy to visualize. The attribute tables generated by the software were manually reviewed and duplicate entities were removed. All analyses were performed with VOSviewer software version 1.6 using only Scopus metadata because it is a larger database. The graphical outputs of the distribution of scientific production among countries, areas and scientific journals were generated with Prisma version 8.1 software and the relationship maps with VOSviewer. The size of the bubbles in the maps represents the mean of the analyzed elements and the color the number of clusters where the data are grouped [38,39]. An analysis of variance fitted to a general linear model was employed to determine which of the medicinal plants have received the most attention during the pandemic. Species were coded as treatments and countries as blocks to form (factors) and number of investigations of each species by country as the only response variable (data transformed to Log10) (Table S1). Means were compared by paired pairwise comparison using a Tukey test at a significance level α 0.05.

VOSviewer approach
The VOSviewer software is part of the artificial intelligence programs that work with techniques for monitoring, surveillance and mapping of scientific information that allows analyzing and examining large volumes of information, simplifying it and visualizing it through scientific maps. Its analytical approach is based on Jaccard's similarity measures and Pearson's correlation where distances indicate the relationship and strength between elements, i.e., in graphical visualizations a smaller distance indicates a stronger relationship [38,39].

Results of the literature search
A total of 24,046 articles were found among the four databases consulted. The database with the highest number of records was Scopus with 14,953 articles distributed between the two search fields used (Table 1). "Traditional medicine and Covid-19" were the field with the highest number of documents in all databases, Scopus (10,852), Scien-ceDirect (5733) and PubMed (2224). According to Scopus, 72.6% of the information at the date of the search has been published as research articles with 7880 and 27.4% as reviews with 2972 documents. The distribution of documents by year showed that during the year 2021 to the date of consultation the production was higher with a total of 7511 (69%) publications, higher than the 365 days of the previous year where the production was 31% with 3341 articles. China and USA were the countries with the highest number of publications with 2725 (28%) and 2638 (27%) respectively. Biomolecular Structure and Dynamics and Molecules were the journals with the highest number of publications with 225 (38%) and 155 (25%) respectively. In terms of the number of publications by academic area, medicine had the highest number of publications with 5710 as of the date of the search (Fig. 2). The distribution of paper by affiliation showed that the Ministry of Education of China had the largest share of publications with 187 papers followed by Huazhong University of Science and Technology (183), Harvard Medical School (166), Tongji Medical School (162), and University of Toronto (137). Some articles that at the date of the search were cited at least 100 times within the data sample are shown in Table 2 Fig. 3A). In addition, there was a slight correlation between number of published articles and total link strength and number of citations with a Pearson's coefficient of r 2 = 0.672 and r 2 = 0.519 respectively. The top keywords with the highest occurrence within the dataset and linking strength within the network were "Human" and "Covid-19" with 1497 and 1189 respectively (Fig. 3B, Table S3).

Medicinal plants with increased attention during the pandemic
The species Nigella sativa L. (299), Zingiber officinale Roscoe (275) and Glycyrrhiza glabra L. (243) have been the most important during the pandemic with a significant increase in investigations (Table 3). Species such as Panax ginseng C.A.Mey (59), Glycyrrhiza uralensis Fisch (56) and G. glabra (51) have been the major occurrences in the papers produced in

Main approaches and characteristics of the studies analyzed
Most of the studies have been approached especially from scientific approaches namely phytochemistry, biochemistry, pharmacology and molecular biology. In the case of N. sativa, the research objectives have focused on evaluating phytocompounds responsible for the antiviral effect, especially the ability to inhibit virus entry. Other species such as Z. officinale and G. glabra have described the potential to counteract respiratory effects caused by Covid-19. In all approaches Covid-19 was the strongest keyword in the studies, followed by SARS-CoV-2, human and review (Fig. 5).

Importance of medicinal plants during the pandemic
This study quantitatively explored the scientific production related to the plausible role of traditional medicine in the management of the Covid-19 pandemic. Our study also identified 10 superior medicinal plants that have received the most attention during the pandemic.

Mechanisms of action of the phytocompounds
The healing potential of some medicinal plants seems to be closely related to their chemical compounds. At the same time, they become a promising source for the design of specific drugs. For example, the anticovid-19 potential of A. racemosus species may be related to its compounds such as Asparoside-C and Asparoside-F. Both with good binding affinities to the spike receptor and endoribonuclease NSP15   Based on Scopus data only.  with binding energies of 6261 and 55.19 kcal/mol respectively. In other words these compounds could function as inhibitors of Covid-19 proteins [48]. The efficacy of R. emodi against the new coronavirus is related to compounds such as emodin, aloe-emodin, antrarufin, alizarin and danthron, which show binding affinity in the three potential active sites of the RNA-binding domain of the virus nucleocapsid phosphoprotein. These phytocompounds alone or in combination could be a good therapeutic alternative for managing of SARS-Cov-2 [49]. Compounds such as 27-hydroxyethanolide B, anaferin, 12-deoxy-contramonolide and withastramonolide found in W. somnifera. Others such as Limonin, Solvanol and Azadiradionolide present in N. sativa, Solanum nigrum L., and A. indica respectively could target non-structural proteins (NSP) of SARS-Cov-2 [50]. N. sativa in particular is a plant with particular antiviral characteristics. The antiviral effect is related to the name compound "thymoquinone" which is similar to chloroquine and hydroxychloroquine. In addition, the antiviral spectrum of this compound has been found to be superior to that of hydroxychloroquine, and it is speculated that it may neutralize the new coronavirus [26,27]. Thymoquinone in combination with nigelimine may be a potential remedy to combat Covid-19. One of the reasons is that the combination could lead to blockade of SARS-CoV-2 entry by the action of angiotensinconverting enzyme 2 (ACE2) in pneumocytes. This potential could also be enhanced by Zn supplementation, enhancing innate and adaptive immunity during infection [51]. The presence of compounds including thymoquinone, dithymoquinone, thimohydroquinone and nigelimine together with antiviral properties, e.g., antioxidant, anti-inflammatory, anticoagulant, immunomodulatory, and bronchodilator makes N. sativa a species with the ability to enhance the immune responses of some common drugs such as hydroxychloroquine, chloroquine, lopinavir/ritonavir and remdesivir [26,51]. Dithiomoquinone for example has shown a higher binding affinity in SARS-CoV-2 (− 8.6 kcal/mol) than chloroquine (− 7.2 kcal/ mol). This suggests that the compound could function as a potential inhibitor of virus-host interactions [52]. Therefore, N. sativa could easily be considered for the design of new antiviral drugs against Covid-19, as well as other plants such as A. sativum, Allium cepa L. and Z. officinale, because its safety and efficacy is well established [24,25,53]. E. globulus other of the best-known and most widely used plants worldwide, its two bioactive compounds apigenin-o-7-glucuronide and ellagic acid also promise a beneficial role against Covid-19 through inhalation therapies. Easily these compounds could be directed to the respiratory tract. This is considering that SARS-CoV-2 enters the host through the nasal cavity and infects the oral cavity [54]. Easily these compounds could be directed to the respiratory tract. Therefore, the effect against respiratory diseases, including SARS-CoV-2, is closely related to its compounds mentioned above [46,54].
A. paniculata and C. cyminum are species whose role in the management of Covid-19 has also been recognized. These species have been attributed with the potential to alleviate symptoms such as fever and cough in patients infected with Covid-19 and others such as T. vulgaris, G. glabra, A. sativum, Althea officinalis L. and P. ginseng could modulate the immune system and exert a preventive therapeutic role [25]. A. paniculata for example, has shown versatile biological activities including immunomodulation and SARS-CoV-2 binding site determination, which may exert a key role against Covid-19 [55]. Other compounds such as methyl rosmarinate and myricitrin found in H. atrorubens and Myrica cerifera L. respectively, have shown better binding affinity and docking score than control drugs (nelfinavir and prulifloxacin).
This suggests that the potential of these compounds may be comparable to some commonly used medications for the management of complex respiratory infections [56]. However, more long-term clinical and preclinical trials are needed to confirm efficacy with more scientific rationale, as so far there are no reliable trials on Covid-19 supported by medicinal plants [2,10,25,57].

Brief historical data on the use of medicinal plants against viral diseases
Historical evidence shows that medicinal plants for centuries have played a plausible role in the management of historical diseases that transcended to pandemics among them Zika virus (ZIKV) , Ebola virus (EBOV) [58,59] y Asian Flu (H2N2) [60,61]. Many of the medicinal plants documented in this study in particular A. membranaceus, A. indica, A. sativum, C. longa, N. sativa have historical background in viral disease management, mainly dengue virus and influenza virus (H1N1), which in part has allowed their visibility during the Covid-19 pandemic as the latter is a viral-like disease [62][63][64][65][66]. However, the medicinal potential among plants seems to be different, which is associated with the effectiveness of the compounds found in a certain plant [48,52,64,67]. Brief evidences of the use of medicinal plants against historical viral diseases are presented in Table 4. Evidences suggest that during the present pandemic, in many rural areas the vaccines arrived late around the globe and the holders of traditional knowledge were protagonists in these regions that was contrary to what happened in major cities.

Conclusion
This study showed that N. sativa, Z. officinale, G. glabra, A. sativum, A. indica and W. somnifera were the species that have received the most attention in the midst of the pandemic according to the number of investigations. However, the number of studies of the first three plants mentioned were statistically significant in contrast to the rest of the plants recorded. According to the literature, some of these species show a promising potential against which are related to bioactive compounds such as thymoquinone found in N. sativa and 27-hydroxyethanolide B, anaferin, 12-deoxy-contramonolide and withastramonolide found in W. somnifera, which seem to have an important efficacy against Covid-19 infection. We believe that traditional medicine could be an important ally of modern medicine in helping to manage future respiratory diseases by searching for and creating new specific antiviral drugs. However, more large-scale clinical trials are still needed to demonstrate the efficacy of phytocompounds. It is stressed that mainly the traditional  [80,81] medicines should be patented as a drug where traditional knowledge should be implemented. The cultural, transmission mechanisms and international treaties should be protected thus to strengthen the cultural practice in different regions. The fact that protecting these traditional medicinal practices will also help to protect the uses of biodiversity. Finally, when we were completing this particular article, World Health Organization has declared another disease "Monkey Pox" as a global health alert and the need for governments to redouble their efforts to support traditional medicine has increased as few countries seem to support this initiative.

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.