Summary

The characterization of isolated polyphenolic compounds present in the diet – especially in the context of their therapeutic effect (for instance their antiplatelet activity) – is often based on the generally accepted flavonoid classification. In the case of plant extracts it usually refers to common names of plants rather than scientific botanical nomenclature. Hence, it is often difficult to even roughly estimate how many and which plant taxa exhibit biological activity towards the modula­tion of blood platelet activity. In this paper, based on a review of literature from the last 50 years (1962-2011), we developed a list of seed plants (Spermatophyta) taxa investigated in studies on blood platelets. We used the PubMed database, as well as the database of species’ names – Taxonomy, in order to gather information about the investigated taxa. The review of the literature was made with the use of advanced options, on the basis of keywords (or combinations of keywords) and selected journals. Record search strategies were evaluated on the basis of the sensitivity of search (number of papers meeting the criteria of search strategy) and the specificity of search (number of papers containing in their title and/or abstract information on taxa used in blood platelet research). The publications were considered specific if they reported either Latin or common names of plants (or both). The main search strategy was characterised by high sensitivity, but low specificity. The basis for plant taxonomic specification was the list of 1080 articles, published in 434 journals. The list of taxa used in blood platelet studies covered 98 genera belonging to 47 families of seed plants. The richest in genera, and also in species, appeared to be the families Asteraceae, Fabaceae, and Ro­saceae, the most abundant in species all over the world. This study may be a starting point for the selection of plant species to be used for biomedical research and – at the same time – may help in the search for an effective strategy of literature tracking concerning flavonoids and blood platelets.

Key words:flavonoids • blood platelets • taxon • polyphenolic compounds

Introduction

Polyphenolic compounds of plant origin are very impor­tant components of the human diet due to their antioxi­dant activity, their ability to scavenge free radicals and their potential of reducing tissue damage caused by oxi­dative stress, which accompanies, to a greater or lesser extent, all chronic diseases. A large group of polyphe­nolic compounds present in the diet is constituted by flavonoids and, therefore, it is flavonoids that are most often the subjects of scientific research [72]. It has been observed that the consumption of fruits and vegetables (a diet rich in polyphenols) prevents the development of cardiovascular diseases, such as coronary heart dise­ase or stroke [17,37,88]. The cardioprotective properties of polyphenols are related to, inter alia, the antiplatelet activity of flavonoids, confirmed in numerous publica­tions. Investigations on the regulation of blood plate­let function by polyphenolic compounds involve either reports concerning pure polyphenols with known che­mical structure (e.g. quercetin, an inhibitor of tyrosine kinases) [116] or multi-component plant extracts [121]. The nomenclature of the investigated polyphenolic compounds refers either to the generally accepted clas­sification of flavonoids (in the case of isolated compo­unds) or to the colloquial names of plants (in the case of multi-component extracts). The scientific botanical nomenclature is seldom used or mentioned. Doing so certainly makes a scientific text easier; however, at the same time, it makes the synthesis of study of polyphe­nols as natural inhibitors of blood platelets much more difficult to comprehend in the botanical context. In order to determine the antiplatelet activity of extracts from plants, which are a source of polyphenolic compo­unds, we aimed to develop of a list of taxa of seed plants (Spermatophyta) used worldwide in platelet studies. To achieve this objective, different literature search stra­tegies were employed using PubMed, which were also assessed for their sensitivity and specificity. Therefore, this study may serve as a starting point in the selection of plant species intended for biomedical research and may provide a direction in the effective assessment of the literature on polyphenolic compounds as modula­tors of blood platelet function.

Materials and methods

The literature search was conducted from February to March 2012, using the PubMed database of scientific literature. Plants described in the publications were analysed with respect to their taxonomy, employing a database of species names (Taxonomy). The study cove­red the literature published in the years 1962-2011. All queries were built with advanced search options. The strategy of literature review was adapted to the aim of our research, which was a taxonomical analysis of vascu­lar plants (Euphyllophyta), belonging to the seed plants (Spermatophyta) and excluding spore plants (Monilifor­mopses), that were used in studies dedicated to blood platelets (Fig. 1).

Figure 1. Cladogram showing the phylogenetic relationships among vascular plants

The research was divided into stages. The first stage began with the selection of keywords, allowing us to collect literature in PubMed in a satisfactory number, regardless of the publication date. For this purpose, the following search options were included:
Strategy 1 (#1): flavonoids AND platelet*
Strategy 2 (#2): polyphenols AND platelet*
Strategy 3 (#3): polyphenolic compounds AND platelet*

First, for an optimal search option, the number of publi­cations indexed by PubMed in consecutive years was compared, starting from the year of the oldest publica­tion appeared until 2011. The aim of this stage was to determine the time of the intense increase in the num­ber of publications on the biological activity of poly­phenolic compounds in the context of blood platelet research. The allocation of papers to the groups of publi­cations containing (specific) or not containing (nonspe­cific) the required information on plant taxa used in blood platelet research was conducted in the second stage. Information on plant taxa used in blood platelet research was gained solely from the titles and/or abs­tracts of publications. During the process of gathering information on plant taxa we prepared a list of journals, in which the analysed papers appeared most frequently. This list was used to verify the correctness of the chosen strategy, amongst options #1-#3, by assuming the follo­wing search options #4-#6:
Strategy 4 (#4): flavonoids AND platelet* AND journal
Strategy 5 (#5): polyphenols (NOT flavonoids) AND pla­telet* AND journal
Strategy 6 (#6): (polyphenols OR flavonoids) AND plate­let* AND journal

The third stage was to draw up a list of taxa (genera/ species and families) used in the studies on platelets. In order to avoid omitting taxa relevant to platelet rese­arch, the units of plants occurring in publications (title and/or abstract), which did not refer to studies of blood platelets, were additionally verified with strategy #7:
Strategy 7 (#7): (genus name) AND platelet*

In addition to the list of taxa, a ranking of the families richest in genera/species used in blood platelet research was compiled.

Analysis of results

The basis of this study was the publications indexed by the PubMed database (http://www.ncbi.nlm.nih.gov/ pubmed/). In the compilation of the list of taxa asso­ciated with plants used in blood platelet studies, the Taxonomy database (http://www.ncbi.nlm.nih.gov/taxonomy) was employed. Search strategies were com­pared in terms of sensitivity, determined by the num­ber of studies meeting the criteria of the search strategy. The analysis of publications was carried out in terms of specificity of the search (calculated as the number of articles containing in their title and/or abstract the information on taxa used in blood platelet research). The publications giving the names of taxa according to botanical nomenclature or articles containing common names of plants were regarded as specific. The employed measures of central tendency and diversity were the median and interquartile range (25% to 75%). Depending on the characteristics of distribution, for testing the dif­ferences between the groups, we employed Student’s t test for paired data or Wilcoxon’s test.

Results

Stage 1

For the entire searched time range (i.e. without specify­ing the time range), the number of records found in Pub­Med for strategies #1-#3 varied and amounted to: 1081 (#1), 151 (#2), 45 (#3).

The MeSH database had been primarily used in the study to find MeSH terms for a PubMed search. When we entered the terms „flavonoids”, or „polyphenols” we did not find any other relevant MeSH concepts, whereas by entering the term „platelet” we succeeded in finding over 140 MeSH terms. From our point of view, in terms of taxon analysis, the most relevant results were: blood platelets, platelet function, platelet activation and pla­telet aggregation; however, none of the chosen MeSH terms used for a literature search in conjunction with the term „flavonoids” resulted in finding a larger num­ber of records than the number of records attributed to strategy #1. Thus, finally, for the assessment of search specificity (i.e. for the assessment of the number of publications indexed by the PubMed database according to the topic, as well as for the selection of publications containing information on the taxa of plants used in blood platelet studies), strategy #1 was employed. When using this strategy, we noted that the oldest record returned by PubMed was from 1962, while the most recent was from 2012. Therefore, we decided to ana­lyse the data originating from the literature published in the years 1962-2011, i.e. we included 1080 papers in the analysis. Until 1985, the number of papers indexed by PubMed did not exceed 10 annually. A sharp increase in the number of indexed papers came in the late 1990s, i.e. from 1995 on, since more than 30 papers annually appeared in the database. The average number of publi­cations in the years 1995-2011 was 59 (48-61) [Me (LQ-UQ)]. Figure 2 shows the number of papers indexed by PubMed by decade in the period 1962-2011. What fol­lows is that interest in the subject of antiplatelet func­tion of polyphenolic compounds gradually increased in each decade, but the greatest increase in the number of records on this topic occurred in the last decade of the last century (Fig. 2). In contrast to this, beginning from the second decade, i.e. after 1980, the number of all jour­nals indexed in PubMed decreased (Fig. 2). Interestingly, since 2002, the summed number of records returned by PubMed in the subsequent years of the period 2002-2011 was higher by 52 records than the number of records searched in the database for the period of 2002-2011 (538 records).

Figure 2. The number of records returned by PubMed for strategy #1 (black bars) and the number of all journals referenced in PubMed (white bars) in consecutive decades in the period 1962-2011

Stage 2

Taking into account the titles and abstracts of publica­tions obtained for strategy #1, we assigned a review of seed plant taxa that were used in studies on blood pla­telets. Out of 1080 records, 683 publication titles and/or abstracts did not contain the systematic names of fami­lies, genera or species of plants that served to provide the investigated polyphenolic compounds. Thus, only 397 items out of the initial pool of 1080 records were utilised to compile the taxonomical list of plants used in these studies. Excluded were also two duplicates and one publication on the Pteris genus, which, according to the contemporary systematics of plants, belongs to the group of spore plants Moniliformopses, which was exclu­ded from this study.

Publications from the period of 1962-1984 (n=43) appe­ared to be irrelevant to the elaboration of the taxono­mical list, because neither the titles nor the abstracts (if present) of these records contained any valid infor­mation on taxa. The first work encountered providing the taxonomical plant name was from 1985. In the follo­wing years, the number of such publications increased; after 1997 this figure exceeded 10 per year, and after 2001 it was greater than 20 papers per calendar year. Most records referring to blood platelets and containing information on the taxonomy of the used plants were published in 2008 (42 publications).

In addition to the selection of articles on the basis of information on taxa, we performed a review of the jour­nals, in which publications found with strategy #1 appe­ared. The analysis revealed that 1080 articles returned by PubMed appeared in as many as 434 journals, (on average, 2.5 publications per journal). For comparison, in the period of the last decade (2002-2011), 538 artic­les were published in 269 journals (on average, 2 artic­les per journal). The share of individual journals, in the pool of records determined by strategy #1 is shown in Table 1. The first three positions were occupied by The Journal of Biological Chemistry, Thrombosis Research and Biochemical Pharmacology. Making use of this ranking (i.e. the 10 journals, in which publications on flavonoids and platelets appeared most often), we verified the desira­bility of pursuing strategy #1 by comparing the num­ber of records returned to strategies #4-#6. The average number of records returned by PubMed with strategy #4 was significantly higher than the number of records obtained with strategy #5 (Me; LQ-UQ: 17.5; 16-24 papers vs. 0; 0-1 papers; p=0.002), but it did not differ from the number of publications collected with strategy #6 (18.5; 16-24 records). The partial data for this comparison are summarised in Table 2.

Table 1. Proportion of journals publishing papers on flavonoids and blood platelets

Table 2. Comparison of search sensitivity (number of papers meeting the criteria of the search strategy) for strategies #4-#6

Stage 3

On the basis of the review of literature recorded in the PubMed database in the period of 1962-2011 and found by strategy #1, we developed our list of taxa. Many papers contained in their content (title and/or abstract) common names, such as apple, berry, olive, etc. Not to miss publica­tions of this kind, and yet to avoid a mistake in determining the species names, the taxonomic list contains the names of plant genera and their affiliations to families, assigned according to contemporary plant taxonomy. In the pool of 394 publications containing the information on taxa, about 25% of the papers did not relate directly to blood platelet research, but to other cell types, such as endothelial cells, smooth muscle cells, leukocytes, cancer cells, hepatocytes, etc. Of these papers we distinguished publications refer­ring to 18 plant genera, the significance of which in blood platelet research was verified again using strategy #7 (see M&M). If for strategy #7 the PubMed search database pro­vided a paper concerning a biological activity of a given genus in relation to blood platelets, this genus was placed on the taxa list. Otherwise, the taxon was not taken into consideration. On this basis, the taxa list was expanded by nine genera, while the remaining nine genera were exclu­ded. The group of eliminated genera consisted of: Bauhinia sp., Millettia sp., Gongronema sp., Sarcophyte sp., Machilus sp., Galphimia sp., Hibiscus sp., Cudrania sp., and Apium sp.

Finally, the taxonomical list contained 98 genera belon­ging to 45 families and an additional two families without specified genera (Saururaceae and Orchidaceae) (Table 3). The most abundant in genera, as well as in species, were the families Asteraceae (19.4%), Fabaceae (15.3%) and Rosaceae (6.1%). The share of individual fami­lies in the pool of the presented taxa is shown in Table 4.

Table 3. List of taxa used in blood platelet research

Table 4. Share of families richest in genera/species used in blood platelet studies

Discussion

Polyphenolic compounds, integral components of the diet, constitute a widespread and probably the most numerous group of chemical compounds occurring in higher plants. The cardioprotective effects of polyphe­nolic compounds have been widely reported in both in in vivo and in vitro studies. To a large extent, these effects are related to the antiplatelet activity of polyphenols. In a number of publications, particularly in review papers, the characteristics of known dietary polyphenolic com­pounds with antiplatelet activities is based on the accep­ted classification of flavonoids and, in the case of plant extracts, it often refers merely to the common names of plants, without any details on the botanical nomencla­ture. Therefore, the primary objective of this study was to establish a list of taxa of the seed plants used in blood platelet research. To the best of our knowledge, this is the first study investigating this topic. For the purpose of this analysis, we followed specific search strategies, which were further evaluated during the course of the study. The applied strategies proved to be helpful in the analysis of our results and allowed us to look critically at the effectiveness of the process of collecting literature concerning this subject.

The resulting outcome of the analysis was established in several stages. First of all, keywords were chosen to allow us to collect a satisfactory number of papers. Generally, we deliberately based our literature search on two terms (a broad search strategy) in order to find the highest possible number of specific papers without omitting any important articles in terms of taxono­mic analysis. In our study only strategy #1 provided a satisfactory number of records. This may be related to the historically earliest appearance of the term „flavo­noid” in the MeSH used for indexing PubMed citations. According to the MeSH database the term „flavono­ids” was introduced in 1963, whereas the term „poly­phenols” was only quite recently added to the MeSH database (2010). In turn, the phrase „polyphenolic compounds” has not been added so far to the thesau­rus or MeSH.

The high sensitivity of strategy #1 in relation to the other ones (#2-#3) is evidence of the great interest in flavonoids as a group of polyphenolic compounds com­monly occurring in the world of plants and present in the majority of foods or beverages originating from plants. First, we compared the number of publications indexed by PubMed in consecutive years and decades during the last 50 years. This allowed us to determine that the period of rapid growth of the number of publi­cations on this topic occurred in the second half of the 1990s. This is most likely related to growing interest in the subject of the antiplatelet properties of polypheno­lic compounds rather than to the number of journals referenced in PubMed at that time. Assuming that the time-dependent fluctuations in the number of journals referenced in PubMed containing the analysed reports are proportional to the time-dependent changes in the number of all journals indexed in PubMed, the chance of revealing a positive correlation between the number of collected articles and the number of journals indexed in PubMed and publishing these articles seems low (Fig. 2). It means that the interest in the role of flavonoids in pla­telet function is probably not affected by the number of journals indexed in PubMed in 1990s. This is even more likely considering that 1) the list of currently indexed journals differs from the list of previously indexed jour­nals and 2) the total number of journals, in which the analysed articles have been published is as high as 434 titles. In the course of this analysis, we noted that the total number of records returned by PubMed for each calendar year during the period of 2002-2011 was not equal to the number of records returned by PubMed for the entire decade of 2002-2011. The reason for such an inconsistency was the occurrence of duplicates, which one can convince oneself of when saving the records in a clipboard; when doing so, we did not add records already present in it, thus eliminating duplicates. In the group of eliminated duplicates, we found publications descri­bed with two dates: the release date of publication in the journal and the date of issue in electronic form, available on the Internet; the years of issue of these publications in printed journals differed from the years of publication issue in their electronic forms. This is highly likely to occur when the release of an article in a journal falls at the beginning of the calendar year, and the date of issue of publication in the electronic form precedes the rele­ase in the printed form of a journal by several months. As a consequence, a publication released in a journal, e.g. in 2003, but available online in the preceding year, could be found twice when performing a search of the literature only for 2003 or only for 2002, but only once when searching for the range of 2002-2003.

A selection of papers found with strategy #1, conducted at stage 2, allowed us to determine how many publica­tions provided in their titles or abstracts information on the taxa of plants used in cell research (blood pla­telets by default). Surprisingly, the number of publi­cations forming the basis of the taxa list was 1.7-fold lower compared to the number of papers not conta­ining any information on taxa in their titles or abs­tracts. There were several reasons for the questionable usefulness of almost 683 records in the present study. Most of all, the search strategy, although sensitive in terms of the number of papers found, was not speci­fic enough. The use of a wild card in strategy #1 signi­ficantly increased the number of returned records, but at the same time, the initial pool contained publi­cations not fully meeting the search criteria. A large proportion of the publications did not contain in their title and/or abstract information on the taxa and/or was not related to blood platelet research. Instead of taxa names, often the names of particular polyphenolic compounds of plant origin appeared, including rutin, apigenin, and luteolin. The most commonly repor­ted flavonoids included genistein, quercetin and cate­chins. Given the fact that the mentioned compounds have been the subject of research for many years due to their interesting biological activities and therapeu­tic properties, as well as due to their availability and their sources of origin in nature, the lack of taxono­mical names in these publications is understandable. Most studies involving genistein, an isoflavonoid natu­rally occurring in leguminous plants (Fabaceae family), have focused on the activity of genistein as an inhibitor of tyrosine kinases, as well as the anticancer, cardio­protective and hormonal activity of this polyphenolic compound [26,35]. Quercetin is a flavonoid commonly occurring in fruits and vegetables, as well as in seeds, nuts, flowers, leaves and bark. It is known to possess strong antioxidant and anti-inflammatory properties, which are related to the prevention and treatment of cardiovascular diseases and cancer [52,95]. Catechins, especially abundant in tea leaves, cocoa, apples and red wine, possess antioxidant, antibacterial, antiviral, anti­cancer, hypolipaemic, hypoglycaemic and hypotensive properties [41].

The low specificity of the adopted search strategy also resulted from the presence of articles containing the keyword „platelet”, but often not having, besides the term itself, much in common with blood platelet rese­arch. This collection of records was rich in publications, in which commonly known mediators of cellular respon­ses, such as platelet-derived growth factor (PDGF) [79], platelet-activating factor (PAF) [24] or platelet endothe­lial cell adhesion molecule (PECAM-1; CD31), had been used or studied [62]. Apart from the studies on blood platelets [25,80,81,82], various flavonoids (genistein, quercetin, apigenin, luteolin, isoliquiritigenin, cate­chins, baicalein, delphinidin and silybin) were used in experiments with smooth muscle cells [48,63,64,122], leukocytes [16,76], vascular endothelium [34], tumour cells [19], epithelium [7] or hepatocytes [108,115]. Fla­vonoids were used both for the assessment of cell func­tions and in order to trace the mechanisms underlying the cellular response.

The low specificity of the search strategy was also reflected by the relatively large number of journals with a broad scope, in which the analysed papers appe­ared. On the other hand, strategy #1 appeared to be the most sensitive among the initially considered options, as evidenced by the comparison between the num­bers of records found using strategies #4 and #6 for 10 journals characterised by the highest numbers of the papers of interest.

On the basis of the analysis of publications determined with strategy #1, it can be claimed that in research on blood platelets, 98 genera of seed plants (Spermatophyta), belonging to 47 families, have been used. The highest percentages of described taxa concerned genera repre­senting Asteraceae, Fabaceae, and Rosaceae, the largest seed plant families in the world [113]. Plant prepara­tions used in platelet studies were isolated from various parts of the plant, namely: 1) rhizomes (e.g. Pueraria lobata (Willd.) Ohwi) [18], 2) seeds (e.g. Vitis sp.) [98], 3) roots (e.g. Glycyrrhiza glabra L.) [60], 4) flowers (e.g. Pru­nus mume Siebold & Zucc.) [120], 5) fruits (e.g. Punica gra­natum L.) [73], 6) bark (e.g. Pinus pinaster Aiton) [93], as well as 7) leaves (e.g. Olea europaea L.) [101]. Researchers were particularly interested in polyphenolic compo­unds contained in soy (mainly isoflavones), in beverages (tea, cocoa/chocolate, wine/grapes), in citrus fruits, in extracts from the bark of maritime pine (Pinus pinaster Aiton) and in extracts from ginkgo biloba (Ginkgo biloba L.). This was reflected in a large number of publications on this topic (original and review articles) and explains the seemingly low number of registered taxa in all the analysed papers.

In this study, we omitted the aspect of plant-originating drugs (Diosmin, Troxerutin, Legalon, Venostasin, Flavo­coxid), which were also used in research on blood plate­lets and other cells. Moreover, during the construction of the taxonomical list, we deliberately excluded from the analysis herbal preparations developed according to traditional Chinese and Korean medicine. These inclu­ded the DBT mixture (Danggui Buxue Tang) [27], extract from dragon’s blood (Daemonorops draco BL.) [109], the extract Gua Lou Xie Bai Bai Jiu Tang [42], the seven-com­ponent mixture Hwaotang [89], as well as active substan­ces isolated from Panax notoginseng (Burkill) F.H.Chen ex C.Y.Wu & K.M.Feng [28].

In this study, we were not able to perform a valida­ted analysis of the association between the number of specific papers recorded in a particular year and the number of described genera/species. First, more than a single taxon was often described in a single publica­tion. Second, in a particular year, a given taxon could be described several times in different papers, and/or the investigated extracts could originate from various parts of the same plant species (often with differing physico-chemical and biological properties). Further­more, the content of polyphenols in plants may vary between species, and even between varieties of the same species [43]; thus it would be unwise to equate, for example, the extracts originating from the seeds or peels of grapes [98], resveratrol (biologically active compound isolated from Vitis sp.) [86] and wine [32], i.e. to treat these four specimens (preparations) as identical. Likewise, the oil obtained from olive [23] sho­uld not be identified with the extract isolated from the leaves of the same plant [101].

It should be emphasised that the compiled taxonomical list is based on strategy #1, which, unfortunately, does not fully cover the resources of PubMed. We were able to ascertain that strategy #1 did not exhaust the resour­ces of PubMed thanks to using the auxiliary strategies (#5 option 1; #7 option 2) that enabled us to find other important (specific) records in PubMed. When creating the literature database, we noticed that searching with the use of the criterion „author” (option 3) might also improve the quality of a search.

In summary, the present study resulted in a list of taxa of the seed plants used in blood platelet research and reve­aled the basic features of a search strategy concerning the publications on flavonoids and blood platelets: high sensitivity, but quite low specificity. Even if the chosen strategies turn out not to be „perfect”, we have indica­ted the ways of conducting an effective literature search in order to find as many taxonomic names as possible. Thus, it seems that the effective collection of literature requires the employment of various (often compoun­ding) search options. Currently, the omnipresence of flavonoids in the diet, as well as their biological and the­rapeutic significance, are largely the hallmarks of their widespread usage in research.

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