Pharmacophylogeny of genus Allium L

3.1 Literature survey

The information on medicinal uses of the genus Allium was compiled by broad literature study of published sources from 1920 to 2023. We searched thorough online database by using the keyword “Allium” including reviews of the ethnobotanical uses, pharmacological activities and medicinal uses of the genus Allium. A list of the plant was prepared from the published literature. The nomenclature of all the taxa were studied with the help of Plant of the World Online (https://powo.science.kew.org/), International Plant Naming Index (https://www.ipni.org/), The Plant list (http://www.theplantlist.org/), Biodiversity Heritage Library (https://www.biodiversitylibrary.org/), world flora online (https://www.worldfloraonline.org/), Tropicos (https://www.tropicos.org/home) and World Checklist of Selected Plant Families ( http://apps.kew.org/wcsp/retrievedon17.12.2014). Protologues of all the name and type specimen for the same were also studied and examined. A table of accepted name was prepared for species within genus Allium with the help of published literature and aforementioned databases (supplementary file S1). The literature search components and related review type were documented and illustrated using PRISMA, 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) available at http://www.prisma-statement.org/PRISMAStatement/FlowDiagram. (Fig. 1).

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Fig. 1

PRISMA flow diagram showing studies included in the review literature of Pharmacophylogeny of Genus Allium L.

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3.2 Phylogenetic tree construction

3.2.1

3.2.1 Data retrieval

A comprehensive examination of 185 Allium species representing all as documented in the genus was conducted for the purpose of pharmacophylogenetic analysis (Friesen et al., 2002). In this study, the Internal Transcribed Spacer (ITS-1 and ITS-2) regions of the taxa in question and out group (Friesen et al., 2006) (Fig. 3) were obtained from the National Center for Biotechnology Information (NCBI)/GenBank. This dataset was employed for the construction of a phylogenetic tree (supplementary file S3).

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Fig. 2

Selected Phytochemical from Allium species responsible for Antioxidant and Antidiabetic activity.

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Fig. 3

Hot nodes of Allium species having Antidiabetic & Antioxidant properties due to presence of secondary metabolites.

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5.1 Research in electronic databases

Initially, a comprehensive search using the keyword 'Allium' yielded a total of 598 articles in the electronic database. Google Scholar contained the highest number of articles (78), followed by Science Direct (42) and PubMed Central (6). Contributions from Springer, CABI, MDPI, Wiley, HindaWi, and Taylor & Francis were 8, 2, 7, 8, 2, and 6, respectively. Additionally, 25 records were identified through the Online Database PFAF.org, (PFAF, 2022) comprising information on 20 species, while Dr. Duke's Phytochemical & Ethnobotanical Database (U.S. Department of Agriculture, 2016) included records of 5 distinct species. During the selection process, 455 duplicate articles were excluded after reviewing abstracts and keywords. A total of 168 articles were considered suitable for inclusion in the manuscript, consisting of 126 experimental articles and 27 literature reviews.

5.2 Phytochemical significance and therapeutic potential of Allium species

A dataset comprising 42 records was meticulously curated for pharmacophylogeny, including 39 accepted species names and 3 synonyms (POWO, 2022). These entries were categorized into 139 usage categories. Notably, 29 out of the 42 species were localized within the hot node of the phylogenetic tree (Fig. 3), with data gleaned from 168 published sources. The relevant data pertaining to these categories is delineated in supplementary file S1 and S2. The predominant therapeutic categories included 17 species for digestive system disorders, 15 for cardiovascular diseases, and 15 exhibiting anticancer properties. Notably, 12 of the identified species were specifically utilized in the treatment of diabetes, while 21 were acknowledged for their antioxidant activities, attributed to the presence of bioactive compounds such as allicin, alliin, flavonoids, phenolics, tannins, and glycosides (supplementary file S1).

Allicin, a prominent phytochemical within genus Allium, is well-studied and renowned for conferring the characteristic pungent aroma and taste upon crushing or chopping. This compound is enzymatically synthesized through the interaction of the Alliinase enzyme with the precursor compound alliin (Najeebullah et al., 2021). Wild Alliums additionally serve as rich sources of naturally occurring folic acid, fiber, flavonoids, vitamins, and minerals, including thiamine, riboflavin, carotenes, niacin, pyridoxine, lutein, zeaxanthin etc (Mahajan et al., 2019). Cavallito and Bailey (1940) successfully isolated and characterized allicin. When plant tissues incur damage, the release of the alliinase enzyme catalyzes the conversion of S-alk(en)yl cysteine sulfoxide into chemically unstable OSCs (Organosulphur compounds), spontaneously yielding compounds that confer the medicinal properties and flavor associated with Allium plants (Deka et al., 2022). The exploitation of wild Allium spp. is prevalent among local residents, with all parts of the Allium plant being consumed, excluding perhaps the seeds. Noteworthy phytochemicals such as Kaempferol, Isorhamnetin, Morin, Fisetin, Galangin, (Emir et al., 2022); Ajoene, (Singh et al., 2020); Dillapiole, coniferol, (Mahnashi et al., 2022); Lectin, S-methyl-L-cysteine, Limonene, (Selim & Sakeran, 2014); Quercetin, Alliin, and Allicin (Kim et al., 2018) play a key role in the therapeutic attributes of Allium spp. exhibiting antidiabetic, antioxidant, or dual activities (Fig. 2).

5.3 Phylogenetic distribution of species with therapeutic uses

Phylogenetic trees serve as instrumental tools in unraveling the evolutionary dynamics within genus Allium, providing key insights into the evolutionary relationships among distinct medicinally important species. This information is paramount in comprehending the evolution and divergence of pharmacological traits inherent within the genus Allium. Utilizing hot nodes on the phylogenetic tree (Fig. 3), we recognized species associated with type II diabetes and antioxidant-related symptoms. A total of 29 species within prominent nodes were identified as likely candidates exhibiting antidiabetic, antioxidant, or dual activities. This determination was relied entirely on the investigation of traditional medicinal uses through phylogenetic analysis.

Notably, these lineages include documented antidiabetic and antioxidant activities in species such as A. akaka, A. ampeloprasum, A. ascolanicum, A. angulosum, A. barsczewskii, A. canadense, A. carinatum, A. carolinianum, A. cepa, A. chinense, A. fistulosum, A. consanguineum, A. flavum, A. hookeri, A. humile, A. mongolium, A. nutans, A. paradoxum, A.ramosum, A. roseum, A. rubellum, A. sativum, A. scabriscapum, A. schoenoprasum, A. tuberosum, A. victorialis, A. vineale, A. ursinum, and A. wallichi. The species identified within these hot nodes represent novel lines of inquiry, as they lack any corresponding use reports in the existing literature. Bootstrap values observed in the phylogenetic tree indicate the robustness of branches, with a 100 Bootstrap value suggesting strong support for a particular lineage. Allium species within these high-confidence nodes exhibit potential in the realms of diabetes treatment and free radical scavenging activity.

In the context of reported ethnobotanical uses, 29 out of 42 species were identified within the hot nodes of the phylogenetic tree, from a total of 185 species included in the analysis. The application of the hot nodes approach facilitated the mapping of reported medicinal uses, particularly those related to type II diabetes and antioxidant activity, demonstrating an overabundance of these traits across the phylogeny.

The antidiabetic effects observed in Allium species are attributed to bioactive compounds that enhance insulin sensitivity, inhibit key enzymes in glucose metabolism, and regulate glucose homeostasis. Notably, allicin, previously underestimated in its prevalence within the genus, exhibits potential for both diabetes treatment and free radical scavenging activity (Deka et al., 2021). Additionally, the antioxidant properties observed in these species can be attributed to secondary metabolites that scavenge free radicals, mitigating oxidative stress and averting cellular damage (Hwang et al., 2015).

The pharmacophylogenetic analysis lays the foundation for understanding the distribution of these beneficial traits across related species. This knowledge informs the exploration of Allium species for pharmaceutical purposes, aiding in the identification of potential candidates for drug development. Furthermore, it hightlights the potential of natural resources in traditional medicine and nutraceuticals for managing diabetes and promoting overall health.

The study unveils several distinct clades within the genus Allium characterized by notable antidiabetic and antioxidant properties. The correlation between evolutionary relationships and secondary metabolites provides insights into the molecular underpinnings of these pharmacological activities, emphasizing the potential of Allium species in developing novel therapeutics for diabetes and oxidative stress-related conditions. We identified medicinal applications for 42 Allium spp, including 3 synonyms viz; A. nutans, A. porrum, & A. bodeanum (POWO, 2022) with 29 of these species integrated into a phylogenetic tree. Primarily, 29 species were specifically employed in the treatment of Diabetes and Free radical scavenging activity, categorized as Antidiabetic (12 species), Antihyperglycemia (2 species), Antioxidant (21 species), and Hepatoprotective activity (5 species) (Fig. 4). It is noteworthy that among the 42 species with documented ethnobotanical use, 29 were included in the phylogeny, with a focus on Antioxidant and Diabetes-related symptoms (Fig. 3, supplementary file S2).

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Fig. 4

Number of Allium species cited in the literature used for the treatment of Antidiabetic and Antioxidant activity present in the phylogeny.

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5.4 Medicinal use of the taxa studied

This comprehensive analysis involved the classification of 613 utilization records, derived from 168 published sources (supplementary file S1). These records were systematically organized into 139 distinct use categories (supplementary file, S2), adhering to the Economic Botany Data Collection Standard established and previously employed in studies by (Ernst et al., 2016 & Pellicer et al., 2018). The study is based on the medicinal uses of plant species, including a total of 139 categories, however we focussed on specific therapeutic uses either antidiabetic or antioxidant or both activities in 39 species of genus Allium. Furthermore, the investigation included the extraction of usage records specifically related to diabetes and free radical scavenging activity, denoted by codes such as Antidiabetic (med_19), Antihyperglycemia (med_27), Antioxidant (med_39), and Hepatoprotective (med_95) (supplementary file S1).

5.5 Phytochemical and ethno-medicinal relationship of Allium

The manifestation of antidiabetic and antioxidant properties within a subset of Allium species is attributed to the presence of Allicin, as reported in a specific cohort of taxa (Lu et al., 2011). Especially, Allicin has been identified in seven species, namely A. ampeloprassum, A. ascalonicum, A. cepa, A. chinense, A. fistulosum, A. hookeri, and A. sativum, out of a total of 29 species incorporated within the hot nodes of the phylogenetic tree (Fig. 3). The instances where Allicin presence is confirmed are denoted in bold within the dataset. Additionally, Allicin has been reported in 11 other distinct species, exhibiting involvement in various biological activities (Table 1) & supplementary file S1).

It is noteworthy that among the diverse species identified to contain Allicin, only a selected few were previously acknowledged as primary sources of this compound, probably scarce of detailed investigation in the species of Genus in Question (supplementary file S1). The phylogenetic analysis postulates that the Allicin biosynthesis pathway may be a plesiomorphic character within the genus. Consequently, the widespread distribution of species in genus Allium suggests the potential for utilizing alternative species at the local level for the treatment of diabetes and other related conditions. This hightlights the versatility of Allicin-producing species and their applicability in diverse medicinal contexts within the genus.

5.6 Ethno-medicinal uses of Allium

The majority of Allium species are esteemed for their gustatory qualities, finding extensive utilization as culinary flavors (Sabiu et al., 2019). These botanical entities constitute a prolific reservoir of phytonutrients and bioactive compounds, including flavonoids, glucosides, steroids, phenolics, alkaloids, and an array of organosulfur compounds such as Allicin, Allin, DATS (diallyl trisulfide), DADS (diallyl disulfide), crucial for sustaining daily physiological functions (Kim et al., 2018).

Scientific investigations have substantiated the medicinal properties inherent in the genus Allium. Notably, empirical evidence indicates that highest consumption of Allium vegetables correlates with a diminished likelihood of developing various afflictions, including diabetes, cardiovascular disease, cancer etc (supplementary file S1). The heatmap depicts the presence other biological activities apart from Antidiabetic and Antioxidant activity due to the presence of phytoconstituents in the species on hot node of phylogenetic tree (supplementary file S1). The ethnomedicinal applications of Allium species identified within the hot node of the phylogenetic tree, along with their predominant bioactive constituents and corresponding biological activities, are systematically delineated through the construction of a heatmap (Fig. 5). This comprehensive representation illuminates the multifaceted therapeutic attributes associated with these Allium species, providing a nuanced understanding of their ethno medicinal relevance and potential contributions to human health.

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Fig. 5

Number of Biological activities found in different species on hot node of phylogenetic tree due to presence of frequently found secondary metabolites.

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6.1 Phylogenetic prediction of antidiabetic and antioxidant activity of genus Allium

The genus Allium has long been recognized for its ethnopharmacological significance, owing to its diverse medicinal properties and widespread traditional use across different cultures (Borborah et al., 2014). This study builds upon this rich tradition by investigating into the intricate relationships between phylogeny, pharmacology, and traditional medicinal knowledge within the genus Allium. Pharmacophylogeny, as elucidated by Xiao et al., (2006) and Hao et al., (2022) provides a theoretical framework for understanding how phylogenetic relationships among plants can inform their chemical composition and therapeutic effects. The phylogenetic analysis of 185 species of Allium has unveiled a distinctive clades or lineages within the taxonomic genus Allium, comprising species acknowledged for their pronounced antidiabetic and antioxidant activities. Specifically, the examination of phylogenetic relationships has delineated several clades including species like A. wallichi, A. tuberosum, A. ursinum, A. hookeri, and A. humile, exhibiting concurrent antioxidant and antidiabetic properties. Comparable attributes are detected in another lineage that contain species such as A. cepa, A. fistulosum, A. ascalonicum, and a subclade housing species like A. ampeloprasum and A. sativum. The antioxidant properties are further evident in lineages with species such as A. schonoeprasum, A. chinense, A. carolianum, A. akaka, A. ramosum, A. nutans, A. angulosum, A. mongolicum, A. griffithianum, A. scorodoprasum, A. flavum, A. vineale, A. barsczewskii, A. paradoxum, A. roseum, A. canadense, and A. atroviolaceum. Conversely, the antidiabetic properties are notable in a lineage housing A. victoralis, forming a clade with A. christophii, suggesting a possible extension of the antidiabetic trait to the latter, necessitating empirical validation.

The presence of secondary metabolites, including flavonoids, alkaloids, and phenolic compounds, in these species is postulated to play a pivotal role in conferring these therapeutic properties (Mahajan et al., 2019). These findings corroborate with previous studies highlighting the potential of phylogenetic approaches in predicting medicinal properties of plants (Pellicer et al., 2018). Besides, these findings allude to a potential evolutionary convergence within specific lineages, indicating a concerted development of these pharmacological traits. Our study also emphasizes the significance of phytochemical analysis in elucidating the therapeutic potential of Allium species. Compounds such as allicin, flavonoids, and phenolics have been identified as key bioactive constituents responsible for the observed antidiabetic and antioxidant activities (Najeebullah et al., 2021).