Volume 9, Issue 2 (2023)                   Pharm Biomed Res 2023, 9(2): 85-114 | Back to browse issues page

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Rahamouz-Haghighi S. Biological Activities and Analytical Methods for Detecting Aucubin and Catalpol Iridoid Glycosides in Plantago Species: A Review Study. Pharm Biomed Res 2023; 9 (2) :85-114
URL: http://pbr.mazums.ac.ir/article-1-493-en.html
Biological Activities and Analytical Methods for Detecting Aucubin and Catalpol Iridoid Glycosides in Plantago Species: A Review Study
Samaneh Rahamouz-Haghighi *
Department of Plant Production and Genetics, Faculty of Agriculture, University of Zanjan, Zanjan, Iran.
Keywords: Anti-cancer, Aucubin, Catalpol, Iridoid Glycoside, Isolation, Plantago spp
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Introduction
Iridoid was first isolated at the end of the 19th century. But, the principal structure of the iridoid was identified in 1958 by Halpern and Schmid. Then, several scientific studies were conducted on iridoids relating to agriculture, biosynthesis, botany, and medicinal uses. Up to now, hundreds of iridoids have been recognized in diverse sources [1]. Iridoids are categorized into iridoid glycosides, non-glycosidic iridoids or aglycone, bisiridoids, and secoiridoids groups [2]. Iridoid glycosides are monoterpenes in at least 57 plant families [3]. Their function in plants is mostly protection [4]. Iridoids can be found in the following families: Lamiaceae, Acanthaceae, Plantaginaceae, Gentianales, Cornales Scrophulariaceae, and Rubiaceae [5, 6, 7, 8]. Especially, aucubin and catalpol are found in plant subclasses of Asteridae, including Loganiaceae, Lamiaceae, Ericaceae, Gentianaceae, Verbenaceae, Rubiaceae, Oleaceae, Scrophulariaceae, Valerianaceae, Plantaginaceae, and Menyanthaceae [9].
Consequently, studies on Plantago species have just established growing attention owing to valuable components in these plants, such as aucubin and catalpol. So, the present study reviewed the cytotoxic properties and detection methods of aucubin and catalpol to create a comprehensive reference for utilizing these compounds. 
Aucubin and Catalpol Names
Aucubin is known with CAS: 479-98-1 and chemical formula: (2S,3R,4S,5S,6R)-2-[[(1S,4aR,5S,7aS-5-hydroxy-7-(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-1-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol [10].
Compound summary
Catalpol is introduced with CAS: 2415-24-9 and chemical formula: (2S,3R,4S,5S,6R)-2-{[(1aS,1bS,2S,5aR,6S,6aS)-6-Hydroxy-1a-(hydroxymethyl)-1a,1b,2,5a,6,6ahexahydrooxireno[20,30:4,5]cyclopenta[1,2-c]pyran-2-yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol [10].
Aucubin and catalpol are iridoid glycosides used in herbal medicine (Figure 1).

Biosynthesis of Aucubin and Catalpol 
Iridoids are a group of cyclopentanone monoterpenes found in plants as glycosides and regularly linked to glucose at C-1. The backbone of carbocyclic iridoids (Figure 2) is generally a cyclopentane unit attached to a dihydropyran ring.

On the other hand, secoiridoids are formed due to C-7/C-8 cleavage. These compounds have been classified as chemotaxonomic markers, and their presence provides evidence to explain many species whose taxonomic boundaries are unclear [11, 12].
 Iridoids are often found as glucosides, featuring a b-D-glucopyranosyl unit attached at C-l via a b-hemiacetalic bond (R = glucose) [13].
There are two main biosynthetic pathways for producing iridoids (Figure 3).

The first pathway makes compounds that generally originate in Gentianales and Cornales orders. In this pathway, deoxyloganic acid is synthesized, the precursor of many iridoids with 8β stereochemistry, such as secologanin and loganin. The latter is caused by the oxidative cleavage of the C-7/C-8 linkage of the cyclopentane ring. After an intricate synthesis including tryptamine, secologanin gives rise to indole alkaloids; vinblastine, vincristine, and reserpine, among others, are regularly discovered in the families Rubiaceae, Apocynaceae, and Loganiaceae, order Gentianales. Another group of iridoids is biosynthetically created by the second pathway. This pathway produces 8-epi-deoxyloganic acid, a precursor to iridoids with 8-a carbon substituent, and both C-4 carboxylated and C-4 decarboxylated carbocyclic iridoids, for example, ipolamiide and aucubin, respectively. These compounds are almost particularly established in families of Lamiales [14].
Rønsted et al. have revealed the biosynthesis of aucubin and catalpol, mainly in Plantago major (Figure 4) [15].

Distribution of Aucubin and Catalpol in the Plant Kingdom
Aucubin was first identified in Aucuba japonica in 1905. However, it is also found in many other natural plants such as Plantago asiatica L, Eucommia ulmoides Oliv., and Aucuba japonica Thunb [16]. Aucubin is the most common compound in the iridoid glycoside class [8]. Aucubin is also an intermediate of catalpol (Figure 3) [17]. Catalpol iridoid glucoside is broadly dispensed in many plant families and is mainly acquired from Rehmannia glutinosa Libosch root [18]. The selection for catalpol may have resulted in a reduction in aucubin concentration [19]. Aucubin and catalpol can be applied as potential chemotaxonomic markers to regulate the quality of different plant extracts, such as Plantago species [20].
Plantain is known to have two important aucubin and catalpol compounds [21]. Aucubin is present in almost all Plantago species, whereas catalpol or its derivatives have been reported in some species [22]. Iridoid glycoside concentration also changes with the plant’s developmental parts, age, genetic, and environmental factors such as weather, time of day, soil status, and arbuscular mycorrhizal fungi [3, 23-35]. Temperature, UV light, and soil nutrient conditions can alter the content of the secondary metabolites of plantain [36]. In some studies, the mean content of catalpol in the leaves of P. lanceolata was lower than the aucubin content [33, 37, 38 ], although, in one study, the opposite state was reported [3]. The contents of catalpol in P. lanceolata interrelated adversely with leaf age and the total number of leaves [35]. In Bowers and Stamp’s study, in genotypes of P. lanceolata, the amount of aucubin was more in intermediate leaves compared to mature leaves, while catalpol content was higher in intermediate and young leaves [25]. Increasing leaf age leads to an increase in aucubin content relative to total iridoid glycosides [25]. On the other hand, genotype significantly affects iridoid glycoside content, although an individual plant is quite heterogeneous in terms of iridoid glycoside content. New leaves have twice as many iridoid glycosides as mature leaves [25]. Lastly, Bowers and Stamp concluded that as leaves age, less catalpol is produced, breaks down faster, and translocation occurs in the leaf [25]. Lampert and Bowers indicated that aucubin is most in old leaves, while catalpol is high in young ones [39]. The amounts of aucubin and catalpol and the ratio of catalpol to total iridoid glycosides are impassioned by interactions between the time of harvest and leaf age [40]. The amounts of catalpol in new leaves increase between the harvests, although, in intermediate and mature leaves, harvest date showed no significant influence on catalpol content [40]. 
De Deyn et al. showed that among the full sibling families of P. lanceolata, plants contained high constitutive levels of defensive iridoid glycosides in leaves and roots. They reported that the concentration of aucubin was higher than that of catalpol and was found more in the root than in the shoot tissue [41]. The difference in constitutive iridoid glycoside values in P. lanceolata is genetically regulated to some extent [25, 26, 27, 32].
Furthermore, environmental and ontogeny strongly affect iridoid glycoside amounts in P. lanceolata. Seasonal changes probably affect the content of bioactive compounds in plantain leaves in different ways. Solar emission, nutrient disposal, and air temperature are major issues. Average levels differ among habitats and populations [36] and are mostly higher in plants grown under high light and low nutrient or water situations [28, 37]. Tamura reported that nitrogen source and low light intensity forcefully suppressed the accumulation of aucubin in plantain leaves but had no effect on catalpol concentration [36]. Tamura also explained that relatively high air temperatures (20°C/18°C, day/night) enhanced aucubin and catalpol contents. Therefore, plants grown under high temperatures can accumulate higher aucubin than those produced in low air temperatures (15°C/10°C, day/night) [36]. In total, Tamura and Nishibe assumed that the content of aucubin is more when the air temperature is optimal for growth [34].
Tamura and Nishibe investigated the effect of seasonal changes in the content of bioactive compounds in plantain leaves [34]. The amount of aucubin increased from late spring to midfall, but in midsummer, aucubin levels were relatively constant. In late fall, aucubin levels gradually decreased in Grasslands Lancelot (0.13% °C-1) and Ceres Tonic (0.20% °C-1), relative to the decline in air temperature from 14.7°C to 10.7°C. However, in midfall, when the temperature was still around 20°C, the levels of aucubin in both cultivars’ leaves were the highest. On other hand, catalpol content was very low relative to the contents of aucubin. The seasonal changes in the amount of catalpol were less visible than in aucubin, so the concentration of catalpol increased slightly during the growing season, but its amount was low in the middle of summer. The less clear-cut changes in catalpol can be due to the low base level of its synthesis, which does not respond to environmental changes. However, in Nieminen et al. study, catalpol contents were more than aucubin in mid- and late-summer [42].
Bowers et al. also studied seasonal variations in aucubin and catalpol amounts in plantain leaves [43]. Plants were harvested at 2-week intervals from late spring to early fall (4 times). They showed a significant increase in aucubin and catalpol content during the growing season, but the levels of the compounds decreased in plants harvested in mid-summer compared to those harvested on the other three sampling dates. Since the air temperature in midsummer was very high (around 25-30°C), this result agrees with the previous explanation [34]. Furthermore, P. lanceolata stores more catalpol when grown in soils conditioned by grass species [44].
It is usually presumed that medicinal plants, for their pharmacological uses, should be dried at less than 60°C to minimize the loss of bioactive compounds. Therefore, the concentration of bioactive compounds gradually degenerated in the early drying stages. The reason for the decay in the amounts of catalpol and aucubin could be the presence of enzymes in charge of their degradation. The degradation of iridoid glycosides is because of β-glucosidase action. The activities of these putative enzymes can be neutralized after about 3 and 24 h after the start of drying under natural climatic status and at 60°C, respectively since the compounds’ levels are fixed after these times [34]. Finally, it is suggested that midfall is the best time to harvest plantain for medicinal purposes because the amounts of the active compounds progressively decrease in the early stages of drying both under natural climatic conditions and at a temperature of 60°C [34].
Aucubin and Catalpol Content in Different Plant Parts and In Vitro Cultures
Plantain is applied in traditional medicines and for pasture. As that aucubin is a precursor in catalpol biosynthesis, several studies assessed the content of iridoid glycosides in plantain under different conditions, including the following studies. Aucubin is formed in plantain at very high levels, up to 3% of dry weight, depending on various aspects of the genotype, soil fertility, and so on [28, 32, 45]. The content of iridoid glycosides, including aucubin and catalpol, in a natural population of P. lanceolata, can attain even 9% of dry matter [3]. With increasing leaf age and dry summer conditions, the levels of these compounds increase. Also, cutting the surfaces in detached leaves can significantly increase them [25, 30, 46]. 
Another study reported that the level of aucubin and catalpol in seven Plantago species was up to 0.27% and 1.81% of dry leaf weight, respectively [47]. Furthermore, aucubin and catalpol production increased over time from 0.003% to 8.86% dry weight from seeing seedling pre-reproductive plants [48]. A significant interaction between plant age and tissue indicated differences in iridoid glycoside content between shoots and roots during plant growth. The results are presented in three cases. First, the average of iridoid glycosides was three times higher in the shoots compared to the roots. Second, the mean group differences in aucubin and catalpol among all 7 age classes were similar for the shoot and root tissues. Third, the concentration of aucubin in the shoot compared to the total iridoid glycosides caused more changes during plant ontogeny [48]. Pellissier et al. noted that total iridoid glycosides content, particularly for catalpol, was low (1%–7%) compared to Bowers et al., Stamp and Bowers, and Marak et al. studies [43, 46, 49, 50]. Remarkably, in the two works in which laboratory-reared plants were applied, catalpol contents were exceptionally low (0%–0.6%) [37, 38]. Consequently, Iridoid glycosides contents were lower in the greenhouse-grown plants (0.83±0.09 to 6.41±1.02 mg/g) than in field-grown plants (1.47±0.26% to 8.63±0.26%) [51]. The aucubin content in plants harvested from the field was more than 1.6%–2.7% in Bowers, 0.5%–5% in Darrow and Bowers, and 0.6%–2.2% in Nieminen et al. [3, 33, 42]. Catalpol concentrations were comparable in these studies 0.4%–3.6% in Bowers [3], 0.2%–2.2% in Darrow and Bowers [33], and 0.7%–2.0% in Nieminen et al. [42].
Generally, the aucubin amounts of leaves increased throughout the growing season, ranging from 0.5% to 4%-5% dry matter from July to September and October, respectively. Likewise, the catalpol content of leaves was calculated to be lower in July and increase throughout the season until October. However, it revealed that the catalpol content in the leaves was about half that of aucubin, ranging from about 0.25% dry matter to about 2.5% dry matter. In the reproductive stalks, the aucubin and catalpol levels tended to increase gradually during the early part of the season and decrease sharply between September and October. The total iridoid glycoside content in the reproductive stalks was slightly lower than in the leaves: 1%-5% and 1%-7%, respectively. While the leaves had higher levels of aucubin than catalpol, the reproductive tissues had more contents of catalpol than aucubin [33]. 
In another investigation, two cultivars of P. lanceolata L., i.e., Ceres Tonic and Grasslands Lancelot, were seeded in spring. The difference in aucubin and catalpol levels in the leaves during the growing season and by drying post-harvesting were quantitatively evaluated using high-performance liquid chromatography (HPLC). The content of catalpol was relatively low (between 1% and 2% of dry matter) throughout the growing season, and there was no obvious seasonal change. From spring to midfall, the aucubin content gradually increased from 1.0% to 2.7% in Ceres Tonic and from 2.1% to 4.8% in Grasslands Lancelot [34]. 
Navarrete et al. reported the level of catalpol and aucubin in plantain (cv. Ceres Tonic) during two successive growing seasons (2011–2012 and 2012–2013) [52]. There was almost no concentration of catalpol in plantain (cv. Ceres Tonic), but aucubin concentrations increased during the growing season. The content of aucubin increased from 1.78 to 3.80 mg/g dry matter in the first and from 0.44 to 6.87 mg/g dry matter in the second growing season. In late fall, aucubin amounts steadily decreased in Grasslands Lancelot and Ceres Tonic. In this regard, the content of aucubin and catalpol in different parts of Plantago species has been assessed by researchers with various methods (Table 1).






Aucubin and Catalpol Preparation for Analysis
Aucubin is soluble in water. However, it spontaneously undergoes oxidation and forms insoluble components in aqueous solutions. It is also soluble in methanol and ethanol but is insoluble in organic solvents, such as benzene, chloroform, ether, and petroleum ether [72]. Iridoid glycosides usually tend to be hydrolyzed and undergo rearrangement under slightly acidic conditions [73]. Therefore, they must be treated and analyzed under strictly alkaline conditions. However, some structures are more unstable and may hydrolyze even under alkaline conditions or upon heating [74]. As aucubin is extracted from plants, it is suggested that aucubin be prepared at a low temperature in a weak acidic condition and dark status to increase its output and stability [75]. In Nieminen et al. study, hot water extraction was applied to separate the compounds, which was reproducible and easy. As well, it avoided the application of organic solvents, which burden the environment [42].
As a result, the dry methanolic extract was dissolved in water and partitioned with ETAC (ethyl acetate); for aucubin, only the aqueous layer gave a positive result in the Trim-Hill test [70]. The test (blue color) indicates the presence of iridoid glycosides.
Various methods for the extraction of aucubin have been developed according to its different chemical and physical properties, including cold maceration and reflux extraction. Special enzymes and ultrasound techniques to destroy the plant cell wall have been recommended to increase the permeability of active substances through the cell wall. Extraction by ultrasonic and enzymolysis help isolate aucubin. Also, the microwave extraction method has been used to extract aucubin from Eucommia ulmoides. Li et al. investigated the efficiency of the supercritical CO2 and Soxhlet extraction methods for aucubin from Eucommia ulmoides Oliv seeds. The findings showed that supercritical CO2 extraction provides a higher yield and lower extraction cost [75]. 
Analytical Methods and Techniques for Determination of Aucubin and Catalpol 
Bioactive components are determined by expensive analytical methods that require chemicals, time, high competence, and know-how [76]. 
Commonly, iridoid glycosides (IG) are detected with chromatographic techniques, i.e., gas chromatography (GC), liquid chromatography (LC), or thin-layer chromatography (TLC) [42]. The IG contents (aucubin and catalpol) were analyzed by GC using previously described methods [26, 31, 37, 40, 77, 78, 79]. Some of the studies performed by GC analysis are listed in Table 2. 


Flash chromatography was applied to separate catalpol from aucubin [83]. However, the TLC method was the first option for isolating aucubin and catalpol from the plant extracts [84-86]. Taskova et al. [87] used TLC to investigate iridoids from 44 Bulgarian collections selected from 14 species of Plantago, of which 14 compounds were determined using spectral methods [47]. The aqueous fraction was found to be rich in iridoids by the TLC technique [88]. In this regard, several studies applied analytical methods of high-performance thin-layer chromatography (HPTLC) and TLC for detecting aucubin and catalpol, summarized in Table 3.


Derivatization with other compounds is necessary for the visualization of the spot. So, reagents were used for post-derivatization of aucubin and catalpol, such as 10% alcoholic H2SO4, which burns the glucose molecule in the aucubin giving colored spots, and 10% anisaldehyde which gives a colored spot for aucubin. These reagents are applied by dipping TLC plates in the reagent solutions or by spraying the solutions on the TLC plates [70]. An ethanolic acidic solution of vanillin (1 mL H2SO4 conc., 3 g vanillin, 100 mL EtOH) is used to visualize iridoid glycosides as colored spots.
Rønsted et al. identified the isolated compounds by nuclear magnetic resonance spectroscopy [15, 22]. Their findings showed that the distribution pattern of the iridoids in 34 species of Plantago has a good correlation with the classification of Rahn [89]. The qualitative studies of Plantago atrata, Plantago bellardii, Plantago coronopus, Plantago holosteum, and Plantago reniformis have been reported [15, 87]. In some studies, aucubin and catalpol have been isolated from the genus Plantago (Table 4). 








To quality control herbal samples containing iridoids, it is possible to quantify the levels of various iridoids in a mixed status by a simple method using liquid chromatography equipped with an ultraviolet detector (LC-UV) [60]. Usually, relatively large amounts of weak acids, such as phosphoric acid and acetic acid, are added to the mobile phase to prevent interference and stabilization of tautomeric rearrangements. In this way, a good separation of different iridoids can be achieved [114]. Kim et al. developed a simple LC-UV procedure to overcome such unfavorable interference by adding a small amount of trifluoroacetic acid (TFA) to the mobile phase with aqueous acetonitrile. They could simultaneously determine a small mixture of catalpol and aucubin in the aqueous extract of leaves, seeds, and roasted seeds of P. asiatica [60]. Aucubin and catalpol in the P. lanceolata extract were evaluated using liquid chromatography-mass spectrometry (LC-MS) [68, 70]. HPLC and HPTLC are frequently used to identify bioactive in samples in variety selection programs or to control new varieties [59, 115]. However, several methods can be applied to detect aucubin levels in Plantago extracts; the most common ones are HPLC [34, 116] and HPTLC [117, 118] methods. According to this, an attempt was also made for the quantitative analysis of aucubin in 7 Plantago species using HPLC and HPTLC by Janković et al. [62]. Other researchers also determined these compounds in Plantago species (Table 5).




One of the conditions of HPLC is the absorption spectrum. The absorption spectra of aucubin (220, 255, 290 nm) are used for detecting aucubin extracted from plants [124].
Capillary electrophoresis (CE) is a valuable tool for medicinal plant quality handling, screening, and analysis [65]. All main bioactive secondary metabolite groups can be assayed by one of the CE techniques; MEKC (capillary zone electrophoresis [CZE], Micellar electrokinetic chromatography [MEKC],  microemulsion electrokinetic chromatography [MEEKC], and nonaqueous CE [NACE]) [125]. The analysis of iridoids by the CE method has already been published [2, 126, 127]. CE methods detect metabolites such as iridoid glycosides in Plantago species [2]. 
The CE and micellar electrokinetic capillary chromatography (MECC) methods were also used for evaluating neutral compounds like aucubin and catalpol [47, 128]. CE method has been confirmed to be suitable for the quantitative determination of aucubin and catalpol from aqueous extracts of leaf parts of P. lanceolata, P. major, P. asiatica, and P. lanceolata callus [65]. The content of aucubin and catalpol in P. lanceolata was reliably and quickly determined by MECC [42]. 
Micellar electrokinetic chromatography (MEKC) was used to isolate and analyze aucubin and catalpol in hot water extraction of several Plantago species growing in Croatia: P. altissima L., P. argentea Chaix, P. coronopus L., P. holosteum Scop. (subsp. depauperata, subsp. holosteum and subsp. scopulorum), P. lagopus L., P. lanceolata L., and P. maritima L. Significant differences were exhibited between the iridoid contents in mentioned species using this method [47]. 
An authentic and simple CE-MEKC method has been validated and developed to quantitatively determine aucubin and catalpol of Plantago species, P. lanceolata calli, P. lanceolata matrices, P. altissima, P. major, P. media, and P. maritima [61]. However, TLC pattern analysis could recognize the species mentioned above in a single run in a system commonly applied for the quality management of P. lanceolata leaves. However, P. altissima and P. lanceolata did not represent enough pattern difference to be fully isolated [61]. Consequently, according to iridoid content, P. altissima was chemically indistinguishable from P. lanceolata [61]. 
Also, Gonda et al. evaluated the changes in aucubin and catalpol concentration in dry leaves of P. lanceolata subjected to the atmosphere with different relative humidity (0%, 45%, and 75%) by CE‐MEKC for 24 weeks [115]. CE-MEKC method showed that it is suitable for aqueous extracts of P. lanceolata, P. major, P. asiatica leaves, and P. lanceolata callus culture [65]. 
In another study, aucubin from P. lanceolata was separated and quantified by preparative TLC and then determined by HPTLC fingerprinting. Aucubin that was isolated from the plant material was analyzed by Fourier-transform infrared spectroscopy (FTIR) and LC-MS, respectively [70]. Each TLC-isolated compound exhibited a single spot on the HPTLC plate, which confirms an idea about the purity of the isolated compound. Aucubin accompanied by catalpol were determined using LC-MS in different ionization mode. In continuing, many functional groups were recognized in the TLC-isolated aucubin by FTIR [70]. Nevertheless, aucubin and catalpol in Plantago can be quantified by other different methods such as LC-ESI-MS (liquid chromatography-electrospray ionization tandem-mass spectrometry) [62], MPLC [88], LC-TOF-MS (liquid chromatography-time of flight-mass spectrometry) [80], and uHPLC–TOF-MS (ultra-high performance liquid chromatography combined with time-of-flight mass spectrometry) [35]. Various selection programs require rapid and low-cost methods to analyze bioactive components in thousands of samples. FTNIR (Fourier transform near-infrared spectroscopy) supported using chemometric analysis could be a tool to reduce time and costs. A suitable method has been developed to quantify bioactive compounds in plant species [129, 130].
Understanding the mechanism of measuring tools can help us choose the correct and accurate method for measuring compounds (Table 6).


Techniques for determining aucubin and catalpol in pharmacokinetic studies
Although this study has been performed on the methods of determining aucubin and catalpol in Plantago species, mentioning some methods for detecting these compounds in pharmacokinetics can also be useful. 
A fast and accurate LC-electro spray ionization (ESI)-MS/MS method has been developed and validated to quantify catalpol in rat plasma [133]. Another group of researchers also validated LC-MS/MS method. However, APCI (atmospheric pressure chemical ionization) was replaced by ESI for the determination of catalpol (m/z of 380/165) in rat plasma and cerebrospinal fluid (CSF) [134]. Therefore, LC-MS/MS was validated as a rapid, sensitive, accurate, and robust method and applied for quantifying aucubin, a main bioactive component of P. asiatica, in rat plasma [135, 136]. On the other hand, Xue et al. introduced the LC-ESI-MS/MS method for simultaneously determining aucubin and catalpol in rat plasma [137]. Zhang et al. created a specific and sensitive high-performance liquid chromatography coupled with a tandem mass spectrometric (HPLC-MS/MS) method. The method was developed to simultaneously determine geniposidic acid and aucubin in rat plasma after oral administration of Du-Zhong tea extract [138]. In this regard, the simultaneous determination of catalpol, morroniside, loganin, and acteoside in the plasma of normal and chronic kidney disease rats by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) was developed to investigate the combined medicinal extract of R. glutinosa and Cornus officinalis Sieb [139]. Hu et al. presented a selective, sensitive, and efficient ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneously determining 5 active substances, including aucubin in male and female rat plasma after oral administration with Eucommiae cortex extract [140]. Lian et al. developed a novel method for aucubin determination in rat serum with type 1 diabetes using UPLC-MS/MS with supramolecular solvent (SUPRAS)-based on dispersive liquid-liquid microextraction. In general, regarding instrumental analysis, UPLC-MS combines the resolution capability of chromatography with the benefits of speed, specificity, and sensitivity acquired by mass spectrometry (MS). The analytical community has widely admitted this hyphenated technique as a common tool in pharmacokinetic studies [141]. The UHPLC-MS/MS method for aucubin determination exhibited low limits of quantification, good linearity, high extraction recoveries, acceptable accuracy, precision, and stability, in plasma and tissue samples of mice [142].
Biological Activities of Iridoid Glycosides 
Iridoids, including secoiridoids, glucosides, esters, and aglycones derivatives, have been reported for medicinal applications [143]. Iridoids are classified as dietary supplements, medicinal foods, and drugs. Iridoids or iridoid-rich plants have established the following biological activities in vitro, in vivo, and clinical research [143]. Iridoids act as a defense for specified plant species and cause various medicinal effects in animals [144]. A large number of iridoids isolated from plants used in traditional medicine have shown various biological activities, thus validating their popular use all over the world. A broad range of biological activities has been reported for iridoids which include anti-diabetic, anti-cancer, anti-inflammatory, anti-microbial, anti-bacterial, anti-oxidant, anti-spasmodic, hepatoprotective, hypolipidemic, hypoglycemic, cardioprotective, choleretic, neuroprotective, purgative, molluscicidal, immunomodulatory, stimulation of bile acid excretion, hepatic dysfunction, anti-tumor, antidotal activities for noxious Amanita mushroom poisoning and anti-viral effects against hepatitis B virus [18, 145-153]. Besides, some iridoids have exhibited anti-protozoal effects against Plasmodium spp. [154, 155], Trypanosoma spp. [156], and Leishmania spp. Indeed, the anti-leishmania activity of iridoids has drawn the scientific community’s attention for decades [157, 158].
Pharmaceutical properties of aucubin and catalpol 
Most iridoids, including aucubin and catalpol, have been reported to exhibit significant medicinal properties, such as anti-inflammatory [159], anti-cancer and anti-bacterial activities in vitro and in vivo assay systems. The allure of aucubin and catalpol as cosmetic ingredients in hydrogel formulations was obvious, especially when iridoid glycosides were used as lipid nanoparticles [10]. However, several properties have been reported for the compounds aucubin and catalpol, and understanding the mechanism of action of many of these properties requires more extensive studies.
The study on aucubin confirmed that it possesses extensive pharmacological effects, including anti-aging, anti-bacterial (Table 7), anti-cancer, anti-fibrotic, anti-oxidant, anti-osteoporosis, anti-toxic, neurotrophic, neuroprotective, hepatoprotective, osteoprotective, anti-inflammatory properties as like suppressing the inflammatory act produced by the injection of carrageenan, and healing of skin wounds as like local treatment of oral wounds [152, 160-162].


Aucubin established a significant protective effect against ramanitin intoxication in mice [167]. Aucubin also stimulates the elimination of uric acid from tissues to the blood and the repulsion of uric acid from the kidneys [168]. Aucubin acts as a particular inhibitor of NF-kB (nuclear factor NF-kappa B) in mast cells, which may effectively remedy chronic allergic conditions [169]. 
Aucubin, and to a greater extent catalpol, are deterrents or toxic to generalists [3, 170]. These compounds apply as oviposition and feeding stimulants for some specialist herbivores [43, 58, 171, 172]. 
Catalpol has been assessed widely for its biological properties in vitro and in vivo [18]. Although catalpol is more toxic to generalist herbivores than aucubin [3, 43, 170, 173], the research on its properties has shown various pharmacological effects, including sedative, anti-inflammatory, analgesic, anti-tumor, liver protective, anti-microbial (Table 7), purgative, anti-apoptosis actions, and anti-catarrhal for the upper and lower respiratory tract [174-176]. In addition to the listed activities, catalpol has been confirmed as a significant neuroprotective agent against experimental Alzheimer and Parkinson diseases. Catalpol has shown a potential glucose-lowering activity in experimental type 1 and type 2 diabetes mellitus. These activities may be due to improved glucose use in insulin-sensitive tissues and cured mitochondrial biogenesis/function. In addition, catalpol has shown potentially beneficial results in experimental diabetic complications. The significant protective effect of catalpol on cardiovascular was also confirmed. However, in experimental models, catalpol was effective against asthma, hepatotoxicity, and ovarian failure [18].
Anti-cancer properties of aucubin and catalpol
The researchers reported that aucubin inhibited the proliferation of A549 human non-small lung cancer cells by upregulating the expression of p21 and p53 proteins to prevent cell cycle progression in the G0/G1 phase. However, hydrolyzed aucubin showed better anti-leukemia activity than aucubin [177]. Catalpol significantly affected various cancer models, including lung, breast, stomach, and colorectal cancers. One placebo-controlled clinical study confirmed the effect of catalpol on colorectal cancer, which seems to have an anti-cancer impact due to the reduction of inflammation, apoptosis, angiogenesis, and cell cycle arrest [18].
The researchers’ findings show that aucubin and catalpol are known as potential cancer treatments due to their ability to prevent cancer progression and metastasis and induce the death of cancer cells. Therefore, in the present study, some of the properties of these compounds were briefly described. However, anti-cancer properties have been reported in detail (Table 8).




Conclusion
The iridoid patterns exhibited a significant correlation with morphological and other chemical specifications of the representatives of the genus Plantago. Aucubin has extensively been detected in wild plants and especially in P. asiatica. It was reported that aucubin has only been extracted from plants. However, pure products can barely be obtained due to the unstable structure of aucubin. In some studies on Plantago species, aucubin was also found to be more frequently exist compared to catalpol, which could be related to the fact that aucubin is a biosynthetic precursor of catalpol. However, the catalpol value was also observed to be more compared to aucubin content in some Plantago species (P. lanceolata, P. altissima, P. lagopus, and P. argentea) where both iridoids were existence. As a result, leaf age, plant genotype, seasonal changes, and environmental factors affected these variables and influenced the iridoid glycoside concentrations.
The iridoid glycosides, i.e., aucubin and catalpol, are active components with wide pharmacological activities. These compounds have anti-microbial, anti-oxidative, anti-inflammatory, and anti-fungal properties. Therefore, aucubin and catalpol are compounds with abundant sources, good safety, and various biological effects, which demonstrate high value in pharmaceuticals and deserve further research and development.
Aucubin and catalpol have been identified as biologically active in the Plantago species. Furthermore, aucubin and catalpol play many important roles in the medicinal effects of Plantago species, including their hepatoprotective, spasmolytic, collagen synthesis promoting effects, pancreas-protective, neuroprotective, anti-atherogenic, and anti-arthritic. These results suggest Plantago species and their metabolites may apply to human health beyond their traditional uses. 

Ethical Considerations
Compliance with ethical guidelines
There were no ethical considerations to be considered in this research.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors.

Acknowledgments
The author is thankful to the Zanjan University of Medical Sciences and University of Zanjan.


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Type of Study: Review article | Subject: Phyochemistry
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