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REVIEW ARTICLE
Year : 2022 | Volume
: 8
| Issue : 3 | Page : 350-385
Plants' steroidal saponins - A review on its pharmacology properties and analytical techniques
Sudha Porte1, Veenu Joshi1, Kamal Shah2, Nagendra Singh Chauhan3
1 Center for Basic Sciences, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India
2 Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
3 Drugs Testing Laboratory, Avam Anusandhan Kendra, Raipur, Chhattisgarh, India
Correspondence Address:
Dr. Nagendra Singh Chauhan
Drugs Testing Laboratory Avam Anusandhan Kendra, Raipur (CG)
India
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2311-8571.353503
The plant is a rich repository of useful secondary metabolites with profound medicinal potential. Saponins, one type of bioactive compound, are amphitheatric glycosides with one and more hydrophilic sugar and hydrophobic steroidal and terpenoid part. The former is known as steroidal saponin, and the latter is called terpenoid saponins. Steroidal saponin is mostly distributed among monocotyledon families such as Asparagaceae, Amaryllidaceae, Dioscoreaceae, Smilacaceae, and Liliaceae. Even though it is unusual, it could also be detected to some extent by dicotyledonous angiosperms, such as Plantaginaceae, Zygophyllaceae, Fabaceae, Asteraceae, and Solanaceae. It exhibits diverse pharmacological ability including antimicrobic, anti-inflammatory, cAMP phosphodiesterase inhibitory, antiadipogenic, bactericide, cardioprotective, antitumor, antidiabetic, cytotoxic activity, antifungal, antiviral, antioxidant, and hepatoprotective. Steroidal saponin timosaponin AIII from Anemarrhena asphodeloides has been found to possess antitumor activity. Diosgenin, another steroidal sapogenin, has the potential of preventing neurological diseases by affecting different signaling pathways, increasing bone formation, and increasing antithrombotic activity. Spicatoside A from Liriope platyphylla possesses anti-inflammatory, antiasthma, and antiosteoclastogenic activities. TTB2 from Trillium tschonoskii exhibits anticancer potential. The cell cycle arrest and ROS-dependent autophagy are induced by polyphyllin I. These diverse biological activities of steroidal saponins are attributed to the variability of their structural features. Analysis of steroidal saponins in plant materials mainly utilizes classically and advances thin layer chromatography (TLC) on normal and reverses-phase (high-performance thin-layer chromatography, densitometric TLC), gas chromatography, LC, UPLC, ultra-high-performance liquid chromatography (HPLC), supercritical fluid chromatography, and HPLC coupled to ultraviolet detector and diode array detector. HPLC coupled with MS and Nuclear magnetic resonance is used for online identification of separated saponins. The present review aims to furnish a comprehensive account of the recent advances in analytical methods of determination and medicinal applications of steroidal saponins.
Keywords: Steroidal, Saponins, Glycosides, Antitumour, Antioxidant, Analytical techniques
Since bioactive compounds occurring in the herbal plant are popular as traditional medicine for different diseases. Currently using phytochemicals are treated to be secure and friendly for the human body. Phytochemicals are bioactive compounds naturally occurring which act as medicine and nutrient for the benefits of the human health.[1] Plants are a versatile source of different organic chemicals or phytochemicals. They comprised two groups in respect of their activity in plants as primary and secondary metabolites. The metabolites that are required to complete plant basic metabolic processes are known as primary metabolites, such as fats, carbohydrates, proteins, nucleic acid, and chlorophyll. They found throughout the plant kingdom. They are produced in large quantities and can easily extract. Secondary metabolites are not involved in primary metabolic processes but play a role to protect against abiotic and biotic stresses and ensure their existence in the environment. They usually produced in minor concentration and extraction often difficult and expensive.[2] Some examples are alkaloids, phenolics, terpenes, saponins, flavonoids, glucosides, lignans, curcumins, and plant steroids.[3],[4]
Saponins are a class of naturally occurring bioorganic compounds having steroids and terpenoids of glycosides with distinctive foaming characteristics. The name gets from the Soapwort plant (Saponaria), historically its roots were used as soap.[5] Hydrolysis of saponin gives a fat-soluble (hydrophobic) sapogenin and water-soluble (hydrophilic) sugar part which complement the foaming capability of saponins.[6],[7] Based on the category of sapogenin, saponins split into three major kinds:
Steroid glycosidesTriterpenoid glycosidesAlkaloid glycosides.[8]Many pieces of literature show that saponins are an important class of bioactive compound which possess medicinal properties. In the pharmaceutical industry, they are the substrate of many drugs. Numerous scientists' attention is seeking by steroidal saponins, a type of saponins. The various papers reported its wide spectrum pharmaceutical properties such as antimicrobic, anti-inflammatory, cAMP phosphodiesterase inhibitory, antiadipogenic, bactericide, and cardioprotective.[9],[10],[11],[12],[13],[14] The various medicinal research and its results show the increasing interest in steroidal saponins which will act as bionatural compound. In this review, we briefly account for (1) the chemistry of steroidal saponins, (2) plant sources of saponins, (3) synthesis of steroidal saponins, (4) various pharmaceuticals properties, and finally, (5) different analytical techniques.
Chemistry of Steroidal SaponinsStructurally steroid glycosides or steroidal saponins are modified terpenoids that contain an aglycone and a glycone part with tetracyclic six-membered rings and bicyclic five-membered rings containing 27 carbon atoms [Figure 1].[15] Usually, aglycone part of it contains a furostanol or a spirostanol. Mostly, the glycone parts are oligosaccharides, organized moreover in a branched or linear form, linked to hydroxyl groups via a (2, 3) acetal linkage.[16] The glycone residue of steroidal glycosides made up of one to three sugar chains either linear or branched, which contain usually β-D-galactopyranosyl (Gal), β-D-mannopyranosyl (Man), α-L-rhamnopyranosyl (Rha), β-D-quinovopyranosyl (Qui), β-L-arabinofuranosyl (Ara), β-D-glucopyranosyl (Glc), β-D-xylopyranosyl (Xyl), or β-D-fucopyranosyl (Fuc) residues [Figure 2].[18]
Steroidal saponins could be grouped into three distinct classes according to their aglycone group. They could be categorized into three distinctive groups: a spirostane, a cholestane (open chain), and a furostane compound.[20][Table 1].[22]
Occurrence and Distribution of Steroidal SaponinsSteroidal saponins are synthesized and accumulated by various plant families. They are typically distributed in members of Asparagaceae (Yucca, Agave, Tupistra, Anemarrhena, Sansevieria, Asparagus, Polygonatum, Nolina, Convallaria, Ophipogon, Hosta, Ornithogalum, Ruscus), Amaryllidaceae (Allium and Agapanthus), Dioscoreaceae (Dioscorea), Smilacaceae (Smilax), Fritillaria, Lilium (Liliaceae), Costaceae (Costus), and Melanthiaceae (Paris). Even though it is unusual, steroidal glycosides could also be detected to some extent of dicotyledonous angiosperms, such as Plantaginaceae (Digitalis), Zygophyllaceae (Tribulus, Zygophyllum), Fabaceae (Trigonella), Asteraceae (Vernonia), and Capsicum, Lycopersicon, Solanum (Solanaceae).[14],[19],[23],[24],[25],[26]
Besides plants, some animals also act as a source of it. They have been spotted in marine sponges and starfish.[27],[28],[29]
Biosynthesis of Steroidal SaponinPlants represent the primary producer of steroidal saponins, the majority of monocotyledonous species. Steroidal saponin produces two portions, glycone and aglycone parts during hydrolysis. The aglycone backbone is derived from 2,3 oxidosqualene, a linear precursor of 30C molecules. The synthesis of the committed precursor of steroidal saponins releases three methyl groups to form a 27C aglycone backbone.[30],[31]
The steroidal saponin aglycone backbone is an isopentenyl pyrophosphate (IPP) which is synthesized from acetyl-CoA via a mevalonic acid pathway and MEP (2-C methyl-D-erythritol 4-phosphate) pathway, in cytoplasm and plastids, respectively. The acetyl CoA converted to IPP (5C), which then isomerized to form allylic isomer dimethylallyl pyrophosphate (DMAPP) in the presence of enzyme, isopentnyldisphosphate isomerase. Then, subsequent condensation of two units of IPP and one unit of DMAPP from farmesyl pyrophosphate (FPP) catalyzed by farnesyl pyrophosphate synthetase, the intermediate precursor of finally two FPP unit, forms linear squalane (30C) by condensation reaction catalyzed by SQS (Squalane synthase), which further epoxidized by enzyme squalene epoxidase (SQE) to form 2,3 oxidosqualane. It further cyclized to form cycloartenol, catalyzed by cycloartenol synthase (CAS). The cycloartenol generated a mixture of phytosterols including cholesterol (27C), campesterol (28C), and sitosterol (29C). The series of glycosylation and oxygenation of cholesterol base to furostanol or spirosanol derivative with fused O-heterocycle in formerly core aglycone framework to form steroidal synthesis.[30],[31],[32],[33]
Pharmacological Properties of Steroidal Saponins
Table 2: List of plant species, isolated compounds, extraction methods, therapeutic uses with the mode of action, and parts used in pharmaceutical propertiesCytotoxic property
The cytotoxic action is performed by most of the steroidal saponins via triggering apoptosis stimulation. It also stimulates oncosis, autophagy, and repression of metastatic characteristics of the examined cells, phagocytosis, or vascularization.[18] For example, a steroidal saponin isolated from Paris polyphylla stimulates apoptosis and autophagy via activating caspase 8 and 3, upregulation of Beclin1, and PARP cleavage for the former.[34] It performs cytotoxic activity through mitochondrial caspase-independent and dependent pathway, PI3K/Akt signaling, or cyclin-dependent kinase 1.[35] The commonly known glycoside–dioscin triggered both intrinsic (activation of Bak and Bid proteins and loss of mitochondrial membrane potential) and extrinsic (modulation of death ligands and receptors) apoptosis pathways which is a rare proapoptotic activity mechanism. In addition, the promyelocytes differentiate into granulocytes and monocytes induced by this compound.[18],[36]
Anti-inflammatory activity
Inflammation is the response of the host to stimuli which takes place due to the pro-inflammatory cytokines such as IL1-β, TNF-α, and IL-6 produced by immune cells, recruited to wound sites. The significant anti-inflammatory activity observes due to inhibition of the inflammation mediators. The steroidal saponin diosgenin inhibits some of the inflammatory mediators derived from macrophage.[37]
Antidiabetic activity
Diabetes mellitus is one of the major concerns for a universal health issue that is distinguished by hyperglycemia that generates oxidative stress which leads to free radicals' production.[38] It leads to various complications; for instance, peripheral vascular disease, neuropathy, and retinopathy are some examples of complications resulting from diabetes.[39] Saponins use various mechanisms for lowering blood glucose level such as activation of glycogen synthesis, suppression of the activity of disaccharides, modulation of insulin signaling, regeneration of insulin action, and suppression of gluconeogenesis. For example, diosgenin displays antidiabetic effects by the mitigation of insulin resistance and hyperglycemia.[40] Gestational diabetes is also prevented by diosgenin via targeting sterol regulatory binding protein 1.[41] It prevents high glucose-induced renal tubular fibrosis.[42]
Antitumor activity
Steroidal saponin has shown antitumor activities against different kind of tumors, such as mammary carcinoma, esophageal cancer, cervix cancer, colon cancer, leukemia, gastric carcinoma, prostate cancer, lung cancer, ovarian cancer, and glioblastoma. The listed target tissues were mentioned in the review on saponins in 2016.[43] For example, dioscin steroidal saponin shows antitumor effects through activating intrinsic mitochondrial apoptosis by involving activation of caspase 9 and caspase 3 and decreasing levels of antiapoptotic proteins such as Bcl-xl, Bcl-2, McI-1, and clAP-1.[44],[45],[46] Steroidal saponins encounter antitumor activity via activating different signaling pathways and mechanisms. For example, PI3K/Akt/mTOR and p38 MAPK and JNK signaling pathways and numerous proteins, enzymes, and factors involved in antitumor activities of dioscin.[47]
Hepatoprotective property
The major organ in human for detoxification and assimilation is liver, which often faces numerous stresses that lead multiple pathogeneses. These pathological changes can exhibit cholestasis, fatty liver disease, fibrosis, and injuries. Steroidal saponin, for example, dioscin, involves different mechanisms to protect hepatocytes. It inhibits necrosis, apoptosis, inflammation, necrosis, and oxidative stress to attenuate acute liver injury caused by CCl4 and DMN.[48],[49]
Antifungal
Various steroidal saponins have shown various antifungal activities. Generally, spirostanol skeleton steroidal saponin has shown high levels of antifungal activity than furostanol.[50] Distinct biochemical changes were observed during antifungal activity. For example, dioscin could be effective to show antifungal activity via inducing plasma membrane damage of Candida albicans,[51] cell membrane disruptive activity,[52] effective against C. albicans biofilms,[53],[54] generated excessive ROS, and increased membrane permeability in Saprolegnia parasitica.[47],[55]Allium minutiflorum produced a compound minutosides A–C which showed antifungal activity based on the concentration-dependent manner on listed fungus: Fusarium oxysporum, Alternaria alternata, Fusarium solani, T. harzianum T39, Alternaria porri, Botrytis cinerea, Trichoderma harzianum P1, Pythium ultimum, and Rhizoctonia solani.[17],[19]
Antibacterial
Mohammed (2009) studied that the antibacterial activity of saponin extracted from Tribulus terrestris against the microorganisms examined showed inhibiting effect on both types of Gram bacteria, which show the broad-spectrum antibiotic presence or simply metabolic toxin produced by the plant. Saponins contribute to antibacterial activity maybe via membrane lysis, rather than changing the surface tension of the extracellular fluid, hence being affected by microbial population density.[57]
Cardioprotective
During the treatment of different organs, many drugs produce toxicity for the heart. Some steroidal saponins contribute to protecting the heart, such as diosgenin increased efflux of cholesterol and repressed aortic atherosclerosis.[58] It also contributes cardioprotective role via regulating the opening of potassium channels.[59] The combination of morroniside and diosgenin also plays a role in the prevention of myocardial injury induced by high glucose.[60],[61] In addition, dioscin plays a role to suppress an angiotensin II infusion which induces cardiac hypertrophy via downregulating the MAPK and Akt/GSK3 β/mTOR pathways, which contribute to improving the impaired function of the cardiac.[62]
Antioxidant
Oxidative reactive species or oxidative stress acts as sources of many pathogenesis diseases. Steroidal saponin also acts as an antioxidant. For example, the aqueous extract of Asparagus racemosus root exhibits antistress activity in a mouse by inhibiting the effect of inflammatory cytokines mainly interleukin and tumor necrosis factor.[63]
Antihypertensive property
The T. terrestris possesses antihypertensive activity.[64] The Tribulus extracts possess diuretic properties and enhance nitric oxide release from nerve endings and endothelium; it relaxes smooth muscles and enhances inhibition of the angiotensin-converting enzyme. Thus, it reduces hypertension.[65],[66] However, the mechanism responsible for the antihypertensive activity is still not fully understood.
Other activities
Steroidal saponin also plays a role to control other activities such as antihyperuricemia,[47],[69],[70] antiviral,[47],[61] antifungal,[15],[16],[47] antitumor,[18],[31],[47],[61] lung protective,[47],[61],[74] nephroprotective,[47],[63] cerebral protection,[47] antiatherosclerosis,[47],[67] antiarthritic,[47] antiobesity and diabetes,[47],[61],[67] and antiosteoporosis.[47] In addition, they have been reported to improve sperm motility.[6]
Different Cell LinesHuman cancer cell lines - 3T3, cervical: HeLa, Caski; prostate cell: PC; liver: Hep-G2, SMMC-7721, Hep3B; gastric cell: SGC7901, SGC-7902, AGS cell, BGC-823, HGC-27; breast: BT549, MDA-MB-231, MCF7, MDA-MB-435; colon: SW480, HT-29, Caco-2, HCT 116; leukemia: HL-60, Jurkat, K562; stomach: SGC-7901, BGC-823, MGC-803; lung: A549, 95D, LU-1, NCI-H460; adenocarcinoma: MKN-7, SPCA-1 cell; glioblastoma: U87MG, U251; melanoma: A375, SK-MEL-2; ovary: SK-OV-3Human normal cell lines - Kidney embryonic: HEK293; fibroblastsAnimal normal cell lines - Cardiomyoblasts: H9c2; embryonic fibroblast: 3T3. Test for the Presence of Saponin Foam test
About 12.5 mg standard Quil-A® saponin (≥95% purity, InvivoGen, USA) and the test samples each were taken in 250 ml measuring cylinders, separately in triplicate. Then, distilled water (87.5 ml) was added to all the measuring cylinders. After that, the measuring cylinders were shaken vigorously about 30 times by closing the mouth of a cylinder with a stopper. After shaking, the stopper was removed and the mouth of the cylinder was covered with aluminum foil. Three observations were recorded, immediately after shaking, after 30 min, and after overnight standing.[147]
Analytical TechniquesPlant extract consists of a mixture of the different bioactive compounds with distinct polarities, their partition, and characterization being a still big challenge. However, the initial steps to take advantage of the bioactive compound of plant resources are eradication, pharmaceutical screening, isolation and characterization of the active biological compound, toxicology screen, and clinical study. The primary two steps, extraction and identification are described as tedious processes of saponin from the plant material. The saponin extraction includes conventional and green technologies. The Soxhlet and reflux extraction, Maceration extraction, and subsequent extraction are the examples of conventional techniques whereas ultrasound-assisted extraction, accelerated solvent extraction, and microwave-assisted extraction are the green technologies.[7],[15] Analytical methods such as high-performance thin-layer chromatography (HPTLC), high-performance liquid chromatography (HPLC), TLC, gas chromatography (GC), ultra-HPLC (UHPLC) associated with detectors such as tandem ultraviolet (UV) detector, evaporative light scattering detector, and diode array detector.[148] UHPLC, supercritical fluid chromatography (SFC), ultra-high-performance supercritical fluid chromatography (UHPSFC), and some different spectroscopy techniques such as nuclear magnetic resonance (NMR) and X-ray diffraction. A summary of the general techniques used for extraction and identification of steroidal saponins obtained from different plant extracts is presented in [Table 3].
Thin liquid chromatography
TLC is a user-friendly, quick, and cheap technique that helps in the separation of various compounds from the mixture. It is used for the separation, identification, and characterization of steroidal saponin.[15],[149] The identification of constitutes in the mixture was done by comparing Rf values of compound and known compound. In addition, some techniques involve TLC plate with one mobile and one stationary phase for confirming the identification and purity of the isolated compounds via involving phytochemical screening spray, which leads to color changes according to existing phytochemicals or observes under the UV light.
High-performance liquid chromatography
The HPLC technique is predominately used for analysis of saponin. In HPLC, the separation of chemicals is achieved by utilizing the fact that each component has different interaction properties, which is responsible for different rates of migration within the particularly given column. Generally, using a single unchanging mobile phase system is accomplished with separation and identification of phytochemicals. As per requirements, the different proportions of the organic solvent to water are used for gradient elution purposes. Diode array detector, UV detector, and evaporative light scattering detector (ELSD) are used for the identification of compound.[149]
High-performance liquid chromatography with evaporative light scattering detector
ELSD is an aerosol-based detector used to facilitate HPLC. It is used for the identification of nonvolatile sample components in volatile elute. The key advantage: it is used for the analysis of sugar. This technique used for the identification of steroidal saponin of Yucca schidigera is reported in Tenon.[150]
High-performance liquid chromatography/mass spectroscopy
It is used for the separation and mass evaluation of a given compound. It could be used for accurate molecular formula determination. Using HPLC/mass spectroscopy (MS), 19 compounds are discovered from the crude elicit of Y. schidigera.[151]
High-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectroscopy/mass spectroscopy
It is a suitable and reliable method used to separate and identify steroidal saponins from plant extracts.
Gas chromatography/mass spectrometry
It is an analytical technique used for separation and molecular weight detection. In GC, the mobile phase is gas, and components are separated in the vapor form. Thus, MS detects the molecular weight of small fragment compounds in the gas phase. To better characterize the purified YSS, GC/MS was used.[150]
Column chromatography
Column chromatography is a widely used technique of separation purpose based on their polarity or hydrophobicity.
Spectroscopy method
Nuclear magnetic resonance spectroscopy
The NMR spectroscopic methods are widely used to determine chemical and physical properties. It is used to deduce the complete structure of steroidal saponins containing the oligosaccharide moiety and its linkage to the sapogenin residue. The two-dimensional (2D) NMR is reported to elucidating the structure of isolated compounds from Allium fistulosum. The pyridine-d5 solution at 500 and 125 MHz is used for getting spectra in the 13C and 1H NMR, respectively, which are used for the study of the A. fistulosum.[152] The spectroscopic methods including 1D and 2D NMR were used for the study of Yucca filamentosa L. Panicum turgidum.[153]
Infrared spectroscopy
Infrared (IR) spectroscopy is a simple and reliable technique used for the detection of the functional groups present in the compound. This technique also play role in the identification of steroidal saponins.
Near-infrared reflectance spectroscopy
Near-IR reflectance spectroscopy is an analytical technique used to quickly determine the compound chemical and physical properties without altering the sample. It is used to determine the ginsenoside Rg1 and Re found in Chinese medicine.[154]
Ultraviolet spectroscopy
It is widely used for the quantitative analysis of different analytes. In this techniques, analyte can be gases and solid.
Polarimeter
A polarimeter is a device for determining the polarization direction of the light or the rotation of an optically active substance. The JASCO DIP-1000 digital polarimeter was used to deduce optical rotation.[152]
Matrix-assisted laser desorption ionization-time of flight mass spectrometry
Matrix-assisted laser desorption ionization-time of flight MS is a widely used technique for analysis purposes. This instrument has a wide range of analytes including oligonucleotides, and proteins.
Gravimetry
One of the first methods that were developed decades ago for measurements of saponin is the Gravimetry method (Hahrbone, 1973). It is based on the saponin's specificity for n-butanol. However, this technique is not suitable for extraction due to its poor specificity and could not visible in the chromatogram. Most important is requires a large amount of petrol-derived organic solvent in each sample which is why it is not considered ecofriendly
Ultra-high-performance liquid chromatography
It is chiefly used to separate components of the sample in lesser time with better resolution. It requires a small volume of samples for analysis. The analysis of the MD sample is well suited to it.
Ultra-high-performance supercritical fluid chromatography
It likely performed speedily and automatically. It is worthwhile for the spirostanol saponins separation that varies in sugar chains and shares the same aglycone. It is easily affected by the position and the number of hydroxyl groups in aglycones. It is a powerful technique with better resolution.
Supercritical fluid chromatography
It could be fruitful to separates the furostanol saponins which shared a portion of the same aglycone through the difference in sugar chains. It was the sensitized type of sugars and their number. It could be useful for separating hydrophilic furostanol saponins.
ConclusionSteroidal saponins are made up of glycosides groups that contain lipophilic components and lipophobic components which are broadly dispersed among monocotyledonous families. It belongs to secondary metabolites. The majority of the world still entrusts folk plant medicine for the treatment of various diseases. Many plants contain saponins, which can generally show account for their remedial action. Diverse pharmacological properties of steroidal saponin have been reported including cytotoxic, antiviral, nephroprotective, hepatoprotective, antitumor, antimicrobial, cardioprotective, antihyperuricemia, antimicrobial, and antifungal. It can be a probable lead molecule in the research field of drug development. Several analytical techniques are used for the quantification of steroidal saponin such as HPTLC, HPLC, LC-MS, and GC-MS. However, recently, some new techniques were also introduced to analyze steroidal saponins such as UHPSFC, SFC, and UHPLC. On the other hand, this review includes the biosynthetic pathway of steroidal saponin in plants which can contribute a significant role to develop new drugs via using synthetic biology approaches. It also includes plant species with their parts showing pharmacological properties, mode of action, various compounds, such as polyphyllin I, dioscin, timosaponin AIII, diosgenin, Paris saponin II, and dioscin, sound to be especially rising as future antitumor agents. Saponins have vast chemical diversity which seeks the interest of the researcher. This review may be helpful for further research in the qualitative and quantitative analysis and is expected to give a wide range of applications of steroidal saponins.[183]
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Conflicts of interest
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References
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