Accepted Manuscript Title: Medicinal plants in the treatment of women’s disorders: analytical strategies to assure quality, safety and efficacy Author: Milena Masullo Paola Montoro Angela Mari Cosimo Pizza Sonia Piacente PII: DOI: Reference:
S0731-7085(15)00197-1 http://dx.doi.org/doi:10.1016/j.jpba.2015.03.020 PBA 10013
To appear in:
Journal of Pharmaceutical and Biomedical Analysis
Received date: Revised date: Accepted date:
12-1-2015 17-3-2015 19-3-2015
Please cite this article as: M. Masullo, P. Montoro, A. Mari, C. Pizza, S. Piacente, Medicinal plants in the treatment of women’s disorders: analytical strategies to assure quality, safety and efficacy, Journal of Pharmaceutical and Biomedical Analysis (2015), http://dx.doi.org/10.1016/j.jpba.2015.03.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Highlights
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The main medicinal plants used for women’s disorders have been reviewed.
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The analytical strategies to assure quality, safety and efficacy have been reported.
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Plants are classified on the basis of the chemical markers used for the quality control.
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Medicinal plants in the treatment of women's disorders: analytical
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strategies to assure quality, safety and efficacy
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Milena Masullo, Paola Montoro, Angela Mari, Cosimo Pizza, Sonia Piacente *
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Dipartimento di Farmacia, Università degli Studi di Salerno, via Giovanni Paolo II n. 132, 84084
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Fisciano (SA), Italy
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*Corresponding author: Tel.: +39 089969763; Fax:+39 089969602
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E-mail address: [email protected]
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Abstract
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During last decades an increasing number of herbal products specifically targeting women’s
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disorders has appeared in the worldwide marketplace. This growth highlights the need for a critical
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evaluation of quality, safety and efficacy of these products.
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Analytical techniques applied to the quality control of the main medicinal plants used for women
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health (relief of menopause and menstrual related symptoms) have been reviewed. Thanks to the
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innovation in analytical technology, identification and detection of secondary metabolites
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dramatically improved. In particular, hyphenated techniques have proved to be the most suitable for
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the rapid identification of compounds in plant matrix. Moreover, taking into account that
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differences in sample quality are not only found in the main compounds or in the chemical markers
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but also in the low-concentration compounds, fingerprint analysis might be a simple way for
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identification and quality control of herbal products containing a large number of low amounts of
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unknown compounds. Furthermore in several papers the information obtained from the analysis of a
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plant have been processed by statistical elaborations.
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Medicinal plants here discussed are classified on the basis of the chemical markers used for their
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quality control.
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Keywords
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women's disorders, herbal products, quality control, metabolic fingerprint, analytical techniques,
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statistical analysis.
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Abbreviations CE Capillary Electrophoresis DAD Diode Array Detector ELSD Evaporative Light Scattering ESI Electrospray Ionization FLD Fluorescence Detector GC-MS Gas Chromatography Mass Spectrometry HPLC High Performance Liquid Chromatography HPTLC High Performance Thin Layer Chromatography HR-MS High Resolution Mass Spectrometry HSCC High-Speed Countercurrent Chromatography HS-SPME Headspace-Solid Phase Microextraction IR Infrared Spectroscopy IT Ion Trap LC-MS Liquid Chromatography Mass Spectrometry MALDI Matrix Assisted Laser Desorbition Ionization MS Mass Spectrometry NIR Near-Infrared Diffuse Reflectance Spectroscopy PAD Photodiode Array Detection PCA Principal Component Analysis PLS-DA Partial Least Squares Discriminant Analysis TLC Thin Layer Chromatography ToF Time of Flight UPLC Ultra-Performance Liquid Chromatography
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Index
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1. Introduction
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2. Analytical methods for plants containing tannins used in the treatment of women’s disorders
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2.1. Alchemilla vulgaris
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2.2. Oenothera biennis
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2.3. Potentilla erecta
85
3. Analytical methods for plants containing anthocyans used in the treatment of women’s disorders
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3.1. Rubus idaeus
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3.2. Vitis vinifera
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4. Analytical methods for plants containing iridoids used in the treatment of women’s disorders
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4.1. Valeriana officinalis
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4.2. Verbena officinalis
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4.3. Vitex agnus castus
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5. Analytical methods for plants containing flavonoids used in the treatment of women’s disorders
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5.1. Capsella bursa-pastoris
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5.2. Carthamus tinctorius
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5.3. Glycine max
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5.4. Medicago sativa
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5.5. Paeonia spp.
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5.5.2. Paeonia officinalis
5.5.1. Paeonia lactiflora
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5.6. Passiflora edulis
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5.7. Polygonum spp.
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5.7.1. Polygonum cuspidatum
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5.7.2. Polygonum hydropiper 5 Page 5 of 95
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5.7.3. Polygonum aviculare 5.8. Rubia cordifolia
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5.9. Trifolium pratense
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6. Analytical methods for plants containing phenolic acids used in the treatment of women’s
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disorders
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6.1. Angelica sinensis
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6.2. Artemisia spp.
6.2.2. Artemisia capillaris
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6.2.3. Artemisia frigida
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6.2.4. Artemisia vulgaris 6.3. Chamaemelum nobile
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6.4. Curcuma spp.
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6.4.1. Curcuma longa
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6.4.2. Curcuma xanthorrhiza
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6.4.3. Curcuma zeodaria
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6.5. Echinacea purpurea
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6.6. Humulus lupulus
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6.7. Magnolia officinalis
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6.8. Pimenta dioica
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6.9. Piper methysticum
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7. Analytical methods for plants containing terpenes used in the treatment of women’s disorders
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7.1. Alisma orientalis
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7.2. Calendula officinalis
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7.3. Caulophyllum thalictroides
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7.6. Cyperus rotundus
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7.7. Foeniculum vulgare
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7.8. Panax ginseng
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7.9. Pelargonium graveolens
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7.10. Salvia spp.
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7.10.1. Salvia sclarea
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7.10.2. Salvia miltiorrhizae
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7.11. Tanacetum parthenium
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8 Analytical methods for plants containing steroids used in the treatment of women’s disorders
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8.1. Dioscorea spp.
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9. Concluding remarks
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1. Introduction
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During last decades an increasing number of herbal products specifically targeting women in
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menopause and with menstrual affections has appeared in the worldwide marketplace. This growth
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highlights the need for a critical evaluation of quality, safety and efficacy of these products.
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Ensuring that plant-based products are of suitable quality is important for several reasons. Herbs are
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natural products and, for this reason, they do not have a consistent, standardized composition [i1].
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Plants contain numerous chemical constituents and if we analyze different parts of the plant (e.g.
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roots, leaves), we certainly find a different qualitative and quantitative profile of constituents. The
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reason of this variability is that the content and concentration of constituents can be influenced by
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several factors including climate, growing conditions, time of harvesting, and post-harvesting
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factors, such as storage conditions (e.g. light, temperature, humidity) and processing (e.g. extraction
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and drying). The quality of plant raw materials can also be influenced by human adulterations due
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to dishonesty or unscrupulous operators. Errors could be accidental botanical substitution
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(misidentification of plant species) or intentional botanical substitution (deliberate exchange with
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other, sometimes more toxic, plant species). The variability in the content and concentrations of
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constituents of plant material, together with the range of extraction techniques and processing steps
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used by different manufacturers, results in marked variability in the quality of commercially
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available herbal products [i]. Thus quality control of herbal products is needed to ensure their
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consistency, safety, and efficacy.
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The current approaches to the quality control of herbal products are either compound-oriented or
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pattern-oriented [ii2], the former targeting specific components with known chemical structures, the
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latter targeting all detectable components. Regarding this latter approach, fingerprint analysis is
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often accepted by regulatory authorities as a tool to identify herbal formulations and to assess their
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quality. A fingerprint is a characteristic profile or pattern which chemically represents the sample
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[iii3].
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In the first approach, selection of chemical markers is crucial for the quality control of herbal
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products. Ideally, chemical markers should be components that contribute to the therapeutic effects
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of a medicinal plant. Considering that only a small number of chemical compounds were shown to
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have clear pharmacological actions, and a large number of plants are not studied for their bioactive
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metabolites, other chemical components can be used as markers. The European Medicines Agency
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(EMEA) [iv4] defines chemical markers as chemically defined constituents or groups of
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constituents of a medicinal plant which are of interest for quality control purposes regardless of
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whether they possess any therapeutic activity. The quantity of a chemical marker can be an
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indicator of the quality of a herbal medicine. This point is very important, because the chemical
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marker approach for quality control is realized by means of both qualitative and quantitative
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analyses. The analysis of chemical markers requires specific analytical methods for qualitative
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analysis and validated, accurate, precise, and robust methods for quantitative analysis.
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The purpose of this review is to assess the evidence for quality of the main medicinal plants used
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for women health (relief of menopause and menstrual related symptoms) with a specific focus on
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their phytochemical composition. Medicinal plants used with this purpose are classified on the basis
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of the chemical markers, not always corresponding to the active constituents, used for the quality
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control (Table 1).
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2. Analytical methods for plants containing tannins used in the treatment of women’s
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disorders
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Tannins are a heterogeneous group of high molecular weight polyphenolic compounds with the
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capacity to form reversible and irreversible complexes with proteins, polysaccharides, alkaloids,
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nucleic acids and minerals. On the basis of their structural characteristics it is possible to divide
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them into four major groups: gallotannins, ellagitannins, complex tannins, and condensed tannins
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[v5].
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(1) Gallotannins are tannins in which galloyl units or their meta-depsidic derivatives are linked to
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diverse polyol-, catechin-, or triterpenoid units.
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(2) Ellagitannins are tannins in which at least two galloyl units are C–C coupled to each other.
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(3) Complex tannins are tannins in which a catechin unit is glycosidically linked to a gallotannin or
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an ellagitannin unit.
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(4) Condensed tannins are all oligomeric and polymeric proanthocyanidins formed by linkage of C-
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4 of one catechin with C-8 or C-6 of the next monomeric catechin.
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In traditional medicine, the tannin-containing plant extracts are used as astringents, against
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diarrhoea, as diuretics, against stomach and duodenal tumours, and as antiinflammatory, antiseptic,
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antioxidant and haemostatic pharmaceuticals [vi6]. Anti-inflammatory and haemostatic activity
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make this compounds, and principally proanthocyanidins, largely used to treat menstrual affection.
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The activity of tannins for relieving menopausal symptoms is also known, and a patent related to
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the use of proanthocyanidins in relieving menopausal and perimenopausal symptoms was published
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[vii7].
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2.1. Alchemilla vulgaris
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Alchemilla vulgaris L. (Rosaceae), also known as lady's mantles for its ornamental leaves is a wild
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plant used for women's disorders and reported for the presence of flavonoids and tannins [viii8]. A.
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vulgaris belongs to a number of herbal drugs included in The European Pharmacopoeia (Ph. Eur.)
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analyzed only by their tannin content. The tannin content, determined using the non specific Folin-
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Ciocalteu method, an old colorimetric method involving redox chemistry, is calculated relative to a
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pyrogallol standard and expressed as percentage of pyrogallol. Thus, Moller et al. developed a
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method based on a reversed-phase gradient HPLC system coupled to DAD, fluorescence,
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electrochemical and MS detectors. The HPLC system developed with UV detection at 250 nm
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provided characteristic fingerprints of the herbal drugs. Methanolysis of A. vulgaris extracts
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generated methyl gallate and ellagic acid, which were analyzed by HPLC [ix9]. Successively, a new
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method based on HPLC coupled with four kinds of detectors, DAD, FLD, electrochemical
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amperometric and MS assembled by a micro-splitter valve was developed for the characterization
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and differentiation of A. vulgaris extracts adding 2,5-dihydroxybenzoic acid to the sample solution
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in order to eliminate the drift interference of retention time [x10].
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2.2. Oenothera biennis
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Evening primrose (Oenothera biennis L., Onagraceae) is a native North American traditional
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medicinal plant. All the parts of this plant have been widely used as a traditional remedy for several
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disorders. It has been receiving a lot of attention all over the world for its seed oil (up to 25%) rich
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in polyunsaturated fatty acids mainly linoleic acid (LA, 60-80%) and γ-linolenic acid (GLA, 8-
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14%). These omega-6 fatty acids are now becoming increasingly popular as oral and topical
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remedies for neurodermatitis. Their mechanism of action is based on the concept that the disease is
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caused by an underlying metabolic disorder of long-chained essential fatty acids which are, in turn,
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precursors of the highly active prostaglandins E1 and E2. Evening primrose oil has been tested in
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several studies to support its use for breast pain, premenstrual symptoms (PMS), eczema, cirrhosis,
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rheumatoid arthritis, menopause [xi11]. In particular, it is reported to relieve the discomforts of
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PMS, menopause, menstruation, endometriosis and fibrocystic breasts by interfering with the
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production of inflammatory prostaglandins released during menstruation. Many PMS sufferers are
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found to have unusually low levels of GLA, which is why food supplements containing this fatty
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acid might help so much. In women with fibrocystic breasts, essential fatty acids can minimise
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breast inflammation and promote the absorption of iodine, a mineral that can be present in
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abnormally low levels in women with this condition. In menopause, it is widely reported that
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evening primrose oil reduces hot flushes and increases feelings of well being. The oil of O. biennis
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must be subjected to rigorous analyses as part of any quality control program. GC is generally
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applied for the determination of fatty acid contents (mainly the content of -linolenic acid is dosed),
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but more sophisticated methodology may be necessary for the structural analysis of triacylglycerols,
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for example. Methods for analysis of evening primrose oil were reviewed in 1999 [xii12]. The
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analysis of triacilglycerols is generally used for standardization of the oil from the plant [xiii13].
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Although most of the queries for quality control of this species are focused on the oil, the plant
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contains as further bioactive compounds ellagitannins, that can have a role as anti-inflammatory
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principles relieving menstrual symptoms. Leaves and roots of O. biennis were investigated for the
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presence of hexameric and heptameric ellagitannins, by using HPLC coupled with DAD and HR-
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MS [xiv14]. A previous analytical approach was carried out with the aim of determining low
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molecular weight phenolics with antioxidant properties from the seeds of the plant [xv15].
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2.3. Potentilla erecta
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The rhizome of Potentilla erecta (L.) Raeuschel (Rosaceae), known with the trivial name of
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tormentil, is a medicinal and food source used as nutritional supplement for its effects against
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inflammation, gastrointestinal disorders and Pre-Menstrual Symptoms (PMS) [xvi16]. Most of the
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positive effects can be attributed to the high amounts of polyphenols in all the plant parts [xvii17].
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The chemical composition of P. erecta is mostly based on the presence of different flavonoids,
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triterpenoids, organic and phenolic carboxylic acids, most of which isolated from the roots and
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rhizomes. In addiction, P. erecta is considered a tannin-rich plant [xvi], for the high concentration
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of proanthocyanidin oligomers in its underground parts. In a recent paper, a strategy based on direct
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flow injection-ESI-IT-MS has been used to profile proanthocyanidins (PAs) occurring in this
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species. To achieve deeper structural information and to focus the analysis on PAs with high
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polimerization degree (DP), MALDI-ToF-MS, was used. Finally, LC-MS2 analyses were executed
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by using a diol stationary phase to detect PAs [xvi].
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3. Analytical methods for plants containing anthocyans used in the treatment of women’s
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disorders
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Anthocyans (ACNs), i.e. anthocyanins and anthocyanidins, belong to the group of plant
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constituents, collectively known as flavonoids, which occur in the western diet at relatively high
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concentrations. ACNs show the ability to scavenge reactive oxygen species and display a variety of
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pharmacological properties which make them potential anti-inflammatory agents. The molecular
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basis for their pharmacological activity includes the regulation of different mechanisms mainly
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involved in: (1) suppression of the inflammatory response through targeting phospholipase A2,
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PI3K/Akt,
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growth/differentiation control and tumor suppression (4) reduction of diabetes incidence through
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modulation of insulin sensitivity and glucose utilization (5) neuroprotection through amelioration of
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oxidative stress and Aβ deposition and (6) hepatoprotective activity through interference with TNF-
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α and TGF-β in the liver. The estrogen-like activity of anthocyans could be utilized in cancer and
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hormone-replacement therapy. The molecular mechanisms of protective and therapeutic activity of
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anthocyans in various pathological conditions, which may not be attributed solely to their
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antioxidant activity but also to direct blockage of signaling pathways [xviii18]. Related to these
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important evidences, is the action on women disorders [xix19].
pathways
(2)
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3.1. Rubus idaeus
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Raspberry (Rubus ideaus L., Rosaceae) flavonoids and mainly anthocyans have significant
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antioxidant activity and several biological activities in moderate and chronic disorders, and
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women's disorders. Differences in anthocyanin composition of juices obtained from different berry
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fruits create the possibility of detecting the adulterations of expensive raspberry and black currant
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juices with cheap strawberry and red currant juices on the basis of anthocyanin analysis [xx20].
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With similar purposes the analysis of selected organic acids was proposed too [xxi21].
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In 1999 flavonoids and anthocyans from R. ideaus and other selected berries were analysed by
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HPLC-ESI-MS. For the identification of aglycons, DAD was also used [xxii22]. A paper on the
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analysis of anthocyanins was published in 2002 [xxiii23]. Anthocyanins from red raspberries were 13 Page 13 of 95
extracted from the fruit by homogenization in acidified methanol. The methanolic extract was
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centrifuged and the supernatant analyzed by reversed-phase HPLC. The eluent was monitored at
299
371 and 520 nm before being introduced into a single quadrupole mass spectrometer through an
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atmosphere pressure chemical ionization probe operating in positive ion mode. This method
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allowed the identification of eight anthocyanins. A method based on tandem mass spectrometry
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(MS/MS) coupled with HPLC was described in 2005 [xxiv24]. Scan for the precursor ions of
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commonly found anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, petunidin, and
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peonidin) using LC/MS/MS on a triple quadrupole instrument allowed the specific detection of each
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anthocyanin. Further characterization of each anthocyanin was performed using MS/MS product-
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ion analysis, common-neutral-loss analysis, and selected reaction monitoring (SRM). In 2008 a
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method for the analysis of anthocyanins from raspberries by MALDI–ToF-MS was reported
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[xxv25]. Furthermore, in 2008 a method based on Direct Introduction MS was proposed for the
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analysis of polyphenols in berries, including Rubus [xxvi26]. In last years other papers have been
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published applying and improving these methods of analysis [xxvii27, 28] [xxix29]. Also extraction
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of phytochemicals from raspberry, principally assisted by ultrasound [xxx30] and by microwave
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[xxxi31], has been reported. Investigation of the fruit flavor by using SPME coupled with
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stereoselective GC-MS was reported in 2010 [xxxii32]. Authors have used HS-SPME and GC-MS
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to determine the enantiomeric ratios of chiral flavor and fragrance indicators in the raw materials
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and in the products.
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Other studies involve the analysis of ellagitannins [xxxiii33]. The use of gradient RP-HPLC with
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DAD and MSn detection for the analysis of ellagitannins, ellagic acid conjugates and quercetin
318
conjugates in raspberries is described. MSn is a particularly powerful tool for the analysis of trace
319
levels of natural products in the extracts as interpretation of fragmentation patterns.
xxviii
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3.2. Vitis vinifera
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Grape seed (Vitis vinifera L., Vitaceae) proanthocyanidins and flavonoids are reported to be
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effective in improving the physical and psychological symptoms of menopause increasing muscle
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mass and reducing blood pressure in middle-aged women [xxxiv34].
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Quality control of V. vinifera products involves principally wine, the principal product obtained
326
from V. vinifera berries, however in this context we will evaluate only the improvement in analysis
327
of grapes or functional foods derived from grapes. In 2008 Cavaliere and coworkers described a
328
method for the analysis of polyphenols in grape berries by Rapid Resolution LC-MS [xxxv].
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A simple and precise LC-MS method was developed for the quantification of anthocyanidins in
330
fifteen grape juice samples, four grape berries and four grape skins [xxxv35]. An improved LC-MS
331
method was published in 2012 by Xu and coworkers: under optimized conditions, five major
332
anthocyanidins including delphinidin, cyanidin, petunidin, peonidin and malvidin in the hydrolyzed
333
grape extracts were detected [xxxvi36].
334
The application of MS for the analysis of berries polyphenols has recently been reviewed
335
[xxxvii37]. MS has been shown to play a very important role in the research of polyphenols in
336
grape and wine and in the quality control of products. The soft ionization of LC-MS makes these
337
techniques suitable to study the structures of polyphenols and anthocyanins in grape extract and to
338
characterize polyphenolic derivatives. The coupling of the several MS techniques presented is
339
shown to be highly effective in the structural characterization of the large number of low and high
340
molecular weight polyphenols in grape and can be highly effective in the study of grape
341
metabolomics.
342
NMR is a technique largely applied to this matrix. Most of these techniques are able to discriminate
343
adulteration, mainly to identify the grape fruits’ extract from extracts obtained from other berries; in
344
fact differences in anthocyanin composition of juices obtained from different berry fruits create the
345
possibility of detecting the adulterations [xxxviii38].
346
Two headspace-based methodologies have been proposed to characterize the aroma of grape juice:
347
static headspace (SHS) and HS-SPME [xxxix39].
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4. Analytical methods for plants containing iridoids used in the treatment of women’s
350
disorders
351
Iridoids represent a large group of cyclopentapyrane monoterpenoids that occur widespread in
352
nature, mainly in Dicotyledonous plant families like Apocynaceae, Scrophulariaceae, Diervillaceae,
353
Lamiaceae, Loganiaceae and Rubiaceae. Recently, more extensive studies revealed that iridoids
354
exhibit a wide range of bioactivities, such as neuroprotective, antinflammatory and
355
immunomodulator, hepatoprotective and cardioprotective. Iridoids are marker compounds of
356
different species with a specific traditional use against menstrual symptomatology and menopausal
357
disorders [xl40].
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4.1. Valeriana officinalis
360
Valeriana officinalis L. (Valerianaceae), valerian, is a bushy plant whose roots and rhizomes have
361
been used since the 11th century for their tranquilizing, menstruation, and sedative effects. Its
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antispasmodic activity on smooth muscles has been demonstrated both in vivo and in vitro [xli41].
363
Currently, valerian is prescribed for reducing pain, cyclic cramps, anxiety, and stress. It is also used
364
to treat the cramps associated with dysmenorrhea; in 2011 a clinical trial has been conducted in this
365
regard [xli]. Phytochemical researches led to the discovery of a number of sesquiterpenoids and
366
iridoids among which germacrane-type sesquiterpenoids, volvalerenals A−E and volvalerenic acids
367
A−C,
368
epoxyvalechlorine, valeriotriate B, jatamanvaltrate B, jatamanvaltrate C, valerenic acid, and
369
acetoxyvalerenic acid [xlii42,xliii43].
370
Analysis of V. officinalis was run principally on essential oils and iridoids by GC methods. In 2002
371
V. officinalis was analysed with other sedative plants in a sedative herbal preparation by GC-MS
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[xliv44]. In 2005 electronic nose was applied with the aim to discriminate several valerian varieties
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[xlv45]. To overcome the major limitations of the current methods used for the analysis of tinctures,
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together
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isovaleroxyhydroxydihydrovaltrate,
1,5-dihydroxy-3,8-
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a new approach based on NMR spectroscopy and MS was tested with different tinctures. Diffusion-
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edited 1H-NMR (1D-DOSY) and 1H-NMR with suppression of the EtOH and water signals were
376
applied for the first time to the direct analysis of commercial herbal tinctures derived from
377
Echinacea purpurea, Hypericum perforatum, Ginkgo biloba, and V. officinalis. The direct injection
378
of the tinctures in the MS detector to obtain the corresponding metabolic profiles was also
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performed. Using both NMR and MS methods it was possible to obtain metabolic fingerprints
380
which allowed to differentiate tinctures prepared with different plants [xlvi46]. In a recent paper the
381
application of HPTLC to the analysis of the extracts of V. officinalis was explored [xlvii47]. A
382
strategy based on multi-wavelength chromatography fingerprinting of herbal materials, using HPLC
383
with a UV-Vis diode array detector has been applied to the analysis of V. officinalis. The enhanced
384
fingerprints were constructed by compiling into a single data vector the chromatograms from four
385
wavelengths (226, 254, 280 and 326 nm) [xlviii48].
M
an
us
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ip t
374
d
386
4.2. Verbena officinalis
388
Verbena officinalis L. (Verbenaceae) is a medicinal plant traditionally used because of its diuretic,
389
expectorant and anti-rheumatic effects. Moreover, anti-inflammatory, analgesic and antioxidant
390
activities have been reported for this plant [xlix49]. Analgesic and anti-inflammatory activity justify
391
its use to relieve menstrual symptoms. Main secondary metabolites present in the plant are iridoids,
392
phenylpropanoids, flavonoids, triterpenes and monoterpenes, with verbenalin (iridoid) and
393
verbascoside (phenylpropanoid) as the major constituents [xlix]. The European Pharmacopeia
394
defines verbenalin as the quality determining compound with a minimum content of 1.5%. For this
395
reason, quality control of V. officinalis often is run with respect of this marker compound. Several
396
analytical techniques like HPLC, HPTLC, GC and micellar electrokinetic capillary chromatography
397
for qualitative or quantitative analysis of the chemical constituents in V. officinalis has been
398
reported [xlix]. Among these reports, Bilia and coworkers developed an HPLC-DAD-ESI-MS
399
method for the analysis of the constituents of aqueous preparations of verbena and lemon verbena
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and the evaluation of their antioxidant activity [l50]. Successively simultaneous determination by
401
HPLC of four bioactive compounds in Verbena officinalis L. has been reported by Liu and
402
coworkers [li51]. A recent paper proposes a method based on Attenuated-Total-Reflectance IR
403
(ATR-IR) and NIR in hyphenation with multivariate analysis to quantify verbenalin and
404
verbascoside in V. officinalis. In addition a HPLC method as a reference was established and
405
validated and compared with the spectroscopic method [xlix]. Identification of V. officinalis, as
406
described above, is performed based on morphological and phytochemical analyses, which
407
unfortunately are not reliable enough to distinguish V. officinalis from other relevant species of the
408
genus Verbena. Thus the most important adulterations could remain undetected. In 2009 a method
409
was proposed based on comparison of ITS (Internal Transcribed Spacers) sequences and molecular
410
markers (RAPD) [lii52].
M
an
us
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400
411
4.3. Vitex agnus castus
413
Vitex agnus-castus L. (Verbenaceae), chasteberry, is one of the most popular and effective herbs
414
used for the prevention and treatment of pre-menstrual syndrome (PMS) [liii53] and
415
hyperprolactinemia because of its hormone-like effects [liv54]. The chemical composition of the
416
unpolar fraction is characterized by the presence of diterpenoids, essential oils and ketosteroids,
417
while flavonoids are described in polar extracts [liii- [lv55]. Among these latter, casticin, a
418
methoxylated flavone, is considered by European Pharmacopoeia (Ph. Eur.) the reference standard
419
for standardization of dry extracts of the species. An analytical HPLC method for the quantitative
420
determination of casticin in V. agnus-castus fruits has already been developed [lvi56]. Recently
421
several studies have been published reporting the use of LC-MS techniques for the quality control
422
of the polar fractions of V. agnus-castus [lv] fruits and a comparison in the chemical composition of
423
different part of plants was performed by HR-MS [liii].
424
Many analytical studies are reported about V. agnus-castus essential oils, most of them realized by
425
GC-MS techniques [lvii57,lviii58].
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426
5. Analytical methods for plants containing flavonoids used in the treatment of women’s
428
disorders
429
Flavonoids are polyphenolic compounds ubiquitous in nature. More than 4,000 flavonoids have
430
been recognised, many of which occur in vegetables, fruits and beverages like tea, coffee and fruit
431
drinks. Flavonoids occur as aglycones, glycosides and methylated derivatives. Small amount of
432
aglycones are frequently present and occasionally represent a considerably important proportion of
433
the total flavonoid compounds in the plant. Flavonoids have gained much attention because of their
434
broad biological and pharmacological activities including antimicrobial, cytotoxic, anti-
435
inflammatory as well as cancer preventing activities and principally the capacity to be powerful
436
antioxidants which can protect the human body from free radicals and reactive oxygen species.
437
Antiinflammatory and antioxidant activity make these compounds largely used to treat menstrual
438
affection. Among flavonoids, isoflavonoids constitute a characteristic and very important subclass
439
of flavonoids. Their structures are based on the 3-phenylcromen skeleton that is chemically derived
440
from the 2-phenylchromen skeleton by an aryl-migration mechanism. Structurally, isoflavonoids
441
can be classified according to the oxidation of the C15 skeleton, their complexity and the internal
442
formation of the heterocyclic rings. Due to their ubiquitous distribution in food and the claimed
443
beneficial health effects of foods containing isoflavones, their distribution in foods and their healthy
444
properties have been reviewed [lix59]. Isoflavones have been proposed to have estrogenic activity
445
and play a putative role in the control of menopause disorders.
cr
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446
ip t
427
447
5.1. Capsella bursa-pastoris
448
Capsella bursa-pastoris (L.) Medik. (Brassicaceae), also known as shepherd's purse, is a wild herb
449
with high nutritional value that can be eaten raw or cooked. It is reported in the list of the plants
450
used for women's disorders. Investigation of different extracts of its aerial parts led to the
451
identification of phenolic compounds quantified by HPLC-DAD, organic acids, and amino acids 19 Page 19 of 95
detected by HPLC-UV, and free fatty acids and sterols analyzed by GC-IT-MS. The plant material
453
was found rich in kaempferol-3-O-rutinoside, quinic acid, arginine, palmitic acid, and β-sitosterol
454
[lx60]. Karioti and coworkers developed an HPLC-DAD-MS method to analyse the “Olivis”
455
preparation, a blend of four herbal drugs, namely Crataegus oxyacantha L., Olea europea L.,
456
Capsella bursa-pastoris L. and Fumaria officinalis L. [lxi61]. The lack of the marker constituents
457
of some of the declared plant species (i.e. C. bursa-pastoris) and the presence of banned
458
adulterants, responsible for the strong antihypertensive effect of the supplement prompted to
459
analyze this herb. The analyses proved the presence of indole alkaloids belonging to the group of
460
Rauwolfia sp., such as ajmaline, reserpine and yohimbine. Seven flavonoids and two caffeoyl acid
461
derivatives were found in C. bursa-pastoris [lxi].
an
M
462
us
cr
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452
5.2. Carthamus tinctorius
464
Carthamus tinctorius L. or safflower, commonly called Honghua in China, is an annual or biennial
465
herbal plant belonging to the family Compositae. Safflower is considered to promote blood
466
circulation, to remove blood stasis, promote menstruation and alleviate pain. In the aspect of
467
clinical practice, safflower is mainly applied for blood-stasis syndrome with dysmenorrhea,
468
amenorrhea, post-partum abdominal pain and mass [lxii62]. Many chemical constituents such as
469
quinochalcones, flavonoids, alkaloids, polyacetylenes, alkane-diol, fatty acids, steroids, lignans,
470
have been isolated from safflower. Among them, quinochalcones and flavonoids are considered as
471
the biologically active constituents of safflower. The quinocalchone hydroxysafflor yellow A is
472
considered as one of the standard compounds to evaluate the quality of crude drug safflower and
473
related preparations containing safflower; also kaempferide is chosen as standard to evaluate the
474
quality of safflower. Several reports regard the quality control of Chinese herbal preparation like
475
“Danhong”, “Shu-Jin-Zhi-Tong”, "Xuebijing" with C. tinctorius as constituent [lxiii63, 64,lxv65].
476
However, the two marker compounds might be insufficient to fully illustrate the quality of
477
safflower since 104 compounds have been isolated and identified [lxii]. So, Li developed an HPLC–
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20 Page 20 of 95
DAD method for the simultaneous determination of four marker compounds, kaempferol-3-O-
479
rutinoside, safflomin A, safflomin B and bidenoside C, in the extract of the flowers of C. tinctorius
480
[lxvi66]. Fan and coworkers developed an HPLC-DAD method to evaluate the quality of 46 batches
481
of C. tinctorius from different areas through a simultaneous quantitation of 10 components.
482
Significant variations were found in the content of these compounds in these tinctures [lxvii67]. A
483
fingerprinting method has been developed to describe the chemical constituents and to control the
484
quality of many Chinese Material Medicas. HPLC fingerprinting has been applied to evaluate the
485
quality of safflower from different producing areas, indicating similar chemical profiles for
486
safflower from various habitats [lxviii68].
us
cr
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478
an
487
5.3. Glycine max
489
Soy (Glycine max (L.) Merrill, Fabaceae), a legume originating from Asia, is widely distributed
490
throughout the world, for preparing food products. More recently its consumption is linked, among
491
different properties, to the reduction of menopausal symptoms. This finding has resulted in the
492
development and commercialization of many functional foods and food supplements based on soy
493
ingredients. Soy extracts contain a mixture of isoflavones belonging to the group of phytoestrogens.
494
The major isoflavones in soybeans include daidzein, glycitein, genistein, their glycosides, glycoside
495
malonates and glycoside acetates, in which the predominant isoflavone forms in soybeans and non-
496
fermented soy products are the glycoside malonates, 6''-O-malonylgenistin and 6''-O-
497
malonyldaidzin [lxix69]. Studies have shown that they play an important role in reducing
498
climacteric symptoms in menopausal and postmenopausal women [lxx70].
499
A recent review reports the sample preparation and analysis for the quantification of isoflavones in
500
soybeans and soy foods. Modern techniques including ultrasound-assisted extraction, pressurized
501
liquid extraction, supercritical fluid extraction and microwave-assisted extraction, and analysis by
502
HPLC are reported [lxxi71]. In the quality control of soy the amount of isoflavones, both aglycones
503
and glycosides, is usually determined by means of reversed-phase HPLC-UV [lxxi,lxxii72].
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Although the HPLC methods have some advantages when they are applied to the analysis of
505
isoflavones in terms of specificity, sensitivity, and straightforward operation, they require a
506
relatively long period of time, normally from 20 min to 65 min. So, the use of high-throughput
507
liquid chromatography technologies has been reported in the last decade for isoflavone analysis,
508
reducing the chromatographic time to less than 10 min. These techniques allow the use of short
509
columns, packed with 3 μm particles, supporting elevated pressures, thus reducing analysis time,
510
solvent consumption, and, consequently, environmental impact [lxxiii73]. Among these studies,
511
Apers and coworkers developed an HPLC method using two linked monolithic silica-based
512
reversed-phase C18 columns. This method for determination of isoflavones in soy extracts needs less
513
than 25 min. Among the high-throughput methods reported in the literature for isoflavones analysis,
514
UPLC and ultra-fast liquid chromatography (UFLC) are cited for their determination in soybeans
515
cultivars, soy bits, soymilk, texturized soy protein, and soy-based nutritional supplements [lxxiii].
516
Several research groups have analyzed isoflavones from different types of soy seeds by LC-MS
517
[lxxiv74, 75,lxxvi76]. Caligiani and coworkers performed the quali-quantitative determination of
518
isoflavones in soybean extracts by 1H NMR [lxxvii77]. The complexity of natural soy isoflavones
519
makes the rigorous standardisation difficult to achieve, and most chromatographic methods only
520
quantify the main isoflavone forms as total isoflavone content [lxxviii78]. Garcia and coworkers
521
optimized methods for conventional and perfusion RP-HPLC to characterize 26 commercial
522
soybean products. Characterization of soybean products was carried out on the basis of their protein
523
profiles obtained by both chromatographic methods [lxxix79].
cr
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lxxv
Ac ce p
524
ip t
504
525
5.4. Medicago sativa
526
Alfalfa (Medicago sativa L., Fabaceae) is the main Medicago species widely grown throughout the
527
world, predominantly as a source of high quality forage for livestock, renewable energy production,
528
phytoremediation and as a source of phytochemicals [lxxx80]. It is also used as a human food
529
ingredient, consumed as sprouts in salads, sandwiches or soups, as leaf protein concentrates or as 22 Page 22 of 95
food supplements [lxxxi81]. Despite this use, alfalfa have pharmacological activities, being used in
531
some human health disfunctions, and among these anemia, endometriosis, osteoporosis and
532
menopausal symptoms [lxxi].
533
The plant contains many important constituents including saponins, sterols, coumarins, flavonoids,
534
phenolics, vitamins, proteins, minerals, and other nutrients [lxxxii82]. As above reported for
535
Glycine max, to isoflavones present in M. sativa are ascribable some of the pharmacological activity
536
of alfalfa. Murphy and coworkers analyzed isoflavones in retail and institutional foods (alfalfa and
537
soy) by HPLC [lxxxiii83]. Further HPLC [lxxxiv84, 85,lxxxvi , ESI-MS [lxxxiv,lxxxv], and CE
538
[lxxxvii87] methods were employed to analyze flavonoid content in M. sativa. More recently, two
539
glycosides (daidzin and genistin) and six aglycones (daidzein, glycitein, genistein, formononetin,
540
prunetin and biochanin A) were determined by HPLC-DAD in three different extracts (aqueous,
541
hydroalcoholic and alcoholic) of M. sativa [lxxxi]. Abo Markeb quantified 5- and 7-hydroxyflavone
542
in the M. sativa samples by HPLC-FLD [lxxxviii88]. A study compared the isoflavone production
543
of the callus cell suspension cultures of M. sativa to the original plants. The extracts were analyzed
544
by LC-MS for their isoflavones, mainly formononetin, biochanin A, daidzein, and genistein
545
[lxxxix89].
546
In the sprouts of M. sativa and G. max, phenolic compounds, sterols and triterpenes were
547
determined by HPLC-DAD, organic acids by HPLC-UV and fatty acids and volatile compounds by
548
GC-IT/MS [lxxx]. The metabolic profiling of triterpene saponins in M. sativa was also investigated
549
using HPLC-ESI-MS [xc90].
cr
us 86]
te
d
M
an
lxxxv
Ac ce p
550
ip t
530
551
5.5. Paeonia spp. (Paeoniaceae)
552
5.5.1. Paeonia lactiflora
553
Paeonia lactiflora Pallas, also named Chinese Paeony, is a Chinese herb. A decoction of its root has
554
been used to treat painful or inflammatory disorders in traditional Chinese medicine.
555
Different compounds have been isolated from this plant. These include monoterpenoid glucosides, 23 Page 23 of 95
flavonoids, tannins, stilbenoids, triterpenoids and steroids, and phenols. Biological activities include
557
antioxidant, antitumor, antipathogenic, immune-system-modulation activities, cardiovascular-
558
system-protective activities and central-nervous-system activities [xci91].
559
A water/ethanol extract of Radix Paeoniae is known as total glycosides of paeony (TGP), of which
560
paeoniflorin is the major active component. Preclinical studies show that TGP/paeoniflorin is able
561
to diminish pain, joint swelling, synovial hypertrophy, and the severity of bone erosion and
562
cartilage degradation in experimental arthritis [xcii92].
563
P. lactiflora was clinically tested on Polycystic ovary syndrome (PCOS), a prevalent, complex
564
endocrine disorder characterised by polycystic ovaries, chronic anovulation and hyperandrogenism
565
leading to symptoms of irregular menstrual cycles, hirsutism, acne and infertility [xciii93].
566
Recently an advanced method has been proposed for the quality control of this species. In this
567
study, an UPLC- PDA-QToF-MS based chemical profiling was established for rapid global quality
568
evaluation of Radix Peoniae. By virtue of the high resolution, high speed of UPLC and the accurate
569
mass measurement of ToF-MS, a total of 40 components including 29 monoterpene glycosides, 8
570
galloyl glucosides and 3 phenolic compounds were simultaneously separated within 12 min,
571
identified through the matching of formulas with those of published components in a library, and
572
were further elucidated by adjusted lower energy collision-induced dissociation (CID). The
573
established method was successfully applied to rapidly and globally compare the quality of Radix
574
Paeonia alba and Radix Paeoniae rubra, two post-harvesting handled products of Radix Paeoniae.
575
Thus UPLC-PDA-QToF-MS based chemical profiling resulted a powerful approach for the global
576
quality evaluation of Radix Paeoniae [xciv94].
577
A similar method, integrated with Multivariate Data Analysis was published in 2013 [xcv95].
578
An interesting new method, performed directly on the herbal material, was proposed in 2015
579
[xcvi96]. To assess the inherent quality of different grades and of different tissues in roots of P.
580
lactiflora, laser microdissection coupled with UPLC-QToF-MS was applied. The results show that
581
the quantity of the main components decreased with increase in root diameter from 0.3 cm to 0.7
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556
24 Page 24 of 95
cm. Above 0.7 cm of diameter, quantity and diversity of these components increased proportionally
583
with the increase in root diameter. The tissue-specific study indicated that the high content of
584
paeoniflorin and albiflorin are mainly distributed in the cork and cortex. According to the results of
585
this study, roots of P. lactiflora greater than 1.7 cm in diameter can be considered of better quality
586
for medicinal use than smaller.
ip t
582
cr
587
5.5.2. Paeonia officinalis
589
Paeonia officinalis L. is native to South Eastern Europe but it has been widely introduced elsewhere
590
as a garden plant in many varieties. Dried and powdered roots of P. officinalis are used as a
591
medicine in both Indian and Chinese system of medicines. The roots are cleansed carefully in cold
592
water with a brush and allowed to remain in water for a short period of time, then they are spread
593
out on trays in the sun. Phytochemical screening revealed that the roots of P. officinalis contain
594
alkaloids, tannins, saponins, glycosides, carbohydrates, flavonoids, terpenes, steroids and proteins
595
[xcvii97]. Peony root has been used medicinally for over 2,000 years and it gained a reputation as a
596
treatment for epilepsy and to promote menstruation. The root is harvested in the autumn from plants
597
that are at least two years old and is dried for later use. Quality control of this species is reported by
598
TLC [xcviii98], and by HPLC fingerprint [xcix99].
an
M
d
te
Ac ce p
599
us
588
600
5.6. Passiflora edulis
601
Passiflora edulis Sims (passion fruit) belongs to the family Passifloraceae. P. edulis extracts of the
602
leaves have been used for centuries as sedatives by native Brazilians, and also for women's
603
disorders. A drink from the flower is used to treat asthma, bronchitis, and whooping cough [c100].
604
The leaves of P. edulis, traditionally used in American countries to treat both anxiety and
605
nervousness by folk medicine, are rich in polyphenols, which have been reported as natural
606
antioxidant. Several methods for the quality control of Passiflora species are reported in literature.
25 Page 25 of 95
HPLC and HPLC coupled to MS were also approached with the aim to quantify polar compounds
608
in extracts of P. edulis [cii,ci101]. A method based on GC-MS for the assessment of quality focused
609
on flavor has been reported [xxxii]. Chemical characterizations can provide authentication of
610
samples, detection of adulterations, and differentiation between closely related species. Different
611
methods based on modern planar chromatography techniques are reported for P. edulis
612
[cii102, 103, 104,cv105]. civ
cr
ciii
ip t
607
613
5.7. Polygonum spp. (Poligonaceae)
615
5.7.1. Polygonum cuspidatum
616
Polygonum cuspidatum Sieb. et Zucc., a traditional, popular Chinese medicinal herb, is widely
617
distributed in Southern China and Japan. The root of Polygonum cuspidatum has been used in the
618
treatment of inflammation, female disorders, infection, jaundice, skin burns and hyperlipemia
619
diseases [cvi].
620
Currently, over 67 compounds from the root of this plant have been isolated and identified; they are
621
quinones, stilbenes, flavonoids, coumarins, lignans and others. At present, emodin and polydatin are
622
used as the marker compounds to characterize the quality of this plant in the Pharmacopoeia of the
623
People's Republic of China [cvi106].
624
Emodin, resveratrol, and polydatin are the main active components of the rhizome. In 2005 a simple
625
densitometric HPTLC method for quantification of these compounds was reported [cvii107]. The
626
same compounds, with the addition of physcion, were determined in 2010 by HPLC [cviii108]. A
627
rapid and accurate UPLC-PDA method was established for simultaneous detection of 5 compounds
628
including polydatin, resveratrol, emodin-8-glucoside, emodin, and physcion [cix109].
Ac ce p
te
d
M
an
us
614
629 630
5.7.2. Polygonum hydropiper
631
Flavones and flavonoid glycosides, such as quercetin galactosides, a sesquiterpene acid, viscosumic
632
acid, oxymethylanthraquinones and polygonic acid were identified in all the parts of Polygonum 26 Page 26 of 95
hydropiper. Plant by its own or mixed with other herbs is used in the treatment of diarrhoea,
634
dyspepsia, itching skin, excessive menstrual bleeding, hemorrhoids and other diseases [cx110].
635
2D-TLC was applied to the quality control of P. hydropiper. Micro two-dimensional separations
636
were performed on polar bonded stationary phases of the type cyanopropyl-silica using non-
637
aqueous eluents as the first direction eluents and aqueous eluents as the second direction eluents.
638
The chromatographic process was performed in micro scale using 5 × 5 cm plates, small volume of
639
eluents and 10 mL of plant extracts to obtain satisfying separation [cxi111]. Analysis of flavonoids
640
by means of LC-MS was also reported for this species and proposed for quality control [cxii112].
us
cr
ip t
633
641
5.7.3. Polygonum aviculare
643
Polygonum aviculare L., also known as knotgrass, is an annual herbaceous plant commonly found
644
in all the continents. P. aviculare L. is widely used as an herbal remedy and has its monograph in
645
the European Pharmacopoeia. Infusions prepared from the herb of P. aviculare have been
646
traditionally used in the treatment of upper respiratory disorders as well as externally as a remedy
647
for skin affections and female diseases [cxiii113]. Previous studies have shown that extracts from P.
648
aviculare possess anti-inflammatory activity probably due to flavonoids [cxiv114]. There have been
649
several studies focused on the flavonoid composition of P. aviculare [cxiii,cxv115].
650
A study by HPLC–DAD–MSn addressed to the flavonoid constituents of knotgrass aerial parts
651
showed that, apart from well-defined compounds, it contains a series of flavonol glucuronides
652
which could not be unequivocally identified without isolation [cxiii]. It has also been shown that
653
flavonol glucuronides are dominating constituents in P. aviculare [cxiii].
654
UHPLC-DAD coupled with ion trap or time of flight mass detectors together with the analysis of
655
acidic hydrolysis products allowed a comprehensive determination of flavonoid composition.
656
Among dominating compounds, the occurrence of myricetin, kaempferol, isorhamnetin and
657
kaempferide glucuronides was reported. The developed method can be used as a suitable tool for a
Ac ce p
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642
27 Page 27 of 95
658
more insightful, metabolome-based standardization of flavonoid rich fractions of P. avicularis
659
[cxiii].
660
5.8. Rubia cordifolia
662
Different classes of compounds were isolated from Rubia cordifolia L. (Rubiaceae) such as
663
anthraquinones, naphthoquinones, bicyclic hexapeptides, terpenes and carbohydrates. Anti-
664
proliferative and antioxidant activities are reported for R. cordifolia L., used in Chinese Traditional
665
Medicine for relieving the symptoms due to endometriosis, such as menstrual abdominal pain, post-
666
menstrual abdominal pain, lumbosacral pain, and bearing-down pain and distention in inferior belly
667
[cxvi116].
668
Very few report on analytical approaches for this plant are available in literature. In 2007 a paper
669
focused on the analysis of anthraquinones was published by Mishchenko et al. [cxvii117]. In 2014 a
670
rapid, simple and specific RP-HPLC method has been developed for the quantitative determination
671
of alizarin in the methanolic extracts of roots and aerial parts of R. cordifolia [cxviii118]. In a
672
research work published in 2010 an attempt was made to establish systems of standardization of
673
herbal supplements based on R. cordifolia [cxix119].
cr
us
an
M
d
te
Ac ce p
674
ip t
661
675
5.9. Trifolium pratense
676
Plants from the genus Trifolium (Fabaceae) have been used in traditional medicine by many
677
cultures. In Turkish folk medicine, for example, some Trifolium species are used for their
678
expectorant, analgesic, antiseptic properties and also to treat rheumatic aches. Some species are also
679
grown as pasture crops for animals in the Mediterranean. The high quercetin concentration and
680
soyasaponin occurrence make the seeds of some Trifolium species a potential source of health
681
beneficial phytochemicals to be use in human nutrition. However, T. pratense L. (red clover) has
682
also gained popularity for the treatment of menopausal symptoms [cxx120].
28 Page 28 of 95
683
Pope et al. (1953) isolated biochanin A from red clover extracts. In 1965, Schultz showed that
684
biochanin A and formononetin occur as glycosides in red clover [cxx]. More recently, isoflavones,
685
their glycosides, their malonate glycosides and their acetyl glycosides were determined in red clover
686
extracts using chromatographic and spectrometric methods [cxx- [ 121, 122,cxxiii123].
687
Quality control of red clover was reviewed in 2004; this review highlights practical considerations
688
of value to basic science and clinical investigators engaged in the study of botanical supplements.
689
Lessons and examples are drawn from the authors' experience in designing and developing a red
690
clover standardized extract for evaluation in Phase I and Phase II clinical trials [cxxiv124].
691
Wu and coworkers developed a method for the quality control of Red Flower Oil preparation, a
692
mixture of several plant essential oils, among which T. pretense, used in Traditional Chinese
693
Medicine. Fourier transform IR (FT-IR) was applied and two-dimensional correlation IR
694
spectroscopy (2D IR) was used to enhance the resolution [cxxv125]. More recently, HPLC
695
[cxxvi126] and HPTLC [cxxvii127] methods were developed for the analysis of T. pretense.
696
Finally, red clover was included in a classification study, with the aim to classify some markers of
697
common herbs used in Western medicine according to the Biopharmaceutical Classification System
698
(BCS) [cxxviii128].
te
d
M
an
us
cr
ip t
cxxii
Ac ce p
699
cxxi
700
6. Analytical methods for plants containing phenolic acids used in the treatment of women’s
701
disorders
702
The term “phenolic acids” describes phenols that possess one carboxylic acid functionality. The
703
naturally occurring phenolic acids contain two distinguishing constitutive carbon frameworks: the
704
hydroxycinnamic and hydroxybenzoic structures. Although the basic skeleton remains the same, the
705
numbers and positions of the hydroxyl groups on the aromatic ring create the variety. Phenolic
706
compounds in many plants are polymerized into larger molecules such as hydrolizable tannins.
707
Moreover, phenolic acids may arise in food plants as glycosides or esters with other natural
708
compounds such as sterols, alcohols, glycosides and hydroxyfatty acids. Several biological 29 Page 29 of 95
709
activities are reported for phenolic compounds and among these activity against menstrual
710
disorders, and activity on the vascular and uterine smooth muscles.
711
6.1. Angelica sinensis
713
The dried root of Angelica sinensis (Oliv.) Diels (Umbelliferae), known as Danggui in China, is
714
commonly used in Traditional Chinese Medicine (TCM). This herb is used to treat menstrual
715
disorders, amenorrhea, dysmenorrheal and is in common use in dietary supplements available in
716
China, USA and Europe as health benefits food products for women [cxxix129]. As for the
717
menstrual cycle and treatment of menopausal symptoms caused by the hormonal changes, it can
718
produce favorable effects, so it is also known as “female ginseng” in Europe [cxxx130]. Danggui
719
cultivated in Gansu Province, China, is considered to be an authentic high-quality herb on the basis
720
of thousands of years of traditional experience. Several other substitute herbs are also used in
721
clinical applications in other districts and countries, such as Angelica acutiloba in Japan, Levisticum
722
officinale Koch in Europe, and Angelica gigas in Taiwan. The roots of L. officinale are called
723
European Danggui and are listed in the German Pharmacopeia [cxxxi131].
724
Over 70 compounds have been separated and identified from A. sinensis, including those from
725
essential oils (mainly including monomeric phthalides), phthalide dimers, coumarins, organic acids
726
and their esters, polysaccharides, polyacetylenes, vitamins, amino acids, and others [cxxxii132].
727
Recent phytochemical and pharmacological studies reveal that the major bioactive components of
728
A. sinensis are phenolic acids and phthalides [cxxxiii133].
729
Z-Ligustilide (3-butylidene-4,5-dihydroisobenzofuranone) is one of the main active components of
730
A. sinensis, which exhibits significant effects on improving blood fluidity and strong antioxidant
731
activity, inhibits the contractile function of the vascular and uterine smooth muscles and the
732
proliferation of the vascular smooth muscle cells [cxxxiv134]. Therefore, Z-ligustilide has been
733
chosen as a ‘marker compound’ to assess the quality of Radix Angelicae sinensis and its products
734
[cxxxv135], together with ferulic acid, also used to study the pharmacokinetics of A. sinensis
Ac ce p
te
d
M
an
us
cr
ip t
712
30 Page 30 of 95
[cxxxii]. Various analytical methods have been reported to analyze the chemical constituents of A.
736
sinensis [cxxxiv]. Among these methods, HPLC-UV, HPLC-PAD and HPLC-PAD-MS have been
737
mostly employed to determine phthalides, ferulic acid, coniferyl ferulate, falcarindiol, α-linolenic
738
acid and linoleic acid in A. sinensis. However, using HPLC-PAD or HPLC-MS to identify chemical
739
constituents, it is still necessary to directly compare UV spectra or mass spectra and
740
chromatographic retention times with standards. Wang and coworkers [cxxxiv] developed an
741
HPLC-PAD-API/MS method for analysing the chemical constituents of A. sinensis. ESI and APCI
742
spectra, in both positive ion (PI) and negative ion (NI) modes, provided very useful information
743
concerning the molecular weights of detected compounds, allowing the detection of 15 constituents.
744
Many analytical methods including LC and GC have been previously developed for the quality
745
evaluation of DG [cxxxiii]. However, Z-ligustilide is a volatile and unstable compound,
746
decomposing rapidly at high temperature to form other phthalides through oxidation, isomerization,
747
dimerization [cxxxiv], and therefore GC techniques should not be suitable for analyzing the
748
thermolabile components such as coniferyl ferulate and (Z)-ligustilide. Fingerprinting methods to
749
assess the consistency of A. sinensis dietary supplements were developed using both HPLC-DAD
750
and flow-injection mass spectrometric (FIMS). The components responsible for the chemical
751
differences were pinpointed by the loadings plots of PCA [cxxxvi136].
752
Recently, Bai developed an HPLC-DAD combined with UHPLC-QToF-MS/MS (ultra high
753
performance liquid chromatography photodiode array detector quadrupole time-of-flight mass
754
spectrometry) method for simultaneously determining ten bioactive components belonging to
755
phenolic acids, alkyl phthalides, hydroxylphthalides and phthalide dimers to quantitatively evaluate
756
the effect of seven drying methods on the quality of A. sinensis [cxxxiii]. Cinnamic acid, ferulic
757
acids and derivatives of quercetin were also analyzed by HPLC-PDA [cxxxvii137].
Ac ce p
te
d
M
an
us
cr
ip t
735
758 759
6.2. Artemisia spp. (Asteraceae)
31 Page 31 of 95
The genus Artemisia is grown worldwide and includes several well-known medicinal herbs, and
761
among these A. abrotanum, A. capillaris, A. frigida and A.vulgaris.
762
6.2.1. Artemisia abrotanum
763
Analytical methods are reported for the essential oil and artemisinin content of A. abrotanum L., by
764
GC-MS and LC-MS [cxxxviii138,cxxxix139]. A sample of leaf oil of A. abrotanum, collected in
765
Cuba, was studied by GC and GC-MS, leading to the identification of fifty-seven compounds of
766
which trans-sabinyl acetate (33.4%) was the major component [cxxxix].
767
6.2.2. Artemisia capillaris
768
A. capillaris Thunb. has been widely used in East Asia for the treatment of circulatory disorders,
769
such as dysmenorrhea [cxl140]. It is reported to contain phenolic compounds, chlorogenic acid
770
analogues [cxli141], and sesquiterpenoid derivatives (arteannuin B, artemisitene, artemisinin,
771
dihydroartemisinic acid and artemisinic acid) [cxlii142]. Avula developed LC-UV, LC-ELSD and
772
LC–MS analytical methods for the quantitative determination of sesquiterpenoids from various
773
species of Artemisia samples, among which A. capillaris [cxlii]. Zhao reported the presence in A.
774
capillaris of nine chlorogenic acid analogues (chlorogenic acid, cryptochlorogenic acid,
775
neochlorogenic acid, 3,5-dicaffeoyl-quinic acid, 4,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic
776
acid, chlorogenic acid methyl ester, cryptochlorogenic acid methylester, neochlorogenic acid
777
methylester) by a LC-MS technique [cxli]. Chlorogenic acid, 3,5-di-O-caffeoylquinic acid, 4,5-di-
778
O-caffeoylquinic acid, jaceosidin, and eupatilin were detected in A. capillaris by UPLC-DAD
779
analysis and comparison with A. annua was performed by multivariate analytical methods
780
[cxliii143].
781
6.2.3. Artemisia frigida
782
GC-MS analysis was performed on the essential oil isolated from the aerial parts of A. frigida
783
Willd., showing an high content of 1,8-cineole and camphor [cxliv144].
784
6.2.4. Artemisia vulgaris
Ac ce p
te
d
M
an
us
cr
ip t
760
32 Page 32 of 95
Artemisia vulgaris L., commonly known as mugwort, is a shrub of temperate zones of Europe,
786
Asia, North Africa, and North America. A. vulgaris is reported as uterine stimulant. Phytochemical
787
analysis of A. vulgaris showed that the major chemical constituents were eudesmanolides
788
(sesquiterpene lactones), essential oils (such as cineole, wormwood oil, thujone), triterpenes,
789
coumarin, flavonoids [cxlv145]. The presence of flavonoids eriodictyol and apigenin in A. vulgaris
790
with their weak estrogenic activity, may account for its folkloric use to treat menstrual disorders, as
791
an emmenagogue and uterine relaxant. Furthermore, relaxing activities in other smooth muscles, the
792
ileum and the trachea, are reported. Although not directly tested on the uterus, the smooth muscle
793
relaxing effect could explain why it has been reported to be an uterine antispasmodic [cxlvi146].
794
Melguizo-Melguizo et al., reported the presence of 22 compounds, of which 15 were phenolic
795
compounds, mainly chlorogenic acid derivatives or flavonoids, using an HPLC coupled ESI-QToF-
796
MS [cxlvii147]. In this report the most abundant compound was found to be 3,5-O-dicaffeoylquinic
797
acid. Also protocatechuic acid and quinic acid were present in high amounts while flavonoids
798
showed a significantly lower concentration.
799
Alaerts and coworkers obtained fingerprints by a HPLC-DAD method aimed to the distinction,
800
identification and quality control of four different Artemisia species, i.e. A. vulgaris, A. absinthium,
801
A. annua and A. capillaris samples. The lowest similarity between the fingerprints of the four
802
species occurred at 214 nm. The distinction of the four species of Artemisia was visualised by PCA
803
in score plots [iii].
cr
us
an
M
d
te
Ac ce p
804
ip t
785
805
6.3. Chamaemelum nobile
806
Adulteration of commercial chamomile products is one of the most significant drawbacks in the
807
promotion of herbal chamomile products. Roman chamomile (Anthemis nobilis, syn. Chamaemelum
808
nobile L. (All.), Asteraceae) is known to contain several classes of biologically active lipophilic and
809
hydrophilic molecules including essential oils, coumarins and several polyphenols (primarily the
810
flavonoids). The main constituents of the Roman chamomile oil have been reported to be primarily 33 Page 33 of 95
angelate, tiglate and butyrate esters [cxlviii148]. In addition, the Roman chamomile oils often
812
contain monoterpene and sesquiterepene derivatives. Among these biologically important
813
molecules, spiroethers and coumarins are of interest due to their unique biological activity profiles.
814
Of the two spiroether isomers, the cis form was reported to exhibit more potent antispasmodic and
815
anti-inflammatory activity than the trans form and herniarin is reported to possess spasmolytic
816
activity [cxlix149]. Ma and coworkers developed an HPLC-PAD-MS method to validate and
817
quantitatively determine cis-en-yn-dicycloether and trans-en-yn-dicycloether as well as a major
818
coumarin compound, hernarin [cxlix]. The use of HPLC-PAD-MS allowed the isolation and
819
identification of other constituents such as umbelliferone, phytol, luteolin-7-O-β-glucoside, (Z)-2-β-
820
glucopyranosyloxyl-4-methoxycinnamic
821
acid,
822
glucoside, and 4,5-dicaffeoylquinic acid. Flowers contained large amount of spiroethers with higher
823
contents of trans-spiroether than the cis form in both flowers [cxlix]. Avula and coworkers used a
824
method based on high separation efficiency UHPLC with UV and QToF detection for the
825
quantification of phenolic compounds (cis-GMCA, chlorogenic acid, trans-GMCA, quercetagetin-
826
7-O-β-glucopyranoside, luteolin-7-O-β-glucoside, apigetrin, chamaemeloside apigenin-7-(6''-O-
827
acetyl)-glucoside, apigenin, and one poly-acetylene (tonghaosu) in C. nobile [cl150]. Roman
828
chamomile samples confirmed the presence of chamamaeloside and apigenin as major compounds.
829
PLS-DA was used to discriminate between commercial chamomile samples.
830
An analytical method based on the GC-MS analysis was developed by Wang [cxlviii] and applied
831
to the analysis of non-polar compounds in various chamomile samples.
an
(E)-2-β-glucopyranosyloxyl-4-methoxycinnamic
apigenin-7-(6''-O-acetyl)-glucoside,
umbelliferone
7-O-β-
Ac ce p
te
d
M
apigenin-7-O-β-glucoside,
acid,
us
cr
ip t
811
832 833
6.4. Curcuma spp. (Zingiberaceae)
834
6.4.1. Curcuma longa
835
Curcuma longa L., also known as turmeric, is a plant native of Southern Asia and is cultivated
836
extensively throughout the warmer parts of the world. The drug is represented by the rhizome and 34 Page 34 of 95
tuberous root. Among its several activities, it is most commonly used in postpartum recovery, and is
838
reported to treat excessive vaginal discharges and menstrual disorders [cxlvi]. Turmeric is a spice
839
most subjected to adulteration since it is frequently traded in ground form. Turmeric powder is
840
adulterated with rhizomes of cheaply available Curcuma species especially with those containing
841
the coloring pigment curcumin such as Curcuma zedoaria (Christm.) Rosc. or ‘yellow shoti’ syn.
842
Curcuma xanthorrhiza Roxb. ‘Manjakua’ and Curcuma malabarica Vel. leading to toxicity and
843
poor quality of the product [cli151].
844
Characteristic constituents responsible for the therapeutic effect of C. longa are the curcuminoids,
845
namely curcumin, desmethoxycurcumin and bisdesmethoxycurcumin [clii152]. The three
846
curcuminoids are the basis for the quality control of C. longa and derived preparations.
847
Quali-quantitative analysis of curcuminoids by different methods including TLC [cliii153], HPTLC
848
[cliv154,clv155], NIR spectroscopy [clvi156], microemulsion electrokinetic chromatography
849
[clvii157], CE [clviii158] supercritical fluid chromatography [clix159], and direct analysis in real
850
time (DART), an ion source technique [clx160] has been reported. Methods based on LC–ESI-MS2
851
[clxi161, 162,clxiii163] and LC coupled with a hybrid triple quadrupole linear ion trap [clxiv164]
852
were employed. HPLC-DAD and HPLC–ESI-MS methods were also developed to analyze the
853
tinctures of turmeric [clxv165]. Since by HPLC is difficult to produce complete separation of the
854
three curcuminoids (special stationary phase is needed) and the analysis is time consuming (10 min
855
at least), UPLC methods for simultaneous quantification of the three curcuminoids were developed
856
[clxvi166,clxvii167].
cr
us
an
M
d
te
clxii
Ac ce p
857
ip t
837
858
6.4.2. Curcuma xanthorrhiza
859
Curcuma xanthorrhiza Roxb. is one of the most commonly used ingredients in Indo-Malaysian
860
traditional
861
bisdemethoxycurcumin) of C. xanthorrhiza were quantified by HPLC [clxviii168], and later Ruslay
medicines.
The
known
curcuminoids
(curcumin,
demethoxycurcumin
and
35 Page 35 of 95
and coworkers developed an HPLC-DAD and HPLC-DAD-ESI-MSn to identify in the rhizome of
863
this species the three compounds [clxix169].
864
6.4.3. Curcuma zeodaria
865
Curcuminoids of C. zeodaria Rosc. have been analyzed by HPLC [clxx170,clxxi171] and by
866
UPLC-UV-MS methods [clxvii].
867
GC-MS methods were developed for qualitative and/or quantitative determination of volatiles of C.
868
longa, C. xanthorrizha, C. zeodaria [clxxii172,clxxiii173].
us
869
cr
ip t
862
6.5. Echinacea purpurea
871
Echinacea purpurea (L.) Moench (Asteraceae), also known as the purple coneflower, is an herbal
872
medicine that has been used for centuries, for the treatment of common cold, coughs, bronchitis,
873
upper respiratory infections, and some inflammatory conditions. Recently papers reporting an use in
874
circulation disorders, feminine endocrine disorders and menstrual symptoms have been published
875
[clxxiv174,clxxv175]. The three species currently used are Echinacea angustifolia DC., E. pallida
876
(Nutt.) Nutt. and E. purpurea [clxxvi176]. Due to their close taxonomic alliance, it is difficult to
877
distinguish between them and incidences of incorrectly labeled commercial products have been
878
reported. The main chemical constituents include alkamides, phenylpropanoids, polysaccharides
879
and volatile oils, as well as minor constituents such as flavonoids. The chemical composition
880
determined using LC, is traditionally used to establish the quality of plant material and preparations,
881
as well as to identify the species [clxxvi]. Different analytical methods were applied to this topic,
882
and in particular in 2003 HPLC coupled with UV photodiode-array detection and LC-ESI-MS were
883
developed for the simultaneous analysis of caffeic acid derivates and alkamides in the roots and
884
extracts of E. purpurea. The method was proposed for the quality control of plant material and
885
extracts [clxxvii177]. An accurate analysis focused on caffeic acid derivatives was proposed in
886
2004 by Li et al. The method was applied to 16 differents commercial preparation and proposed for
887
quality control [clxxviii178]. HPLC coupled with mass spectrometry was applied successively to
Ac ce p
te
d
M
an
870
36 Page 36 of 95
the simultaneous analysis of caffeic acid derivatives and alkamides [clxxix179]. E. purpurea was
889
distinguished from E. angustifolia by means of HPLC coupled to ELSD, and the method was
890
applied to raw material and extracts [clxxx180]. NMR was proposed as an alternative quality
891
control method: Diffusion-edited 1H-NMR (1D-DOSY) and 1H-NMR with suppression of the EtOH
892
and water signals were applied for the first time to the direct analysis of commercial herbal tinctures
893
derived from E. purpurea [clxxxi181]. UPLC was explored for the same purpose in 2011
894
[clxxxii182], and in 2013 commercial products of E. purpurea were analysed for their content in
895
phenylpropanoid by TLC with video Densitometry [clxxxiii183]. Finally a chemometric approach
896
was proposed to process data obtained from hyperspectral imaging of roots and leaves of raw
897
material of E. purpurea [clxxxiv184].
an
us
cr
ip t
888
M
898
6.6. Humulus lupulus
900
Humulus lupulus L. (Cannabaceae) is well-known throughout the world as the raw material in the
901
brewing industry. The female inflorescences (hop cones or “hops”) are widely used to preserve beer
902
and to give it a characteristic aroma and flavour. In addition hop cones have long been used for
903
medicinal purposes. In particular, hop preparations were mainly recommended for the treatment of
904
sleeping disorders, as a mild sedative, and for the activation of gastric function as bitter stomachic
905
[clxxxv185]. In addition, hop extracts reduce hot flushes in menopausal women, and a placebo-
906
controlled study on the use of a standardized (8-prenylnaringenin) hop extract revealed that the
907
daily administration in menopausal women decreased the incidence of hot flushes and other
908
discomforts associated to estrogen deficiency (sweating, insomnia, heart palpitation, irritability).
909
Moreover vaginal dryness in postmenopausal women was significantly reduced by the topical
910
application of a gel containing hyaluronic acid, liposomes, vitamin E and hop extract [clxxxv].
911
Hop cones are characterized by a unique and complex pool of secondary metabolites, comprising
912
both prenylflavonoids and prenylphloroglucinols. Three classes of compounds are of particular
913
relevance in relation to bitterness intensity, sensorial properties and health benefits: prenylchalcones
Ac ce p
te
d
899
37 Page 37 of 95
(xanthohumol, desmethylxanthohumol), prenylflavanones (isoxanthohumol, 6-prenylnaringenin, 8-
915
prenylnaringenin) and prenylphloroglucinols, also known as bitter acids or hop acids [clxxxv]. The
916
well-known 8-prenylnaringenin has been shown to be one of the most potent phytoestrogens
917
currently known. Therefore, xanthohumol, isoxanthohumol, 6-prenylnaringenin, 8-prenylnaringenin
918
are appropriate active constituents for the chemical standardization of hop dietary supplements to be
919
used by menopausal women, except the chalcone desmethylxanthohumol which is unstable and
920
readily cyclizes to form 6-prenylnaringenin and 8-prenylnaringenin [clxxxvi186].
921
Several analytical methods to quantify these compounds in various matrices, such as hop extracts,
922
hop products, beer, dietary supplements, human urine, serum, rat plasma, tissues have been
923
developed [clxxxvii187]. As regards hop extracts, methods based on HPLC-UV, HPLC coupled
924
ECD, CE and HPTLC were applied for the analysis of prenylated flavonoids [clxxxvii].
925
Prenylflavonoids and hop bitter acids in hop extracts have also been analyzed using HPLC-MS
926
[clxxxviii188].
927
Magalhães developed a methodology based on the sample purification by adsorption of phenolic
928
compounds from the matrix to polyvinylpolypyrrolidone (PVPP) and subsequent desorption of the
929
adsorbed polyphenols followed by the analysis of the extract by HPLC-DAD and HPLC-ESI-MS2
930
[clxxxvi].
931
Recently, Prencipe and coworkers developed an analytical method for the metabolite fingerprinting
932
of bioactive compounds in hop, together with a simple extraction procedure. Different extraction
933
techniques, including maceration, heat reflux extraction (HRE), ultrasound-assisted extraction
934
(UAE) and microwave-assisted extraction (MAE) were compared in order to obtain a high yield of
935
the target analytes. The analysis of hop constituents, including prenylflavonoids and
936
prenylphloroglucinols (bitter acids) was carried out by means of HPLC-UV/DAD, HPLC-ESI-MS
937
and MS2 [clxxxix189].
938
A broad spectrum of preparation and analytical liquid chromatography techniques, coupled with
939
mass spectroscopy (MS) have been applied to the analysis of various proanthocyanidins in hops
Ac ce p
te
d
M
an
us
cr
ip t
914
38 Page 38 of 95
940
[cxc190]. Fingerprints of commercial cultivars of H. lupulus have been also obtained coupling 2D
941
NMR datasets with PCA [cxci191]
942
6.7. Magnolia officinalis
944
Magnoliae officinalis Cortex (Houpo) is the dried stem bark, root bark or branch bark of Magnolia
945
officinalis Rehd. et Wils (Magnoliaceae). It has been used as a TCM for more than 2000 years for
946
the treatment of epigastric stuffiness, vomiting and diarrhea, abdominal distention and constipation,
947
cough and dyspnea [cxcii192]. Neolignans, sesquiterpenes, sesquiterpene neolignans, and
948
phenylpropanoids have been identified in M. officinalis. Oligomeric neolignans present in the plant
949
are linked through the aromatic rings. The quality control of this herbal medicine is currently based
950
on the assay of two active biphenolic compounds, namely magnolol (M) and honokiol (H) by TLC
951
or HPLC. Advanced methods for the analysis of M. officinalis cortex were proposed in last years.
952
An UPLC-DAD-ToF-MS fingerprinting method was developed for the quality control and source
953
discrimination of Cortex Magnoliae officinalis produced in Zhejiang Province (Wen-Hou-Po). Data
954
were statistically evaluated using similarity analysis, hierarchical cluster analysis (HCA) and
955
discriminant analysis [cxciii193].
956
In 2012 a method based on 1H NMR coupled with chemometric analysis was proposed to identify
957
the metabolites contributing to the differences between the samples and to discriminate different
958
medicinal parts and geographical origins of these samples. The correlation between the data from
959
1
960
Honokiol and magnolol were the main compounds responsible for the discrimination of samples
961
from different batches, thus proving that the choice of these two compounds as markers for quality
962
assessment by HPLC is relevant. The two sources of Magnoliae officinalis Cortex recorded in the
963
Chinese Pharmacopoeia, M. officinalis and M. officinalis var. biloba, could be differentiated by 1H-
964
NMR data, but the pattern recognition analysis by PLS-DA was unsuccessful in discriminating
Ac ce p
te
d
M
an
us
cr
ip t
943
H-NMR and HPLC was performed with the mixOmics software based on an unsupervised method.
39 Page 39 of 95
1
965
samples from various geographical origins. The combination of
H-NMR that gives a
966
comprehensive profile of the metabolites and HPLC that targets two biomarkers is an efficient mean
967
for the quality control of M. officinalis Cortex [cxcii].
ip t
968
6.8. Pimenta dioica
970
Pimenta dioica (Merr.) L., syn. Pimenta officinalis (Berg) L. (Myrtaceae) is widely distributed in
971
West Indies, Mexico, and South America and traditionally known as allspice, pimenta, pimento,
972
clove pepper and Jamaica pepper. The plant has been cultivated in Egypt, where it is known as
973
“fulful afrangi”. It is traditionally used as a spice and condiment and as a remedy against menstrual
974
disorders, while it is industrially used for tanning purposes and as flavouring and perfuming agent
975
in soaps, tonics, as well as for appetizing medicines. The plant shows high content and biological
976
diversity of the active constituents, phenolic acids, flavonoids, catechins, galloylglucosides,
977
phenylpropanoids, diterpenes and lupeol [cxciv194].
978
Analytical approaches to this species, involve both essential oils and phenolic compounds. For the
979
first aspect, in 2013 Amma and coworkers studied extensively essential oils by using a comparative
980
approach based on GC and GC-MS [cxcv195]. In 2006 analysis of the essential oils was approached
981
by multidimensional GC [cxcvi196]. Polyphenolic compounds were studied and analysed in a
982
recent paper that deals with the separation of 27 known compounds and two new polyphenolic
983
glucosides from the berries of Pimenta dioica [cxcvii197]. Standardization of preparations obtained
984
from P. dioica was gained both based on essential oil or salycilic acid [cxcviii198].
us
an
M
d
te
Ac ce p
985
cr
969
986
6.9. Piper methysticum
987
Kava (Piper methysticum G. Forster) is the name of a plant and drink traditionally prepared by
988
macerating its roots in cool water or coconut water [cxcix199]. It has been used for many centuries
989
in the South Pacific and Hawaii for social ceremonies, relaxation, medicine, and a multitude of
990
other purposes [cxcix]. More recently, standardized kava extracts, containing 30% active 40 Page 40 of 95
constituents, have been used globally as an anxiolytic [cxcix]. Additionally, a tight inverse
992
correlation between high rates of kava consumption and low incidences of cancer for populations in
993
the South Pacific has been reported. Some evidence points to the efficacy of black cohosh, exercise,
994
and possibly kava kava (P. methysticum) in the treatment of menopausal symptoms [cc200]. In the
995
last two decades various procedures concerning the separation and detection of kavalactones have
996
been routinely carried out by GC (without previous derivatization of kavalactones) [cci201] and
997
HPLC [ccii202] but most of them are not validated or only partially validated. Recently, analyses
998
by supercritical fluid chromatography and micellar electrokinetic chromatography have also been
999
reported. Both GC and HPLC can be used for the analysis of kavalactones with some advantages
1000
and disadvantages for each method. Using GC analysis, methysticin and yangonin, which are two of
1001
the major components, are generally not separated. In addition, the high temperature caused the
1002
decomposition of methysticin. Concerning HPLC analyses, the reversed-phase is generally better
1003
because highly reproducible with a very low detection limit for all compounds even if the
1004
quantitative analysis of the kavalactones by LC needs to be carried out in the absence of light to
1005
prevent the cis/trans isomerisation of yangonin. Recently analysis of Kavalactone has been
1006
reviewed by Bilia et al. [cciii203].
1007
DNA based analysis was applied for the correct identification of plant species and subspecies. This
1008
was object of a patent in 2007 [cciv204]. NIR spectroscopy coupled with chemiometric methods
1009
was applied to the quality control of kava kava, and in particular classification by PLS. The
1010
measurements were reproducible and showed repeatability on par with the HPLC method [ccv205].
cr
us
an
M
d
te
Ac ce p
1011
ip t
991
1012
7. Analytical methods for plants containing terpenes used in the treatment of women’s
1013
disorders
1014
Terpenoids are a class of natural products widespread in nature, mainly in plants as constituents of
1015
essential oils. Their building block is the hydrocarbon isoprene, CH2=C(CH3)-CH=CH2. Terpene
1016
hydrocarbons therefore have molecular formula (C5H8)n and they are classified according to the 41 Page 41 of 95
number of isoprene units, as hemiterpenoids, consisting of a single isoprene unit, monoterpenoids,
1018
consisting of two isoprene units, sesquiterpenes, diterpenes, triterpenes and tetraterpenoids with
1019
three, four, six and eight isoprene units, respectively. Most of the terpenoids have multicyclic
1020
structures that differ from one another by their functional groups and basic carbon skeletons. These
1021
types of natural lipids can be found in every class of living things, and therefore considered as the
1022
largest group of natural products. Several medicinal plants for women's healthcare contain terpenes
1023
which are responsible to induce menstruation or abortion, to reduce menstrual bleeding and
1024
postpartum hemorrhage and to alleviate menstrual diseases [cxlvi].
1025
The detection of triterpene glycosides using UV is well known for its insensitivity because of the
1026
weak chromophoric functionality of triterpene glycosides in the 200–210 nm region. LC-MS or LC-
1027
MS2 methods may work well for the identification and quantification of the wide range of triterpene
1028
glycosides [ccvi206]. However, such equipment is expensive and may not be readily available.
1029
Thus, the development of an alternative HPLC method with a reliable and reproducible detection is
1030
desirable. The inexpensive ELSD may be suitable for the routine analysis of plant matrix containing
1031
triterpenes [ccvi].
cr
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an
M
d
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Ac ce p
1032
ip t
1017
1033
7.1. Alisma orientalis
1034
Alisma orientalis Sam. belongs to Alismataceae family and its dried tuber is known in traditional
1035
Chinese medicine (TCM) as Rhizoma Alismatis or Zexie. Terpenes, including protostane
1036
triterpenoids, kaurane diterpenes, and guaiane sesquiterpenes, are the major chemical constituents
1037
of this plant [ccvii207]. To date, all protostane triterpenes occur only in Alisma plants, and they are
1038
considered to be chemotaxonomic markers of the genus. Alisolide, alisol O and alisol P, alisol A,
1039
alisol B, alisol B 23-acetate, 25-O-methylalisol A, 25-anhydroalisol A 24-acetate, 25-anhydroalisol
1040
A, alisol E 23-acetate, as well as 13β,17β-epoxyalisol A were isolated from the rhizome of A.
1041
orientalis.
42 Page 42 of 95
A. orientalis is a component, together other five herbal medicine (Paeonia lactiflora, Angelica
1043
sinensis, Ligusticum chuanxiong, Poria cocos, Atractylodis macrocephalae) of Danggui-Shaoyao-
1044
San (DSS), a famous traditional Chinese medicine formula, used as a classical gynecological
1045
remedy in China for centuries. Chen and coworkers developed an HPLC-DAD-ESI-MS2 method for
1046
the qualitative and quantitative analysis of the major constituents of this herbal product [ccviii208].
1047
Chemical profiles of A. orientalis have been investigated by TLC, HPCE-UV, HPLC-UV, HPLC-
1048
ELSD, and HPLC-IT-MS [ccix209]. In all these reports only three compounds, namely alisol A,
1049
alisol A 24-actetate, and alisol B 23-actetate were isolated and investigated. Liu developed an
1050
UPLC/Q-ToF-MS method for the analysis of protostane triterpenoids in A. orientalis. 20
1051
components were simultaneously separated within 7 min, and identified either through comparing
1052
the retention time (Rt) and CID fragmentation behaviors with those of the reference standards, or
1053
matching empirical molecular formulae with those of published compounds. Moreover, Liu
1054
reported firstly the CID fragmentation pathway of protostane triterpenoids [ccix].
1055
te
d
M
an
us
cr
ip t
1042
7.2. Calendula officinalis
1057
Calendula officinalis L. (Asteraceae) is an annual herb, native of the Mediterranean region, also
1058
known as marigold. Its flowers have been widely used in traditional medicine and also used as
1059
female diseases. The major constituents of C. officinalis include steroids, terpenoids, triterpenoids
1060
(isolated in both free and ester form), flavonoids, phenolic acids and carotenes [ccx210]. Faradiol,
1061
rutin, caffeic acid and chlorogenic acid have all been isolated from C. officinalis and have shown
1062
biological activities. The most potent anti-inflammatory effects of C. officinalis have been attributed
1063
to the faradiol monoesters, compounds belonging to the triterpenoid family [ccx]. Neukirch et al.
1064
quantified simultaneously eight pentacyclic terpenoids using reversed-phase HPLC of 10 varieties
1065
of C. officinalis, showing that the variety Calypso Orange Florensis produces the largest amounts of
1066
the bioactive terpenoids, in particular of faradiol laurate which is present in the whole flowers of
1067
this variety at levels which are two-fold higher than those previously determined in the specialised
Ac ce p
1056
43 Page 43 of 95
ray florets [ccxi211]. Loescher and coworkers compared HPTLC and HPLC for qualitative and
1069
quantitative analysis of the major constituents of C. officinalis and to investigate the effect of
1070
different extraction techniques on the composition of C. officinalis extracts from different parts of
1071
the plant [ccx]. They observed that HPTLC analysis is able to provide useful qualitative data for the
1072
quick determination of key standards in samples, with easy comparisons to be made between
1073
different extracts. Quantitatively, however, HPTLC data showed high variability which may be due
1074
in part to limitations in the sensitivity of the software. Authors claimed that HPLC is a more robust
1075
method and is preferred for quantitative analysis.
1076
Several reports on the essential oil composition of C. officinalis showed as the quantitative amount
1077
of the monoterpenes, sesquiterpenes and sesquiterpene alcohols, varies from country to country
1078
[ccxii212].
M
an
us
cr
ip t
1068
1079
7.3. Caulophyllum thalictroides
1081
Caulophyllum thalictroides (L.) Michx (Berberidaceae) is a perennial plant that grows in the United
1082
States and Canada. This plant is called blue cohosh and is well-known as a traditional women’s
1083
herb to ease childbirth and to treat uterine inflammation among Native Americans
1084
[ccxiii213,ccxiv214]. Traditionally the roots and rhizomes of C. thalictroides are used for the
1085
treatment of menstrual difficulties and to induce uterine contractions. Extracts of the underground
1086
parts of C. thalictroides are used as an herbal dietary supplement for regulation of the menstrual
1087
cycle and women’s diseases and as an antispasmodic [ccxiii,ccxiv]. Alkaloids (caulophyllumines A,
1088
caulophyllumines
1089
caulophyllosaponin), and triterpene glycosides have been isolated and identified. Saponins in blue
1090
cohosh are considered to be responsible for the uterine stimulant effects together with teratogenic
1091
alkaloids [ccxiii,ccxiv]. As this regards, there is considerable concern about the safety of blue
1092
cohosh with reports of new born babies having heart attacks or strokes after the mother consumed
1093
blue cohosh to induce labor. Analytical methods have been reported for the analysis of alkaloids
Ac ce p
te
d
1080
B,
and
magnoflorine),
steroidal
glycosides
(caulosaponin
and
44 Page 44 of 95
alone or for alkaloids and saponins. Alkaloid levels were firstly determined by TLC densitometric
1095
and HPLC methods in in the extract of C. thalictroides [ccxv215] and also by GC in dietary
1096
supplements that contain blue cohosh [ccxiv]. Successively, HPLC methods were developed for the
1097
quantitative analysis of alkaloids and saponins from C. thalictroides roots [ccxvi216] and from
1098
extracts of blue cohosh roots and dietary supplements [ccxvii217]. More recently, analytical
1099
methods including HPLC, UPLC and HPTLC have been reported for the determination of major
1100
alkaloids and triterpene saponins in the roots of C. thalictroides and in dietary supplements
1101
claiming to contain blue cohosh [ccxiii].
us
cr
ip t
1094
1102
7.3. Cimicifuga racemosa
1104
Cimicifuga racemosa (L.) Nutt., or Actaea racemosa (Ranunculaceae) commonly known as black
1105
cohosh, is native to North America. The roots and rhyzomes have been used traditionally by Native
1106
Americans for gynecological conditions [ccvi]. Various preparations of this plant have also been
1107
used for the treatment of menopausal disorders in Germany for over 50 years, and are presently
1108
available in USA as dietary supplements. A number of clinical studies have been published in
1109
support of the use of black cohosh as alternative treatment of menopausal symptoms [ccvi].
1110
Chemically, C. racemosa extracts contain triterpene glycosides, such as actein, 26-deoxyactein, and
1111
phenolic compounds, such as ferulic acid and isoferulic acid, flavonoids, such as formononetin
1112
[ccvi]. Currently, the standardization of black cohosh preparations is based on the content of
1113
triterpene glycosides, calculated as 26-deoxyactein. In general, RP-HPLC with UV detection is used
1114
for the analysis of C. racemosa samples, but triterpene glycosides of C. racemosa have a weak UV
1115
absorbance. Ganzera et al. reported an HPLC-ELSD method for the determination of actein, 26-
1116
deoxyactein, and cimiracemoside A [ccxviii218] while Li developed an HPLC method with ELSD
1117
and PAD for the quantitative analysis of 16 constituents of C. racemosa [ccvi]. Avula et al.
1118
developed an HPLC-ELSD method for the analysis of terpenoids in different C. racemosa samples
1119
[ccxix219]. Because of the increase in botanical trade between the USA and China in recent years,
Ac ce p
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1103
45 Page 45 of 95
Chinese species of Actaea, including ‘shengma’, have become an adulterant in US-made black
1121
cohosh products. Moreover, due to overlap of the distribution area and similarity of leaf appearance
1122
of some species with black cohosh, some American species of Actaea might also be misidentified as
1123
black cohosh. Canadian Health have found that several cases of liver toxicity were associated with
1124
people who took black cohosh products adulterated with related herbal species. For this reason,
1125
Jiang et al. evaluated the authencity and described the phytochemical profile of 11 C. racemosa
1126
products by HPLC-DAD and selected ion monitoring (SIM)-LC-MS [ccxx220].
1127
LC-Atmospheric pressure chemical ionization (APCI)-MS for triterpene glycosides [ccxxi221], an
1128
LC-turbo ion spray (TIS)-MS method to examine the LC-MS chromatography or “fingerprint
1129
profile” of C. racemosa samples and derived products [ccxxii222] have been reported. Ma et al.
1130
studied the metabolite profiling of C. racemosa extracts by HPLC–ESI-ToF-MS technique and
1131
principal component analysis identifying 15 chemical markers [ccxxiii223]. Moreover, the
1132
phytochemical fingerprints of fifteen species of Cimicifuga were established using HPLC-PDA and
1133
LC-MS techniques. Polyphenols and triterpene glycosides made the black cohosh clearly
1134
distinguishable from most other species of Cimicifuga [ccxxiv224].
cr
us
an
M
d
te
Ac ce p
1135
ip t
1120
1136
7.4. Crocus sativus
1137
Saffron, which is obtained from the dried red stigmas of Crocus sativus L. (Iridaceae), is the most
1138
expensive spice in the world. It has broad use in the food industry as an additive for coloring and
1139
flavoring foods. It is also employed as a drug in traditional medicine and in Persian traditional
1140
medicine saffron is used to treat menstrual disorders [ccxxv225]. Saffron has also been found to be
1141
effective in relieving symptoms of premenstrual symptoms (PMS), dysmenorrhea and irregular
1142
menstruation [ccxxv]. The typical color, taste, aroma and flavor of saffron are determined by the
1143
following
1144
neapolitanose or triglucoses as the saccharidic moieties) are responsible for the strong coloring
1145
capacity, picrocrocin (the glucosylated monoterpene precursor of safranal) confers the bitter taste
compounds:
crocins
(glycosylated apocarotenoids
with glucose,
gentiobiose,
46 Page 46 of 95
and safranal (a monoterpene aldehyde derived from the chemical or enzymatic dehydration of
1147
picrocrocin during saffron handling, drying and storage) gives rise to its characteristic odor and
1148
aroma.
1149
The quality of saffron and its commercial value are determined by specifications described within
1150
the ISO/TS-3632 standard [ccxxvi226] that establishes the spectrophotometric quantification of
1151
picrocrocin and safranal in aqueous saffron extracts by absorbance measurements at 440, 257 and
1152
330 nm. Unfortunately, this method presents some disadvantages because safranal is just barely
1153
water soluble and also exhibits adsorption in the same (320 e 340 nm) range as cis-crocin isomers
1154
[ccxxvii227].
1155
Several works concerning different qualitative aspects of saffron are present in literature; different
1156
analytical techniques have been applied, primarily UV e Vis spectrophotometry and NIRS, to
1157
determine the characteristic chemical compounds [ccxxvi]. Mass spectrometry combined with GC,
1158
HPLC and LC analysis have been focused on the identification of volatile molecules, coloring
1159
pigments or taste compounds [ccxxvi- [ccxxviii228].
1160
Studies reported the investigation of saffron as performed by MIR (Mid-Infrared spectroscopy)
1161
[ccxxix229], and by multi-element stable isotope analysis [ccxxx230]. The recourse to DNA
1162
fingerprinting for food authentication is reported for routine quality control. A method based on
1163
Sequence-Characterized Amplified Regions (SCARs) was applied to 24 different food products
1164
containing different amounts of saffron in order to detect adulteration/contamination with seven
1165
common bulking agents [ccxxxi231]. Also NMR combined with PCA was used to discriminate
1166
between Iranian saffron and commercial samples by analyzing methanol extracts [ccxxxii232],
1167
between authentic Greek saffron and four typical plant-derived materials utilized as bulking agents
1168
in saffron, i.e., Crocus sativus stamens, safflower, turmeric, and gardenia [ccxxxiii233] and
1169
between Italian Protected Designation of Origin (PDO) saffron from L'Aquila, S. Gimignano and
1170
Sardinia and commercial saffron samples available on the Italian market [ccxxvi]. Due to its high
1171
market value, perceived value, demanding production, and premium price, attempts have been made
Ac ce p
te
d
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1146
47 Page 47 of 95
to adulterate saffron with various substances with similar color and morphology to increase the
1173
volume and weight of commercial lots. The most frequently incorporated materials are Carthamus
1174
tinctorius, Calendula officinalis and Arnica montana flowers, Bixa orellana seeds, Hemerocallis sp.
1175
petals, Curcuma longa rhizomes and Crocus vernus stigmas [ccxxxi].
ip t
1172
1176
7.6. Cyperus rotundus
1178
Cyperus rotundus L. (purple nut sedge), belonging to the family Cyperaceae, is a perennial herb,
1179
used in Chinese Traditional Medicine for the treatment of primary dysmenorrhea [ccxxxiv234].
1180
Several reports have stated the presence of sesquiterpenes, such as valencene and nootkatone,
1181
furochromones, sterols, flavonoids, and triterpenes in the rhizomes of this plant [ccxxxv235]. GC-
1182
MS methods have been developed to analyze essential oil composition of C. rotundus
1183
[ccxxxvi236,ccxxxvii237]. Priya Rani developed HPTLC and HPLC methods with UV detection to
1184
identify three sesquiterpenoids solavetivone, aristolone and nootkatone in the acetone extract of C.
1185
rotundus [ccxxxviii238]. Kumar and coworkers studied the hydroalcoholic fraction of C. rotundus
1186
by LC-ESI-MS/MS, identifying the presence of polyphenols, flavonoids and sesquiterpenes
1187
[ccxxxv].
1188
Jaiswal et al. obtained a metabolite profiling and determined the content of (+)-nootkatone in
1189
rhizome of C. rotundus. Laser dissected tissues, namely, the cortex, hypodermal fiber bundles,
1190
endodermis, amphivasal vascular bundles, and whole rhizomes were analyzed by UHPLC-QToF-
1191
MS. GC-MS analysis was used for profiling essential oil constituents and quantitation of (+)-
1192
nootkatone [ccxxxix239]. The quantitative determination of ferulic acid in C. rotundus by HPLC
1193
was also reported [ccxl240].
Ac ce p
te
d
M
an
us
cr
1177
1194 1195
7.7. Foeniculum vulgare
1196
Fennel (Foeniculum vulgare Mill., Ombrelliferae) is an aromatic perennial herb with a deep thick
1197
taproot. Different varieties are cultivated as a spice or vegetable, for an essential oil used to flavor 48 Page 48 of 95
foods, and in some countries, for medicinal purposes. Few extracts of F. vulgare and isolated
1199
compounds have been evaluated for several activities, namely, antiaging, anti-inflammatory,
1200
antimicrobial and antispasmodic [ccxli241].
1201
It seems that fennel can be effective in reducing the severity of dysmenorrhea, but it has an
1202
unpleasant taste in view of most of the volunteers [ccxlii242].
1203
Most of analytical literature on fennel regards the analysis of essential oil, markers for quality
1204
control of the species. Most of the analyses were performed by GC and mono and bi-dimensional
1205
GC-MS [ccxliii243,ccxliv244].
1206
In 2005 Raman spectroscopy was proposed as an alternative to GC for the anlaysis of fennel
1207
essential oil [ccxlv245]. Cross-sections of fennel seeds were investigated by the use of Raman
1208
spectroscopy and Raman mapping to localize the essential oil and to analyze its chemical
1209
composition directly in the plant. Furthermore the practicability of a home-built mobile
1210
transportable Raman spectrometer to perform on-site measurements was successfully tested.
1211
An interesting paper, focused on a metabolomics approach for quality control of herbs, introduced
1212
fennel in the analyses. The direct infusion of the samples in ESI-MS and the analyses in both
1213
positive and negative ion mode led to a clear differentiation of the different samples. To verify if the
1214
same approach could be effective also for mixtures of plant extracts, five different commercial
1215
dietary supplements were analyzed by ESI-MS. The data were evaluated by multivariate data
1216
analysis and the obtained results suggested that the method allows a satisfactory and rapid
1217
characterization of complex mixtures of commercial dietary supplements [ccxlvi246].
1218
A simple HPTLC method has been developed for the simultaneous quantification of umbelliferone,
1219
psoralen, and eugenol in the fruit of Foeniculam vulgare. The technique enables rapid and sensitive
1220
simultaneous analysis in different samples. The method was validated for precision, repeatability,
1221
and accuracy in accordance with ICH guidelines [ccxlvii247]. Adulteration issues on this species
1222
are reported in literature, and generally for the essential oil the method with better results in the
Ac ce p
te
d
M
an
us
cr
ip t
1198
49 Page 49 of 95
1223
identification of adulterations is isotopic ratio MS [ccxlviii248]. Anethole, an active compound of
1224
F. vulgare, was also analyzed in different samples of F. vulgare [ccxlix249].
1225
7.8. Panax ginseng
1227
Panax ginseng L. roots (Araliaceae) have been widely used in Chinese traditional medicine since
1228
ancient times owing to their stimulating and tonic properties. Ginseng roots have been used to treat
1229
various diseases, including cancer and cardiovascular diseases, in East Asian countries. Considering
1230
these effects, ginseng may hold value in treating postmenopausal women. A previous randomized
1231
controlled trial (RCT) reported that ginseng extract alleviated some menopausal symptoms, such as
1232
depression, and also improved general health and well-being [ccl250]. The pharmacological
1233
activities of ginseng or its crude extracts are based on the presence of a mixture of triterpenic
1234
saponins referred to as ginsenosides. Ginsenosides are classified into three groups according to the
1235
type of aglycones, i.e., dammarane, ocotillol and oleanane triterpenes. Furthermore, the dammarane
1236
type to which most ginsenosides belong can be generally classified as protopanaxadiol (PPD;
1237
ginsenosides Rb1 (Rb1), Rc, Rd, Rg3, Rh2, etc.) or protopanaxatriol (PPT; Rg1, Re, Rg2, Rh1,
1238
etc.). Although the sugar chains in the PPD-type group are attached to C-3 or C-20, the sugar chains
1239
in the PPT-type group are linked to a hydroxyl moiety at C-6 or C-20. In addition, the two types can
1240
be further differentiated based on the types of sugar chains and the aliphatic chain at C-17 [ccli251].
1241
Methods based on TLC, HPTLC, HPLC coupled with many different kinds of detectors, including
1242
UV, DAD, ELSD, charged aerosol detector (CAD), pulsed amperometric (PAD) detectors have
1243
been applied [cclii252] to the analysis of P. ginseng roots. Among these, ELSD analyses produce
1244
good chromatographic parameters, including high precision and accuracy, and the limit of detection
1245
(LOD) for ginsenosides has been determined at approximately 100 ng. CAD was developed as an
1246
alternative to ELSD to detect poor UV-responsive analytes. Using an HPLC-CAD system, Wang et
1247
al. quantified ginsenosides in P. ginseng founding that CAD produced improved chromatographic
1248
parameters, including sensitivity, linearity and reproducibility, over UV and ELSD [ccliii253]. MS
Ac ce p
te
d
M
an
us
cr
ip t
1226
50 Page 50 of 95
techniques have been widely used in the analysis of P. ginseng root [ccliv254]. Atmospheric
1250
pressure chemical ionization (APCI) and ESI are typically used in ginseng analysis, with ESI being
1251
more common. MALDI has been used for the mass spectrometric imaging of ginsenoside
1252
localization in P. ginseng root [cclii]. Quadrupole (Q), triple quadrupole (QqQ), ion trap (IT), ToF
1253
and Fourier transform ion cyclotron resonance (FT-ICR) are used as mass analyzers for ginseng
1254
analysis [cclii]. Recently, UPLC coupled with quadrupole time-of-flight mass spectroscopy (UPLC-
1255
QToF-MS) has been applied as a powerful analytical tool for rapid analysis of the complex
1256
components or metabolites and chemical transformations in ginseng-related products [ccli].
1257
Metabolite profiling and fingerprint analysis were obtained by 1H NMR spectroscopy to identify
1258
potential biomarkers capable of distinguishing different ginseng species, varieties, and commercial
1259
products [cclv255].
M
an
us
cr
ip t
1249
1260
7.9. Pelargonium graveolens
1262
Pelargonium graveolens L. Her.ex Ait (known also as Geranium graveolens) (Geraniaceae) is used
1263
traditionally for the treatment of hyperglycaemia in multiple folk medicine systems. Geranium spp.
1264
are also used as astringent, diuretic, antidiabetic, antispasmodic for stomach troubles and menstrual
1265
symptoms, and as gargle for throatand tonsils. FDA (US Food and Drug Administration) classified
1266
geranium oils as GRAS (Generally Recognised As Safe) for food use [cclvi256]. Hence, geraniums
1267
are promoted as important aromatic plants and flavoring agents in perfumery, cosmetic, food and
1268
pharmaceutical industries [cclvii257]. Quality control of this species is focused mainly on essential
1269
oils, analyzed by GC-MS, but also by vibrational spectroscopy [cclvi]. The standardization of
1270
geranium oil along with its bioactivity, toxicity and adulterations have been reported in a review
1271
published in 2002 [cclviii258].
Ac ce p
te
d
1261
1272 1273 1274
7.10. Salvia spp. (Lamiaceae) 51 Page 51 of 95
7.10.1. Salvia sclarea
1276
Salvia sclarea L. (clary sage) is one of the most popular Salvia species in Turkey and many
1277
Countries. Clary sage seed has approximately 29% oil content and this oil contains >50% of α-
1278
linolenic acid. This plant, occurring in the Mediterranean basin and Iran, is one of the most
1279
important aromatic plants cultivated worldwide as a source of essential oil. The essential oil or
1280
extracts of the aerial parts of S. sclarea have a broad spectrum of effects including analgesic,
1281
antiinflammatory, antioxidant, antifungal, and antibacterial [cclix259].
1282
In 2008 clary sage essential oils obtained by hydro-distillation of dried aerial parts were analyzed
1283
by GC and GC-MS [cclx260]. Fifty components were characterized in cultivated plants with linalyl
1284
acetate (35.9%), germacrene D (13.3%), linalool (12.8%) and sclareol (9.27%) as dominating
1285
constituents, while 45 constituents were identified for wild plants with linalyl acetate (34.0%),
1286
linalool (18.5%), germacrene D (10.0%) and sclareol (8.7%) as the major constituents. In 2011
1287
Yalcin and coworkers published a study evaluating the effect of γ-irradiation on bioactivity, fatty
1288
acid composition and volatile compounds of clary sage seed based on the fact that γ-irradiation is
1289
widely applied in the preservation of spice quality [cclxi261].
1290
TLC was in addition proposed for a rapid fingerprint of Salvia sclarea [cclxii262]. Most of the
1291
adulterations of S. sclarea are valuable by essential oil composition and bioactivity [cclxiii263].
cr
us
an
M
d
te
Ac ce p
1292
ip t
1275
1293
7.10.2. Salvia miltiorrhiza
1294
Radix Salvia miltiorrhizae Bunge, a plant native in China, is listed in the Chinese Pharmacopoeia
1295
with the name of Dan-Shen and used in Chinese folk medicine for the treatment of different
1296
pathologies. Two classes of major bioactive components in Dan-shen, including water soluble
1297
phenolic acids and lipophilic diterpenoid quinones, have effectiveness in treating coronary heart
1298
disease, heart-stroke, cerebrovascular diseases, menstrual disorders, miscarriage, hepatitis and
1299
insomnia. The study of S. miltiorrhiza components is very complex, therefore selective and efficient
1300
analytical methods are required to simultaneously determine their structures for further studies of 52 Page 52 of 95
the pharmacological effects and to control the quality of the preparations. Currently, there are many
1302
methods for the determination of phenolic compounds and diterpenes among which LC-MS2 was
1303
shown to be a powerful method for separation and identification of individual molecules in complex
1304
samples [cclxiv264].
1305
Cryptotanshinone, tanshinone I and anshinone IIA are important active constituents in S.
1306
miltiorrhiza Bunge. Cryptotanshinone is usually used against inflammation, tanshinone I for
1307
therapy of angina pectoris and anshinone IIA for improving blood circulation [cclxv265].
1308
Separation and determination of the constituents of this medicinal plant was gained mainly by
1309
HPLC-MS. A simple and sensitive HPLC-DAD method was established and validated to
1310
simultaneously quantify 7 major saponins, i.e., notoginsenoside R1, ginsenoside Re, Rg1, Rb1,
1311
Rh1, Rg2 and Rd, in "Danshen Dropping Pills" (DSDP), the best sold traditional Chinese medicine.
1312
The method involved the solid-phase extraction (SPE) and chromatographic separation on a
1313
reversed-phase Agilent Zorbax SB-C18 column [cclxvi266]. In a paper published in 2009 the
1314
chemical characteristics of S. miltiorrhiza collected from different locations in China were revealed,
1315
and salvianolic acid B, rosmarinic acid, cryptotanshinone, and tanshinones I and IIA were
1316
optimized as markers for the quality control of S. miltiorrhiza. The comparison was done on the
1317
basis of the simultaneous quantitative determination of 13 hydrophilic and lipophilic compounds,
1318
by UPLC and hierarchical analysis. The entire chromatographic pattern showed that S. miltiorrhiza
1319
was significantly different from its adulterant Salvia przewalskii [cclxvii267]. A paper reporting
1320
TLC analysis fingerprint was also published in 2006 [cclxviii268].
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1321
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1301
1322
7.11. Tanacetum partenium
1323
Feverfew (Tanacetum parthenium L.) (Asteraceae) is a medicinal plant traditionally used for the
1324
treatment of fevers, migraine headaches, rheumatoid arthritis, stomach aches, toothaches, insect
1325
bites, infertility, and problems with menstruation and labor during childbirth. The feverfew herb has
1326
a long history of use in traditional and folk medicine, especially among Greek and early European 53 Page 53 of 95
herbalists. The plant contains a large number of natural products, but the active principles probably
1328
include one or more sesquiterpene lactones, including parthenolide. Other potentially active
1329
constituents include flavonoid glycosides and pinenes [cclxix269]
1330
The chemistry of feverfew is now well defined. The most important biologically active principles
1331
are sesquiterpene lactones, the principal one being parthenolide. Parthenolide is found in the
1332
superficial leaf glands (0.2%–0.5%), but not in the stems, and comprises up to 85% of the total
1333
sesquiterpene content [cclxix]. More than 30 sesquiterpene lactones have been identified in
1334
feverfew. In general, there are 5 different types of sesquiterpene lactones, which may be classified
1335
by chemical ring structures. Feverfew contains eudesmanolides, germacranolides, and guaianolides.
1336
Parthenolide is a germacranolide [cclxix].
1337
This plant is marketed in the United States in a variety of forms and compositions. Although its
1338
therapeutic efficacy is still uncertain, the sesquiterpene lactone parthenolide is the constituent
1339
recommended to be measured for quality control of feverfew preparations.
1340
Quality control of T. parthenium was firstly proposed in 1992 [cclxx270]. Three physicochemical
1341
methods (HPLC, NMR spectroscopy, and HPLC of a derivative) have been used to measure
1342
parthenolide in authenticated Tanacetum parthenium (feverfew) and in several commercial
1343
products. Similar results were obtained for all three physicochemical assays and also for the
1344
bioassay. Authenticated T. parthenium grown in the UK contained a high level of parthenolide in
1345
leaves, flowering tops and seeds but a low level in stalks and roots [cclxx].
1346
In 2000 a validated liquid chromatographic method was developed and used to estimate
1347
parthenolide in a number of U.S. feverfew market products formulated as capsules, tablets, or crude
1348
powder [cclxxi271]. In the same year, efficacy and safety of this plant and its preparations was
1349
reviewed [cclxxii272].
1350
A NMR spectroscopic and pattern recognition analytical approach to investigate composition and
1351
variability of different samples of T. partenium was proposed in 2002. 1H-NMR spectroscopy and
1352
PCA was used to discriminate between batches of 14 commercially available feverfew samples
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1327
54 Page 54 of 95
based on multi-component metabolite profiles [cclxxiii273]. Improvement was gained only in 2013,
1354
when a paper describing the analysis by a spectrophotometric method of the different sesquiterpene
1355
lactones in the plant was published [cclxxiv274]. Standardization of formulation based on T.
1356
parthenium was developed in 2009. A spray-dried extract was standardized in the content of the
1357
sesquiterpene lactone parthenolide. The total flavonoid and parthenolide contents in the spray-dried
1358
extract were 1.31 % and 0.76% wt /wt. The spray-dried allowed its tableting by direct compression.
1359
Tablet properties were in accordance with the proposed specifications [cclxxv275].
cr
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1353
us
1360
8. Analytical methods for plants containing steroids used in the treatment of women’s
1362
disorders
1363
Steroids (Greek, stereos = solids), widely distributed in the animal and plant kingdom, present a
1364
tetracyclic system arranged in the form of a perhydrocyclopentanophenanthrene. They include great
1365
variations in structure and encompass compounds of vital importance to life, such as cholesterol, the
1366
bile acids, sex hormones, vitamin D, corticoid hormones, cardiac aglycones, antibiotics, and insect
1367
molting hormones.
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1368
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1361
1369
8.1. Dioscorea spp.
1370
Yam is the common name for rhizomes of plants from the genus Dioscorea (Dioscoreaceae) which
1371
are widely distributed all over the world. Over 50 steroidal saponins have been identified from
1372
various Dioscorea species. Steroidal saponins, furostanol glycosides such as methyl parvifloside
1373
and protodeltonin and spirostanol glycosides like deltonin and glucosidodeltonin, are reported to be
1374
the major physiologically active constituents in yam [cclxxvi276]. The most well-known species of
1375
this genus is Dioscorea villosa L., also called wild yam. The rhizomes and roots of this plant are
1376
used for their phytoestrogenic properties in the treatment of menstrual and menopause complaints
1377
and are claimed to improve women's health [cclxxvi].
55 Page 55 of 95
Analytical methods for the determination of steroidal compounds using HSCC-ELSD and HPLC-
1379
ELSD have been reported for Dioscorea villosa and Dioscorea spp [cclxxvii277,cclxxviii278]. A
1380
UHPLC method with shorter retention times and good resolution and sensitivity for quantitative
1381
determination of 11 steroidal saponins from the rhizomes and roots of Dioscorea villosa, D. alata
1382
and D. opposite, was developed by Avula and coworkers [cclxxvi]. Detection of the saponins was
1383
achieved by the use of an ELS detector. A highly sensitive UHPLC-MS to identify and confirm the
1384
structure of compounds in Dioscorea samples and dietary supplements that claimed to contain D.
1385
villosa was developed. FT-IR spectroscopy combined with multivariate analysis was used to predict
1386
dioscin content from African yam tubers (D. alata L.) [cclxxix279].
us
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1378
an
1387
9. Concluding remarks
1389
As highlighted, several strategies have been applied for the quality control of medicinal plants
1390
employed in the treatment of women's disorders. Thanks to the innovation in analytical technology,
1391
identification and detection of secondary metabolites dramatically improved. In particular,
1392
hyphenated techniques have proved to be the most suitable for the rapid identification of
1393
compounds in plant matrix. Advanced methods have been proposed for the quality control of these
1394
species in order to obtain specificity, sensitivity, and straightforward operation, reducing the
1395
analysis time. Often, powerful analytical techniques such as HPLC-DAD–MS, UPLC-MS, HPLC–
1396
MS/MS, NMR were employed to obtain a metabolic fingerprint. Medicinal plants here discussed
1397
were classified on the basis of the chemical markers used for the quality control, in plants
1398
containing tannins, antocyans, iridoids, flavonoids, phenolic acids, terpenes and steroids. This
1399
classification allows to select the most suitable analytical technique on the basis of the chemical
1400
composition of the medicinal plant. Qualitative profiles of the herbal products have been discussed,
1401
taking in consideration that differences in sample quality is not only found in the main compounds
1402
or in the chemical markers but also in the low-concentration compounds, and so fingerprint analysis
1403
might be an interesting way for identification and quality control of herbal products, containing a
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56 Page 56 of 95
large number of low amounts of unknown compounds. In many cases, quantitative analysis of the
1405
selected medicinal plants showed that the content in chemical markers can be influenced by several
1406
factors including climate, growing conditions, time of harvesting, and post-harvesting factors, such
1407
as storage conditions and processing and varies not ony in different parts of the plants but also from
1408
country to country. In several papers information obtained from the analysis of a plant was
1409
processed by statistical elaborations. The most widely used approach is multivariate data analysis,
1410
in PCA, a method that allows the differentiation among groups of samples, providing valuable
1411
information on the origin and/or among technological treatments. The analytical strategies here
1412
reported can be used during the standardization process with the aim to assure quality, safety and
1413
efficacy to herbal products. In several cases the discussed analytical approaches allow to explore the
1414
eventual adulteration and substitution with similar common herbs, often characterized by different
1415
bioactivity profiles and lower commercial value.
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57 Page 57 of 95
1417
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control method for geranium oil based on vibrational spectroscopy and chemometric data analysis, Vib. Spectrosc. 57 (2011) 242-247. [cclix] L. Kuźma, D. Kalemba, M. Różalski, B. Różalska, M. Więckowska-Szakiel, U. Krajewska, H. Wysokińska, Chemical Composition and Biological Activities of Essential Oil from Salvia sclarea Plants Regenerated in vitro, Molecules 14 (2009) 1438-1447. [cclx] S. Nasermoadeli, V. Rowshan, Comparison of Salvia sclarea L. essential oil components in wild and field population, Int. J. Agric. Crop Sci. 5 (2013) 828-831. 89 Page 89 of 95
[cclxi] H. Yalcin, I. Ozturk, E. Tulukcu, O. Sagdic, Effect of γ-irradiation on bioactivity, fatty acid compositions and volatile compounds of clary sage seed (Salvia sclarea L.), J. Food Sci. 76 (2011) C1056-C1061.
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[cclxii] L. Ciesla, D. Staszek, M. Hajnos, T. Kowalska, M. Waksmundzka-Hajnos, Development of chromatographic and free radical scavenging activity fingerprints by thin-layer
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[cclxiii] M. Lis-Balchin, S.G. Deans, E. Eaglesham, Relationship between bioactivity and
chemical composition of commercial essential oils. Flavour Frag. J. 13 (1998) 98-104.
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[cclxiv] De Palma, R. Rossi, M. Carai, C. Cabras, G. Colombo, L. Arnoldi, N. Fuzzati, A. Riva, P. Morazzoni, P.L. Mauri, Pharmaceutical and biomedical analysis of terpene constituents in
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Salvia miltiorrhiza, Curr. Pharm. Anal. 4 (2008) 249-257.
[cclxv] R. Kasimu, K. Tanaka, Y. Tezuka, Z.N. Gong, J.X. Li, P. Basnet, T. Namba, S. Kadota,
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Comparative study of seventeen Salvia plants: aldose reductase inhibitory activity of water and
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MeOH extracts and liquid chromatography-mass spectrometry (LC-MS) analysis of water
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extracts, Chem. Pharm. Bull. 46 (1998) 500-504. [cclxvi] Z.L. Ye, C.C. Hu, X.H. Fan, Y.Y. Cheng, Simultaneous Analysis of Seven Major Saponins in Compound Danshen Dropping Pills using Solid Phase Extraction and HPLC with DAD and ESI-MS Detectors, J. Liq. Chrom. Rel. Technol. 29 (2006) 1575-1587. [cclxvii]
G.X. Zhong, P. Li, L.J. Zeng, J. Guan, D.Q. Li, S.P. Li, Chemical characteristics of
Salvia miltiorrhiza (Danshen) collected from different locations in China, J. Agricult. Food Chem. 57 (2009) 6879-6887. [cclxviii] M. Gu, Z. Su, F. Ouyang, Fingerprinting of Salvia miltiorrhiza Bunge by Thin-Layer Chromatography Scan Compared with High Speed Countercurrent Chromatography, J. Liq. Chrom. Rel. Technol. 29 (2006) 1503-1514.
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[cclxix] A. Pareek, M. Suthar, G.S. Rathore, V. Bansal. Feverfew (Tanacetum parthenium L.): A systematic review, Pharmacogn. Rev. 5 (2011) 103-110. [cclxx] S. Heptinstall, D.V. Awang, B.A. Dawson, D. Kindack, D.W. Knight, J. May ,
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Parthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip. Estimation of commercial and authenticated feverfew products, J. Pharm. Pharmacol. 44 (1992)
cr
391-395.
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[cclxxi] E.A. Abourashed, I.A. Khan, Determination of parthenolide in selected feverfew products by liquid chromatography. J AOAC Int. 83 (2000) 789-792.
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[cclxxii] E. Ernst, M.H. Pittler, The efficacy and safety of feverfew (Tanacetum parthenium L.): an update of a systematic review, Public Health Nutr. 3 (2000) 509-514.
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[cclxxiii] N.J. Bailey, J. Sampson, P.J. Hylands, J.K. Nicholson, E. Holmes, Multi-component metabolic classification of commercial feverfew preparations via high-field
1
H-NMR
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spectroscopy and chemometrics, Planta Med. 68 (2002) 734-738.
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[cclxxiv] H. Salapovic, J. Geier, G. Reznicek, Quantification of Sesquiterpene Lactones in
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Asteraceae Plant Extracts: Evaluation of their Allergenic Potential, Sci. Pharm. 81 (2013) 807818.
[cclxxv] J. S. Chaves, F. Batista Da Costa, L.A. Pedro de Freitas, Development of enteric
coated tablets from spray dried extract of feverfew (Tanacetum parthenium L.), Braz. J. Pharm. Sci. 45 (2009) 573-584.
[cclxxvi] B. Avula, Y.H. Wang, Z. Ali, T.J. Smillie, I.A. Khan, Chemical fingerprint analysis and quantitative determination of steroidal compounds from Dioscorea villosa, Dioscorea species and dietary supplements using UHPLC-ELSD, Biomed. Chromatogr. 28 (2014) 281– 294.
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[cclxxvii] K.D. Yoon, Y.W. Chin, M.H. Yang, J. Choi, J. Kim, Application of highspeed countercurrent chromatography-evaporative light scattering detection for the separation of seven steroidal saponins from Dioscorea villosa, Phytochem. Anal. 23 (2012) 462–468.
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[cclxxviii] D.J. Yang, T.J. Lu, S.H. Lucy, Simultaneous determination of furostanol and spirostanol glycosides in Taiwanese Yam (Dioscorea spp.) Cultivars by HPLC. J. Food Drug.
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Anal. 2 (2003) 271–276.
us
[cclxxix] Y.K. Kwon, E.Y. Jie, A. Sartie, D.J. Kim, J.R. Liu, B.W. Min, S.W. Kim, Rapid metabolic discrimination and prediction of dioscin content from African yam tubers using
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Fourier transforminfrared spectroscopy combined with multivariate analysis, Food Chem. 166
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(2015) 389-396.
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Table 1. Medicinal plants discussed in the present review with relative chemical markers, analytical techniques and references.
LC–UV, LC–ELSD, LC–MS, UPLCDAD GC-MS
[141-143]
flavonoids, phenolic acids, triterpenoid
HPLC-DAD, HPLC-ESI-QTOF-MS, HPLC-DAD HPLC, HPTLC
[3,147]
flavonoids, caffeoyl acids quinochalcones, flavonoids alkaloids, steroidal glycosides triterpene glycoside spiroethers and coumarins, flavonoids, phenolic acids triterpene glycosides
HPLC-DAD-MS
[61]
d
phenolic acids and phthalides
HPLC–DAD
te
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Chamaemelum nobile
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terpenes
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Artemisia abrotanum Artemisia capillaris Artemisia frigida Artemisia vulgaris Calendula officinalis Capsella bursa-pastoris Carthamus tinctorius Caulophyllum thalictroides
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References [9,10]
essential oils, sesquiterpene phenolic, chlorogenic acids, sesquiterpenoids essential oil
Analytical techniques HPLC-DAD, HPLC-FLD, HPLC-ADC, LC-MS HPLC-DAD-ESI-MS/MS, UPLC/QTOF-MS HPLC-UV, HPLC-PAD, HPLC-PADMS, HPLC-PAD-API/MS, UHPLCQTOF-MS/MS, HPLC-PAD GC-MS, LC-MS
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Chemical Markers flavonoids, tannins
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Plants Alchemilla vulgaris Alisma orientalis Angelica sinensis
[133,134,136,137] [138,139]
[144]
[210-212]
[66-68]
TLC, HPLC, GC, UPLC
[213-217]
HPLC-PAD-MS, UHPLC-UV-MS, GC-MS
[148,149] [206,217-220]
[168,169] [167,170,171]
Crocus sativus
monoterpenes
Curcuma longa
phenolic compounds
Curcuma xanthorrhiza Curcuma zeodaria
phenolic compounds
HPLC-UV, HPLC–ELSD, HPLC-PAD, LC-MS LC-MS, SIM-LC-MS, APCILC-MS, LC-TIS-MS, HPLC–TOF-ESIMS, HPLC-PDA UV e Vis spectrophotometry, NIRS, GCMS, HPLC, LC, FTNIR, MIR, multielement stable isotope analysis, SCARs TLC, HPTLC, NIR, microemulsion electrokinetic chromatography, CE, SFC, DART, LC–ESI-MS/MS and LC-ESI(QqQ)-MS, HPLC-DAD and HPLC–ESIMS HPLC-DAD, HPLC-DAD-ESI-MSn
phenolic compounds
HPLC, UPLC-UV-MS
Cimicifuga racemosa
[208-209]
[226-233] [153-167]
93 Page 93 of 95
[276]
steroidal saponin
HSCC-ELSD, HPLC-ELSD, UHPLCELSD, UHPLC-MS, TLC with video Densitometry, HPLCDAD, LC-ESI-MS, HPLC-ELSD, NMR,
[276-278],
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[276,279]
us
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alkamides, phenylpropanoids, polysaccharides, volatile oils, flavonoids essential oil GC, GC-MS, Raman spectroscopy, ESIMS, HPTLC isoflavones HPLC-UV, LC-MS, UPLC, UFLC, NMR prenylchalcones, HPLC-UV, HPLC-DAD, HPLC-ECD, prenylflavonoids, capillary electrophoresis, HPTLC, prenylphloroglucinols HPLC-MS, HPLC-MS2, NMR phenolics TLC, HPLC, UPLC-DAD-TOF-MS, NMR isoflavones HPLC-UV, HPLC-DAD, HPLC-FLD, LC-MS, GC-IT/MS fatty acids, tannins GC-MS, HPLC-DAD, HPLC-HRMS
[176-183]
[243-249] [71-79] [186-191] [192,193] [83-90] [12-15]
monoterpenes, phenolic compounds, flavonoids alkaloids, tannins, saponins, glycosides, carbohydrates, flavonoids, terpenes, steroids triterpenes
UPLC- PDA-QTOF-MS, UPLC-QTOF- [94-96] MS TLC, HPLC
[98,99]
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Paeonia officinalis
UHPLC-ELSD, UHPLC-MS,
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Magnolia officinalis Medicago sativa Oenothera biennis Paeonia lactiflora
steroidal saponin
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Humulus lupulus
[235-240]
steroidal saponin
GC-MS, HPTLC, HPLC-UV, LC–ESIMS/MS, UHPLC-QTOF-MS, UHPLC-ELSD, UHPLC-MS, FT-IR
d
Foenicum vulgare Glycine max
sesquiterpenes
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Cyperus rotundus Dioscorea alata Dioscorea opposita Dioscorea villosa Echinacea purpurea
Panax ginseng
Passiflora edulis
TLC, HPTLC, HPLC-UV, HPLC-DAD, [252-255] HPLC-ELSD, HPLC-CAD, HPLC-PAD, LC-APCI-MS, LC-ESI-MS UPLCQToF-MS, NMR phenolic compounds, TLC, HPLC, HPLC-MS, GC-MS [32,101-105] thiols, terpenes, fatty acid esters, alcohols essential oil GC-MS, Vibrational spectroscopy [256,258]
Pelargonium graveolens Pimenta dioica essential oils, phenolic compounds Piper lactones methysticum Polygonum quinones, stilbenes cuspidatum
GC, GC-MS, HPLC
[195-198]
GC, HPLC, DNA based analysis, NIR,
[201-205]
HPTLC, HPLC, UPLC-PDA, HPLC- [107-109] DAD-FICL 94 Page 94 of 95
flavonoids
HPLC–DAD–MSn, UHPLC-DAD
[113,115]
sesquiterpenoids, iridoids iridoids flavonoids
HPLC-UV, NMR
[270-275]
cr
[22-33]
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essential oil phenolic compounds, diterpenes monoterpenes, sesquiterpene lactones, flavonoid glycosides isoflavones
flavonoids, anthocyans
[118]
HPLC-DAD, HPLC-ESI-MS, HPLCMS-MS, MALDI-TOF-MS, MS, GCMS, HPLC-MS GC, GC-MS, TLC LC-MS/MS, HPLC-DAD, TLC,
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flavonoids, anthocyans
[16]
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flavonoids, LC-MS, MALDI-TOF-MS triterpenoids, organic, phenolic acids, tannins anthraquinones HPLC
[260-263] [266-268],
IR, HPLC, HPTLC
[124-127]
HPTLC, HPLC-DAD, GC-MS, MS, NMR ATR-IR, NIR, HPLC, HPLC-DAD-ESIMS, HPLC-DAD HPLC, LC-MS, HR-MS, GC/MS
[44-48]
LC-MS, NMR
[35-39]
[49-52] [53,55-58]
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Trifolium pratense Valeriana officinalis Verbena officinalis Vitex agnuscastus Vitis vinifera
[111-112]
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Salvia sclarea Salvia miltiorrhizae Tanacetum parthenium
2D-TLC, LC-MS
d
Rubia cordifolia Rubus idaeus
flavonoids
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Polygonum hydropiper Polygonum aviculare Potentilla erecta
95 Page 95 of 95
S0731-7085(15)00197-1 http://dx.doi.org/doi:10.1016/j.jpba.2015.03.020 PBA 10013
To appear in:
Journal of Pharmaceutical and Biomedical Analysis
Received date: Revised date: Accepted date:
12-1-2015 17-3-2015 19-3-2015
Please cite this article as: M. Masullo, P. Montoro, A. Mari, C. Pizza, S. Piacente, Medicinal plants in the treatment of women’s disorders: analytical strategies to assure quality, safety and efficacy, Journal of Pharmaceutical and Biomedical Analysis (2015), http://dx.doi.org/10.1016/j.jpba.2015.03.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Highlights
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The main medicinal plants used for women’s disorders have been reviewed.
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The analytical strategies to assure quality, safety and efficacy have been reported.
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Plants are classified on the basis of the chemical markers used for the quality control.
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Medicinal plants in the treatment of women's disorders: analytical
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strategies to assure quality, safety and efficacy
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Milena Masullo, Paola Montoro, Angela Mari, Cosimo Pizza, Sonia Piacente *
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Dipartimento di Farmacia, Università degli Studi di Salerno, via Giovanni Paolo II n. 132, 84084
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Fisciano (SA), Italy
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*Corresponding author: Tel.: +39 089969763; Fax:+39 089969602
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E-mail address: [email protected]
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Abstract
30
During last decades an increasing number of herbal products specifically targeting women’s
31
disorders has appeared in the worldwide marketplace. This growth highlights the need for a critical
32
evaluation of quality, safety and efficacy of these products.
33
Analytical techniques applied to the quality control of the main medicinal plants used for women
34
health (relief of menopause and menstrual related symptoms) have been reviewed. Thanks to the
35
innovation in analytical technology, identification and detection of secondary metabolites
36
dramatically improved. In particular, hyphenated techniques have proved to be the most suitable for
37
the rapid identification of compounds in plant matrix. Moreover, taking into account that
38
differences in sample quality are not only found in the main compounds or in the chemical markers
39
but also in the low-concentration compounds, fingerprint analysis might be a simple way for
40
identification and quality control of herbal products containing a large number of low amounts of
41
unknown compounds. Furthermore in several papers the information obtained from the analysis of a
42
plant have been processed by statistical elaborations.
43
Medicinal plants here discussed are classified on the basis of the chemical markers used for their
44
quality control.
46 47 48
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Keywords
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women's disorders, herbal products, quality control, metabolic fingerprint, analytical techniques,
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statistical analysis.
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Abbreviations CE Capillary Electrophoresis DAD Diode Array Detector ELSD Evaporative Light Scattering ESI Electrospray Ionization FLD Fluorescence Detector GC-MS Gas Chromatography Mass Spectrometry HPLC High Performance Liquid Chromatography HPTLC High Performance Thin Layer Chromatography HR-MS High Resolution Mass Spectrometry HSCC High-Speed Countercurrent Chromatography HS-SPME Headspace-Solid Phase Microextraction IR Infrared Spectroscopy IT Ion Trap LC-MS Liquid Chromatography Mass Spectrometry MALDI Matrix Assisted Laser Desorbition Ionization MS Mass Spectrometry NIR Near-Infrared Diffuse Reflectance Spectroscopy PAD Photodiode Array Detection PCA Principal Component Analysis PLS-DA Partial Least Squares Discriminant Analysis TLC Thin Layer Chromatography ToF Time of Flight UPLC Ultra-Performance Liquid Chromatography
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54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78
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Index
80
1. Introduction
81
2. Analytical methods for plants containing tannins used in the treatment of women’s disorders
82
2.1. Alchemilla vulgaris
83
2.2. Oenothera biennis
84
2.3. Potentilla erecta
85
3. Analytical methods for plants containing anthocyans used in the treatment of women’s disorders
86
3.1. Rubus idaeus
87
3.2. Vitis vinifera
88
4. Analytical methods for plants containing iridoids used in the treatment of women’s disorders
89
4.1. Valeriana officinalis
90
4.2. Verbena officinalis
91
4.3. Vitex agnus castus
92
5. Analytical methods for plants containing flavonoids used in the treatment of women’s disorders
93
5.1. Capsella bursa-pastoris
94
5.2. Carthamus tinctorius
95
5.3. Glycine max
96
5.4. Medicago sativa
97
5.5. Paeonia spp.
98
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99
5.5.2. Paeonia officinalis
5.5.1. Paeonia lactiflora
100
5.6. Passiflora edulis
101
5.7. Polygonum spp.
102
5.7.1. Polygonum cuspidatum
103
5.7.2. Polygonum hydropiper 5 Page 5 of 95
104
5.7.3. Polygonum aviculare 5.8. Rubia cordifolia
106
5.9. Trifolium pratense
107
6. Analytical methods for plants containing phenolic acids used in the treatment of women’s
108
disorders
109
6.1. Angelica sinensis
110
6.2. Artemisia spp.
6.2.2. Artemisia capillaris
113
6.2.3. Artemisia frigida
114
6.2.4. Artemisia vulgaris 6.3. Chamaemelum nobile
116
6.4. Curcuma spp.
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6.2.1. Artemisia abrotanum
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6.4.1. Curcuma longa
118
6.4.2. Curcuma xanthorrhiza
119
6.4.3. Curcuma zeodaria
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120
6.5. Echinacea purpurea
121
6.6. Humulus lupulus
122
6.7. Magnolia officinalis
123
6.8. Pimenta dioica
124
6.9. Piper methysticum
125
7. Analytical methods for plants containing terpenes used in the treatment of women’s disorders
126
7.1. Alisma orientalis
127
7.2. Calendula officinalis
128
7.3. Caulophyllum thalictroides
129
7.4. Cimicifuga racemosa 6 Page 6 of 95
7.6. Cyperus rotundus
132
7.7. Foeniculum vulgare
133
7.8. Panax ginseng
134
7.9. Pelargonium graveolens
135
7.10. Salvia spp.
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136
7.10.1. Salvia sclarea
137
7.10.2. Salvia miltiorrhizae
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7.5. Crocus sativus
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7.11. Tanacetum parthenium
139
8 Analytical methods for plants containing steroids used in the treatment of women’s disorders
140
8.1. Dioscorea spp.
141
9. Concluding remarks
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1. Introduction
145
During last decades an increasing number of herbal products specifically targeting women in
146
menopause and with menstrual affections has appeared in the worldwide marketplace. This growth
147
highlights the need for a critical evaluation of quality, safety and efficacy of these products.
148
Ensuring that plant-based products are of suitable quality is important for several reasons. Herbs are
149
natural products and, for this reason, they do not have a consistent, standardized composition [i1].
150
Plants contain numerous chemical constituents and if we analyze different parts of the plant (e.g.
151
roots, leaves), we certainly find a different qualitative and quantitative profile of constituents. The
152
reason of this variability is that the content and concentration of constituents can be influenced by
153
several factors including climate, growing conditions, time of harvesting, and post-harvesting
154
factors, such as storage conditions (e.g. light, temperature, humidity) and processing (e.g. extraction
155
and drying). The quality of plant raw materials can also be influenced by human adulterations due
156
to dishonesty or unscrupulous operators. Errors could be accidental botanical substitution
157
(misidentification of plant species) or intentional botanical substitution (deliberate exchange with
158
other, sometimes more toxic, plant species). The variability in the content and concentrations of
159
constituents of plant material, together with the range of extraction techniques and processing steps
160
used by different manufacturers, results in marked variability in the quality of commercially
161
available herbal products [i]. Thus quality control of herbal products is needed to ensure their
162
consistency, safety, and efficacy.
163
The current approaches to the quality control of herbal products are either compound-oriented or
164
pattern-oriented [ii2], the former targeting specific components with known chemical structures, the
165
latter targeting all detectable components. Regarding this latter approach, fingerprint analysis is
166
often accepted by regulatory authorities as a tool to identify herbal formulations and to assess their
167
quality. A fingerprint is a characteristic profile or pattern which chemically represents the sample
168
[iii3].
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In the first approach, selection of chemical markers is crucial for the quality control of herbal
170
products. Ideally, chemical markers should be components that contribute to the therapeutic effects
171
of a medicinal plant. Considering that only a small number of chemical compounds were shown to
172
have clear pharmacological actions, and a large number of plants are not studied for their bioactive
173
metabolites, other chemical components can be used as markers. The European Medicines Agency
174
(EMEA) [iv4] defines chemical markers as chemically defined constituents or groups of
175
constituents of a medicinal plant which are of interest for quality control purposes regardless of
176
whether they possess any therapeutic activity. The quantity of a chemical marker can be an
177
indicator of the quality of a herbal medicine. This point is very important, because the chemical
178
marker approach for quality control is realized by means of both qualitative and quantitative
179
analyses. The analysis of chemical markers requires specific analytical methods for qualitative
180
analysis and validated, accurate, precise, and robust methods for quantitative analysis.
181
The purpose of this review is to assess the evidence for quality of the main medicinal plants used
182
for women health (relief of menopause and menstrual related symptoms) with a specific focus on
183
their phytochemical composition. Medicinal plants used with this purpose are classified on the basis
184
of the chemical markers, not always corresponding to the active constituents, used for the quality
185
control (Table 1).
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186 187
2. Analytical methods for plants containing tannins used in the treatment of women’s
188
disorders
189
Tannins are a heterogeneous group of high molecular weight polyphenolic compounds with the
190
capacity to form reversible and irreversible complexes with proteins, polysaccharides, alkaloids,
191
nucleic acids and minerals. On the basis of their structural characteristics it is possible to divide
192
them into four major groups: gallotannins, ellagitannins, complex tannins, and condensed tannins
193
[v5].
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(1) Gallotannins are tannins in which galloyl units or their meta-depsidic derivatives are linked to
195
diverse polyol-, catechin-, or triterpenoid units.
196
(2) Ellagitannins are tannins in which at least two galloyl units are C–C coupled to each other.
197
(3) Complex tannins are tannins in which a catechin unit is glycosidically linked to a gallotannin or
198
an ellagitannin unit.
199
(4) Condensed tannins are all oligomeric and polymeric proanthocyanidins formed by linkage of C-
200
4 of one catechin with C-8 or C-6 of the next monomeric catechin.
201
In traditional medicine, the tannin-containing plant extracts are used as astringents, against
202
diarrhoea, as diuretics, against stomach and duodenal tumours, and as antiinflammatory, antiseptic,
203
antioxidant and haemostatic pharmaceuticals [vi6]. Anti-inflammatory and haemostatic activity
204
make this compounds, and principally proanthocyanidins, largely used to treat menstrual affection.
205
The activity of tannins for relieving menopausal symptoms is also known, and a patent related to
206
the use of proanthocyanidins in relieving menopausal and perimenopausal symptoms was published
207
[vii7].
208
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2.1. Alchemilla vulgaris
210
Alchemilla vulgaris L. (Rosaceae), also known as lady's mantles for its ornamental leaves is a wild
211
plant used for women's disorders and reported for the presence of flavonoids and tannins [viii8]. A.
212
vulgaris belongs to a number of herbal drugs included in The European Pharmacopoeia (Ph. Eur.)
213
analyzed only by their tannin content. The tannin content, determined using the non specific Folin-
214
Ciocalteu method, an old colorimetric method involving redox chemistry, is calculated relative to a
215
pyrogallol standard and expressed as percentage of pyrogallol. Thus, Moller et al. developed a
216
method based on a reversed-phase gradient HPLC system coupled to DAD, fluorescence,
217
electrochemical and MS detectors. The HPLC system developed with UV detection at 250 nm
218
provided characteristic fingerprints of the herbal drugs. Methanolysis of A. vulgaris extracts
219
generated methyl gallate and ellagic acid, which were analyzed by HPLC [ix9]. Successively, a new
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method based on HPLC coupled with four kinds of detectors, DAD, FLD, electrochemical
221
amperometric and MS assembled by a micro-splitter valve was developed for the characterization
222
and differentiation of A. vulgaris extracts adding 2,5-dihydroxybenzoic acid to the sample solution
223
in order to eliminate the drift interference of retention time [x10].
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224
2.2. Oenothera biennis
226
Evening primrose (Oenothera biennis L., Onagraceae) is a native North American traditional
227
medicinal plant. All the parts of this plant have been widely used as a traditional remedy for several
228
disorders. It has been receiving a lot of attention all over the world for its seed oil (up to 25%) rich
229
in polyunsaturated fatty acids mainly linoleic acid (LA, 60-80%) and γ-linolenic acid (GLA, 8-
230
14%). These omega-6 fatty acids are now becoming increasingly popular as oral and topical
231
remedies for neurodermatitis. Their mechanism of action is based on the concept that the disease is
232
caused by an underlying metabolic disorder of long-chained essential fatty acids which are, in turn,
233
precursors of the highly active prostaglandins E1 and E2. Evening primrose oil has been tested in
234
several studies to support its use for breast pain, premenstrual symptoms (PMS), eczema, cirrhosis,
235
rheumatoid arthritis, menopause [xi11]. In particular, it is reported to relieve the discomforts of
236
PMS, menopause, menstruation, endometriosis and fibrocystic breasts by interfering with the
237
production of inflammatory prostaglandins released during menstruation. Many PMS sufferers are
238
found to have unusually low levels of GLA, which is why food supplements containing this fatty
239
acid might help so much. In women with fibrocystic breasts, essential fatty acids can minimise
240
breast inflammation and promote the absorption of iodine, a mineral that can be present in
241
abnormally low levels in women with this condition. In menopause, it is widely reported that
242
evening primrose oil reduces hot flushes and increases feelings of well being. The oil of O. biennis
243
must be subjected to rigorous analyses as part of any quality control program. GC is generally
244
applied for the determination of fatty acid contents (mainly the content of -linolenic acid is dosed),
245
but more sophisticated methodology may be necessary for the structural analysis of triacylglycerols,
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for example. Methods for analysis of evening primrose oil were reviewed in 1999 [xii12]. The
247
analysis of triacilglycerols is generally used for standardization of the oil from the plant [xiii13].
248
Although most of the queries for quality control of this species are focused on the oil, the plant
249
contains as further bioactive compounds ellagitannins, that can have a role as anti-inflammatory
250
principles relieving menstrual symptoms. Leaves and roots of O. biennis were investigated for the
251
presence of hexameric and heptameric ellagitannins, by using HPLC coupled with DAD and HR-
252
MS [xiv14]. A previous analytical approach was carried out with the aim of determining low
253
molecular weight phenolics with antioxidant properties from the seeds of the plant [xv15].
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254
2.3. Potentilla erecta
256
The rhizome of Potentilla erecta (L.) Raeuschel (Rosaceae), known with the trivial name of
257
tormentil, is a medicinal and food source used as nutritional supplement for its effects against
258
inflammation, gastrointestinal disorders and Pre-Menstrual Symptoms (PMS) [xvi16]. Most of the
259
positive effects can be attributed to the high amounts of polyphenols in all the plant parts [xvii17].
260
The chemical composition of P. erecta is mostly based on the presence of different flavonoids,
261
triterpenoids, organic and phenolic carboxylic acids, most of which isolated from the roots and
262
rhizomes. In addiction, P. erecta is considered a tannin-rich plant [xvi], for the high concentration
263
of proanthocyanidin oligomers in its underground parts. In a recent paper, a strategy based on direct
264
flow injection-ESI-IT-MS has been used to profile proanthocyanidins (PAs) occurring in this
265
species. To achieve deeper structural information and to focus the analysis on PAs with high
266
polimerization degree (DP), MALDI-ToF-MS, was used. Finally, LC-MS2 analyses were executed
267
by using a diol stationary phase to detect PAs [xvi].
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268 269
3. Analytical methods for plants containing anthocyans used in the treatment of women’s
270
disorders
12 Page 12 of 95
Anthocyans (ACNs), i.e. anthocyanins and anthocyanidins, belong to the group of plant
272
constituents, collectively known as flavonoids, which occur in the western diet at relatively high
273
concentrations. ACNs show the ability to scavenge reactive oxygen species and display a variety of
274
pharmacological properties which make them potential anti-inflammatory agents. The molecular
275
basis for their pharmacological activity includes the regulation of different mechanisms mainly
276
involved in: (1) suppression of the inflammatory response through targeting phospholipase A2,
277
PI3K/Akt,
278
growth/differentiation control and tumor suppression (4) reduction of diabetes incidence through
279
modulation of insulin sensitivity and glucose utilization (5) neuroprotection through amelioration of
280
oxidative stress and Aβ deposition and (6) hepatoprotective activity through interference with TNF-
281
α and TGF-β in the liver. The estrogen-like activity of anthocyans could be utilized in cancer and
282
hormone-replacement therapy. The molecular mechanisms of protective and therapeutic activity of
283
anthocyans in various pathological conditions, which may not be attributed solely to their
284
antioxidant activity but also to direct blockage of signaling pathways [xviii18]. Related to these
285
important evidences, is the action on women disorders [xix19].
pathways
(2)
protection
from
cr
NF-κB
cardiovascular
disease
(3)
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3.1. Rubus idaeus
288
Raspberry (Rubus ideaus L., Rosaceae) flavonoids and mainly anthocyans have significant
289
antioxidant activity and several biological activities in moderate and chronic disorders, and
290
women's disorders. Differences in anthocyanin composition of juices obtained from different berry
291
fruits create the possibility of detecting the adulterations of expensive raspberry and black currant
292
juices with cheap strawberry and red currant juices on the basis of anthocyanin analysis [xx20].
293
With similar purposes the analysis of selected organic acids was proposed too [xxi21].
294
In 1999 flavonoids and anthocyans from R. ideaus and other selected berries were analysed by
295
HPLC-ESI-MS. For the identification of aglycons, DAD was also used [xxii22]. A paper on the
296
analysis of anthocyanins was published in 2002 [xxiii23]. Anthocyanins from red raspberries were 13 Page 13 of 95
extracted from the fruit by homogenization in acidified methanol. The methanolic extract was
298
centrifuged and the supernatant analyzed by reversed-phase HPLC. The eluent was monitored at
299
371 and 520 nm before being introduced into a single quadrupole mass spectrometer through an
300
atmosphere pressure chemical ionization probe operating in positive ion mode. This method
301
allowed the identification of eight anthocyanins. A method based on tandem mass spectrometry
302
(MS/MS) coupled with HPLC was described in 2005 [xxiv24]. Scan for the precursor ions of
303
commonly found anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, petunidin, and
304
peonidin) using LC/MS/MS on a triple quadrupole instrument allowed the specific detection of each
305
anthocyanin. Further characterization of each anthocyanin was performed using MS/MS product-
306
ion analysis, common-neutral-loss analysis, and selected reaction monitoring (SRM). In 2008 a
307
method for the analysis of anthocyanins from raspberries by MALDI–ToF-MS was reported
308
[xxv25]. Furthermore, in 2008 a method based on Direct Introduction MS was proposed for the
309
analysis of polyphenols in berries, including Rubus [xxvi26]. In last years other papers have been
310
published applying and improving these methods of analysis [xxvii27, 28] [xxix29]. Also extraction
311
of phytochemicals from raspberry, principally assisted by ultrasound [xxx30] and by microwave
312
[xxxi31], has been reported. Investigation of the fruit flavor by using SPME coupled with
313
stereoselective GC-MS was reported in 2010 [xxxii32]. Authors have used HS-SPME and GC-MS
314
to determine the enantiomeric ratios of chiral flavor and fragrance indicators in the raw materials
315
and in the products.
316
Other studies involve the analysis of ellagitannins [xxxiii33]. The use of gradient RP-HPLC with
317
DAD and MSn detection for the analysis of ellagitannins, ellagic acid conjugates and quercetin
318
conjugates in raspberries is described. MSn is a particularly powerful tool for the analysis of trace
319
levels of natural products in the extracts as interpretation of fragmentation patterns.
xxviii
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3.2. Vitis vinifera
14 Page 14 of 95
Grape seed (Vitis vinifera L., Vitaceae) proanthocyanidins and flavonoids are reported to be
323
effective in improving the physical and psychological symptoms of menopause increasing muscle
324
mass and reducing blood pressure in middle-aged women [xxxiv34].
325
Quality control of V. vinifera products involves principally wine, the principal product obtained
326
from V. vinifera berries, however in this context we will evaluate only the improvement in analysis
327
of grapes or functional foods derived from grapes. In 2008 Cavaliere and coworkers described a
328
method for the analysis of polyphenols in grape berries by Rapid Resolution LC-MS [xxxv].
329
A simple and precise LC-MS method was developed for the quantification of anthocyanidins in
330
fifteen grape juice samples, four grape berries and four grape skins [xxxv35]. An improved LC-MS
331
method was published in 2012 by Xu and coworkers: under optimized conditions, five major
332
anthocyanidins including delphinidin, cyanidin, petunidin, peonidin and malvidin in the hydrolyzed
333
grape extracts were detected [xxxvi36].
334
The application of MS for the analysis of berries polyphenols has recently been reviewed
335
[xxxvii37]. MS has been shown to play a very important role in the research of polyphenols in
336
grape and wine and in the quality control of products. The soft ionization of LC-MS makes these
337
techniques suitable to study the structures of polyphenols and anthocyanins in grape extract and to
338
characterize polyphenolic derivatives. The coupling of the several MS techniques presented is
339
shown to be highly effective in the structural characterization of the large number of low and high
340
molecular weight polyphenols in grape and can be highly effective in the study of grape
341
metabolomics.
342
NMR is a technique largely applied to this matrix. Most of these techniques are able to discriminate
343
adulteration, mainly to identify the grape fruits’ extract from extracts obtained from other berries; in
344
fact differences in anthocyanin composition of juices obtained from different berry fruits create the
345
possibility of detecting the adulterations [xxxviii38].
346
Two headspace-based methodologies have been proposed to characterize the aroma of grape juice:
347
static headspace (SHS) and HS-SPME [xxxix39].
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348
4. Analytical methods for plants containing iridoids used in the treatment of women’s
350
disorders
351
Iridoids represent a large group of cyclopentapyrane monoterpenoids that occur widespread in
352
nature, mainly in Dicotyledonous plant families like Apocynaceae, Scrophulariaceae, Diervillaceae,
353
Lamiaceae, Loganiaceae and Rubiaceae. Recently, more extensive studies revealed that iridoids
354
exhibit a wide range of bioactivities, such as neuroprotective, antinflammatory and
355
immunomodulator, hepatoprotective and cardioprotective. Iridoids are marker compounds of
356
different species with a specific traditional use against menstrual symptomatology and menopausal
357
disorders [xl40].
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M
358
4.1. Valeriana officinalis
360
Valeriana officinalis L. (Valerianaceae), valerian, is a bushy plant whose roots and rhizomes have
361
been used since the 11th century for their tranquilizing, menstruation, and sedative effects. Its
362
antispasmodic activity on smooth muscles has been demonstrated both in vivo and in vitro [xli41].
363
Currently, valerian is prescribed for reducing pain, cyclic cramps, anxiety, and stress. It is also used
364
to treat the cramps associated with dysmenorrhea; in 2011 a clinical trial has been conducted in this
365
regard [xli]. Phytochemical researches led to the discovery of a number of sesquiterpenoids and
366
iridoids among which germacrane-type sesquiterpenoids, volvalerenals A−E and volvalerenic acids
367
A−C,
368
epoxyvalechlorine, valeriotriate B, jatamanvaltrate B, jatamanvaltrate C, valerenic acid, and
369
acetoxyvalerenic acid [xlii42,xliii43].
370
Analysis of V. officinalis was run principally on essential oils and iridoids by GC methods. In 2002
371
V. officinalis was analysed with other sedative plants in a sedative herbal preparation by GC-MS
372
[xliv44]. In 2005 electronic nose was applied with the aim to discriminate several valerian varieties
373
[xlv45]. To overcome the major limitations of the current methods used for the analysis of tinctures,
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with
valtrate,
isovaleroxyhydroxydihydrovaltrate,
1,5-dihydroxy-3,8-
16 Page 16 of 95
a new approach based on NMR spectroscopy and MS was tested with different tinctures. Diffusion-
375
edited 1H-NMR (1D-DOSY) and 1H-NMR with suppression of the EtOH and water signals were
376
applied for the first time to the direct analysis of commercial herbal tinctures derived from
377
Echinacea purpurea, Hypericum perforatum, Ginkgo biloba, and V. officinalis. The direct injection
378
of the tinctures in the MS detector to obtain the corresponding metabolic profiles was also
379
performed. Using both NMR and MS methods it was possible to obtain metabolic fingerprints
380
which allowed to differentiate tinctures prepared with different plants [xlvi46]. In a recent paper the
381
application of HPTLC to the analysis of the extracts of V. officinalis was explored [xlvii47]. A
382
strategy based on multi-wavelength chromatography fingerprinting of herbal materials, using HPLC
383
with a UV-Vis diode array detector has been applied to the analysis of V. officinalis. The enhanced
384
fingerprints were constructed by compiling into a single data vector the chromatograms from four
385
wavelengths (226, 254, 280 and 326 nm) [xlviii48].
M
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d
386
4.2. Verbena officinalis
388
Verbena officinalis L. (Verbenaceae) is a medicinal plant traditionally used because of its diuretic,
389
expectorant and anti-rheumatic effects. Moreover, anti-inflammatory, analgesic and antioxidant
390
activities have been reported for this plant [xlix49]. Analgesic and anti-inflammatory activity justify
391
its use to relieve menstrual symptoms. Main secondary metabolites present in the plant are iridoids,
392
phenylpropanoids, flavonoids, triterpenes and monoterpenes, with verbenalin (iridoid) and
393
verbascoside (phenylpropanoid) as the major constituents [xlix]. The European Pharmacopeia
394
defines verbenalin as the quality determining compound with a minimum content of 1.5%. For this
395
reason, quality control of V. officinalis often is run with respect of this marker compound. Several
396
analytical techniques like HPLC, HPTLC, GC and micellar electrokinetic capillary chromatography
397
for qualitative or quantitative analysis of the chemical constituents in V. officinalis has been
398
reported [xlix]. Among these reports, Bilia and coworkers developed an HPLC-DAD-ESI-MS
399
method for the analysis of the constituents of aqueous preparations of verbena and lemon verbena
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and the evaluation of their antioxidant activity [l50]. Successively simultaneous determination by
401
HPLC of four bioactive compounds in Verbena officinalis L. has been reported by Liu and
402
coworkers [li51]. A recent paper proposes a method based on Attenuated-Total-Reflectance IR
403
(ATR-IR) and NIR in hyphenation with multivariate analysis to quantify verbenalin and
404
verbascoside in V. officinalis. In addition a HPLC method as a reference was established and
405
validated and compared with the spectroscopic method [xlix]. Identification of V. officinalis, as
406
described above, is performed based on morphological and phytochemical analyses, which
407
unfortunately are not reliable enough to distinguish V. officinalis from other relevant species of the
408
genus Verbena. Thus the most important adulterations could remain undetected. In 2009 a method
409
was proposed based on comparison of ITS (Internal Transcribed Spacers) sequences and molecular
410
markers (RAPD) [lii52].
M
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us
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400
411
4.3. Vitex agnus castus
413
Vitex agnus-castus L. (Verbenaceae), chasteberry, is one of the most popular and effective herbs
414
used for the prevention and treatment of pre-menstrual syndrome (PMS) [liii53] and
415
hyperprolactinemia because of its hormone-like effects [liv54]. The chemical composition of the
416
unpolar fraction is characterized by the presence of diterpenoids, essential oils and ketosteroids,
417
while flavonoids are described in polar extracts [liii- [lv55]. Among these latter, casticin, a
418
methoxylated flavone, is considered by European Pharmacopoeia (Ph. Eur.) the reference standard
419
for standardization of dry extracts of the species. An analytical HPLC method for the quantitative
420
determination of casticin in V. agnus-castus fruits has already been developed [lvi56]. Recently
421
several studies have been published reporting the use of LC-MS techniques for the quality control
422
of the polar fractions of V. agnus-castus [lv] fruits and a comparison in the chemical composition of
423
different part of plants was performed by HR-MS [liii].
424
Many analytical studies are reported about V. agnus-castus essential oils, most of them realized by
425
GC-MS techniques [lvii57,lviii58].
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426
5. Analytical methods for plants containing flavonoids used in the treatment of women’s
428
disorders
429
Flavonoids are polyphenolic compounds ubiquitous in nature. More than 4,000 flavonoids have
430
been recognised, many of which occur in vegetables, fruits and beverages like tea, coffee and fruit
431
drinks. Flavonoids occur as aglycones, glycosides and methylated derivatives. Small amount of
432
aglycones are frequently present and occasionally represent a considerably important proportion of
433
the total flavonoid compounds in the plant. Flavonoids have gained much attention because of their
434
broad biological and pharmacological activities including antimicrobial, cytotoxic, anti-
435
inflammatory as well as cancer preventing activities and principally the capacity to be powerful
436
antioxidants which can protect the human body from free radicals and reactive oxygen species.
437
Antiinflammatory and antioxidant activity make these compounds largely used to treat menstrual
438
affection. Among flavonoids, isoflavonoids constitute a characteristic and very important subclass
439
of flavonoids. Their structures are based on the 3-phenylcromen skeleton that is chemically derived
440
from the 2-phenylchromen skeleton by an aryl-migration mechanism. Structurally, isoflavonoids
441
can be classified according to the oxidation of the C15 skeleton, their complexity and the internal
442
formation of the heterocyclic rings. Due to their ubiquitous distribution in food and the claimed
443
beneficial health effects of foods containing isoflavones, their distribution in foods and their healthy
444
properties have been reviewed [lix59]. Isoflavones have been proposed to have estrogenic activity
445
and play a putative role in the control of menopause disorders.
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427
447
5.1. Capsella bursa-pastoris
448
Capsella bursa-pastoris (L.) Medik. (Brassicaceae), also known as shepherd's purse, is a wild herb
449
with high nutritional value that can be eaten raw or cooked. It is reported in the list of the plants
450
used for women's disorders. Investigation of different extracts of its aerial parts led to the
451
identification of phenolic compounds quantified by HPLC-DAD, organic acids, and amino acids 19 Page 19 of 95
detected by HPLC-UV, and free fatty acids and sterols analyzed by GC-IT-MS. The plant material
453
was found rich in kaempferol-3-O-rutinoside, quinic acid, arginine, palmitic acid, and β-sitosterol
454
[lx60]. Karioti and coworkers developed an HPLC-DAD-MS method to analyse the “Olivis”
455
preparation, a blend of four herbal drugs, namely Crataegus oxyacantha L., Olea europea L.,
456
Capsella bursa-pastoris L. and Fumaria officinalis L. [lxi61]. The lack of the marker constituents
457
of some of the declared plant species (i.e. C. bursa-pastoris) and the presence of banned
458
adulterants, responsible for the strong antihypertensive effect of the supplement prompted to
459
analyze this herb. The analyses proved the presence of indole alkaloids belonging to the group of
460
Rauwolfia sp., such as ajmaline, reserpine and yohimbine. Seven flavonoids and two caffeoyl acid
461
derivatives were found in C. bursa-pastoris [lxi].
an
M
462
us
cr
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452
5.2. Carthamus tinctorius
464
Carthamus tinctorius L. or safflower, commonly called Honghua in China, is an annual or biennial
465
herbal plant belonging to the family Compositae. Safflower is considered to promote blood
466
circulation, to remove blood stasis, promote menstruation and alleviate pain. In the aspect of
467
clinical practice, safflower is mainly applied for blood-stasis syndrome with dysmenorrhea,
468
amenorrhea, post-partum abdominal pain and mass [lxii62]. Many chemical constituents such as
469
quinochalcones, flavonoids, alkaloids, polyacetylenes, alkane-diol, fatty acids, steroids, lignans,
470
have been isolated from safflower. Among them, quinochalcones and flavonoids are considered as
471
the biologically active constituents of safflower. The quinocalchone hydroxysafflor yellow A is
472
considered as one of the standard compounds to evaluate the quality of crude drug safflower and
473
related preparations containing safflower; also kaempferide is chosen as standard to evaluate the
474
quality of safflower. Several reports regard the quality control of Chinese herbal preparation like
475
“Danhong”, “Shu-Jin-Zhi-Tong”, "Xuebijing" with C. tinctorius as constituent [lxiii63, 64,lxv65].
476
However, the two marker compounds might be insufficient to fully illustrate the quality of
477
safflower since 104 compounds have been isolated and identified [lxii]. So, Li developed an HPLC–
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20 Page 20 of 95
DAD method for the simultaneous determination of four marker compounds, kaempferol-3-O-
479
rutinoside, safflomin A, safflomin B and bidenoside C, in the extract of the flowers of C. tinctorius
480
[lxvi66]. Fan and coworkers developed an HPLC-DAD method to evaluate the quality of 46 batches
481
of C. tinctorius from different areas through a simultaneous quantitation of 10 components.
482
Significant variations were found in the content of these compounds in these tinctures [lxvii67]. A
483
fingerprinting method has been developed to describe the chemical constituents and to control the
484
quality of many Chinese Material Medicas. HPLC fingerprinting has been applied to evaluate the
485
quality of safflower from different producing areas, indicating similar chemical profiles for
486
safflower from various habitats [lxviii68].
us
cr
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478
an
487
5.3. Glycine max
489
Soy (Glycine max (L.) Merrill, Fabaceae), a legume originating from Asia, is widely distributed
490
throughout the world, for preparing food products. More recently its consumption is linked, among
491
different properties, to the reduction of menopausal symptoms. This finding has resulted in the
492
development and commercialization of many functional foods and food supplements based on soy
493
ingredients. Soy extracts contain a mixture of isoflavones belonging to the group of phytoestrogens.
494
The major isoflavones in soybeans include daidzein, glycitein, genistein, their glycosides, glycoside
495
malonates and glycoside acetates, in which the predominant isoflavone forms in soybeans and non-
496
fermented soy products are the glycoside malonates, 6''-O-malonylgenistin and 6''-O-
497
malonyldaidzin [lxix69]. Studies have shown that they play an important role in reducing
498
climacteric symptoms in menopausal and postmenopausal women [lxx70].
499
A recent review reports the sample preparation and analysis for the quantification of isoflavones in
500
soybeans and soy foods. Modern techniques including ultrasound-assisted extraction, pressurized
501
liquid extraction, supercritical fluid extraction and microwave-assisted extraction, and analysis by
502
HPLC are reported [lxxi71]. In the quality control of soy the amount of isoflavones, both aglycones
503
and glycosides, is usually determined by means of reversed-phase HPLC-UV [lxxi,lxxii72].
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Although the HPLC methods have some advantages when they are applied to the analysis of
505
isoflavones in terms of specificity, sensitivity, and straightforward operation, they require a
506
relatively long period of time, normally from 20 min to 65 min. So, the use of high-throughput
507
liquid chromatography technologies has been reported in the last decade for isoflavone analysis,
508
reducing the chromatographic time to less than 10 min. These techniques allow the use of short
509
columns, packed with 3 μm particles, supporting elevated pressures, thus reducing analysis time,
510
solvent consumption, and, consequently, environmental impact [lxxiii73]. Among these studies,
511
Apers and coworkers developed an HPLC method using two linked monolithic silica-based
512
reversed-phase C18 columns. This method for determination of isoflavones in soy extracts needs less
513
than 25 min. Among the high-throughput methods reported in the literature for isoflavones analysis,
514
UPLC and ultra-fast liquid chromatography (UFLC) are cited for their determination in soybeans
515
cultivars, soy bits, soymilk, texturized soy protein, and soy-based nutritional supplements [lxxiii].
516
Several research groups have analyzed isoflavones from different types of soy seeds by LC-MS
517
[lxxiv74, 75,lxxvi76]. Caligiani and coworkers performed the quali-quantitative determination of
518
isoflavones in soybean extracts by 1H NMR [lxxvii77]. The complexity of natural soy isoflavones
519
makes the rigorous standardisation difficult to achieve, and most chromatographic methods only
520
quantify the main isoflavone forms as total isoflavone content [lxxviii78]. Garcia and coworkers
521
optimized methods for conventional and perfusion RP-HPLC to characterize 26 commercial
522
soybean products. Characterization of soybean products was carried out on the basis of their protein
523
profiles obtained by both chromatographic methods [lxxix79].
cr
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d
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lxxv
Ac ce p
524
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504
525
5.4. Medicago sativa
526
Alfalfa (Medicago sativa L., Fabaceae) is the main Medicago species widely grown throughout the
527
world, predominantly as a source of high quality forage for livestock, renewable energy production,
528
phytoremediation and as a source of phytochemicals [lxxx80]. It is also used as a human food
529
ingredient, consumed as sprouts in salads, sandwiches or soups, as leaf protein concentrates or as 22 Page 22 of 95
food supplements [lxxxi81]. Despite this use, alfalfa have pharmacological activities, being used in
531
some human health disfunctions, and among these anemia, endometriosis, osteoporosis and
532
menopausal symptoms [lxxi].
533
The plant contains many important constituents including saponins, sterols, coumarins, flavonoids,
534
phenolics, vitamins, proteins, minerals, and other nutrients [lxxxii82]. As above reported for
535
Glycine max, to isoflavones present in M. sativa are ascribable some of the pharmacological activity
536
of alfalfa. Murphy and coworkers analyzed isoflavones in retail and institutional foods (alfalfa and
537
soy) by HPLC [lxxxiii83]. Further HPLC [lxxxiv84, 85,lxxxvi , ESI-MS [lxxxiv,lxxxv], and CE
538
[lxxxvii87] methods were employed to analyze flavonoid content in M. sativa. More recently, two
539
glycosides (daidzin and genistin) and six aglycones (daidzein, glycitein, genistein, formononetin,
540
prunetin and biochanin A) were determined by HPLC-DAD in three different extracts (aqueous,
541
hydroalcoholic and alcoholic) of M. sativa [lxxxi]. Abo Markeb quantified 5- and 7-hydroxyflavone
542
in the M. sativa samples by HPLC-FLD [lxxxviii88]. A study compared the isoflavone production
543
of the callus cell suspension cultures of M. sativa to the original plants. The extracts were analyzed
544
by LC-MS for their isoflavones, mainly formononetin, biochanin A, daidzein, and genistein
545
[lxxxix89].
546
In the sprouts of M. sativa and G. max, phenolic compounds, sterols and triterpenes were
547
determined by HPLC-DAD, organic acids by HPLC-UV and fatty acids and volatile compounds by
548
GC-IT/MS [lxxx]. The metabolic profiling of triterpene saponins in M. sativa was also investigated
549
using HPLC-ESI-MS [xc90].
cr
us 86]
te
d
M
an
lxxxv
Ac ce p
550
ip t
530
551
5.5. Paeonia spp. (Paeoniaceae)
552
5.5.1. Paeonia lactiflora
553
Paeonia lactiflora Pallas, also named Chinese Paeony, is a Chinese herb. A decoction of its root has
554
been used to treat painful or inflammatory disorders in traditional Chinese medicine.
555
Different compounds have been isolated from this plant. These include monoterpenoid glucosides, 23 Page 23 of 95
flavonoids, tannins, stilbenoids, triterpenoids and steroids, and phenols. Biological activities include
557
antioxidant, antitumor, antipathogenic, immune-system-modulation activities, cardiovascular-
558
system-protective activities and central-nervous-system activities [xci91].
559
A water/ethanol extract of Radix Paeoniae is known as total glycosides of paeony (TGP), of which
560
paeoniflorin is the major active component. Preclinical studies show that TGP/paeoniflorin is able
561
to diminish pain, joint swelling, synovial hypertrophy, and the severity of bone erosion and
562
cartilage degradation in experimental arthritis [xcii92].
563
P. lactiflora was clinically tested on Polycystic ovary syndrome (PCOS), a prevalent, complex
564
endocrine disorder characterised by polycystic ovaries, chronic anovulation and hyperandrogenism
565
leading to symptoms of irregular menstrual cycles, hirsutism, acne and infertility [xciii93].
566
Recently an advanced method has been proposed for the quality control of this species. In this
567
study, an UPLC- PDA-QToF-MS based chemical profiling was established for rapid global quality
568
evaluation of Radix Peoniae. By virtue of the high resolution, high speed of UPLC and the accurate
569
mass measurement of ToF-MS, a total of 40 components including 29 monoterpene glycosides, 8
570
galloyl glucosides and 3 phenolic compounds were simultaneously separated within 12 min,
571
identified through the matching of formulas with those of published components in a library, and
572
were further elucidated by adjusted lower energy collision-induced dissociation (CID). The
573
established method was successfully applied to rapidly and globally compare the quality of Radix
574
Paeonia alba and Radix Paeoniae rubra, two post-harvesting handled products of Radix Paeoniae.
575
Thus UPLC-PDA-QToF-MS based chemical profiling resulted a powerful approach for the global
576
quality evaluation of Radix Paeoniae [xciv94].
577
A similar method, integrated with Multivariate Data Analysis was published in 2013 [xcv95].
578
An interesting new method, performed directly on the herbal material, was proposed in 2015
579
[xcvi96]. To assess the inherent quality of different grades and of different tissues in roots of P.
580
lactiflora, laser microdissection coupled with UPLC-QToF-MS was applied. The results show that
581
the quantity of the main components decreased with increase in root diameter from 0.3 cm to 0.7
Ac ce p
te
d
M
an
us
cr
ip t
556
24 Page 24 of 95
cm. Above 0.7 cm of diameter, quantity and diversity of these components increased proportionally
583
with the increase in root diameter. The tissue-specific study indicated that the high content of
584
paeoniflorin and albiflorin are mainly distributed in the cork and cortex. According to the results of
585
this study, roots of P. lactiflora greater than 1.7 cm in diameter can be considered of better quality
586
for medicinal use than smaller.
ip t
582
cr
587
5.5.2. Paeonia officinalis
589
Paeonia officinalis L. is native to South Eastern Europe but it has been widely introduced elsewhere
590
as a garden plant in many varieties. Dried and powdered roots of P. officinalis are used as a
591
medicine in both Indian and Chinese system of medicines. The roots are cleansed carefully in cold
592
water with a brush and allowed to remain in water for a short period of time, then they are spread
593
out on trays in the sun. Phytochemical screening revealed that the roots of P. officinalis contain
594
alkaloids, tannins, saponins, glycosides, carbohydrates, flavonoids, terpenes, steroids and proteins
595
[xcvii97]. Peony root has been used medicinally for over 2,000 years and it gained a reputation as a
596
treatment for epilepsy and to promote menstruation. The root is harvested in the autumn from plants
597
that are at least two years old and is dried for later use. Quality control of this species is reported by
598
TLC [xcviii98], and by HPLC fingerprint [xcix99].
an
M
d
te
Ac ce p
599
us
588
600
5.6. Passiflora edulis
601
Passiflora edulis Sims (passion fruit) belongs to the family Passifloraceae. P. edulis extracts of the
602
leaves have been used for centuries as sedatives by native Brazilians, and also for women's
603
disorders. A drink from the flower is used to treat asthma, bronchitis, and whooping cough [c100].
604
The leaves of P. edulis, traditionally used in American countries to treat both anxiety and
605
nervousness by folk medicine, are rich in polyphenols, which have been reported as natural
606
antioxidant. Several methods for the quality control of Passiflora species are reported in literature.
25 Page 25 of 95
HPLC and HPLC coupled to MS were also approached with the aim to quantify polar compounds
608
in extracts of P. edulis [cii,ci101]. A method based on GC-MS for the assessment of quality focused
609
on flavor has been reported [xxxii]. Chemical characterizations can provide authentication of
610
samples, detection of adulterations, and differentiation between closely related species. Different
611
methods based on modern planar chromatography techniques are reported for P. edulis
612
[cii102, 103, 104,cv105]. civ
cr
ciii
ip t
607
613
5.7. Polygonum spp. (Poligonaceae)
615
5.7.1. Polygonum cuspidatum
616
Polygonum cuspidatum Sieb. et Zucc., a traditional, popular Chinese medicinal herb, is widely
617
distributed in Southern China and Japan. The root of Polygonum cuspidatum has been used in the
618
treatment of inflammation, female disorders, infection, jaundice, skin burns and hyperlipemia
619
diseases [cvi].
620
Currently, over 67 compounds from the root of this plant have been isolated and identified; they are
621
quinones, stilbenes, flavonoids, coumarins, lignans and others. At present, emodin and polydatin are
622
used as the marker compounds to characterize the quality of this plant in the Pharmacopoeia of the
623
People's Republic of China [cvi106].
624
Emodin, resveratrol, and polydatin are the main active components of the rhizome. In 2005 a simple
625
densitometric HPTLC method for quantification of these compounds was reported [cvii107]. The
626
same compounds, with the addition of physcion, were determined in 2010 by HPLC [cviii108]. A
627
rapid and accurate UPLC-PDA method was established for simultaneous detection of 5 compounds
628
including polydatin, resveratrol, emodin-8-glucoside, emodin, and physcion [cix109].
Ac ce p
te
d
M
an
us
614
629 630
5.7.2. Polygonum hydropiper
631
Flavones and flavonoid glycosides, such as quercetin galactosides, a sesquiterpene acid, viscosumic
632
acid, oxymethylanthraquinones and polygonic acid were identified in all the parts of Polygonum 26 Page 26 of 95
hydropiper. Plant by its own or mixed with other herbs is used in the treatment of diarrhoea,
634
dyspepsia, itching skin, excessive menstrual bleeding, hemorrhoids and other diseases [cx110].
635
2D-TLC was applied to the quality control of P. hydropiper. Micro two-dimensional separations
636
were performed on polar bonded stationary phases of the type cyanopropyl-silica using non-
637
aqueous eluents as the first direction eluents and aqueous eluents as the second direction eluents.
638
The chromatographic process was performed in micro scale using 5 × 5 cm plates, small volume of
639
eluents and 10 mL of plant extracts to obtain satisfying separation [cxi111]. Analysis of flavonoids
640
by means of LC-MS was also reported for this species and proposed for quality control [cxii112].
us
cr
ip t
633
641
5.7.3. Polygonum aviculare
643
Polygonum aviculare L., also known as knotgrass, is an annual herbaceous plant commonly found
644
in all the continents. P. aviculare L. is widely used as an herbal remedy and has its monograph in
645
the European Pharmacopoeia. Infusions prepared from the herb of P. aviculare have been
646
traditionally used in the treatment of upper respiratory disorders as well as externally as a remedy
647
for skin affections and female diseases [cxiii113]. Previous studies have shown that extracts from P.
648
aviculare possess anti-inflammatory activity probably due to flavonoids [cxiv114]. There have been
649
several studies focused on the flavonoid composition of P. aviculare [cxiii,cxv115].
650
A study by HPLC–DAD–MSn addressed to the flavonoid constituents of knotgrass aerial parts
651
showed that, apart from well-defined compounds, it contains a series of flavonol glucuronides
652
which could not be unequivocally identified without isolation [cxiii]. It has also been shown that
653
flavonol glucuronides are dominating constituents in P. aviculare [cxiii].
654
UHPLC-DAD coupled with ion trap or time of flight mass detectors together with the analysis of
655
acidic hydrolysis products allowed a comprehensive determination of flavonoid composition.
656
Among dominating compounds, the occurrence of myricetin, kaempferol, isorhamnetin and
657
kaempferide glucuronides was reported. The developed method can be used as a suitable tool for a
Ac ce p
te
d
M
an
642
27 Page 27 of 95
658
more insightful, metabolome-based standardization of flavonoid rich fractions of P. avicularis
659
[cxiii].
660
5.8. Rubia cordifolia
662
Different classes of compounds were isolated from Rubia cordifolia L. (Rubiaceae) such as
663
anthraquinones, naphthoquinones, bicyclic hexapeptides, terpenes and carbohydrates. Anti-
664
proliferative and antioxidant activities are reported for R. cordifolia L., used in Chinese Traditional
665
Medicine for relieving the symptoms due to endometriosis, such as menstrual abdominal pain, post-
666
menstrual abdominal pain, lumbosacral pain, and bearing-down pain and distention in inferior belly
667
[cxvi116].
668
Very few report on analytical approaches for this plant are available in literature. In 2007 a paper
669
focused on the analysis of anthraquinones was published by Mishchenko et al. [cxvii117]. In 2014 a
670
rapid, simple and specific RP-HPLC method has been developed for the quantitative determination
671
of alizarin in the methanolic extracts of roots and aerial parts of R. cordifolia [cxviii118]. In a
672
research work published in 2010 an attempt was made to establish systems of standardization of
673
herbal supplements based on R. cordifolia [cxix119].
cr
us
an
M
d
te
Ac ce p
674
ip t
661
675
5.9. Trifolium pratense
676
Plants from the genus Trifolium (Fabaceae) have been used in traditional medicine by many
677
cultures. In Turkish folk medicine, for example, some Trifolium species are used for their
678
expectorant, analgesic, antiseptic properties and also to treat rheumatic aches. Some species are also
679
grown as pasture crops for animals in the Mediterranean. The high quercetin concentration and
680
soyasaponin occurrence make the seeds of some Trifolium species a potential source of health
681
beneficial phytochemicals to be use in human nutrition. However, T. pratense L. (red clover) has
682
also gained popularity for the treatment of menopausal symptoms [cxx120].
28 Page 28 of 95
683
Pope et al. (1953) isolated biochanin A from red clover extracts. In 1965, Schultz showed that
684
biochanin A and formononetin occur as glycosides in red clover [cxx]. More recently, isoflavones,
685
their glycosides, their malonate glycosides and their acetyl glycosides were determined in red clover
686
extracts using chromatographic and spectrometric methods [cxx- [ 121, 122,cxxiii123].
687
Quality control of red clover was reviewed in 2004; this review highlights practical considerations
688
of value to basic science and clinical investigators engaged in the study of botanical supplements.
689
Lessons and examples are drawn from the authors' experience in designing and developing a red
690
clover standardized extract for evaluation in Phase I and Phase II clinical trials [cxxiv124].
691
Wu and coworkers developed a method for the quality control of Red Flower Oil preparation, a
692
mixture of several plant essential oils, among which T. pretense, used in Traditional Chinese
693
Medicine. Fourier transform IR (FT-IR) was applied and two-dimensional correlation IR
694
spectroscopy (2D IR) was used to enhance the resolution [cxxv125]. More recently, HPLC
695
[cxxvi126] and HPTLC [cxxvii127] methods were developed for the analysis of T. pretense.
696
Finally, red clover was included in a classification study, with the aim to classify some markers of
697
common herbs used in Western medicine according to the Biopharmaceutical Classification System
698
(BCS) [cxxviii128].
te
d
M
an
us
cr
ip t
cxxii
Ac ce p
699
cxxi
700
6. Analytical methods for plants containing phenolic acids used in the treatment of women’s
701
disorders
702
The term “phenolic acids” describes phenols that possess one carboxylic acid functionality. The
703
naturally occurring phenolic acids contain two distinguishing constitutive carbon frameworks: the
704
hydroxycinnamic and hydroxybenzoic structures. Although the basic skeleton remains the same, the
705
numbers and positions of the hydroxyl groups on the aromatic ring create the variety. Phenolic
706
compounds in many plants are polymerized into larger molecules such as hydrolizable tannins.
707
Moreover, phenolic acids may arise in food plants as glycosides or esters with other natural
708
compounds such as sterols, alcohols, glycosides and hydroxyfatty acids. Several biological 29 Page 29 of 95
709
activities are reported for phenolic compounds and among these activity against menstrual
710
disorders, and activity on the vascular and uterine smooth muscles.
711
6.1. Angelica sinensis
713
The dried root of Angelica sinensis (Oliv.) Diels (Umbelliferae), known as Danggui in China, is
714
commonly used in Traditional Chinese Medicine (TCM). This herb is used to treat menstrual
715
disorders, amenorrhea, dysmenorrheal and is in common use in dietary supplements available in
716
China, USA and Europe as health benefits food products for women [cxxix129]. As for the
717
menstrual cycle and treatment of menopausal symptoms caused by the hormonal changes, it can
718
produce favorable effects, so it is also known as “female ginseng” in Europe [cxxx130]. Danggui
719
cultivated in Gansu Province, China, is considered to be an authentic high-quality herb on the basis
720
of thousands of years of traditional experience. Several other substitute herbs are also used in
721
clinical applications in other districts and countries, such as Angelica acutiloba in Japan, Levisticum
722
officinale Koch in Europe, and Angelica gigas in Taiwan. The roots of L. officinale are called
723
European Danggui and are listed in the German Pharmacopeia [cxxxi131].
724
Over 70 compounds have been separated and identified from A. sinensis, including those from
725
essential oils (mainly including monomeric phthalides), phthalide dimers, coumarins, organic acids
726
and their esters, polysaccharides, polyacetylenes, vitamins, amino acids, and others [cxxxii132].
727
Recent phytochemical and pharmacological studies reveal that the major bioactive components of
728
A. sinensis are phenolic acids and phthalides [cxxxiii133].
729
Z-Ligustilide (3-butylidene-4,5-dihydroisobenzofuranone) is one of the main active components of
730
A. sinensis, which exhibits significant effects on improving blood fluidity and strong antioxidant
731
activity, inhibits the contractile function of the vascular and uterine smooth muscles and the
732
proliferation of the vascular smooth muscle cells [cxxxiv134]. Therefore, Z-ligustilide has been
733
chosen as a ‘marker compound’ to assess the quality of Radix Angelicae sinensis and its products
734
[cxxxv135], together with ferulic acid, also used to study the pharmacokinetics of A. sinensis
Ac ce p
te
d
M
an
us
cr
ip t
712
30 Page 30 of 95
[cxxxii]. Various analytical methods have been reported to analyze the chemical constituents of A.
736
sinensis [cxxxiv]. Among these methods, HPLC-UV, HPLC-PAD and HPLC-PAD-MS have been
737
mostly employed to determine phthalides, ferulic acid, coniferyl ferulate, falcarindiol, α-linolenic
738
acid and linoleic acid in A. sinensis. However, using HPLC-PAD or HPLC-MS to identify chemical
739
constituents, it is still necessary to directly compare UV spectra or mass spectra and
740
chromatographic retention times with standards. Wang and coworkers [cxxxiv] developed an
741
HPLC-PAD-API/MS method for analysing the chemical constituents of A. sinensis. ESI and APCI
742
spectra, in both positive ion (PI) and negative ion (NI) modes, provided very useful information
743
concerning the molecular weights of detected compounds, allowing the detection of 15 constituents.
744
Many analytical methods including LC and GC have been previously developed for the quality
745
evaluation of DG [cxxxiii]. However, Z-ligustilide is a volatile and unstable compound,
746
decomposing rapidly at high temperature to form other phthalides through oxidation, isomerization,
747
dimerization [cxxxiv], and therefore GC techniques should not be suitable for analyzing the
748
thermolabile components such as coniferyl ferulate and (Z)-ligustilide. Fingerprinting methods to
749
assess the consistency of A. sinensis dietary supplements were developed using both HPLC-DAD
750
and flow-injection mass spectrometric (FIMS). The components responsible for the chemical
751
differences were pinpointed by the loadings plots of PCA [cxxxvi136].
752
Recently, Bai developed an HPLC-DAD combined with UHPLC-QToF-MS/MS (ultra high
753
performance liquid chromatography photodiode array detector quadrupole time-of-flight mass
754
spectrometry) method for simultaneously determining ten bioactive components belonging to
755
phenolic acids, alkyl phthalides, hydroxylphthalides and phthalide dimers to quantitatively evaluate
756
the effect of seven drying methods on the quality of A. sinensis [cxxxiii]. Cinnamic acid, ferulic
757
acids and derivatives of quercetin were also analyzed by HPLC-PDA [cxxxvii137].
Ac ce p
te
d
M
an
us
cr
ip t
735
758 759
6.2. Artemisia spp. (Asteraceae)
31 Page 31 of 95
The genus Artemisia is grown worldwide and includes several well-known medicinal herbs, and
761
among these A. abrotanum, A. capillaris, A. frigida and A.vulgaris.
762
6.2.1. Artemisia abrotanum
763
Analytical methods are reported for the essential oil and artemisinin content of A. abrotanum L., by
764
GC-MS and LC-MS [cxxxviii138,cxxxix139]. A sample of leaf oil of A. abrotanum, collected in
765
Cuba, was studied by GC and GC-MS, leading to the identification of fifty-seven compounds of
766
which trans-sabinyl acetate (33.4%) was the major component [cxxxix].
767
6.2.2. Artemisia capillaris
768
A. capillaris Thunb. has been widely used in East Asia for the treatment of circulatory disorders,
769
such as dysmenorrhea [cxl140]. It is reported to contain phenolic compounds, chlorogenic acid
770
analogues [cxli141], and sesquiterpenoid derivatives (arteannuin B, artemisitene, artemisinin,
771
dihydroartemisinic acid and artemisinic acid) [cxlii142]. Avula developed LC-UV, LC-ELSD and
772
LC–MS analytical methods for the quantitative determination of sesquiterpenoids from various
773
species of Artemisia samples, among which A. capillaris [cxlii]. Zhao reported the presence in A.
774
capillaris of nine chlorogenic acid analogues (chlorogenic acid, cryptochlorogenic acid,
775
neochlorogenic acid, 3,5-dicaffeoyl-quinic acid, 4,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic
776
acid, chlorogenic acid methyl ester, cryptochlorogenic acid methylester, neochlorogenic acid
777
methylester) by a LC-MS technique [cxli]. Chlorogenic acid, 3,5-di-O-caffeoylquinic acid, 4,5-di-
778
O-caffeoylquinic acid, jaceosidin, and eupatilin were detected in A. capillaris by UPLC-DAD
779
analysis and comparison with A. annua was performed by multivariate analytical methods
780
[cxliii143].
781
6.2.3. Artemisia frigida
782
GC-MS analysis was performed on the essential oil isolated from the aerial parts of A. frigida
783
Willd., showing an high content of 1,8-cineole and camphor [cxliv144].
784
6.2.4. Artemisia vulgaris
Ac ce p
te
d
M
an
us
cr
ip t
760
32 Page 32 of 95
Artemisia vulgaris L., commonly known as mugwort, is a shrub of temperate zones of Europe,
786
Asia, North Africa, and North America. A. vulgaris is reported as uterine stimulant. Phytochemical
787
analysis of A. vulgaris showed that the major chemical constituents were eudesmanolides
788
(sesquiterpene lactones), essential oils (such as cineole, wormwood oil, thujone), triterpenes,
789
coumarin, flavonoids [cxlv145]. The presence of flavonoids eriodictyol and apigenin in A. vulgaris
790
with their weak estrogenic activity, may account for its folkloric use to treat menstrual disorders, as
791
an emmenagogue and uterine relaxant. Furthermore, relaxing activities in other smooth muscles, the
792
ileum and the trachea, are reported. Although not directly tested on the uterus, the smooth muscle
793
relaxing effect could explain why it has been reported to be an uterine antispasmodic [cxlvi146].
794
Melguizo-Melguizo et al., reported the presence of 22 compounds, of which 15 were phenolic
795
compounds, mainly chlorogenic acid derivatives or flavonoids, using an HPLC coupled ESI-QToF-
796
MS [cxlvii147]. In this report the most abundant compound was found to be 3,5-O-dicaffeoylquinic
797
acid. Also protocatechuic acid and quinic acid were present in high amounts while flavonoids
798
showed a significantly lower concentration.
799
Alaerts and coworkers obtained fingerprints by a HPLC-DAD method aimed to the distinction,
800
identification and quality control of four different Artemisia species, i.e. A. vulgaris, A. absinthium,
801
A. annua and A. capillaris samples. The lowest similarity between the fingerprints of the four
802
species occurred at 214 nm. The distinction of the four species of Artemisia was visualised by PCA
803
in score plots [iii].
cr
us
an
M
d
te
Ac ce p
804
ip t
785
805
6.3. Chamaemelum nobile
806
Adulteration of commercial chamomile products is one of the most significant drawbacks in the
807
promotion of herbal chamomile products. Roman chamomile (Anthemis nobilis, syn. Chamaemelum
808
nobile L. (All.), Asteraceae) is known to contain several classes of biologically active lipophilic and
809
hydrophilic molecules including essential oils, coumarins and several polyphenols (primarily the
810
flavonoids). The main constituents of the Roman chamomile oil have been reported to be primarily 33 Page 33 of 95
angelate, tiglate and butyrate esters [cxlviii148]. In addition, the Roman chamomile oils often
812
contain monoterpene and sesquiterepene derivatives. Among these biologically important
813
molecules, spiroethers and coumarins are of interest due to their unique biological activity profiles.
814
Of the two spiroether isomers, the cis form was reported to exhibit more potent antispasmodic and
815
anti-inflammatory activity than the trans form and herniarin is reported to possess spasmolytic
816
activity [cxlix149]. Ma and coworkers developed an HPLC-PAD-MS method to validate and
817
quantitatively determine cis-en-yn-dicycloether and trans-en-yn-dicycloether as well as a major
818
coumarin compound, hernarin [cxlix]. The use of HPLC-PAD-MS allowed the isolation and
819
identification of other constituents such as umbelliferone, phytol, luteolin-7-O-β-glucoside, (Z)-2-β-
820
glucopyranosyloxyl-4-methoxycinnamic
821
acid,
822
glucoside, and 4,5-dicaffeoylquinic acid. Flowers contained large amount of spiroethers with higher
823
contents of trans-spiroether than the cis form in both flowers [cxlix]. Avula and coworkers used a
824
method based on high separation efficiency UHPLC with UV and QToF detection for the
825
quantification of phenolic compounds (cis-GMCA, chlorogenic acid, trans-GMCA, quercetagetin-
826
7-O-β-glucopyranoside, luteolin-7-O-β-glucoside, apigetrin, chamaemeloside apigenin-7-(6''-O-
827
acetyl)-glucoside, apigenin, and one poly-acetylene (tonghaosu) in C. nobile [cl150]. Roman
828
chamomile samples confirmed the presence of chamamaeloside and apigenin as major compounds.
829
PLS-DA was used to discriminate between commercial chamomile samples.
830
An analytical method based on the GC-MS analysis was developed by Wang [cxlviii] and applied
831
to the analysis of non-polar compounds in various chamomile samples.
an
(E)-2-β-glucopyranosyloxyl-4-methoxycinnamic
apigenin-7-(6''-O-acetyl)-glucoside,
umbelliferone
7-O-β-
Ac ce p
te
d
M
apigenin-7-O-β-glucoside,
acid,
us
cr
ip t
811
832 833
6.4. Curcuma spp. (Zingiberaceae)
834
6.4.1. Curcuma longa
835
Curcuma longa L., also known as turmeric, is a plant native of Southern Asia and is cultivated
836
extensively throughout the warmer parts of the world. The drug is represented by the rhizome and 34 Page 34 of 95
tuberous root. Among its several activities, it is most commonly used in postpartum recovery, and is
838
reported to treat excessive vaginal discharges and menstrual disorders [cxlvi]. Turmeric is a spice
839
most subjected to adulteration since it is frequently traded in ground form. Turmeric powder is
840
adulterated with rhizomes of cheaply available Curcuma species especially with those containing
841
the coloring pigment curcumin such as Curcuma zedoaria (Christm.) Rosc. or ‘yellow shoti’ syn.
842
Curcuma xanthorrhiza Roxb. ‘Manjakua’ and Curcuma malabarica Vel. leading to toxicity and
843
poor quality of the product [cli151].
844
Characteristic constituents responsible for the therapeutic effect of C. longa are the curcuminoids,
845
namely curcumin, desmethoxycurcumin and bisdesmethoxycurcumin [clii152]. The three
846
curcuminoids are the basis for the quality control of C. longa and derived preparations.
847
Quali-quantitative analysis of curcuminoids by different methods including TLC [cliii153], HPTLC
848
[cliv154,clv155], NIR spectroscopy [clvi156], microemulsion electrokinetic chromatography
849
[clvii157], CE [clviii158] supercritical fluid chromatography [clix159], and direct analysis in real
850
time (DART), an ion source technique [clx160] has been reported. Methods based on LC–ESI-MS2
851
[clxi161, 162,clxiii163] and LC coupled with a hybrid triple quadrupole linear ion trap [clxiv164]
852
were employed. HPLC-DAD and HPLC–ESI-MS methods were also developed to analyze the
853
tinctures of turmeric [clxv165]. Since by HPLC is difficult to produce complete separation of the
854
three curcuminoids (special stationary phase is needed) and the analysis is time consuming (10 min
855
at least), UPLC methods for simultaneous quantification of the three curcuminoids were developed
856
[clxvi166,clxvii167].
cr
us
an
M
d
te
clxii
Ac ce p
857
ip t
837
858
6.4.2. Curcuma xanthorrhiza
859
Curcuma xanthorrhiza Roxb. is one of the most commonly used ingredients in Indo-Malaysian
860
traditional
861
bisdemethoxycurcumin) of C. xanthorrhiza were quantified by HPLC [clxviii168], and later Ruslay
medicines.
The
known
curcuminoids
(curcumin,
demethoxycurcumin
and
35 Page 35 of 95
and coworkers developed an HPLC-DAD and HPLC-DAD-ESI-MSn to identify in the rhizome of
863
this species the three compounds [clxix169].
864
6.4.3. Curcuma zeodaria
865
Curcuminoids of C. zeodaria Rosc. have been analyzed by HPLC [clxx170,clxxi171] and by
866
UPLC-UV-MS methods [clxvii].
867
GC-MS methods were developed for qualitative and/or quantitative determination of volatiles of C.
868
longa, C. xanthorrizha, C. zeodaria [clxxii172,clxxiii173].
us
869
cr
ip t
862
6.5. Echinacea purpurea
871
Echinacea purpurea (L.) Moench (Asteraceae), also known as the purple coneflower, is an herbal
872
medicine that has been used for centuries, for the treatment of common cold, coughs, bronchitis,
873
upper respiratory infections, and some inflammatory conditions. Recently papers reporting an use in
874
circulation disorders, feminine endocrine disorders and menstrual symptoms have been published
875
[clxxiv174,clxxv175]. The three species currently used are Echinacea angustifolia DC., E. pallida
876
(Nutt.) Nutt. and E. purpurea [clxxvi176]. Due to their close taxonomic alliance, it is difficult to
877
distinguish between them and incidences of incorrectly labeled commercial products have been
878
reported. The main chemical constituents include alkamides, phenylpropanoids, polysaccharides
879
and volatile oils, as well as minor constituents such as flavonoids. The chemical composition
880
determined using LC, is traditionally used to establish the quality of plant material and preparations,
881
as well as to identify the species [clxxvi]. Different analytical methods were applied to this topic,
882
and in particular in 2003 HPLC coupled with UV photodiode-array detection and LC-ESI-MS were
883
developed for the simultaneous analysis of caffeic acid derivates and alkamides in the roots and
884
extracts of E. purpurea. The method was proposed for the quality control of plant material and
885
extracts [clxxvii177]. An accurate analysis focused on caffeic acid derivatives was proposed in
886
2004 by Li et al. The method was applied to 16 differents commercial preparation and proposed for
887
quality control [clxxviii178]. HPLC coupled with mass spectrometry was applied successively to
Ac ce p
te
d
M
an
870
36 Page 36 of 95
the simultaneous analysis of caffeic acid derivatives and alkamides [clxxix179]. E. purpurea was
889
distinguished from E. angustifolia by means of HPLC coupled to ELSD, and the method was
890
applied to raw material and extracts [clxxx180]. NMR was proposed as an alternative quality
891
control method: Diffusion-edited 1H-NMR (1D-DOSY) and 1H-NMR with suppression of the EtOH
892
and water signals were applied for the first time to the direct analysis of commercial herbal tinctures
893
derived from E. purpurea [clxxxi181]. UPLC was explored for the same purpose in 2011
894
[clxxxii182], and in 2013 commercial products of E. purpurea were analysed for their content in
895
phenylpropanoid by TLC with video Densitometry [clxxxiii183]. Finally a chemometric approach
896
was proposed to process data obtained from hyperspectral imaging of roots and leaves of raw
897
material of E. purpurea [clxxxiv184].
an
us
cr
ip t
888
M
898
6.6. Humulus lupulus
900
Humulus lupulus L. (Cannabaceae) is well-known throughout the world as the raw material in the
901
brewing industry. The female inflorescences (hop cones or “hops”) are widely used to preserve beer
902
and to give it a characteristic aroma and flavour. In addition hop cones have long been used for
903
medicinal purposes. In particular, hop preparations were mainly recommended for the treatment of
904
sleeping disorders, as a mild sedative, and for the activation of gastric function as bitter stomachic
905
[clxxxv185]. In addition, hop extracts reduce hot flushes in menopausal women, and a placebo-
906
controlled study on the use of a standardized (8-prenylnaringenin) hop extract revealed that the
907
daily administration in menopausal women decreased the incidence of hot flushes and other
908
discomforts associated to estrogen deficiency (sweating, insomnia, heart palpitation, irritability).
909
Moreover vaginal dryness in postmenopausal women was significantly reduced by the topical
910
application of a gel containing hyaluronic acid, liposomes, vitamin E and hop extract [clxxxv].
911
Hop cones are characterized by a unique and complex pool of secondary metabolites, comprising
912
both prenylflavonoids and prenylphloroglucinols. Three classes of compounds are of particular
913
relevance in relation to bitterness intensity, sensorial properties and health benefits: prenylchalcones
Ac ce p
te
d
899
37 Page 37 of 95
(xanthohumol, desmethylxanthohumol), prenylflavanones (isoxanthohumol, 6-prenylnaringenin, 8-
915
prenylnaringenin) and prenylphloroglucinols, also known as bitter acids or hop acids [clxxxv]. The
916
well-known 8-prenylnaringenin has been shown to be one of the most potent phytoestrogens
917
currently known. Therefore, xanthohumol, isoxanthohumol, 6-prenylnaringenin, 8-prenylnaringenin
918
are appropriate active constituents for the chemical standardization of hop dietary supplements to be
919
used by menopausal women, except the chalcone desmethylxanthohumol which is unstable and
920
readily cyclizes to form 6-prenylnaringenin and 8-prenylnaringenin [clxxxvi186].
921
Several analytical methods to quantify these compounds in various matrices, such as hop extracts,
922
hop products, beer, dietary supplements, human urine, serum, rat plasma, tissues have been
923
developed [clxxxvii187]. As regards hop extracts, methods based on HPLC-UV, HPLC coupled
924
ECD, CE and HPTLC were applied for the analysis of prenylated flavonoids [clxxxvii].
925
Prenylflavonoids and hop bitter acids in hop extracts have also been analyzed using HPLC-MS
926
[clxxxviii188].
927
Magalhães developed a methodology based on the sample purification by adsorption of phenolic
928
compounds from the matrix to polyvinylpolypyrrolidone (PVPP) and subsequent desorption of the
929
adsorbed polyphenols followed by the analysis of the extract by HPLC-DAD and HPLC-ESI-MS2
930
[clxxxvi].
931
Recently, Prencipe and coworkers developed an analytical method for the metabolite fingerprinting
932
of bioactive compounds in hop, together with a simple extraction procedure. Different extraction
933
techniques, including maceration, heat reflux extraction (HRE), ultrasound-assisted extraction
934
(UAE) and microwave-assisted extraction (MAE) were compared in order to obtain a high yield of
935
the target analytes. The analysis of hop constituents, including prenylflavonoids and
936
prenylphloroglucinols (bitter acids) was carried out by means of HPLC-UV/DAD, HPLC-ESI-MS
937
and MS2 [clxxxix189].
938
A broad spectrum of preparation and analytical liquid chromatography techniques, coupled with
939
mass spectroscopy (MS) have been applied to the analysis of various proanthocyanidins in hops
Ac ce p
te
d
M
an
us
cr
ip t
914
38 Page 38 of 95
940
[cxc190]. Fingerprints of commercial cultivars of H. lupulus have been also obtained coupling 2D
941
NMR datasets with PCA [cxci191]
942
6.7. Magnolia officinalis
944
Magnoliae officinalis Cortex (Houpo) is the dried stem bark, root bark or branch bark of Magnolia
945
officinalis Rehd. et Wils (Magnoliaceae). It has been used as a TCM for more than 2000 years for
946
the treatment of epigastric stuffiness, vomiting and diarrhea, abdominal distention and constipation,
947
cough and dyspnea [cxcii192]. Neolignans, sesquiterpenes, sesquiterpene neolignans, and
948
phenylpropanoids have been identified in M. officinalis. Oligomeric neolignans present in the plant
949
are linked through the aromatic rings. The quality control of this herbal medicine is currently based
950
on the assay of two active biphenolic compounds, namely magnolol (M) and honokiol (H) by TLC
951
or HPLC. Advanced methods for the analysis of M. officinalis cortex were proposed in last years.
952
An UPLC-DAD-ToF-MS fingerprinting method was developed for the quality control and source
953
discrimination of Cortex Magnoliae officinalis produced in Zhejiang Province (Wen-Hou-Po). Data
954
were statistically evaluated using similarity analysis, hierarchical cluster analysis (HCA) and
955
discriminant analysis [cxciii193].
956
In 2012 a method based on 1H NMR coupled with chemometric analysis was proposed to identify
957
the metabolites contributing to the differences between the samples and to discriminate different
958
medicinal parts and geographical origins of these samples. The correlation between the data from
959
1
960
Honokiol and magnolol were the main compounds responsible for the discrimination of samples
961
from different batches, thus proving that the choice of these two compounds as markers for quality
962
assessment by HPLC is relevant. The two sources of Magnoliae officinalis Cortex recorded in the
963
Chinese Pharmacopoeia, M. officinalis and M. officinalis var. biloba, could be differentiated by 1H-
964
NMR data, but the pattern recognition analysis by PLS-DA was unsuccessful in discriminating
Ac ce p
te
d
M
an
us
cr
ip t
943
H-NMR and HPLC was performed with the mixOmics software based on an unsupervised method.
39 Page 39 of 95
1
965
samples from various geographical origins. The combination of
H-NMR that gives a
966
comprehensive profile of the metabolites and HPLC that targets two biomarkers is an efficient mean
967
for the quality control of M. officinalis Cortex [cxcii].
ip t
968
6.8. Pimenta dioica
970
Pimenta dioica (Merr.) L., syn. Pimenta officinalis (Berg) L. (Myrtaceae) is widely distributed in
971
West Indies, Mexico, and South America and traditionally known as allspice, pimenta, pimento,
972
clove pepper and Jamaica pepper. The plant has been cultivated in Egypt, where it is known as
973
“fulful afrangi”. It is traditionally used as a spice and condiment and as a remedy against menstrual
974
disorders, while it is industrially used for tanning purposes and as flavouring and perfuming agent
975
in soaps, tonics, as well as for appetizing medicines. The plant shows high content and biological
976
diversity of the active constituents, phenolic acids, flavonoids, catechins, galloylglucosides,
977
phenylpropanoids, diterpenes and lupeol [cxciv194].
978
Analytical approaches to this species, involve both essential oils and phenolic compounds. For the
979
first aspect, in 2013 Amma and coworkers studied extensively essential oils by using a comparative
980
approach based on GC and GC-MS [cxcv195]. In 2006 analysis of the essential oils was approached
981
by multidimensional GC [cxcvi196]. Polyphenolic compounds were studied and analysed in a
982
recent paper that deals with the separation of 27 known compounds and two new polyphenolic
983
glucosides from the berries of Pimenta dioica [cxcvii197]. Standardization of preparations obtained
984
from P. dioica was gained both based on essential oil or salycilic acid [cxcviii198].
us
an
M
d
te
Ac ce p
985
cr
969
986
6.9. Piper methysticum
987
Kava (Piper methysticum G. Forster) is the name of a plant and drink traditionally prepared by
988
macerating its roots in cool water or coconut water [cxcix199]. It has been used for many centuries
989
in the South Pacific and Hawaii for social ceremonies, relaxation, medicine, and a multitude of
990
other purposes [cxcix]. More recently, standardized kava extracts, containing 30% active 40 Page 40 of 95
constituents, have been used globally as an anxiolytic [cxcix]. Additionally, a tight inverse
992
correlation between high rates of kava consumption and low incidences of cancer for populations in
993
the South Pacific has been reported. Some evidence points to the efficacy of black cohosh, exercise,
994
and possibly kava kava (P. methysticum) in the treatment of menopausal symptoms [cc200]. In the
995
last two decades various procedures concerning the separation and detection of kavalactones have
996
been routinely carried out by GC (without previous derivatization of kavalactones) [cci201] and
997
HPLC [ccii202] but most of them are not validated or only partially validated. Recently, analyses
998
by supercritical fluid chromatography and micellar electrokinetic chromatography have also been
999
reported. Both GC and HPLC can be used for the analysis of kavalactones with some advantages
1000
and disadvantages for each method. Using GC analysis, methysticin and yangonin, which are two of
1001
the major components, are generally not separated. In addition, the high temperature caused the
1002
decomposition of methysticin. Concerning HPLC analyses, the reversed-phase is generally better
1003
because highly reproducible with a very low detection limit for all compounds even if the
1004
quantitative analysis of the kavalactones by LC needs to be carried out in the absence of light to
1005
prevent the cis/trans isomerisation of yangonin. Recently analysis of Kavalactone has been
1006
reviewed by Bilia et al. [cciii203].
1007
DNA based analysis was applied for the correct identification of plant species and subspecies. This
1008
was object of a patent in 2007 [cciv204]. NIR spectroscopy coupled with chemiometric methods
1009
was applied to the quality control of kava kava, and in particular classification by PLS. The
1010
measurements were reproducible and showed repeatability on par with the HPLC method [ccv205].
cr
us
an
M
d
te
Ac ce p
1011
ip t
991
1012
7. Analytical methods for plants containing terpenes used in the treatment of women’s
1013
disorders
1014
Terpenoids are a class of natural products widespread in nature, mainly in plants as constituents of
1015
essential oils. Their building block is the hydrocarbon isoprene, CH2=C(CH3)-CH=CH2. Terpene
1016
hydrocarbons therefore have molecular formula (C5H8)n and they are classified according to the 41 Page 41 of 95
number of isoprene units, as hemiterpenoids, consisting of a single isoprene unit, monoterpenoids,
1018
consisting of two isoprene units, sesquiterpenes, diterpenes, triterpenes and tetraterpenoids with
1019
three, four, six and eight isoprene units, respectively. Most of the terpenoids have multicyclic
1020
structures that differ from one another by their functional groups and basic carbon skeletons. These
1021
types of natural lipids can be found in every class of living things, and therefore considered as the
1022
largest group of natural products. Several medicinal plants for women's healthcare contain terpenes
1023
which are responsible to induce menstruation or abortion, to reduce menstrual bleeding and
1024
postpartum hemorrhage and to alleviate menstrual diseases [cxlvi].
1025
The detection of triterpene glycosides using UV is well known for its insensitivity because of the
1026
weak chromophoric functionality of triterpene glycosides in the 200–210 nm region. LC-MS or LC-
1027
MS2 methods may work well for the identification and quantification of the wide range of triterpene
1028
glycosides [ccvi206]. However, such equipment is expensive and may not be readily available.
1029
Thus, the development of an alternative HPLC method with a reliable and reproducible detection is
1030
desirable. The inexpensive ELSD may be suitable for the routine analysis of plant matrix containing
1031
triterpenes [ccvi].
cr
us
an
M
d
te
Ac ce p
1032
ip t
1017
1033
7.1. Alisma orientalis
1034
Alisma orientalis Sam. belongs to Alismataceae family and its dried tuber is known in traditional
1035
Chinese medicine (TCM) as Rhizoma Alismatis or Zexie. Terpenes, including protostane
1036
triterpenoids, kaurane diterpenes, and guaiane sesquiterpenes, are the major chemical constituents
1037
of this plant [ccvii207]. To date, all protostane triterpenes occur only in Alisma plants, and they are
1038
considered to be chemotaxonomic markers of the genus. Alisolide, alisol O and alisol P, alisol A,
1039
alisol B, alisol B 23-acetate, 25-O-methylalisol A, 25-anhydroalisol A 24-acetate, 25-anhydroalisol
1040
A, alisol E 23-acetate, as well as 13β,17β-epoxyalisol A were isolated from the rhizome of A.
1041
orientalis.
42 Page 42 of 95
A. orientalis is a component, together other five herbal medicine (Paeonia lactiflora, Angelica
1043
sinensis, Ligusticum chuanxiong, Poria cocos, Atractylodis macrocephalae) of Danggui-Shaoyao-
1044
San (DSS), a famous traditional Chinese medicine formula, used as a classical gynecological
1045
remedy in China for centuries. Chen and coworkers developed an HPLC-DAD-ESI-MS2 method for
1046
the qualitative and quantitative analysis of the major constituents of this herbal product [ccviii208].
1047
Chemical profiles of A. orientalis have been investigated by TLC, HPCE-UV, HPLC-UV, HPLC-
1048
ELSD, and HPLC-IT-MS [ccix209]. In all these reports only three compounds, namely alisol A,
1049
alisol A 24-actetate, and alisol B 23-actetate were isolated and investigated. Liu developed an
1050
UPLC/Q-ToF-MS method for the analysis of protostane triterpenoids in A. orientalis. 20
1051
components were simultaneously separated within 7 min, and identified either through comparing
1052
the retention time (Rt) and CID fragmentation behaviors with those of the reference standards, or
1053
matching empirical molecular formulae with those of published compounds. Moreover, Liu
1054
reported firstly the CID fragmentation pathway of protostane triterpenoids [ccix].
1055
te
d
M
an
us
cr
ip t
1042
7.2. Calendula officinalis
1057
Calendula officinalis L. (Asteraceae) is an annual herb, native of the Mediterranean region, also
1058
known as marigold. Its flowers have been widely used in traditional medicine and also used as
1059
female diseases. The major constituents of C. officinalis include steroids, terpenoids, triterpenoids
1060
(isolated in both free and ester form), flavonoids, phenolic acids and carotenes [ccx210]. Faradiol,
1061
rutin, caffeic acid and chlorogenic acid have all been isolated from C. officinalis and have shown
1062
biological activities. The most potent anti-inflammatory effects of C. officinalis have been attributed
1063
to the faradiol monoesters, compounds belonging to the triterpenoid family [ccx]. Neukirch et al.
1064
quantified simultaneously eight pentacyclic terpenoids using reversed-phase HPLC of 10 varieties
1065
of C. officinalis, showing that the variety Calypso Orange Florensis produces the largest amounts of
1066
the bioactive terpenoids, in particular of faradiol laurate which is present in the whole flowers of
1067
this variety at levels which are two-fold higher than those previously determined in the specialised
Ac ce p
1056
43 Page 43 of 95
ray florets [ccxi211]. Loescher and coworkers compared HPTLC and HPLC for qualitative and
1069
quantitative analysis of the major constituents of C. officinalis and to investigate the effect of
1070
different extraction techniques on the composition of C. officinalis extracts from different parts of
1071
the plant [ccx]. They observed that HPTLC analysis is able to provide useful qualitative data for the
1072
quick determination of key standards in samples, with easy comparisons to be made between
1073
different extracts. Quantitatively, however, HPTLC data showed high variability which may be due
1074
in part to limitations in the sensitivity of the software. Authors claimed that HPLC is a more robust
1075
method and is preferred for quantitative analysis.
1076
Several reports on the essential oil composition of C. officinalis showed as the quantitative amount
1077
of the monoterpenes, sesquiterpenes and sesquiterpene alcohols, varies from country to country
1078
[ccxii212].
M
an
us
cr
ip t
1068
1079
7.3. Caulophyllum thalictroides
1081
Caulophyllum thalictroides (L.) Michx (Berberidaceae) is a perennial plant that grows in the United
1082
States and Canada. This plant is called blue cohosh and is well-known as a traditional women’s
1083
herb to ease childbirth and to treat uterine inflammation among Native Americans
1084
[ccxiii213,ccxiv214]. Traditionally the roots and rhizomes of C. thalictroides are used for the
1085
treatment of menstrual difficulties and to induce uterine contractions. Extracts of the underground
1086
parts of C. thalictroides are used as an herbal dietary supplement for regulation of the menstrual
1087
cycle and women’s diseases and as an antispasmodic [ccxiii,ccxiv]. Alkaloids (caulophyllumines A,
1088
caulophyllumines
1089
caulophyllosaponin), and triterpene glycosides have been isolated and identified. Saponins in blue
1090
cohosh are considered to be responsible for the uterine stimulant effects together with teratogenic
1091
alkaloids [ccxiii,ccxiv]. As this regards, there is considerable concern about the safety of blue
1092
cohosh with reports of new born babies having heart attacks or strokes after the mother consumed
1093
blue cohosh to induce labor. Analytical methods have been reported for the analysis of alkaloids
Ac ce p
te
d
1080
B,
and
magnoflorine),
steroidal
glycosides
(caulosaponin
and
44 Page 44 of 95
alone or for alkaloids and saponins. Alkaloid levels were firstly determined by TLC densitometric
1095
and HPLC methods in in the extract of C. thalictroides [ccxv215] and also by GC in dietary
1096
supplements that contain blue cohosh [ccxiv]. Successively, HPLC methods were developed for the
1097
quantitative analysis of alkaloids and saponins from C. thalictroides roots [ccxvi216] and from
1098
extracts of blue cohosh roots and dietary supplements [ccxvii217]. More recently, analytical
1099
methods including HPLC, UPLC and HPTLC have been reported for the determination of major
1100
alkaloids and triterpene saponins in the roots of C. thalictroides and in dietary supplements
1101
claiming to contain blue cohosh [ccxiii].
us
cr
ip t
1094
1102
7.3. Cimicifuga racemosa
1104
Cimicifuga racemosa (L.) Nutt., or Actaea racemosa (Ranunculaceae) commonly known as black
1105
cohosh, is native to North America. The roots and rhyzomes have been used traditionally by Native
1106
Americans for gynecological conditions [ccvi]. Various preparations of this plant have also been
1107
used for the treatment of menopausal disorders in Germany for over 50 years, and are presently
1108
available in USA as dietary supplements. A number of clinical studies have been published in
1109
support of the use of black cohosh as alternative treatment of menopausal symptoms [ccvi].
1110
Chemically, C. racemosa extracts contain triterpene glycosides, such as actein, 26-deoxyactein, and
1111
phenolic compounds, such as ferulic acid and isoferulic acid, flavonoids, such as formononetin
1112
[ccvi]. Currently, the standardization of black cohosh preparations is based on the content of
1113
triterpene glycosides, calculated as 26-deoxyactein. In general, RP-HPLC with UV detection is used
1114
for the analysis of C. racemosa samples, but triterpene glycosides of C. racemosa have a weak UV
1115
absorbance. Ganzera et al. reported an HPLC-ELSD method for the determination of actein, 26-
1116
deoxyactein, and cimiracemoside A [ccxviii218] while Li developed an HPLC method with ELSD
1117
and PAD for the quantitative analysis of 16 constituents of C. racemosa [ccvi]. Avula et al.
1118
developed an HPLC-ELSD method for the analysis of terpenoids in different C. racemosa samples
1119
[ccxix219]. Because of the increase in botanical trade between the USA and China in recent years,
Ac ce p
te
d
M
an
1103
45 Page 45 of 95
Chinese species of Actaea, including ‘shengma’, have become an adulterant in US-made black
1121
cohosh products. Moreover, due to overlap of the distribution area and similarity of leaf appearance
1122
of some species with black cohosh, some American species of Actaea might also be misidentified as
1123
black cohosh. Canadian Health have found that several cases of liver toxicity were associated with
1124
people who took black cohosh products adulterated with related herbal species. For this reason,
1125
Jiang et al. evaluated the authencity and described the phytochemical profile of 11 C. racemosa
1126
products by HPLC-DAD and selected ion monitoring (SIM)-LC-MS [ccxx220].
1127
LC-Atmospheric pressure chemical ionization (APCI)-MS for triterpene glycosides [ccxxi221], an
1128
LC-turbo ion spray (TIS)-MS method to examine the LC-MS chromatography or “fingerprint
1129
profile” of C. racemosa samples and derived products [ccxxii222] have been reported. Ma et al.
1130
studied the metabolite profiling of C. racemosa extracts by HPLC–ESI-ToF-MS technique and
1131
principal component analysis identifying 15 chemical markers [ccxxiii223]. Moreover, the
1132
phytochemical fingerprints of fifteen species of Cimicifuga were established using HPLC-PDA and
1133
LC-MS techniques. Polyphenols and triterpene glycosides made the black cohosh clearly
1134
distinguishable from most other species of Cimicifuga [ccxxiv224].
cr
us
an
M
d
te
Ac ce p
1135
ip t
1120
1136
7.4. Crocus sativus
1137
Saffron, which is obtained from the dried red stigmas of Crocus sativus L. (Iridaceae), is the most
1138
expensive spice in the world. It has broad use in the food industry as an additive for coloring and
1139
flavoring foods. It is also employed as a drug in traditional medicine and in Persian traditional
1140
medicine saffron is used to treat menstrual disorders [ccxxv225]. Saffron has also been found to be
1141
effective in relieving symptoms of premenstrual symptoms (PMS), dysmenorrhea and irregular
1142
menstruation [ccxxv]. The typical color, taste, aroma and flavor of saffron are determined by the
1143
following
1144
neapolitanose or triglucoses as the saccharidic moieties) are responsible for the strong coloring
1145
capacity, picrocrocin (the glucosylated monoterpene precursor of safranal) confers the bitter taste
compounds:
crocins
(glycosylated apocarotenoids
with glucose,
gentiobiose,
46 Page 46 of 95
and safranal (a monoterpene aldehyde derived from the chemical or enzymatic dehydration of
1147
picrocrocin during saffron handling, drying and storage) gives rise to its characteristic odor and
1148
aroma.
1149
The quality of saffron and its commercial value are determined by specifications described within
1150
the ISO/TS-3632 standard [ccxxvi226] that establishes the spectrophotometric quantification of
1151
picrocrocin and safranal in aqueous saffron extracts by absorbance measurements at 440, 257 and
1152
330 nm. Unfortunately, this method presents some disadvantages because safranal is just barely
1153
water soluble and also exhibits adsorption in the same (320 e 340 nm) range as cis-crocin isomers
1154
[ccxxvii227].
1155
Several works concerning different qualitative aspects of saffron are present in literature; different
1156
analytical techniques have been applied, primarily UV e Vis spectrophotometry and NIRS, to
1157
determine the characteristic chemical compounds [ccxxvi]. Mass spectrometry combined with GC,
1158
HPLC and LC analysis have been focused on the identification of volatile molecules, coloring
1159
pigments or taste compounds [ccxxvi- [ccxxviii228].
1160
Studies reported the investigation of saffron as performed by MIR (Mid-Infrared spectroscopy)
1161
[ccxxix229], and by multi-element stable isotope analysis [ccxxx230]. The recourse to DNA
1162
fingerprinting for food authentication is reported for routine quality control. A method based on
1163
Sequence-Characterized Amplified Regions (SCARs) was applied to 24 different food products
1164
containing different amounts of saffron in order to detect adulteration/contamination with seven
1165
common bulking agents [ccxxxi231]. Also NMR combined with PCA was used to discriminate
1166
between Iranian saffron and commercial samples by analyzing methanol extracts [ccxxxii232],
1167
between authentic Greek saffron and four typical plant-derived materials utilized as bulking agents
1168
in saffron, i.e., Crocus sativus stamens, safflower, turmeric, and gardenia [ccxxxiii233] and
1169
between Italian Protected Designation of Origin (PDO) saffron from L'Aquila, S. Gimignano and
1170
Sardinia and commercial saffron samples available on the Italian market [ccxxvi]. Due to its high
1171
market value, perceived value, demanding production, and premium price, attempts have been made
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to adulterate saffron with various substances with similar color and morphology to increase the
1173
volume and weight of commercial lots. The most frequently incorporated materials are Carthamus
1174
tinctorius, Calendula officinalis and Arnica montana flowers, Bixa orellana seeds, Hemerocallis sp.
1175
petals, Curcuma longa rhizomes and Crocus vernus stigmas [ccxxxi].
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1172
1176
7.6. Cyperus rotundus
1178
Cyperus rotundus L. (purple nut sedge), belonging to the family Cyperaceae, is a perennial herb,
1179
used in Chinese Traditional Medicine for the treatment of primary dysmenorrhea [ccxxxiv234].
1180
Several reports have stated the presence of sesquiterpenes, such as valencene and nootkatone,
1181
furochromones, sterols, flavonoids, and triterpenes in the rhizomes of this plant [ccxxxv235]. GC-
1182
MS methods have been developed to analyze essential oil composition of C. rotundus
1183
[ccxxxvi236,ccxxxvii237]. Priya Rani developed HPTLC and HPLC methods with UV detection to
1184
identify three sesquiterpenoids solavetivone, aristolone and nootkatone in the acetone extract of C.
1185
rotundus [ccxxxviii238]. Kumar and coworkers studied the hydroalcoholic fraction of C. rotundus
1186
by LC-ESI-MS/MS, identifying the presence of polyphenols, flavonoids and sesquiterpenes
1187
[ccxxxv].
1188
Jaiswal et al. obtained a metabolite profiling and determined the content of (+)-nootkatone in
1189
rhizome of C. rotundus. Laser dissected tissues, namely, the cortex, hypodermal fiber bundles,
1190
endodermis, amphivasal vascular bundles, and whole rhizomes were analyzed by UHPLC-QToF-
1191
MS. GC-MS analysis was used for profiling essential oil constituents and quantitation of (+)-
1192
nootkatone [ccxxxix239]. The quantitative determination of ferulic acid in C. rotundus by HPLC
1193
was also reported [ccxl240].
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1194 1195
7.7. Foeniculum vulgare
1196
Fennel (Foeniculum vulgare Mill., Ombrelliferae) is an aromatic perennial herb with a deep thick
1197
taproot. Different varieties are cultivated as a spice or vegetable, for an essential oil used to flavor 48 Page 48 of 95
foods, and in some countries, for medicinal purposes. Few extracts of F. vulgare and isolated
1199
compounds have been evaluated for several activities, namely, antiaging, anti-inflammatory,
1200
antimicrobial and antispasmodic [ccxli241].
1201
It seems that fennel can be effective in reducing the severity of dysmenorrhea, but it has an
1202
unpleasant taste in view of most of the volunteers [ccxlii242].
1203
Most of analytical literature on fennel regards the analysis of essential oil, markers for quality
1204
control of the species. Most of the analyses were performed by GC and mono and bi-dimensional
1205
GC-MS [ccxliii243,ccxliv244].
1206
In 2005 Raman spectroscopy was proposed as an alternative to GC for the anlaysis of fennel
1207
essential oil [ccxlv245]. Cross-sections of fennel seeds were investigated by the use of Raman
1208
spectroscopy and Raman mapping to localize the essential oil and to analyze its chemical
1209
composition directly in the plant. Furthermore the practicability of a home-built mobile
1210
transportable Raman spectrometer to perform on-site measurements was successfully tested.
1211
An interesting paper, focused on a metabolomics approach for quality control of herbs, introduced
1212
fennel in the analyses. The direct infusion of the samples in ESI-MS and the analyses in both
1213
positive and negative ion mode led to a clear differentiation of the different samples. To verify if the
1214
same approach could be effective also for mixtures of plant extracts, five different commercial
1215
dietary supplements were analyzed by ESI-MS. The data were evaluated by multivariate data
1216
analysis and the obtained results suggested that the method allows a satisfactory and rapid
1217
characterization of complex mixtures of commercial dietary supplements [ccxlvi246].
1218
A simple HPTLC method has been developed for the simultaneous quantification of umbelliferone,
1219
psoralen, and eugenol in the fruit of Foeniculam vulgare. The technique enables rapid and sensitive
1220
simultaneous analysis in different samples. The method was validated for precision, repeatability,
1221
and accuracy in accordance with ICH guidelines [ccxlvii247]. Adulteration issues on this species
1222
are reported in literature, and generally for the essential oil the method with better results in the
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49 Page 49 of 95
1223
identification of adulterations is isotopic ratio MS [ccxlviii248]. Anethole, an active compound of
1224
F. vulgare, was also analyzed in different samples of F. vulgare [ccxlix249].
1225
7.8. Panax ginseng
1227
Panax ginseng L. roots (Araliaceae) have been widely used in Chinese traditional medicine since
1228
ancient times owing to their stimulating and tonic properties. Ginseng roots have been used to treat
1229
various diseases, including cancer and cardiovascular diseases, in East Asian countries. Considering
1230
these effects, ginseng may hold value in treating postmenopausal women. A previous randomized
1231
controlled trial (RCT) reported that ginseng extract alleviated some menopausal symptoms, such as
1232
depression, and also improved general health and well-being [ccl250]. The pharmacological
1233
activities of ginseng or its crude extracts are based on the presence of a mixture of triterpenic
1234
saponins referred to as ginsenosides. Ginsenosides are classified into three groups according to the
1235
type of aglycones, i.e., dammarane, ocotillol and oleanane triterpenes. Furthermore, the dammarane
1236
type to which most ginsenosides belong can be generally classified as protopanaxadiol (PPD;
1237
ginsenosides Rb1 (Rb1), Rc, Rd, Rg3, Rh2, etc.) or protopanaxatriol (PPT; Rg1, Re, Rg2, Rh1,
1238
etc.). Although the sugar chains in the PPD-type group are attached to C-3 or C-20, the sugar chains
1239
in the PPT-type group are linked to a hydroxyl moiety at C-6 or C-20. In addition, the two types can
1240
be further differentiated based on the types of sugar chains and the aliphatic chain at C-17 [ccli251].
1241
Methods based on TLC, HPTLC, HPLC coupled with many different kinds of detectors, including
1242
UV, DAD, ELSD, charged aerosol detector (CAD), pulsed amperometric (PAD) detectors have
1243
been applied [cclii252] to the analysis of P. ginseng roots. Among these, ELSD analyses produce
1244
good chromatographic parameters, including high precision and accuracy, and the limit of detection
1245
(LOD) for ginsenosides has been determined at approximately 100 ng. CAD was developed as an
1246
alternative to ELSD to detect poor UV-responsive analytes. Using an HPLC-CAD system, Wang et
1247
al. quantified ginsenosides in P. ginseng founding that CAD produced improved chromatographic
1248
parameters, including sensitivity, linearity and reproducibility, over UV and ELSD [ccliii253]. MS
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50 Page 50 of 95
techniques have been widely used in the analysis of P. ginseng root [ccliv254]. Atmospheric
1250
pressure chemical ionization (APCI) and ESI are typically used in ginseng analysis, with ESI being
1251
more common. MALDI has been used for the mass spectrometric imaging of ginsenoside
1252
localization in P. ginseng root [cclii]. Quadrupole (Q), triple quadrupole (QqQ), ion trap (IT), ToF
1253
and Fourier transform ion cyclotron resonance (FT-ICR) are used as mass analyzers for ginseng
1254
analysis [cclii]. Recently, UPLC coupled with quadrupole time-of-flight mass spectroscopy (UPLC-
1255
QToF-MS) has been applied as a powerful analytical tool for rapid analysis of the complex
1256
components or metabolites and chemical transformations in ginseng-related products [ccli].
1257
Metabolite profiling and fingerprint analysis were obtained by 1H NMR spectroscopy to identify
1258
potential biomarkers capable of distinguishing different ginseng species, varieties, and commercial
1259
products [cclv255].
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1260
7.9. Pelargonium graveolens
1262
Pelargonium graveolens L. Her.ex Ait (known also as Geranium graveolens) (Geraniaceae) is used
1263
traditionally for the treatment of hyperglycaemia in multiple folk medicine systems. Geranium spp.
1264
are also used as astringent, diuretic, antidiabetic, antispasmodic for stomach troubles and menstrual
1265
symptoms, and as gargle for throatand tonsils. FDA (US Food and Drug Administration) classified
1266
geranium oils as GRAS (Generally Recognised As Safe) for food use [cclvi256]. Hence, geraniums
1267
are promoted as important aromatic plants and flavoring agents in perfumery, cosmetic, food and
1268
pharmaceutical industries [cclvii257]. Quality control of this species is focused mainly on essential
1269
oils, analyzed by GC-MS, but also by vibrational spectroscopy [cclvi]. The standardization of
1270
geranium oil along with its bioactivity, toxicity and adulterations have been reported in a review
1271
published in 2002 [cclviii258].
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7.10. Salvia spp. (Lamiaceae) 51 Page 51 of 95
7.10.1. Salvia sclarea
1276
Salvia sclarea L. (clary sage) is one of the most popular Salvia species in Turkey and many
1277
Countries. Clary sage seed has approximately 29% oil content and this oil contains >50% of α-
1278
linolenic acid. This plant, occurring in the Mediterranean basin and Iran, is one of the most
1279
important aromatic plants cultivated worldwide as a source of essential oil. The essential oil or
1280
extracts of the aerial parts of S. sclarea have a broad spectrum of effects including analgesic,
1281
antiinflammatory, antioxidant, antifungal, and antibacterial [cclix259].
1282
In 2008 clary sage essential oils obtained by hydro-distillation of dried aerial parts were analyzed
1283
by GC and GC-MS [cclx260]. Fifty components were characterized in cultivated plants with linalyl
1284
acetate (35.9%), germacrene D (13.3%), linalool (12.8%) and sclareol (9.27%) as dominating
1285
constituents, while 45 constituents were identified for wild plants with linalyl acetate (34.0%),
1286
linalool (18.5%), germacrene D (10.0%) and sclareol (8.7%) as the major constituents. In 2011
1287
Yalcin and coworkers published a study evaluating the effect of γ-irradiation on bioactivity, fatty
1288
acid composition and volatile compounds of clary sage seed based on the fact that γ-irradiation is
1289
widely applied in the preservation of spice quality [cclxi261].
1290
TLC was in addition proposed for a rapid fingerprint of Salvia sclarea [cclxii262]. Most of the
1291
adulterations of S. sclarea are valuable by essential oil composition and bioactivity [cclxiii263].
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1293
7.10.2. Salvia miltiorrhiza
1294
Radix Salvia miltiorrhizae Bunge, a plant native in China, is listed in the Chinese Pharmacopoeia
1295
with the name of Dan-Shen and used in Chinese folk medicine for the treatment of different
1296
pathologies. Two classes of major bioactive components in Dan-shen, including water soluble
1297
phenolic acids and lipophilic diterpenoid quinones, have effectiveness in treating coronary heart
1298
disease, heart-stroke, cerebrovascular diseases, menstrual disorders, miscarriage, hepatitis and
1299
insomnia. The study of S. miltiorrhiza components is very complex, therefore selective and efficient
1300
analytical methods are required to simultaneously determine their structures for further studies of 52 Page 52 of 95
the pharmacological effects and to control the quality of the preparations. Currently, there are many
1302
methods for the determination of phenolic compounds and diterpenes among which LC-MS2 was
1303
shown to be a powerful method for separation and identification of individual molecules in complex
1304
samples [cclxiv264].
1305
Cryptotanshinone, tanshinone I and anshinone IIA are important active constituents in S.
1306
miltiorrhiza Bunge. Cryptotanshinone is usually used against inflammation, tanshinone I for
1307
therapy of angina pectoris and anshinone IIA for improving blood circulation [cclxv265].
1308
Separation and determination of the constituents of this medicinal plant was gained mainly by
1309
HPLC-MS. A simple and sensitive HPLC-DAD method was established and validated to
1310
simultaneously quantify 7 major saponins, i.e., notoginsenoside R1, ginsenoside Re, Rg1, Rb1,
1311
Rh1, Rg2 and Rd, in "Danshen Dropping Pills" (DSDP), the best sold traditional Chinese medicine.
1312
The method involved the solid-phase extraction (SPE) and chromatographic separation on a
1313
reversed-phase Agilent Zorbax SB-C18 column [cclxvi266]. In a paper published in 2009 the
1314
chemical characteristics of S. miltiorrhiza collected from different locations in China were revealed,
1315
and salvianolic acid B, rosmarinic acid, cryptotanshinone, and tanshinones I and IIA were
1316
optimized as markers for the quality control of S. miltiorrhiza. The comparison was done on the
1317
basis of the simultaneous quantitative determination of 13 hydrophilic and lipophilic compounds,
1318
by UPLC and hierarchical analysis. The entire chromatographic pattern showed that S. miltiorrhiza
1319
was significantly different from its adulterant Salvia przewalskii [cclxvii267]. A paper reporting
1320
TLC analysis fingerprint was also published in 2006 [cclxviii268].
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1301
1322
7.11. Tanacetum partenium
1323
Feverfew (Tanacetum parthenium L.) (Asteraceae) is a medicinal plant traditionally used for the
1324
treatment of fevers, migraine headaches, rheumatoid arthritis, stomach aches, toothaches, insect
1325
bites, infertility, and problems with menstruation and labor during childbirth. The feverfew herb has
1326
a long history of use in traditional and folk medicine, especially among Greek and early European 53 Page 53 of 95
herbalists. The plant contains a large number of natural products, but the active principles probably
1328
include one or more sesquiterpene lactones, including parthenolide. Other potentially active
1329
constituents include flavonoid glycosides and pinenes [cclxix269]
1330
The chemistry of feverfew is now well defined. The most important biologically active principles
1331
are sesquiterpene lactones, the principal one being parthenolide. Parthenolide is found in the
1332
superficial leaf glands (0.2%–0.5%), but not in the stems, and comprises up to 85% of the total
1333
sesquiterpene content [cclxix]. More than 30 sesquiterpene lactones have been identified in
1334
feverfew. In general, there are 5 different types of sesquiterpene lactones, which may be classified
1335
by chemical ring structures. Feverfew contains eudesmanolides, germacranolides, and guaianolides.
1336
Parthenolide is a germacranolide [cclxix].
1337
This plant is marketed in the United States in a variety of forms and compositions. Although its
1338
therapeutic efficacy is still uncertain, the sesquiterpene lactone parthenolide is the constituent
1339
recommended to be measured for quality control of feverfew preparations.
1340
Quality control of T. parthenium was firstly proposed in 1992 [cclxx270]. Three physicochemical
1341
methods (HPLC, NMR spectroscopy, and HPLC of a derivative) have been used to measure
1342
parthenolide in authenticated Tanacetum parthenium (feverfew) and in several commercial
1343
products. Similar results were obtained for all three physicochemical assays and also for the
1344
bioassay. Authenticated T. parthenium grown in the UK contained a high level of parthenolide in
1345
leaves, flowering tops and seeds but a low level in stalks and roots [cclxx].
1346
In 2000 a validated liquid chromatographic method was developed and used to estimate
1347
parthenolide in a number of U.S. feverfew market products formulated as capsules, tablets, or crude
1348
powder [cclxxi271]. In the same year, efficacy and safety of this plant and its preparations was
1349
reviewed [cclxxii272].
1350
A NMR spectroscopic and pattern recognition analytical approach to investigate composition and
1351
variability of different samples of T. partenium was proposed in 2002. 1H-NMR spectroscopy and
1352
PCA was used to discriminate between batches of 14 commercially available feverfew samples
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1327
54 Page 54 of 95
based on multi-component metabolite profiles [cclxxiii273]. Improvement was gained only in 2013,
1354
when a paper describing the analysis by a spectrophotometric method of the different sesquiterpene
1355
lactones in the plant was published [cclxxiv274]. Standardization of formulation based on T.
1356
parthenium was developed in 2009. A spray-dried extract was standardized in the content of the
1357
sesquiterpene lactone parthenolide. The total flavonoid and parthenolide contents in the spray-dried
1358
extract were 1.31 % and 0.76% wt /wt. The spray-dried allowed its tableting by direct compression.
1359
Tablet properties were in accordance with the proposed specifications [cclxxv275].
cr
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1353
us
1360
8. Analytical methods for plants containing steroids used in the treatment of women’s
1362
disorders
1363
Steroids (Greek, stereos = solids), widely distributed in the animal and plant kingdom, present a
1364
tetracyclic system arranged in the form of a perhydrocyclopentanophenanthrene. They include great
1365
variations in structure and encompass compounds of vital importance to life, such as cholesterol, the
1366
bile acids, sex hormones, vitamin D, corticoid hormones, cardiac aglycones, antibiotics, and insect
1367
molting hormones.
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1368
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1361
1369
8.1. Dioscorea spp.
1370
Yam is the common name for rhizomes of plants from the genus Dioscorea (Dioscoreaceae) which
1371
are widely distributed all over the world. Over 50 steroidal saponins have been identified from
1372
various Dioscorea species. Steroidal saponins, furostanol glycosides such as methyl parvifloside
1373
and protodeltonin and spirostanol glycosides like deltonin and glucosidodeltonin, are reported to be
1374
the major physiologically active constituents in yam [cclxxvi276]. The most well-known species of
1375
this genus is Dioscorea villosa L., also called wild yam. The rhizomes and roots of this plant are
1376
used for their phytoestrogenic properties in the treatment of menstrual and menopause complaints
1377
and are claimed to improve women's health [cclxxvi].
55 Page 55 of 95
Analytical methods for the determination of steroidal compounds using HSCC-ELSD and HPLC-
1379
ELSD have been reported for Dioscorea villosa and Dioscorea spp [cclxxvii277,cclxxviii278]. A
1380
UHPLC method with shorter retention times and good resolution and sensitivity for quantitative
1381
determination of 11 steroidal saponins from the rhizomes and roots of Dioscorea villosa, D. alata
1382
and D. opposite, was developed by Avula and coworkers [cclxxvi]. Detection of the saponins was
1383
achieved by the use of an ELS detector. A highly sensitive UHPLC-MS to identify and confirm the
1384
structure of compounds in Dioscorea samples and dietary supplements that claimed to contain D.
1385
villosa was developed. FT-IR spectroscopy combined with multivariate analysis was used to predict
1386
dioscin content from African yam tubers (D. alata L.) [cclxxix279].
us
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1378
an
1387
9. Concluding remarks
1389
As highlighted, several strategies have been applied for the quality control of medicinal plants
1390
employed in the treatment of women's disorders. Thanks to the innovation in analytical technology,
1391
identification and detection of secondary metabolites dramatically improved. In particular,
1392
hyphenated techniques have proved to be the most suitable for the rapid identification of
1393
compounds in plant matrix. Advanced methods have been proposed for the quality control of these
1394
species in order to obtain specificity, sensitivity, and straightforward operation, reducing the
1395
analysis time. Often, powerful analytical techniques such as HPLC-DAD–MS, UPLC-MS, HPLC–
1396
MS/MS, NMR were employed to obtain a metabolic fingerprint. Medicinal plants here discussed
1397
were classified on the basis of the chemical markers used for the quality control, in plants
1398
containing tannins, antocyans, iridoids, flavonoids, phenolic acids, terpenes and steroids. This
1399
classification allows to select the most suitable analytical technique on the basis of the chemical
1400
composition of the medicinal plant. Qualitative profiles of the herbal products have been discussed,
1401
taking in consideration that differences in sample quality is not only found in the main compounds
1402
or in the chemical markers but also in the low-concentration compounds, and so fingerprint analysis
1403
might be an interesting way for identification and quality control of herbal products, containing a
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56 Page 56 of 95
large number of low amounts of unknown compounds. In many cases, quantitative analysis of the
1405
selected medicinal plants showed that the content in chemical markers can be influenced by several
1406
factors including climate, growing conditions, time of harvesting, and post-harvesting factors, such
1407
as storage conditions and processing and varies not ony in different parts of the plants but also from
1408
country to country. In several papers information obtained from the analysis of a plant was
1409
processed by statistical elaborations. The most widely used approach is multivariate data analysis,
1410
in PCA, a method that allows the differentiation among groups of samples, providing valuable
1411
information on the origin and/or among technological treatments. The analytical strategies here
1412
reported can be used during the standardization process with the aim to assure quality, safety and
1413
efficacy to herbal products. In several cases the discussed analytical approaches allow to explore the
1414
eventual adulteration and substitution with similar common herbs, often characterized by different
1415
bioactivity profiles and lower commercial value.
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1417
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ip t
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[ii] D. K. W. Mok, F. T. Chau, Chemical information of Chinese medicine: A challenge to
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chemist, Chemom. Intell. Lab. Syst. 82 (2006) 210–217.
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[iii] G. Alaerts, S. Pieters, H. Logie, J. Van Erps, M. Merino-Arévalo, B. Dejaegher, J. Smeyers-
Verbeke, Y. Vander Heyden, Exploration and classification of chromatographic fingerprints
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[iv] The European Medicines Agency: Reflection paper on markers used for quantitative and
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[vi] L. Giovannelli, G. Carderni, C. Cecchini, S. Silvi, C. Orpianesi, A. Cresci, Red wine
polyphenols influence carcinogenesis, intestinal microflora, oxidative damage and gene expression profiles of colonic mucosa in F344 rats. Mutat. Res. 591 (2005) 237–246. [vii] P. Rohdewald, Method and compositions for relieving menopausal and perimenopausal symptoms U.S. Pat. Appl. Publ. (2007), US 20070269541 A1 20071122. [viii] L.M. D’Agostino, I. Dini, E. Ramundo and F. Senatore, Flavonoid Glycosides of Alchemilla vulgaris, Phytother. Res. 12 (1998) S162–S163. [ix] C. Moller, S.H. Hansen, C. Cornett, Characterisation of tannin containing herbal drugs by
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containing herbal drugs by HPLC fingerprints, Pharmazie 68 (2013) 155–159. [xi] N. Sekeroglu, Evening primrose: Oenothera biennis L., Recent Progress in Medicinal Plants,
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[xii] J. de la Cruz, Antioxidant potential of evening primrose oil administration in hyperlipemic
P.R. Redden, Y.S. Huang, X. Lin, D.F. Horrobin, Separation and quantification of the
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triacylglycerols in evening primrose and borage oils by reversed-phase high-performance liquid
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chromatography. J. Chromatogr. A 694 (1995) 381-389.
[xiv] M. Karonen, J. Parker, A. Agrawal, J.P. Salminen, First evidence of hexameric and
M
heptameric ellagitannins in plants detected by liquid chromatography/ electrospray ionization mass spectrometry, Rapid Commun. Mass Sp. 24 (2010) 3151-3156.
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[xv] M. Wettasinghe, F. Shahidi, R. Amarowicz, Identification and Quantification of Low
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Molecular Weight Phenolic Antioxidants in Seeds of Evening Primrose (Oenothera biennis L.),
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J. Agricult. Food Chem. 50 (2002) 1267-1271. [xvi] A. Mari, D. Eletto, C. Pizza, P. Montoro, S. Piacente, Integrated mass spectrometry approach to profile proanthocyanidins occurring in food supplements: Analysis of Potentilla erecta L. rhizomes. Food Chem. 141 (2013) 4171-4178. [xvii] A. Bazylko, M. Tomczyk, A. Flazinska, A. Legas, Chemical fingerprint of Potentilla species by using HPTLC method, JPC-J. Planar. Chromat. 24 (2011) 441-444. [xviii] R. Domitrovic, The molecular basis for the pharmacological activity of anthocyans, Curr.
Med. Chem. 29 (2011) 454-469. [xix] P.J. Curtis, P.A. Kroon, W.J. Hollands, R. Walls, G. Jenkins, C.D. Kay, A. Cassidy,
Cardiovascular disease risk biomarkers and liver and kidney function are not altered in
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92 Page 92 of 95
Table 1. Medicinal plants discussed in the present review with relative chemical markers, analytical techniques and references.
LC–UV, LC–ELSD, LC–MS, UPLCDAD GC-MS
[141-143]
flavonoids, phenolic acids, triterpenoid
HPLC-DAD, HPLC-ESI-QTOF-MS, HPLC-DAD HPLC, HPTLC
[3,147]
flavonoids, caffeoyl acids quinochalcones, flavonoids alkaloids, steroidal glycosides triterpene glycoside spiroethers and coumarins, flavonoids, phenolic acids triterpene glycosides
HPLC-DAD-MS
[61]
d
phenolic acids and phthalides
HPLC–DAD
te
Ac ce p
Chamaemelum nobile
cr
terpenes
us
Artemisia abrotanum Artemisia capillaris Artemisia frigida Artemisia vulgaris Calendula officinalis Capsella bursa-pastoris Carthamus tinctorius Caulophyllum thalictroides
ip t
References [9,10]
essential oils, sesquiterpene phenolic, chlorogenic acids, sesquiterpenoids essential oil
Analytical techniques HPLC-DAD, HPLC-FLD, HPLC-ADC, LC-MS HPLC-DAD-ESI-MS/MS, UPLC/QTOF-MS HPLC-UV, HPLC-PAD, HPLC-PADMS, HPLC-PAD-API/MS, UHPLCQTOF-MS/MS, HPLC-PAD GC-MS, LC-MS
an
Chemical Markers flavonoids, tannins
M
Plants Alchemilla vulgaris Alisma orientalis Angelica sinensis
[133,134,136,137] [138,139]
[144]
[210-212]
[66-68]
TLC, HPLC, GC, UPLC
[213-217]
HPLC-PAD-MS, UHPLC-UV-MS, GC-MS
[148,149] [206,217-220]
[168,169] [167,170,171]
Crocus sativus
monoterpenes
Curcuma longa
phenolic compounds
Curcuma xanthorrhiza Curcuma zeodaria
phenolic compounds
HPLC-UV, HPLC–ELSD, HPLC-PAD, LC-MS LC-MS, SIM-LC-MS, APCILC-MS, LC-TIS-MS, HPLC–TOF-ESIMS, HPLC-PDA UV e Vis spectrophotometry, NIRS, GCMS, HPLC, LC, FTNIR, MIR, multielement stable isotope analysis, SCARs TLC, HPTLC, NIR, microemulsion electrokinetic chromatography, CE, SFC, DART, LC–ESI-MS/MS and LC-ESI(QqQ)-MS, HPLC-DAD and HPLC–ESIMS HPLC-DAD, HPLC-DAD-ESI-MSn
phenolic compounds
HPLC, UPLC-UV-MS
Cimicifuga racemosa
[208-209]
[226-233] [153-167]
93 Page 93 of 95
[276]
steroidal saponin
HSCC-ELSD, HPLC-ELSD, UHPLCELSD, UHPLC-MS, TLC with video Densitometry, HPLCDAD, LC-ESI-MS, HPLC-ELSD, NMR,
[276-278],
ip t
[276,279]
us
cr
alkamides, phenylpropanoids, polysaccharides, volatile oils, flavonoids essential oil GC, GC-MS, Raman spectroscopy, ESIMS, HPTLC isoflavones HPLC-UV, LC-MS, UPLC, UFLC, NMR prenylchalcones, HPLC-UV, HPLC-DAD, HPLC-ECD, prenylflavonoids, capillary electrophoresis, HPTLC, prenylphloroglucinols HPLC-MS, HPLC-MS2, NMR phenolics TLC, HPLC, UPLC-DAD-TOF-MS, NMR isoflavones HPLC-UV, HPLC-DAD, HPLC-FLD, LC-MS, GC-IT/MS fatty acids, tannins GC-MS, HPLC-DAD, HPLC-HRMS
[176-183]
[243-249] [71-79] [186-191] [192,193] [83-90] [12-15]
monoterpenes, phenolic compounds, flavonoids alkaloids, tannins, saponins, glycosides, carbohydrates, flavonoids, terpenes, steroids triterpenes
UPLC- PDA-QTOF-MS, UPLC-QTOF- [94-96] MS TLC, HPLC
[98,99]
Ac ce p
Paeonia officinalis
UHPLC-ELSD, UHPLC-MS,
an
Magnolia officinalis Medicago sativa Oenothera biennis Paeonia lactiflora
steroidal saponin
M
Humulus lupulus
[235-240]
steroidal saponin
GC-MS, HPTLC, HPLC-UV, LC–ESIMS/MS, UHPLC-QTOF-MS, UHPLC-ELSD, UHPLC-MS, FT-IR
d
Foenicum vulgare Glycine max
sesquiterpenes
te
Cyperus rotundus Dioscorea alata Dioscorea opposita Dioscorea villosa Echinacea purpurea
Panax ginseng
Passiflora edulis
TLC, HPTLC, HPLC-UV, HPLC-DAD, [252-255] HPLC-ELSD, HPLC-CAD, HPLC-PAD, LC-APCI-MS, LC-ESI-MS UPLCQToF-MS, NMR phenolic compounds, TLC, HPLC, HPLC-MS, GC-MS [32,101-105] thiols, terpenes, fatty acid esters, alcohols essential oil GC-MS, Vibrational spectroscopy [256,258]
Pelargonium graveolens Pimenta dioica essential oils, phenolic compounds Piper lactones methysticum Polygonum quinones, stilbenes cuspidatum
GC, GC-MS, HPLC
[195-198]
GC, HPLC, DNA based analysis, NIR,
[201-205]
HPTLC, HPLC, UPLC-PDA, HPLC- [107-109] DAD-FICL 94 Page 94 of 95
flavonoids
HPLC–DAD–MSn, UHPLC-DAD
[113,115]
sesquiterpenoids, iridoids iridoids flavonoids
HPLC-UV, NMR
[270-275]
cr
[22-33]
us
essential oil phenolic compounds, diterpenes monoterpenes, sesquiterpene lactones, flavonoid glycosides isoflavones
flavonoids, anthocyans
[118]
HPLC-DAD, HPLC-ESI-MS, HPLCMS-MS, MALDI-TOF-MS, MS, GCMS, HPLC-MS GC, GC-MS, TLC LC-MS/MS, HPLC-DAD, TLC,
an
flavonoids, anthocyans
[16]
ip t
flavonoids, LC-MS, MALDI-TOF-MS triterpenoids, organic, phenolic acids, tannins anthraquinones HPLC
[260-263] [266-268],
IR, HPLC, HPTLC
[124-127]
HPTLC, HPLC-DAD, GC-MS, MS, NMR ATR-IR, NIR, HPLC, HPLC-DAD-ESIMS, HPLC-DAD HPLC, LC-MS, HR-MS, GC/MS
[44-48]
LC-MS, NMR
[35-39]
[49-52] [53,55-58]
Ac ce p
Trifolium pratense Valeriana officinalis Verbena officinalis Vitex agnuscastus Vitis vinifera
[111-112]
M
Salvia sclarea Salvia miltiorrhizae Tanacetum parthenium
2D-TLC, LC-MS
d
Rubia cordifolia Rubus idaeus
flavonoids
te
Polygonum hydropiper Polygonum aviculare Potentilla erecta
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