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Medicinal plants and their agents that affect uterine contractility
Journal Pre-proof Medicinal plants and their agents that affect uterine contractility Enitome Evi Bafor, Sajeera Kupittayanant
PII:
S2468-8673(19)30134-8
DOI:
https://doi.org/10.1016/j.cophys.2019.09.004
Reference:
COPHYS 218
To appear in:
Current Opinion in Physiology
Please cite this article as: Bafor EE, Kupittayanant S, Medicinal plants and their agents that affect uterine contractility, Current Opinion in Physiology (2019), doi: https://doi.org/10.1016/j.cophys.2019.09.004
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Medicinal plants and their agents that affect uterine contractility Enitome Evi Bafor*1 and Sajeera Kupittayanant2 1
Department of Pharmacology and Toxicology, University of Benin, Benin City, Edo State Nigeria
2
School of Preclinical Science, Institute of Science, Suranaree University of Technology, Thailand
*Corresponding author: Enitome Evi Bafor
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Email address: [email protected]
Abstract
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Some pathologies alter uterine contractility causing labour complications. Medicinal plants have been documented in folklore for use in the management of painful menstruation, preventing miscarriages, preventing early births and to hasten birth. The effects of medicinal plants on uterine contractility have been investigated utilizing ex vivo animal or human models of the isolated uterus. This review showed that 15 plant families affect uterine contractility. While some plants showed uterine stimulation others showed inhibition. Some plants showed both inhibiting and stimulating activities. The flavonoid metabolites were major compounds with uterine effects, followed closely by phenolic acids and then alkaloids. Chlorophylls are emerging compounds shown to have both uterine stimulating and inhibiting effects. This review therefore shows the importance of medicinal plants in the study of new drugs for modulating uterine contractility and also proffer suggestions for improving standardization of experiments involving medicinal plants on uterine contractility.
Abbreviations
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Keywords: Medicinal plants; Uterus; Uterine contractility; Secondary metabolites; Flavonoids.
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UC, uterine contractions; VOCC, voltage-operated calcium channels; 5-HT, 5-hydroxytryptamine; IP3, inositol triphosphate; DAG, diacylglycerol; HSP27, heat shock protein 27; PGF2α, prostaglandin F2 alpha; PA, phenolic acid.
1. Introduction
The uterus has been known to consist of 3 layers, the perimetrium (outer layer), the myometrium (the muscular layer) and the endometrium (the inner layer) [1]. The myometrium, which is made up of both circular and longitudinal layers of muscles, is the focus of this review [1]. The myometrium functions to promote the expulsion of the fetus once pregnancy has progressed to term [2]. It also helps in the regulation of postpartum bleeding and the expulsion of the endometrial layer during the menstrual cycle [3]. These effects are brought about by contraction of the uterus facilitated by receptor action. The major 1
receptors which play a role in regulating uterine contraction (UC) are oxytocin receptors (agonist), estrogen receptors (agonist), prostaglandin receptors (agonist/antagonist), progesterone receptors (antagonist) and β2-adrenergic receptors (antagonist) [2]. By interacting with these receptors, drugs are able to modulate Ca2+ and subsequently UC. The role of cytokine receptors in UC is also evolving [4]. The key role of the uterus is in reproduction. In the non-pregnant female, the uterus prepares itself monthly for the care of a fertilized ovum and UC functions in this process. Similarly, during pregnancy, the uterus is quiet but at term, large contractions occur which enable the expulsion of the fetus [5]. Clearly, UC is vital in both the non-pregnant and pregnant female. Therefore, studies of substances that modulate UC are important in developing new treatments and therapeutic options that can assist in the management of the pathologies associated with UC.
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Since prehistoric times, medicinal plants have been widely used as remedies, especially in developing countries [6]. Most modern drugs were derived from medicinal plants [7] and the development of new products from medicinal plants is encouraged as the market of products derived from medicinal plants continues to grow [8,9]. There is currently limited drug development for UC related-problems [10]. Medicinal plants’ effect on UC have been intensively evaluated using both physiological and pharmacological studies in order to find new drugs with increased therapeutic efficacy [11–13].
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Most studies demonstrating medicinal plant effects in recent years have been performed in developing countries confirming their essential value and the rich resource of medicinal plants in these countries [14–17]. This review assesses methods used, subjects studied (animals versus humans), and stage of the uterus (pregnant, non-pregnant, or post-partum). The criteria for plant selection, parts of plants used, and methods of extraction were essentially based on folklore in the study areas [15]. The advantages of a study such as this are to provide knowledge on the role of medicinal plants in modulating uterine contractility which can progress to drugs for clinical trials or provide knowledge for further investigations.
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This review is therefore structured to achieve the following: provide knowledge from recent years on families of plants that modulate UC, provide an update on agents/compounds that have been identified to modulate UC, to identify the mechanisms through which medicinal plants modulate UC and to identify plant parts that are used for modulating uterine contractility. This review summarizes work investigating medicinal plants and their agents that affect uterine contractility in recent years.
2. Plants that modulate uterine contractility
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Several medicinal plants have been investigated in several parts of the world in recent years and found to stimulate or inhibit UC in the non-pregnant and pregnant uterus (Fig. 1). Some medicinal plants display the dual effect of inhibition and augmentation of UC at different concentrations.
3. Compounds isolated from plants that modulate uterine contractility
From recent literature, the flavonoid class of plant secondary metabolites appear to be the most common class of compounds reported to participate in the stimulation and inhibition of uterine contractility (Tables 1, 2 and 3). Over 9000 flavonoids have been reported from plants and they consist of several subclasses, making them a diverse entity [24]. Their diversity and broad range contributes to their varying chemical structure and activity leading to a myriad of pharmacological and physiological effects [24]. The presence of different functional groups contributes to their biological effect. The 2
presence of O-methylation appears to abolish anti-inflammatory activities (which may prevent inhibition of inflammatory mediators such as prostaglandins) [24]. This may therefore imply that Omethylated flavonoids will promote stimulation of UC while flavonoids with O-methylation will inhibit UC. In addition, planar ring flavonoids with hydroxyl groups in ring B and at C7 and C5 of ring A promote inhibition of UC [25]. A review on flavonoids suggested that majority of smooth muscle inhibiting flavonoids act through blockade of calcium channels [26]. Other minor pathways involved include nitric oxide release, K+-channel activation, Rho kinase pathway inhibition, and inhibition of inositol triphosphate (IP3) - mediated calcium release [26].
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Other classes of compounds identified in this review to stimulate UC include cyclopeptides, phenolic acids, alkaloids and pheophytins (Table 1). Cyclopeptides are primarily plants’ defense structures but also possess several biological activities [36]. They are known to interact with oxytocin, vasopressin and corticotropin-releasing factor type 1 receptors [37] making them potent stimulants of UC. Phenolic acids (PA) contain at least an aromatic ring and a hydroxyl group and act as precursor molecules in plants for compounds such as flavonoids, stilbenes, lignans, anthocyanins and chalcones. They largely function as anti-inflammatory agents [25] which may also be responsible for their action on UC. Pheophytins which are chlorophyll derivatives were recently discovered to modulate UC via interaction with the inflammatory pathway and calcium release [38].
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Some other classes of compounds identified in this review to inhibit UC include diarylheptanoid, alkaloids and pheophytins (Table 2). Diarylheptanoids are majorly known to inhibit estrogen receptors [41,42] and also some inflammatory pathways [43]. Antagonism of estrogen receptors support its UC inhibition activity. Alkaloids are a group of secondary plant metabolites that contain a heterocyclic nitrogen from amino acids [44]. The well-known anti-muscarinics, atropine and scopolamine are plant alkaloids [44]. The anti-neoplastic agents vinblastine and vincristine, the opioid morphine, the antimitotic noscapine and the stimulants theophylline and caffeine are all plant alkaloids [44]. Several subclasses of alkaloids exist which confer several chemical structures and therefore contribute to activity of alkaloids either as UC stimulants or inhibitors.
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4. Mechanisms of plants modulation of uterine contraction
Not many of the articles used for this review performed in-depth investigation to ascertain possible or exact mechanisms. However, it is obvious that medicinal plants are able to elaborate active constituents that produce their actions on the uterine smooth muscles through several receptor or channel activity that eventually modulate calcium release. This is evident from studies on some of the phytoconstituents isolated in the articles used for this review. Increased UC can be due to a rise in intracellular Ca2+ concentration on activation of L-type Ca2+ channels, through stimulation of sarcoplasmic reticulum (SR) Ca2+ release and also includes inhibition of myosin light chain (MLC) dephosphorylation (Fig. 2) [45]. Inhibition of UC by medicinal plants has also been found to occur via inhibition of L-type Ca2+channels and/or inhibition of Ca2+- release from internal stores (Fig. 2) [12]. This could be through 3
direct receptor interaction, release of nitric oxide, or activation of K+- channels (Fig. 2). However, in the absence of actual intracellular Ca2+ concentration in most studies, it was difficult to confirm the underlying mechanisms of the plant extracts whether they affect UC via L-type Ca2+ channels or SR Ca2+ release[46][47]. 5. Families of plants that modulate uterine contraction
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There are currently over 450 families of flowering plants. While it is reported that all plants have one or more medicinal value, only about 20 -25 families of plants have been used or investigated [48]. From our review of recent literature, 15 plant families were identified to have UC modulating activity (Tables 1, 2 and 3). Families that specifically produced UC stimulating activity include, Fagaceae, Anacardiaceae, Bromeliaceae, Nymphaceae and Bignoniaceae (Table 1). Those that produced specifically UC inhibiting compounds include Theacea, Solanaceae, Lamiaceae, Fabaceae and Dryopteridaceae (Table 2). The Labiaceae, Zingiberaceae and Moraceae families elucidated both UC stimulating and inhibiting compounds (Table 3). This however does not imply that UC modulating constituents are only present in 15 families. Rather, it illustrates those plant families that have been investigated in recent years. Identification of plant families that produce UC modulating effects will allow investigators focus on these families in the search for new drugs for female reproductive pathologies. 6. Plant parts that have shown uterine contractility and inhibition
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7. Experimental models
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There appears to be no specificity to the plant parts that may elaborate either UC inhibiting or stimulating compounds. However, leaves are the most commonly used parts which may be due to their ease of collection and preparation or because they are the parts utilized as vegetable in our diet. Crude plant extracts which have not been isolated for active compounds, were mostly used while other studies utilized fractions of extracts (extracts that are in the early stages of separation into their active compounds). It was therefore difficult to clarify active compounds that really acted on the myometrium in most studies.
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Animal models were largely utilized in investigating medicinal plant UC activity with very few studies using human models (Tables 1, 2 and 3). This limits the clinical relevance of the data reported. More studies using human myometrium are therefore suggested in order to further establish activities of these plants that will be clinically useful. The most commonly utilized animal was the rat. Of all the animal models available, it has been reported that mice more closely mimics human reproduction [49]. Therefore the use of mice is suggested in animal studies of UC. There were also variations in the state of the uterus used. Some studies investigated drugs used for preterm birth using the non-pregnant uterus. It is suggested that authors utilize the pregnant uterus model where pregnancy related pathologies are being investigated and non-pregnant uterus where non-pregnancy related conditions are being investigated. 8. Conclusion
From our review, it is clear that several medicinal plants are being studied for their effect on UC. Medicinal plants from 15 plant families have been shown to elaborate compounds that can alter UC. The major groups of plant compounds that have shown effect on UC are flavonoids, phenolic acids and alkaloids. Compounds from medicinal plants exert their effect on UC through a variety of mechanisms that involve calcium channel interaction and several receptor interactions. This makes medicinal plants unique in the discovery of new drugs for UC disorders. There is however a lack of appropriate data examining specific active compounds on the myometrium. The studies also included mostly animal models with the use of the rat predominating. However, the mice models are advised for UC studies which should be corroborated as much as possible with the use of human models and will encourage 4
acceptance of medicinal plant research. To be accepted as a viable alternative to modern medicine, there is a need for clinical studies and trials of the active constituents or plant extracts. Financial Interests None Conflict of interest statement None
Acknowledgements
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Some research papers could not be utilized in this review due to lack of access and space limitations. This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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References and recommended reading Papers of particular interest that have been published within the period of review have been highlighted as: *of special interest **of outstanding interest Ilicic M, Butler T, Zakar T, Paul JW: The expression of genes involved in myometrial contractility changes during ex situ culture of pregnant human uterine smooth muscle tissue. J Smooth Muscle Res 2017, 53:73–89.
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Wani SA, Iqbal H, Basir SF: Mechanism of flavonoids action in smooth muscle relaxation. World J Pharm Pharm Sci 2017, 6:514–550.
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Bafor EE, Eze C, Omoruyi O, Elvis-Offiah BU: Green tea inhibits uterine contractility in ex vivo ( non-pregnant ) mice models. Trop J Nat Prod Res 2018, 2:254–261.
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Agoreyo FO, Ohimai BR, Omigie MI: Effect of Solanum nigrun on uterus of non-gravid rats. Ethiop J Health Sci 2017, 27:239–244.
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**Yang L, Chai CZ, Yan Y, Duan YD, Henz A, Zhang BL, Backlund A, Yu BY: Spasmolytic mechanism of aqueous licorice extract on oxytocin-induced uterine contraction through inhibiting the phosphorylation of heat shock protein 27. Molecules 2017, 22:1392.
The authors investigated the effect of a licorice extract from Glycyrrhiza uralensis on uterine contractility. They applied several tools which included, functional uterine contractility assays for measuring contractile response to the extract, histomorphology of extract-treated tissues to identify changes to the architecture of the contractile proteins, liquid chromatography mass 7
spectrometry for quantify the constituents, Western blot analysis and immunofluorescence to identify genes expressed in the presence of the extract, and ChemGPS-NP bionformatic analysis for pathways involved in the mechanism of action. This study provided molecular and functional knowledge on the mechanims of the plant extract studied. 32.
Huang L, Zhang JQ, Li Y Bin, Liu M, Deng HM, Luo YC, Tan YF, Hou J, Yao GW, Guan WW: Effect of Alpinia officinarum Hance alcohol extracts on primary dysmenorrhea. Asian Pac J Trop Med 2016, 9:882–886.
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*Sophonsritsuk A, Wongkanha L, Ochareun A, Vallibhakara SAO, Vallibhakara O, Pinpradap K, Piyachaturawat P, Likittanasombut P: Effect of curcuma comosa on uterine smooth muscle contraction in women with adenomyosis. J Med Assoc Thail 2018, 101:1–7.
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This study investigated the relaxant effect of the plant Curcuma comosa and the major costituent diarylheptanoid, on myometrial strips from non-pregnant women with adenomyosis. The use of human tissue provides good information on the potential of the plant and constituent in the therapeutic management of symptoms of adenomyosis. Bafor EE, Omokaro WO, Uwumarongie OH, Elvis-offiah UB, Omoruyi O, Viegelmann C V, Edrada-ebel R: Dryopteris filix-mas ( Dryopteridaceae ) leaves inhibit mouse uterine activity. J Med Plants Econ Dev 2017, 1:a25.
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*Mirabi P, Hanieh Alamolhoda S, Yazdkhasti M, Mojab F: The effects of lemon balm on menstrual bleeding and the systemic manifestation of dysmenorrhea. Iran J Pharm Res 2018, 17:214–223.
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This study investigated the potential role of lemon balm in the management of excessive bleeding and pain during menstruation. The clinical application of lemon balm provides more knowledge on the potential usefuls of constituents from lemon in the therapeutic management of dysmenorrhoea and/or disordered bleeding during menstruation. Lima S, Benko-Iseppon A, Neto J, Amorim L, Neto J, Crovella S, Pandolfi V: Plants defenserelated cyclic peptides: diversity, structure and applications. Curr Protein Pept Sci 2017, 18:375–390.
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**Bafor EE, Rowan EG, Edrada-Ebel R: Metabolomics-Coupled functional pharmacology of chlorophyll compounds isolated from the leaves of Ficus Exasperata Vahl (Moraceae) provides novel pathways on myometrial activity. Reprod Sci 2017, 25:923–937.
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This study showed possible mechanisms of activity on uterine contractility of chlorophyll compounds derived from Ficus exasperata. The study utilized metabolomic tools (nuclear magnetic resonance and mass spectrometry), bioinformatics and functional pharmacology uterine contractility assays in arriving at the mecahnsims of action of cholorophyll compounds on uterine contractility. This study therefore provided new knowledge on the potential of chlorophyll compounds in modulating uterine contractility. 39.
Deehan M, Degolier T: Raw ginger root juice (Zingiber officinale) produces a biphasic contractile response in isolated mouse uterine tissue under resting baseline tension. J Pharmacogn Phytochem 2017, 6:818–823.
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Liu J, Peng C, Zhou QM, Guo L, Liu ZH, Xiong L: Alkaloids and flavonoid glycosides from the aerial parts of Leonurus japonicus and their opposite effects on uterine smooth muscle. Phytochemistry 2018, 145:128–136.
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diarylheptanoid on human estrogen receptor alpha. J Biomol Struct Dyn 2019, 37:1189– 1203. Thongon N, Boonmuen N, Suksen K, Wichit P, Chairoungdua A, Tuchinda P, Suksamrarn A, Winuthayanon W, Piyachaturawat P: Selective estrogen receptor modulator (SERM)-like activities of Diarylheptanoid, a phytoestrogen from Curcuma comosa, in breast cancer cells, pre-osteoblast cells, and rat uterine tissues. J Agric Food Chem 2017, 65:3490–3496.
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Diao S, Jin M, Sun J, Zhou Y, Ye C, Jin Y, Zhou W, Li G: A new diarylheptanoid and a new diarylheptanoid glycoside isolated from the roots of Juglans mandshurica and their antiinflammatory activities. Nat Prod Res 2019, 33:701–707.
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Arrowsmith S, Kendrick A, Hanley JA, Noble K, Wray S: Myometrial physiology - time to translate? Exp Physiol 2014, 99:495–502.
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Jayarama R: Important medicinal plant families and plant based drugs: A review. In 5th International Conference on Civil, Architecture, Environment and Waste Management (CAEWM-17). . 2017:277–283.
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Munglue P, Eumkep G, Wray S, Kupittayanant S: The effects of watermelon (citrullus lanatus) extracts and L-citrulline on rat uterine contractility. Reprod Sci 2013, 20:437–448.
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Lijuan W, Kupittayanant P, Chudapongse N, Wray S, Kupittayanant S: The effects of wild ginger (Costus speciosus (Koen) Smith) rhizome extract and diosgenin on rat uterine contractions. Reprod Sci 2011, 18:516–524.
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Figures and Figure Captions
Figure 1
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Original representative recordings showing the effect of plant extracts or compounds that inhibit or stimulate uterine contractions. (A) Watermelon flesh extract inhibiting uterine contractions, (B) Wild ginger oil stimulating uterine contractions, (C) Pheophytin a series of chlorophyll compounds from Ficus exasperata inhibiting uterine contractions and (D) Pyropheophorbide from Ficus exasperata inhibiting uterine contractions.[38,50,51].
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Figure 2
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Diagrammatic representation of the different mechanisms associated with plant extracts in modulating uterine contractions. (A) Inhibition by β-sitosterol, (B) Stimulation by ergot alkaloids from plants fungi, (C) Inhibition by citral and (D) Stimulation by citrulline from watermelon. [12]
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Table 1. Medicinal plants and compounds that stimulate uterine contractility VOCC = voltage-operated calcium channels, 5-HT = 5-hydroxytryptamine; - = no information available; EC50Effective concentration producing 50 percent of maximum response.
Plant family
Plant part Active used metabolites Fagaceae (Oak Galls Quercus infectoria[18] family) Spondias mombin Anacardiaceae Leaves L[19] (Cashew family)
Proposed Mechanism(s) VOCC
Bromeliaceae (Monocotyled on flowering plant family) Nymphaeaceae Nymphaea alba (Water lily [21] family) Crescentia cujete Bignoniaceae L.[22] (Bignonias family) Asteraceae Helichrysum (Daisy family) mechowianum [23]
Models Nonpregnant rats Nonpregnant rats
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Edible part
-
5-HT pathway
Pregnant rats and humans
Rhizome
alkaloids, flavonoids and saponins Flavonoids, alkaloids, phenolic acids -
Muscarinic and adrenergic receptors -
Nonpregnant rats
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Ananas comosus [20]
EC50 (mg/ml) -
Prostaglandins, α2-adrenergic receptors, calcium release from intracellular stores
Seed, Fruit Leaves
Prostaglandin pathway, VOCCs
0.00013 0.00001
Nonpregnant mice ± Pregnant rats
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Medicinal Plant
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Table 2. Medicinal plants and compounds that inhibit uterine contractility
Medicinal Plant
Plant family
Plant Active part used metabolites Theaceae Leaves Catechins, (Shrubs and flavonoids, trees family) phenolic acids
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Green tea [27]
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VOCC – voltage-operated calcium channels, 5-HT - 5-hydroxytryptamine; - no information available; EC50Effective concentration producing 50 percent of maximum response, IP3 –inositol triphosphate, DAG diacylglycerol, HSP27 – heat shock protein 27, PGF2α – prostaglandin F2 alpha
Solanum nigrum Solanaceae [28] (Nightshade family) Shakuyakukanzo-to [29]
Proposed EC50 Mechanism(s) (mg/ml) VOCC, prostaglandins, IP3 and DAG
Model
Nonpregnant rats Pregnant rats and humans
Leaves
-
-
-
-
Glycyrrhizin glycyrrhetinic acid, shakuyaku, and paeoniflorin
-
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Nonpregnant rats
Lamiaceae (Mint family)
Stem
Tannin
-
-
Glycyrrhiza uralensis Fisch. [31] Alpinia officinarum Hance [32] Curcuma comosa[33]
Fabaceae (Legume family) Zingiberaceae (Ginger family)
Roots and rhizomes Roots
-
HSP27 pathway
-
Flavonoids and diarylheptanoids
PGF2α and intracellular Ca2+
-
Zingiberaceae
Rhizome
Diarylheptanoid
-
1.50 ± 1.79
Alkaloids, terpenes, porphyrins Rutin
VOCCs
0.66 0.11
-
-
Dryopteris mas[34]
filix- Dryopteridaceae Leaves (Ferns)
Melissa officinalis[35]
Lamiaceae
Not clear
Nonpregnant rats Nonpregnant mice Nonpregnant mice Nonpregnant humans ± Nonpregnant mice Nonpregnant humans
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Tectona grandis Linn. [30]
Table 3. Plants with dual effect of inhibition and contraction on uterine contractility
Plant part used Zingeribaceae Root
Active metabolites
Gingerol, shogaol, galanolactone, dehydrogingerdione and gingerdione (for inhibition) alkaloids and saponins (for contraction) Pheophytins
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Labiaceae Leonurus japonicus Houtt. [40]
Aerial
EC50 (mg/ml)
Model
Nonpregnant mice
Cyclic adenosine monophosphate, dopamine, extracellular signalregulated kinases 1/2, and glutamate pathways For inhibition: flavonoid glycosides (spinosin, linarin, and apigenin-7-O-b-Dglucopyranoside) For stimulation: cyclopeptides (cycloleonuripeptides C and D) and alkaloids (imperialine-3b-D glucoside
Nonpregnant mice
na Leaves
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Ficus Exasperata Moraceae Vahl [38]
Proposed Mechanism(s)
Inhibition of 5-HT and Prostaglandin synthesis (For inhibition)
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Zingiber officinale (Ginger) [39]
Plant family
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Medicinal Plant
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5-HT = 5-hydroxytryptamine
13
Nonpregnant rats
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and leonurine)
14
PII:
S2468-8673(19)30134-8
DOI:
https://doi.org/10.1016/j.cophys.2019.09.004
Reference:
COPHYS 218
To appear in:
Current Opinion in Physiology
Please cite this article as: Bafor EE, Kupittayanant S, Medicinal plants and their agents that affect uterine contractility, Current Opinion in Physiology (2019), doi: https://doi.org/10.1016/j.cophys.2019.09.004
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Medicinal plants and their agents that affect uterine contractility Enitome Evi Bafor*1 and Sajeera Kupittayanant2 1
Department of Pharmacology and Toxicology, University of Benin, Benin City, Edo State Nigeria
2
School of Preclinical Science, Institute of Science, Suranaree University of Technology, Thailand
*Corresponding author: Enitome Evi Bafor
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Email address: [email protected]
Abstract
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Some pathologies alter uterine contractility causing labour complications. Medicinal plants have been documented in folklore for use in the management of painful menstruation, preventing miscarriages, preventing early births and to hasten birth. The effects of medicinal plants on uterine contractility have been investigated utilizing ex vivo animal or human models of the isolated uterus. This review showed that 15 plant families affect uterine contractility. While some plants showed uterine stimulation others showed inhibition. Some plants showed both inhibiting and stimulating activities. The flavonoid metabolites were major compounds with uterine effects, followed closely by phenolic acids and then alkaloids. Chlorophylls are emerging compounds shown to have both uterine stimulating and inhibiting effects. This review therefore shows the importance of medicinal plants in the study of new drugs for modulating uterine contractility and also proffer suggestions for improving standardization of experiments involving medicinal plants on uterine contractility.
Abbreviations
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Keywords: Medicinal plants; Uterus; Uterine contractility; Secondary metabolites; Flavonoids.
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UC, uterine contractions; VOCC, voltage-operated calcium channels; 5-HT, 5-hydroxytryptamine; IP3, inositol triphosphate; DAG, diacylglycerol; HSP27, heat shock protein 27; PGF2α, prostaglandin F2 alpha; PA, phenolic acid.
1. Introduction
The uterus has been known to consist of 3 layers, the perimetrium (outer layer), the myometrium (the muscular layer) and the endometrium (the inner layer) [1]. The myometrium, which is made up of both circular and longitudinal layers of muscles, is the focus of this review [1]. The myometrium functions to promote the expulsion of the fetus once pregnancy has progressed to term [2]. It also helps in the regulation of postpartum bleeding and the expulsion of the endometrial layer during the menstrual cycle [3]. These effects are brought about by contraction of the uterus facilitated by receptor action. The major 1
receptors which play a role in regulating uterine contraction (UC) are oxytocin receptors (agonist), estrogen receptors (agonist), prostaglandin receptors (agonist/antagonist), progesterone receptors (antagonist) and β2-adrenergic receptors (antagonist) [2]. By interacting with these receptors, drugs are able to modulate Ca2+ and subsequently UC. The role of cytokine receptors in UC is also evolving [4]. The key role of the uterus is in reproduction. In the non-pregnant female, the uterus prepares itself monthly for the care of a fertilized ovum and UC functions in this process. Similarly, during pregnancy, the uterus is quiet but at term, large contractions occur which enable the expulsion of the fetus [5]. Clearly, UC is vital in both the non-pregnant and pregnant female. Therefore, studies of substances that modulate UC are important in developing new treatments and therapeutic options that can assist in the management of the pathologies associated with UC.
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Since prehistoric times, medicinal plants have been widely used as remedies, especially in developing countries [6]. Most modern drugs were derived from medicinal plants [7] and the development of new products from medicinal plants is encouraged as the market of products derived from medicinal plants continues to grow [8,9]. There is currently limited drug development for UC related-problems [10]. Medicinal plants’ effect on UC have been intensively evaluated using both physiological and pharmacological studies in order to find new drugs with increased therapeutic efficacy [11–13].
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Most studies demonstrating medicinal plant effects in recent years have been performed in developing countries confirming their essential value and the rich resource of medicinal plants in these countries [14–17]. This review assesses methods used, subjects studied (animals versus humans), and stage of the uterus (pregnant, non-pregnant, or post-partum). The criteria for plant selection, parts of plants used, and methods of extraction were essentially based on folklore in the study areas [15]. The advantages of a study such as this are to provide knowledge on the role of medicinal plants in modulating uterine contractility which can progress to drugs for clinical trials or provide knowledge for further investigations.
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This review is therefore structured to achieve the following: provide knowledge from recent years on families of plants that modulate UC, provide an update on agents/compounds that have been identified to modulate UC, to identify the mechanisms through which medicinal plants modulate UC and to identify plant parts that are used for modulating uterine contractility. This review summarizes work investigating medicinal plants and their agents that affect uterine contractility in recent years.
2. Plants that modulate uterine contractility
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Several medicinal plants have been investigated in several parts of the world in recent years and found to stimulate or inhibit UC in the non-pregnant and pregnant uterus (Fig. 1). Some medicinal plants display the dual effect of inhibition and augmentation of UC at different concentrations.
3. Compounds isolated from plants that modulate uterine contractility
From recent literature, the flavonoid class of plant secondary metabolites appear to be the most common class of compounds reported to participate in the stimulation and inhibition of uterine contractility (Tables 1, 2 and 3). Over 9000 flavonoids have been reported from plants and they consist of several subclasses, making them a diverse entity [24]. Their diversity and broad range contributes to their varying chemical structure and activity leading to a myriad of pharmacological and physiological effects [24]. The presence of different functional groups contributes to their biological effect. The 2
presence of O-methylation appears to abolish anti-inflammatory activities (which may prevent inhibition of inflammatory mediators such as prostaglandins) [24]. This may therefore imply that Omethylated flavonoids will promote stimulation of UC while flavonoids with O-methylation will inhibit UC. In addition, planar ring flavonoids with hydroxyl groups in ring B and at C7 and C5 of ring A promote inhibition of UC [25]. A review on flavonoids suggested that majority of smooth muscle inhibiting flavonoids act through blockade of calcium channels [26]. Other minor pathways involved include nitric oxide release, K+-channel activation, Rho kinase pathway inhibition, and inhibition of inositol triphosphate (IP3) - mediated calcium release [26].
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Other classes of compounds identified in this review to stimulate UC include cyclopeptides, phenolic acids, alkaloids and pheophytins (Table 1). Cyclopeptides are primarily plants’ defense structures but also possess several biological activities [36]. They are known to interact with oxytocin, vasopressin and corticotropin-releasing factor type 1 receptors [37] making them potent stimulants of UC. Phenolic acids (PA) contain at least an aromatic ring and a hydroxyl group and act as precursor molecules in plants for compounds such as flavonoids, stilbenes, lignans, anthocyanins and chalcones. They largely function as anti-inflammatory agents [25] which may also be responsible for their action on UC. Pheophytins which are chlorophyll derivatives were recently discovered to modulate UC via interaction with the inflammatory pathway and calcium release [38].
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Some other classes of compounds identified in this review to inhibit UC include diarylheptanoid, alkaloids and pheophytins (Table 2). Diarylheptanoids are majorly known to inhibit estrogen receptors [41,42] and also some inflammatory pathways [43]. Antagonism of estrogen receptors support its UC inhibition activity. Alkaloids are a group of secondary plant metabolites that contain a heterocyclic nitrogen from amino acids [44]. The well-known anti-muscarinics, atropine and scopolamine are plant alkaloids [44]. The anti-neoplastic agents vinblastine and vincristine, the opioid morphine, the antimitotic noscapine and the stimulants theophylline and caffeine are all plant alkaloids [44]. Several subclasses of alkaloids exist which confer several chemical structures and therefore contribute to activity of alkaloids either as UC stimulants or inhibitors.
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4. Mechanisms of plants modulation of uterine contraction
Not many of the articles used for this review performed in-depth investigation to ascertain possible or exact mechanisms. However, it is obvious that medicinal plants are able to elaborate active constituents that produce their actions on the uterine smooth muscles through several receptor or channel activity that eventually modulate calcium release. This is evident from studies on some of the phytoconstituents isolated in the articles used for this review. Increased UC can be due to a rise in intracellular Ca2+ concentration on activation of L-type Ca2+ channels, through stimulation of sarcoplasmic reticulum (SR) Ca2+ release and also includes inhibition of myosin light chain (MLC) dephosphorylation (Fig. 2) [45]. Inhibition of UC by medicinal plants has also been found to occur via inhibition of L-type Ca2+channels and/or inhibition of Ca2+- release from internal stores (Fig. 2) [12]. This could be through 3
direct receptor interaction, release of nitric oxide, or activation of K+- channels (Fig. 2). However, in the absence of actual intracellular Ca2+ concentration in most studies, it was difficult to confirm the underlying mechanisms of the plant extracts whether they affect UC via L-type Ca2+ channels or SR Ca2+ release[46][47]. 5. Families of plants that modulate uterine contraction
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There are currently over 450 families of flowering plants. While it is reported that all plants have one or more medicinal value, only about 20 -25 families of plants have been used or investigated [48]. From our review of recent literature, 15 plant families were identified to have UC modulating activity (Tables 1, 2 and 3). Families that specifically produced UC stimulating activity include, Fagaceae, Anacardiaceae, Bromeliaceae, Nymphaceae and Bignoniaceae (Table 1). Those that produced specifically UC inhibiting compounds include Theacea, Solanaceae, Lamiaceae, Fabaceae and Dryopteridaceae (Table 2). The Labiaceae, Zingiberaceae and Moraceae families elucidated both UC stimulating and inhibiting compounds (Table 3). This however does not imply that UC modulating constituents are only present in 15 families. Rather, it illustrates those plant families that have been investigated in recent years. Identification of plant families that produce UC modulating effects will allow investigators focus on these families in the search for new drugs for female reproductive pathologies. 6. Plant parts that have shown uterine contractility and inhibition
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7. Experimental models
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There appears to be no specificity to the plant parts that may elaborate either UC inhibiting or stimulating compounds. However, leaves are the most commonly used parts which may be due to their ease of collection and preparation or because they are the parts utilized as vegetable in our diet. Crude plant extracts which have not been isolated for active compounds, were mostly used while other studies utilized fractions of extracts (extracts that are in the early stages of separation into their active compounds). It was therefore difficult to clarify active compounds that really acted on the myometrium in most studies.
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Animal models were largely utilized in investigating medicinal plant UC activity with very few studies using human models (Tables 1, 2 and 3). This limits the clinical relevance of the data reported. More studies using human myometrium are therefore suggested in order to further establish activities of these plants that will be clinically useful. The most commonly utilized animal was the rat. Of all the animal models available, it has been reported that mice more closely mimics human reproduction [49]. Therefore the use of mice is suggested in animal studies of UC. There were also variations in the state of the uterus used. Some studies investigated drugs used for preterm birth using the non-pregnant uterus. It is suggested that authors utilize the pregnant uterus model where pregnancy related pathologies are being investigated and non-pregnant uterus where non-pregnancy related conditions are being investigated. 8. Conclusion
From our review, it is clear that several medicinal plants are being studied for their effect on UC. Medicinal plants from 15 plant families have been shown to elaborate compounds that can alter UC. The major groups of plant compounds that have shown effect on UC are flavonoids, phenolic acids and alkaloids. Compounds from medicinal plants exert their effect on UC through a variety of mechanisms that involve calcium channel interaction and several receptor interactions. This makes medicinal plants unique in the discovery of new drugs for UC disorders. There is however a lack of appropriate data examining specific active compounds on the myometrium. The studies also included mostly animal models with the use of the rat predominating. However, the mice models are advised for UC studies which should be corroborated as much as possible with the use of human models and will encourage 4
acceptance of medicinal plant research. To be accepted as a viable alternative to modern medicine, there is a need for clinical studies and trials of the active constituents or plant extracts. Financial Interests None Conflict of interest statement None
Acknowledgements
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Some research papers could not be utilized in this review due to lack of access and space limitations. This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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References and recommended reading Papers of particular interest that have been published within the period of review have been highlighted as: *of special interest **of outstanding interest Ilicic M, Butler T, Zakar T, Paul JW: The expression of genes involved in myometrial contractility changes during ex situ culture of pregnant human uterine smooth muscle tissue. J Smooth Muscle Res 2017, 53:73–89.
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Wani SA, Iqbal H, Basir SF: Mechanism of flavonoids action in smooth muscle relaxation. World J Pharm Pharm Sci 2017, 6:514–550.
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Bafor EE, Eze C, Omoruyi O, Elvis-Offiah BU: Green tea inhibits uterine contractility in ex vivo ( non-pregnant ) mice models. Trop J Nat Prod Res 2018, 2:254–261.
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Agoreyo FO, Ohimai BR, Omigie MI: Effect of Solanum nigrun on uterus of non-gravid rats. Ethiop J Health Sci 2017, 27:239–244.
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Sumi G, Yasuda K, Tsuji S, Kanamori C, Tsuzuki T, Cho H, Nishigaki A, Okada H, Kanzaki H: Lipid-soluble fraction of Shakuyaku-kanzo-to inhibits myometrial contraction in pregnant women. J Obstet Gynaecol Res 2015, 41:670–679.
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**Yang L, Chai CZ, Yan Y, Duan YD, Henz A, Zhang BL, Backlund A, Yu BY: Spasmolytic mechanism of aqueous licorice extract on oxytocin-induced uterine contraction through inhibiting the phosphorylation of heat shock protein 27. Molecules 2017, 22:1392.
The authors investigated the effect of a licorice extract from Glycyrrhiza uralensis on uterine contractility. They applied several tools which included, functional uterine contractility assays for measuring contractile response to the extract, histomorphology of extract-treated tissues to identify changes to the architecture of the contractile proteins, liquid chromatography mass 7
spectrometry for quantify the constituents, Western blot analysis and immunofluorescence to identify genes expressed in the presence of the extract, and ChemGPS-NP bionformatic analysis for pathways involved in the mechanism of action. This study provided molecular and functional knowledge on the mechanims of the plant extract studied. 32.
Huang L, Zhang JQ, Li Y Bin, Liu M, Deng HM, Luo YC, Tan YF, Hou J, Yao GW, Guan WW: Effect of Alpinia officinarum Hance alcohol extracts on primary dysmenorrhea. Asian Pac J Trop Med 2016, 9:882–886.
33.
*Sophonsritsuk A, Wongkanha L, Ochareun A, Vallibhakara SAO, Vallibhakara O, Pinpradap K, Piyachaturawat P, Likittanasombut P: Effect of curcuma comosa on uterine smooth muscle contraction in women with adenomyosis. J Med Assoc Thail 2018, 101:1–7.
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This study investigated the relaxant effect of the plant Curcuma comosa and the major costituent diarylheptanoid, on myometrial strips from non-pregnant women with adenomyosis. The use of human tissue provides good information on the potential of the plant and constituent in the therapeutic management of symptoms of adenomyosis. Bafor EE, Omokaro WO, Uwumarongie OH, Elvis-offiah UB, Omoruyi O, Viegelmann C V, Edrada-ebel R: Dryopteris filix-mas ( Dryopteridaceae ) leaves inhibit mouse uterine activity. J Med Plants Econ Dev 2017, 1:a25.
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*Mirabi P, Hanieh Alamolhoda S, Yazdkhasti M, Mojab F: The effects of lemon balm on menstrual bleeding and the systemic manifestation of dysmenorrhea. Iran J Pharm Res 2018, 17:214–223.
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This study investigated the potential role of lemon balm in the management of excessive bleeding and pain during menstruation. The clinical application of lemon balm provides more knowledge on the potential usefuls of constituents from lemon in the therapeutic management of dysmenorrhoea and/or disordered bleeding during menstruation. Lima S, Benko-Iseppon A, Neto J, Amorim L, Neto J, Crovella S, Pandolfi V: Plants defenserelated cyclic peptides: diversity, structure and applications. Curr Protein Pept Sci 2017, 18:375–390.
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**Bafor EE, Rowan EG, Edrada-Ebel R: Metabolomics-Coupled functional pharmacology of chlorophyll compounds isolated from the leaves of Ficus Exasperata Vahl (Moraceae) provides novel pathways on myometrial activity. Reprod Sci 2017, 25:923–937.
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This study showed possible mechanisms of activity on uterine contractility of chlorophyll compounds derived from Ficus exasperata. The study utilized metabolomic tools (nuclear magnetic resonance and mass spectrometry), bioinformatics and functional pharmacology uterine contractility assays in arriving at the mecahnsims of action of cholorophyll compounds on uterine contractility. This study therefore provided new knowledge on the potential of chlorophyll compounds in modulating uterine contractility. 39.
Deehan M, Degolier T: Raw ginger root juice (Zingiber officinale) produces a biphasic contractile response in isolated mouse uterine tissue under resting baseline tension. J Pharmacogn Phytochem 2017, 6:818–823.
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Liu J, Peng C, Zhou QM, Guo L, Liu ZH, Xiong L: Alkaloids and flavonoid glycosides from the aerial parts of Leonurus japonicus and their opposite effects on uterine smooth muscle. Phytochemistry 2018, 145:128–136.
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diarylheptanoid on human estrogen receptor alpha. J Biomol Struct Dyn 2019, 37:1189– 1203. Thongon N, Boonmuen N, Suksen K, Wichit P, Chairoungdua A, Tuchinda P, Suksamrarn A, Winuthayanon W, Piyachaturawat P: Selective estrogen receptor modulator (SERM)-like activities of Diarylheptanoid, a phytoestrogen from Curcuma comosa, in breast cancer cells, pre-osteoblast cells, and rat uterine tissues. J Agric Food Chem 2017, 65:3490–3496.
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Diao S, Jin M, Sun J, Zhou Y, Ye C, Jin Y, Zhou W, Li G: A new diarylheptanoid and a new diarylheptanoid glycoside isolated from the roots of Juglans mandshurica and their antiinflammatory activities. Nat Prod Res 2019, 33:701–707.
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Schläger S, Dräger B: Exploiting plant alkaloids. Curr Opin Biotechnol 2016, 37:155–164.
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Wray S, Kupittayanant S, Shmygol a, Smith RD, Burdyga T: The physiological basis of uterine contractility: a short review. Exp Physiol 2001, 86:239–246.
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Arrowsmith S, Kendrick A, Hanley JA, Noble K, Wray S: Myometrial physiology - time to translate? Exp Physiol 2014, 99:495–502.
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Wray S: Insights from physiology into myometrial function and dysfunction. Exp Physiol 2015, 100:1468–1476.
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Jayarama R: Important medicinal plant families and plant based drugs: A review. In 5th International Conference on Civil, Architecture, Environment and Waste Management (CAEWM-17). . 2017:277–283.
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McCarthy R, Martin-Fairey C, Sojka DK, Herzog ED, Jungheim ES, Stout MJ, Fay JC, Mahendroo M, Reese J, Herington JL, et al.: Mouse models of preterm birth: Suggested assessment and reporting guidelines. Biol Reprod 2018, 99:922–937.
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Munglue P, Eumkep G, Wray S, Kupittayanant S: The effects of watermelon (citrullus lanatus) extracts and L-citrulline on rat uterine contractility. Reprod Sci 2013, 20:437–448.
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Lijuan W, Kupittayanant P, Chudapongse N, Wray S, Kupittayanant S: The effects of wild ginger (Costus speciosus (Koen) Smith) rhizome extract and diosgenin on rat uterine contractions. Reprod Sci 2011, 18:516–524.
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Figures and Figure Captions
Figure 1
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Original representative recordings showing the effect of plant extracts or compounds that inhibit or stimulate uterine contractions. (A) Watermelon flesh extract inhibiting uterine contractions, (B) Wild ginger oil stimulating uterine contractions, (C) Pheophytin a series of chlorophyll compounds from Ficus exasperata inhibiting uterine contractions and (D) Pyropheophorbide from Ficus exasperata inhibiting uterine contractions.[38,50,51].
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Figure 2
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Diagrammatic representation of the different mechanisms associated with plant extracts in modulating uterine contractions. (A) Inhibition by β-sitosterol, (B) Stimulation by ergot alkaloids from plants fungi, (C) Inhibition by citral and (D) Stimulation by citrulline from watermelon. [12]
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Table 1. Medicinal plants and compounds that stimulate uterine contractility VOCC = voltage-operated calcium channels, 5-HT = 5-hydroxytryptamine; - = no information available; EC50Effective concentration producing 50 percent of maximum response.
Plant family
Plant part Active used metabolites Fagaceae (Oak Galls Quercus infectoria[18] family) Spondias mombin Anacardiaceae Leaves L[19] (Cashew family)
Proposed Mechanism(s) VOCC
Bromeliaceae (Monocotyled on flowering plant family) Nymphaeaceae Nymphaea alba (Water lily [21] family) Crescentia cujete Bignoniaceae L.[22] (Bignonias family) Asteraceae Helichrysum (Daisy family) mechowianum [23]
Models Nonpregnant rats Nonpregnant rats
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Edible part
-
5-HT pathway
Pregnant rats and humans
Rhizome
alkaloids, flavonoids and saponins Flavonoids, alkaloids, phenolic acids -
Muscarinic and adrenergic receptors -
Nonpregnant rats
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Ananas comosus [20]
EC50 (mg/ml) -
Prostaglandins, α2-adrenergic receptors, calcium release from intracellular stores
Seed, Fruit Leaves
Prostaglandin pathway, VOCCs
0.00013 0.00001
Nonpregnant mice ± Pregnant rats
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Medicinal Plant
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Table 2. Medicinal plants and compounds that inhibit uterine contractility
Medicinal Plant
Plant family
Plant Active part used metabolites Theaceae Leaves Catechins, (Shrubs and flavonoids, trees family) phenolic acids
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Green tea [27]
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VOCC – voltage-operated calcium channels, 5-HT - 5-hydroxytryptamine; - no information available; EC50Effective concentration producing 50 percent of maximum response, IP3 –inositol triphosphate, DAG diacylglycerol, HSP27 – heat shock protein 27, PGF2α – prostaglandin F2 alpha
Solanum nigrum Solanaceae [28] (Nightshade family) Shakuyakukanzo-to [29]
Proposed EC50 Mechanism(s) (mg/ml) VOCC, prostaglandins, IP3 and DAG
Model
Nonpregnant rats Pregnant rats and humans
Leaves
-
-
-
-
Glycyrrhizin glycyrrhetinic acid, shakuyaku, and paeoniflorin
-
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Nonpregnant rats
Lamiaceae (Mint family)
Stem
Tannin
-
-
Glycyrrhiza uralensis Fisch. [31] Alpinia officinarum Hance [32] Curcuma comosa[33]
Fabaceae (Legume family) Zingiberaceae (Ginger family)
Roots and rhizomes Roots
-
HSP27 pathway
-
Flavonoids and diarylheptanoids
PGF2α and intracellular Ca2+
-
Zingiberaceae
Rhizome
Diarylheptanoid
-
1.50 ± 1.79
Alkaloids, terpenes, porphyrins Rutin
VOCCs
0.66 0.11
-
-
Dryopteris mas[34]
filix- Dryopteridaceae Leaves (Ferns)
Melissa officinalis[35]
Lamiaceae
Not clear
Nonpregnant rats Nonpregnant mice Nonpregnant mice Nonpregnant humans ± Nonpregnant mice Nonpregnant humans
ro of
Tectona grandis Linn. [30]
Table 3. Plants with dual effect of inhibition and contraction on uterine contractility
Plant part used Zingeribaceae Root
Active metabolites
Gingerol, shogaol, galanolactone, dehydrogingerdione and gingerdione (for inhibition) alkaloids and saponins (for contraction) Pheophytins
Jo
Labiaceae Leonurus japonicus Houtt. [40]
Aerial
EC50 (mg/ml)
Model
Nonpregnant mice
Cyclic adenosine monophosphate, dopamine, extracellular signalregulated kinases 1/2, and glutamate pathways For inhibition: flavonoid glycosides (spinosin, linarin, and apigenin-7-O-b-Dglucopyranoside) For stimulation: cyclopeptides (cycloleonuripeptides C and D) and alkaloids (imperialine-3b-D glucoside
Nonpregnant mice
na Leaves
ur
Ficus Exasperata Moraceae Vahl [38]
Proposed Mechanism(s)
Inhibition of 5-HT and Prostaglandin synthesis (For inhibition)
lP
Zingiber officinale (Ginger) [39]
Plant family
re
Medicinal Plant
-p
5-HT = 5-hydroxytryptamine
13
Nonpregnant rats
Jo
ur
na
lP
re
-p
ro of
and leonurine)
14