Chemistry and Pharmacology of Cyperaceae Stilbenoids: A Review

Cyperaceae is a cosmopolitan plant family with approx. 5000 species distributed worldwide. Several members of this family are used in traditional medicines for the treatment of different diseases. In the last few decades, constituents with great chemical diversity were isolated from sedges, and a wide range of biological activities were detected either for crude extracts or for pure compounds. Among the isolated compounds, phenolic derivatives are the most important, especially stilbenoids, and flavonoids. To date, more than 60 stilbenoids were isolated from 28 Cyperaceae species. Pharmacological investigation of Cyperaceae stilbenoids revealed that several compounds possess promising activities; mainly antiproliferative, antibacterial, antioxidant and anthelmintic effects. Isolation, synthesis and pharmacological investigation of stilbenes are increasing constantly. As Cyperaceae species are very good sources of a wide variety of stilbenes, and several of them occur in large amount worldwide, they are worthy for phytochemical and pharmacological investigations. Moreover, stilbenes are important from chemotaxonomical point of view, and they play a key role in plant defense mechanisms as well. This review summarizes the stilbenoids isolated from sedges, and their biological activities.


Introduction
Cyperaceae is a cosmopolitan family of monocot plants with approximately 100 genera and 5000 species. Previously, Cyperaceae and Poaceae have been regarded as related plant families [1], but recent cladistic analysis using molecular and morphological data indicates that the Cyperaceae family is more closely allied with the Juncaceae and Thurniaceae families [2]. Members of Cyperaceae, commonly called sedges, are grass-like flowering plants distributed throughout all the continents, except Antarctica. The diversity of genera is far greater in tropical regions [3]. The six largest genera with approximate numbers of species are Carex (n = 2000), Cyperus (n = 650), Rhynchospora (n = 250), and Eleocharis, Fimbristylis and Scleria each with about 200 species. Other notable genera are Bulbostylis, Schoenus, Scirpus and Mapania [3]. Many of the sedges are used in traditional medicines for the treatment of different diseases, e.g., stomach and bowel disorders, amenorrhoea, bronchitis, haematopoietic disorders, tumors, infectious diseases, pain and fever, diabetes, skin diseases, problems concerning the circulation, digestive, respiratory and reproductive organs.
Besides phenolic compounds, e.g., stilbenes, flavonoids, phenolic acids and phenylpropanoids, terpenoids, coumarins, quinones were also isolated from sedges [4]. However, the most significant constituents are stilbenoids. Most of the stilbenes of sedges are derivatives of resveratrol, which is probably the most extensively examined compound. Stilbenes and their derivatives have attracted increasing attention due to their diverse chemical structures and potential pharmacological applications because of their promising biological activities. entry encompasses the accepted and common names, distribution, habitat and economic or ethnobotanical significance [8].

Constituents of Cyperaceae Species
Although Cyperaceae is one of the largest monocot plant families possessing approx. 5000 species, only a small proportion of the species have been studied regarding their chemical composition and biological activities so far. According to the literature data, the majority of the isolated compounds are resveratrol oligomers or other stilbene derivatives, but flavonoids, phenolic acids, phenylpropanoids, coumarins, quinones and terpenoids (sesqui-and triterpenes, sterols) have also been identified from sedges [4,14].
The most extensively investigated species is probably Cyperus rotundus. According to the literature data, several metabolites (e.g., linolenic, myristic and stearic acids, alkaloids, flavonoids, furochromons, saponins, mono-, sesqui-and triterpenes, sitosterin, phenylpropanoids, phenolic acids and iridoids) have been identified from the tubers of C. rotundus. These metabolites are responsible for some of the therapeutic, and insecticidal, fungicidal effects [16][17][18]. The leaves and seeds of C. rotundus contain volatile oil rich in bactericidal and fungicidal compounds [19].

Structural Characteristics of Stilbenes
Stilbenes, a small class of plant phenolics are structurally characterized by a 1,2diphenylethylene nucleus, and occur both as monomers, as well as dimers and complex oligomers. Since in monomeric stilbene aglycone's skeleton the double bond between the two aromatic rings does not allow free rotation, there are only two possibilities of the configuration: the naturally more common and stable trans-(E), and the cis-(Z) configurations (Figures 1 and 2). The two isomeric forms of stilbenes have different chemical characteristics and biological activities. The basic structure is frequently modified by several hydroxy groups, through which further substituents, among them methyl, isoprenyl groups, sugars and other residues can be attached to the stilbene backbone [20]. Oligomeric stilbenes are produced by oxidative coupling between homogeneous and heterogeneous monomers, that are linked by either C-C or C-O-C units. An 1,2-diaryl-dihydrobenzofuran skeleton with trans-oriented aryl rings is the most important framework in stilbene oligomers of this family, and it is considered to be biosynthesized by region and stereoselective pathways [9]. In 2008, Xiao et al. created a classification system, distributing stilbenes into six groups based on their structural characteristics, namely stilbenes, bibenzyls, bisbibenzyls, phenanthrenoids, stilbene oligomers and other stilbenoids [21]. In 2009, Shen et al. elaborated the classification of oligomeric stilbenes into four major groups based on the number of the connective bonds between the monomeric units [22]. Subsequently, the hydroxylation of cinnamic acid by cinnamate 4-hydroxylase provides p-coumaric acid and 4-coumarate CoA ligase, followed by the formation of CoA esters of hydroxycinnamic acids. Stilbene synthase, the pivotal enzyme, catalyzes the biosynthesis of the stilbene backbone from three malonyl-CoA and one CoA-ester of a cinnamic acid derivative through a tetraketide intermediate [20,23]. Regarding the enzymatic features of stilbene biosynthesis, it has been reviewed in detail by Chong et al. in 2009 [23] (Figure 1). Stilbenes may then undergo different types of modifications, e.g., isomerization, methoxylation, glycosylation, isoprenylation and oligomerisation ( Figure 2). Stilbene oligomers may be classified biogenetically into two groups depending on the presence (group I) or lack (group II) of dihydrobenzofuran rings [24]. In group I, the dihydrobenzofuran ring has been attributed mainly to that of ε-viniferin (30) that has been isolated from the members of several plant families (e.g., Cyperaceae, Dipterocarpaceae, Fabaceae, Gnetaceae, and Vitaceae). Each family has a stereospecific biosynthetic pathway for the oxidative condensation of two stilbenoids, which definitely produces one enantiomer, as represented by (+)-and (-)-ε-viniferin. ε-Viniferin (30) is a biogenetically important intermediate of stilbene oligomers in Cyperaceae species.

Biosynthesis of Stilbenes
Stilbenes are synthetized constitutively in some plant tissues, like the bark, roots, fruits, and leaves. In other tissues, however, their synthesis can be induced by either biotic stresses, e.g., pathogen or herbivore attack, or abiotic stresses, e.g., wounding, UV irradiation and ozone [20]. Stilbenes are formed by the general phenylpropanoid pathway and occur in a number of heterogeneous and phylogenetically unrelated plant families, such as Cyperaceae, Dipterocarpaceae, Gnetaceae, Leguminosae, Polygonaceae, Vitaceae, etc. The initial reaction of the stilbene biosynthesis, catalyzed by the enzyme phenylalanineammonia lyase is the formation of cinnamic acid from phenylalanine. Subsequently, the hydroxylation of cinnamic acid by cinnamate 4-hydroxylase provides p-coumaric acid and 4-coumarate CoA ligase, followed by the formation of CoA esters of hydroxycinnamic acids. Stilbene synthase, the pivotal enzyme, catalyzes the biosynthesis of the stilbene backbone from three malonyl-CoA and one CoA-ester of a cinnamic acid derivative through a tetraketide intermediate [20,23]. Regarding the enzymatic features of stilbene biosynthesis, it has been reviewed in detail by Chong et al. in 2009 [23] (Figure 1). Stilbenes may then undergo different types of modifications, e.g., isomerization, methoxylation, glycosylation, isoprenylation and oligomerisation ( Figure 2). Stilbene oligomers may be classified biogenetically into two groups depending on the presence (group I) or lack (group II) of dihydrobenzofuran rings [24]. In group I, the dihydrobenzofuran ring has been attributed mainly to that of ε-viniferin (30) that has been isolated from the members of several plant families (e.g., Cyperaceae, Dipterocarpaceae, Fabaceae, Gnetaceae, and Vitaceae). Each family has a stereospecific biosynthetic pathway for the oxidative condensation of two stilbenoids, which definitely produces one enantiomer, as represented by (+)-and (-)-ε-viniferin. ε-Viniferin (30) is a biogenetically important intermediate of stilbene oligomers in Cyperaceae species.

Isolation Procedures of Stilbenes from Cyperaceae Species
Stilbenes possess diverse structural characteristics, therefore, various separation methods have been applied to obtain these kind of metabolites from natural sources. According to the literature data, isolation of stilbenes is feasible from every part of Cyperaceae species.
In some cases, stilbenes were isolated from the whole plant [25,26], however, other plant parts (rhizome or root [27,28], leaf [29], and seed [30]) were found to be a better source of stilbenes. The initial step of the isolation process is the extraction of the plant material. In most cases, pure methanol was used for the extraction, however, in some cases, ethyl acetate [29] or acetone [31] or the mixture of acetone-methanol [32] were used. In other cases (e.g., Carex distachya), less polar solvents, like hexane [33] were applied. The crude extract is usually subjected to solvent-solvent partition with solvents of increasing polarity, among the most frequent ones were hexane, diethyl ether, ethyl acetate and dichloromethane. The following step is commonly a normal or reversed phase column chromatography (CC) performed on silica gel or Sephadex LH-20 gel using gradient elution. Typical solvent systems for normal phase CC are mixtures of hexane-ethyl acetate, hexane-acetone, chloroform-methanol, dichloromethane-methanol, dichloromethane-ethyl acetate and dichloromethane-acetone. Typical mobile phases applied for reversed phase CC were mixtures of acetonitrile-water, methanol-water and acetonitrile-methanol-water. After column chromatography, further chromatographic procedures are often required to obtain stilbenes in a pure form. These procedures include preparative thin layer chromatography (PTLC), and medium-and high-pressure liquid chromatography (MPLC/HPLC). In case of HPLC methods, reversed phase separations (mainly C18-columns [9,30,31,[34][35][36]) are more frequently used than normal phase ones.
Stilbenes can be found in relatively high amounts in several Cyperaceae species, for instance the total content of this type of metabolites in the roots and rhizome of Carex fedia var. miyabei was estimated over 0.15% (w/w of fresh material) [28]. Cyperus longus is another good source of stilbenoids, its main constituents, scirpusins A (31) and B (32) could be detected in the rhizome at 0.028% and 0.008% (w/w of dried material), respectively [26]. In case of Carex pumila, the main constituent was miyabenol A (64) presented at 0.23% (w/w of dried material) in the plant [27].
The stilbenoids, isolated from C. fedia var. miyabei are derivatives of resveratrol (1); 30 is the dimer of two units of 1, miyabenol C (43) is a trimer and miyabenols A (64) and B (65) are tetramers ( Figure 6). 65 is formed from 64 via intramolecular oxidative cyclization involving a hydroxy group and a double bond in the trans-stilbene residue, while 43 is a biogenetic intermediate between 30 and 64 and 65. The total content of these metabolites in the underground part of the plant was estimated over 0.15% (w/w of fresh plant), miyabenol A (64) being the predominant stilbenoid with more than 0.1% [28].

Pharmacological Activities of Cyperaceae Species and the Isolated Compounds
Stilbenes and their derivatives have attracted increasing attention due to their diverse biological activities and potential pharmacological applications. Some of these secondary metabolites have been recognized as phyotoalexins and associated with the defense mechanisms of plants as they are produced after infection by pathogens or exposure to UV radiation and present antifungal activities. Probably, the most extensively investigated compound is resveratrol (trans-3,5,4 -trihydroxystilbene, 1), of which over 2000 papers have been published. Resveratrol (1) has gained attention when being associated with "the French paradox", the well-documented phenomenon of the relatively low incidence of coronary heart disease despite high dietary intake of saturated fats in southern France, that can be explained by the protective effect of moderate wine consumption [58,59]. It has been proven by several studies that the favorable cardiovascular effect of red wine is mainly due to its content of phenolic compounds, especially resveratrol. Since then, numerous biological activities of resveratrol (1) have been reported, among them antioxidant, anticancer, anti-inflammatory, antidiabetic, cardioprotective, antiaging effects and it was proven to be a phytoestrogen as well [60].
Pharmacokinetic studies of resveratrol (1) indicated that during circulation in the plasma it is extensively metabolized and its oral bioavailability is close to zero, due to factors such as limited absorption, limited chemical stability, and degradation by intestinal microflora and intestinal enzymes [61]. The major metabolites identified in the plasma and urine by metabolic studies are resveratrol glucuronides and sulphates [62]. In case of the dimer ε-viniferin (30), it was observed that its intestinal absorption rate is low and negligible compared to that of resveratrol [61]. However, these findings are controversial with the multitude biological effects of resveratrol (1) confirmed in vivo. This can be explained by the capability of 1 to bind to transport proteins, like human serum albumin and lipoproteins forming complexes, in which resveratrol is more stable and can enter into different tissues as well [63][64][65]. Another possible explanation is that the concentration of the glucuronide and sulphate type metabolites in the blood is higher than the initial concentration of 1, proposing that resveratrol might be released locally in the target organ/tissue from these metabolites [60,63]. The "broad spectrum" of biological activities is likely a reflection of the intrinsic reactivity of the trihydroxylated stilbene 1 as a redox-active molecule. Mounting evidence suggests that resveratrol and its oligomers exert their effects via interference with signal transduction cascades and epigenetic pathways rather than direct inhibition of enzymes designated for specific purposes [66,67].
Besides resveratrol, other monomeric (e.g., piceatannol, combretastatin A-4, etc.) and oligomeric (e.g., α-viniferin, hopeaphenol A, miyabenol C and kobophenol B) stilbenes with promising biological activities have also been isolated from natural sources in recent years. An enormous number of studies have been undertaken to define their diverse structures and biological activities. As a result, there are several review articles summarizing the phytochemistry and pharmacology of naturally occurring stilbenes [21,22,[68][69][70][71][72]. Stilbenes possess a wide range of multi-faceted biological activities, among them antitumor, antioxidant, antiplatelet, antimicrobial, antidiabetic, anti-inflammatory, neuro-, cardio-and hepatoprotective, spasmolytic, ecdysteroid antagonist and tyrosinase inhibitory activities. Therefore, stilbenes are of significant interest for researchers in the process of developing new drugs and medicines [73].
In this part of the review, those Cyperaceae species are discussed from which stilbenoids were isolated and their pharmacological activities were also tested ( Table 2).    Resveratrol (1) possesses a wide range of biological effects, including suppressing the growth of a wide variety of tumor cells (e.g., breast, prostate, hepatic, skin, lung, colon, and pancreas cells) through inhibition of DNA polymerase and ribonucleotide reductase, and by inducing cell cycle arrest or apoptosis initiating caspase-8-dependent or caspase-9-dependent pathways [79]. Resveratrol (1) was found to be a natural killer (NK) cell activator; it had a synergistic effect with IL-2 on enhancing the cytolytic activity of NK cells and activated Akt by regulating Mammalian Target of Rapamycin Complex 2 (mTORC2) via phosphatase and tensin homolog (PTEN) and ribosomal protein S6 kinase beta-1 (S6K1) [80]. Moreover, it was observed that resveratrol (1) increases the susceptibility of aggressive cancer cells to T-cell-mediated cell death via disrupting the glycosylation and dimerization of programmed death ligand-1 (PD-L1) and impeding the PD-1 interaction surface of PD-L1 [81].
The antiproliferative effect of oligostilbenoids, isolated from the rhizome of C. rotundus, were demonstrated against human T-cell leukemia Jurkat cells. Among the tested compounds, the racemates (48 and 49)

Antioxidant Activity
The incidence of tumor increases after exposure to free radicals. The antioxidant capacity of free radical scavengers is responsible for their antimutagenic effects [82]. Therefore, the antiradical activities of compounds could also be worthy for investigation [83].

Anti-Inflammatory Activity
The acidic and amphiphilic character of stilbenoids causes their enrichment in biomembranes, where many of their targets occur (COX, 5-LOX, protein kinase B) [85]. Antiinflammatory and antioxidant activities stand behind nearly all of the other positive pharmacological effects of stilbenoids. When compared to oligomeric stilbenoids the monomers have been studied much more intensely. This is probably related to their higher abundance in nature and simple structure enabling their easier identification and further structural modification towards novel derivatives [86].
It has been shown that resveratrol derivatives with additional ortho-hydroxy group exhibit more potent antioxidant and anti-inflammatory effects in vitro due to the ability to form semiquinone radical. For example, piceatannol (5) was reported to be about 400 times more selective towards the inhibition of COX-2 enzyme than resveratrol [92], and it activated more potently heme oxygenase-1 (HO-1) enzyme as well [93]. Piceatannol (5) was found to impede the nuclear translocation of p65 [a subunit of nuclear factor kappa B (NF-κB)] and the secretion of proinflammatory cytokines, including interleukin-6 (IL-6), TNF-α and interleukin-8 (IL-8) as well as it inhibited the inflammatory NF-κB pathway [84].
Carexanes 16, 22, and 27 were able to enhance the antioxidant response of HspBtransfected human gastric epithelial (AGS) cells. Among them, carexane I (27) proved to be the most active; it was able to reduce Keap-1 gene expression and induce NQO1 gene expression in AGS cells. Moreover, it reduced COX-2 gene expression in HspB-transfected AGS cells [42].

Antimicrobial Activity
Miyabenol A (64), a metabolite of C. fedia var. miyabei, showed antimicrobial activities against Staphylococcus aureus and Bacillus subtilis at a level of less than 10 µg/8 mm diameter paper disc [28].
6.1.6. Anthelmintic Activity C. baccans has been traditionally used in Northeast India to get rid of intestinal worm infections. In an experiment, in vivo cestocidal activity of root tuber extract of the plant and its stilbene constituent resveratrol (1) was tested against the zoonotic cestode Hymenolepis diminuta. The activity was determined by monitoring the egg per gram (EPG) counts in feces of different treat groups of rats. At 50 mg/kg of plant extract, and 4.56 mg/kg body weight of resveratrol (1), both possessed significant anthelmintic effect against the worm. Both reduced EPG count (56.0% and 46.1%) and decreased worm burden by 44.3% and 31.0%, respectively. Praziquantel was used as a positive control [13]. The anthelmintic effect of resveratrol (1) and α-viniferin (42) was evaluated against Raillietina echinobothrida in comparison to the reference drug praziquantel. It was observed that the parasites ceased movement at 9.4, 11.4, and 0.2 h followed by death at 23.7, 34.2, and 1.9 h, respectively. Moreover, a significant decrease in the activity of acetylcholinesterase (46.1% and 65.9%) and nitric oxide synthase (61.2% and 55.0%) were detected in comparison with the controls Nω-nitro-l-arginine (29.6%) and pyridostigmine (63.6%). Therefore, it can be concluded that the anthelmintic effect of these compounds is mediated through inhibition of two vital enzymes [47].

Antidiabetic Activity
Numerous studies on diabetic rats revealed the anti-hyperglycemic action of resveratrol (1). Among different beneficial effects of resveratrol found in diabetes, the ability of this compound to reduce hyperglycemia seems to be the best documented. The antihyperglycemic action of resveratrol was demonstrated in obese rodents and in two animal models of diabetes: in rats with streptozotocin induced diabetes or with streptozotocinnicotinamide-induced diabetes. Some studies also revealed that administration of resveratrol (1) to diabetic rats resulted in diminished levels of glycosylated hemoglobin (HbA1C), which reflects the prolonged reduction of glycaemia [96,97]. The anti-hyperglycemic effect of resveratrol observed in diabetic animals is thought to result from its stimulatory action on intracellular glucose transport through increased expression of the insulin-dependent glucose transporter GLUT4 [98].
Piceatannol (5) promoted glucose uptake, AMPK phosphorylation and GLUT4 translocation to plasma membrane in L6 myocytes in vitro, and it decreased the rises in blood glucose levels at early stages and improved the impaired glucose tolerance at late stages in vivo in type 2 diabetic model in mice [99].

Vasorelaxant Activity
Arginase catalyzes hydrolysis of L-arginine to L-ornithine and urea and plays an important role in the ammonia detoxification in mammals. By substrate competition, it also plays a crucial role in the bioavailability of L-arginine for nitric oxide synthase (NOS). The result of this competition is the decrease of nitric oxide (NO) production and the increase of L-ornithine production. This latter is converted into polyamines or proline that can promote cell proliferation and collagen production, resulting in various health problems, in particular at the cardiovascular level. Compounds with arginase inhibitory activity may have use to treat e.g., microbial or parasitic infections, cancers and inflammatory or cardiovascular diseases [100].
Resveratrol (1) could prevent the hypoxia-induced increased arginase activity, arginase II mRNA and protein expression, and proliferation in hPASMC (human pulmonary artery smooth muscle cell). It also prevented the hypoxia-induced Akt activation, and attenuated chronic hypoxia-induced RVH (right ventricular hypertrophy) in neonatal rats by normalization of RV/(LV S) ratios [101].
Piceatannol (5) Plants can response to different infections in several ways. One of the best-known and longest-studied one is the induced accumulation of antimicrobial, low-moleculeweight secondary metabolites known as phytoalexins. Phytoalexins are chemically diverse molecules, including simple phenylpropanoid derivatives, flavonoids and isoflavonoids, sesquiterpenes and polyketides. They may be biosynthetically derived from one or several biosynthetic pathways [102].
The growth inhibitory and allelopathic activity of stilbenes 1, 5, 31 and 32 isolated from S. maritimus were investigated in different test systems (inhibition of 3PS leukaemia in mice, inhibition of potato crown gall tumors on discs of potato tubers, brine shrimp toxicity, fall army worm antifeedant activity, and growth inhibition of duckweed). The activities detected in these tests contribute to the ability of Scirpus species to survive and often dominate in various wetland plant communities [15].
Carexanes I (27) and K (23) significantly stimulated the root growth of Dactylis hispanica, Petrorhagia velutina, and Phleum subulatum at the highest (10 −4 M) concentration, while pallidol (40) and distachyasin (24) were the most toxic on P. subulatum. All tested compounds (13, 16-27, and 40) inhibited or slightly stimulated the seedling growth with the only exception of P. velutina that was stimulated over 50% by the seco-carexane 25 [29]. Carexanes (16, 18-21, 23, 25-27) were also tested for their phytotoxicity on the seeds of Lactuca sativa. The metabolites induced a weak decrease of germination (20%) of test organism. Furthermore, the compounds showed a stimulating effect on seedling growth. This effect was more evident on shoot elongation. Compound 18 stimulated shoot elongation at a lower concentration, while 21 increased shoot elongation in all tested concentrations [43].

Pest Control by Acting on the Regulation of Insect Growth
Ecdysteroids are essential for insects in their physiological processes (e.g., in moulting). Phytoecdysteroids have the potential to disrupt physiological processes of susceptible insect species. Susceptible insect species would absorb such phytoecdysteroids into the hemolymph in an unregulated manner where these would bind to existing receptors and act to produce abnormal physiological situations during insect growth and development [104]. Based on these properties, phytoecdysteroids can be used for pest control.

Side Effects of Stilbenes Occurring in Cyperaceae Species
Similarly to the pharmacological activities of stilbenes, the most information about their adverse effects is available in the case of resveratrol (1). Although many studies have indicated that 1 is a well-tolerated and safe compound in humans [105], some have reported on its toxic effects in vitro and in vivo [106][107][108]. These controversial effects of resveratrol (1) are due to its biphasic dose-dependent effects, which means that at low doses it has a stimulating effect associated usually with the beneficial (among others the antioxidant) effects, while at higher doses it possesses inhibitory properties resulting in the toxic effects (e.g., pro-oxidant feature) of this compound. In some cases, both effects can be advantageous, e.g., low concentrations can be useful in the prevention of cancer formation (chemopreventive) while higher doses can be used in the treatment of cancer (cytotoxic) [63,109]. All the toxic side effects (e.g., ulcerogenicity, renal toxicity, and detrimental cardiovascular effects) of 1 are mentioned to be related to its high-dosageassociated hormetic effects in vitro and in vivo [104][105][106][110][111][112][113].
In addition, it was shown that 1 interacts with several drugs. These interactions are harmful since, in most cases, they could attenuate the activities of these drugs [114]. It was reported that resveratrol (1) alters or inhibits the enzyme CYP3A4 [115] leading to possible alteration of the metabolism of a high percentage of marketed drugs. Furthermore, resveratrol was proven to inhibit the function and expression of drug transporters [like P-glycoprotein, multidrug resistance-associated protein 2 (MRP2), or organic anion transporters (OAT1/OAT3)], thus enhancing the bioavailability of certain drugs, e.g., nicardip-ine [116], methotrexate [117] and fexofenadine [118]. Other type of drug interactions were also detected [63], resveratrol (1) attenuating the effect of human immunodeficiency virus (HIV) protease inhibitors [119] and potentiating the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors [120] and calcium channel agonists [121].
Additionally, long-term intake of resveratrol (1) can act as a thyroid disruptor and a goitrogen [122]. In case of other stilbenes, only limited data were published in the literature about their adverse effects.

Conclusions
According to the literature data, plants belonging to the family Cyperaceae are rich sources of stilbenoids. The presence of stilbenes in sedges is not restricted to any organ, but they can be found in underground parts and seeds in a higher ratio. Similarly to other stilbene-containing plant families, resveratrol (1) is the most common monomer in Cyperaceae species. Oligostilbenoids are composed of building block compounds of resveratrol (1) and piceatannol (5), which produces the fused skeletons of heterocyclic (forming a tetrahydrofurane ring) and bicyclic systems. Some Carex species accumulate a large amount (>1000 ppm) of oligostilbenoids, especially tetramers. It is interesting that up to now, tetrastilbenes were isolated only from Carex and Kobresia species. Prenylsubstituted stilbenes were isolated from sedges only in monomeric forms. Carexanes from C. distachya are unique tetracyclic stilbenoids originating from prenylated stilbenes by cyclization. Interestingly, besides prenyl-substituted stilbenes, prenyl substituted flavonoids were also detected in S. nigricans, proving that stilbenes and flavonoids arose in the same biosynthetic pathway. Cyperaceae species accumulate monomeric, di-, tri-and tetrameric stilbenes; among them monomers are substituted with hydroxy, methyl, methoxy, glucose, prenyl and carboxyl moieties, while in cases of di-, tri-and tetramers only hydroxy-substitution occurs.
As a result of the ethylene bridge, stilbenes can occur as cisand trans-isomers, of which the trans-isomer (E) is the most common as it is more stable than the cis one. Different pathways lead to cis-trans isomerization, e.g., direct photoisomerization under solar or UV irradiation, or thermal isomerization. The same observation could be detected in case of Cyperaceae stilbenes; only two compounds were published with cis configuration [cis-miyabenol A (64) and cis-miyabenol C (43)]. In these cases, it was observed that if they were exposed to light, trans-isomerization was performed. Probably, this is the reason that much less cis-isomers are isolated.
Some pharmacological results confirm the traditional uses of plants (e.g., use of C. baccans as an anthelmintic), but almost all data are derived from in vitro investigations, therefore, to certify the effectiveness of these plants in human therapy further investigations, especially in vivo and human studies are needed. Moreover, because of the controversial effects of resveratrol (1), the molecular mechanism of actions of bioactive stilbenes, isolated from sedges, need to be identified.
In conclusion, Cyperaceae species are promising sources of biologically active stilbenes, and hopefully even more research groups will deal with the phytochemistry, pharmacology, bioavailability and potential utilization of sedges.