key: cord-267284-3uz0v29k
authors: Schneiderová, Kristýna; Šmejkal, Karel
title: Phytochemical profile of Paulownia tomentosa (Thunb). Steud.
date: 2014-08-29
journal: Phytochem Rev
DOI: 10.1007/s11101-014-9376-y
sha: 
doc_id: 267284
cord_uid: 3uz0v29k

Paulownia tomentosa, a member of the plant family Paulowniaceae and a rich source of biologically active secondary metabolites, is traditionally used in Chinese herbal medicine. Flavonoids, lignans, phenolic glycosides, quinones, terpenoids, glycerides, phenolic acids, and miscellaneous other compounds have been isolated from different parts of P. tomentosa plant. Recent interest in this species has focused on isolating and identifying of prenylated flavonoids, that exhibit potent antioxidant, antibacterial, and antiphlogistic activities and inhibit severe acute respiratory syndrome coronavirus papain-like protease. They show cytotoxic activity against various human cancer cell lines and inhibit the effects of human cholinesterase, butyrylcholinesterase, and bacterial neuraminidases. Most of the compounds considered here have never been isolated from any other species of plant. This review summarizes the information about the isolated compounds that are active, their bioactivities, and the structure–activity relationships that have been worked out for them.

The plant Paulownia tomentosa (Thunb.) Siebold & Zucc. ex Steud. is a very adaptable and extremely fastgrowing timber tree native to central and western China traditionally used in Chinese Medicine. This deciduous tree is now grown in many areas worldwide, mostly as a decorative ornamental tree (Erbar and G} ulden 2011; Zhu et al. 1986) .

Two related varieties of P. tomentosa have been described-var. tsinlingensis has a round to shallowly cordate leaf base and a glabrous or sparsely hairy lower leaf surface, whereas var. tomentosa is characterized by a cordate leaf blade base and an abaxial surface that is densely hairy when mature (Hong et al. 1998) .

Paulownia was named paulownia in honour of Anna Paulowna (1795 Paulowna ( -1865 , queen consort of The Netherlands and a daughter of Tsar Paul I of Russia. Nowadays, it is commonly known under its synonym Bignonia tomentosa (Zhu et al. 1986) or as the princess-tree, empress-tree, foxglove tree, royal paulownia, kiri, or mao pao tong (yuan bian zhong) (Erbar and G} ulden 2011; Hong et al. 1998) .

The genus Paulownia was first assigned to family Bignoniaceae by Swiss botanist Thunberg (1781). It was then transferred to the Scrophulariaceae family by the Dutch scholars Zuccarini and Siebold (1835) (Zhu et al. 1986 ). At last, Paulownia has been categorized as a family of its own, Paulowniaceae, based on data from the latest molecular phylogenetic studies. This Table 1 Non-prenylated flavonoid aglycones isolated from P. tomentosa 

Leaves (Zhu et al. 1986 ) Weak cytotoxic activity in vitro against human leukaemia (HL-60) and human hepatoma (SMMC-7721) cell lines ; no a-glucosidase inhibitory effect (Zhao et al. 2009 ); weak aldose-reductase inhibitory activity (Kadota et al. 1994) ; moderate inhibitory effect on human immunodeficiency virus-1 protease (Lee et al. 2008) ; no activity against lipopolysaccharide (LPS)induced NO production in RAW 264.7 macrophages (Li et (2) Leaves , flowers Jiang et al. 2004 ) Antioxidant (Prince Vijeya Singh et al. 2004 ); antibacterial, anti-inflammatory, antispasmodic, antidiarrhoic, antiproliferative, vasorelaxant (Jiang et al. 2004 ); neuroprotective (Losi et al. 2004 ); cardioprotective (Psotová et al. 2004 ); chemopreventive activity against skin cancer ); activity reviewed by Shukla and Gupta (2009) and Patel et al. (2007) H H OH H OH Kaempferol (3) Leaves (Si et al. 2008a ) Cytotoxic, pro-apoptic (suppresses cell metastasis via inhibition of the ERK-p38-JNK and AP-1 signaling pathways in U-2 OS human osteosarcoma cells) ; antioxidant (e.g., attenuates bladder hyperactivity caused by potassium chloride after protamine sulphate-induced bladder injury) (Huang et al. 2014) ; impact on human health and cancer chemoprevention reviewed by , Luteolin (4) Leaves (Si et al. 2008a; Li 2011) Memory-improving (Yoo et al. 2013 ); inhibition of aamylase activity (Funke and Melzig 2005) ; cytotoxic (BGC-823 gastric carcinoma xenografts in nude mice) ; vascular protective (Si et al. 2013 (5) Bark (Si et al. 2011b) , leaves (Si et al. 2008a ) Antifibrotic (Yoon et al. 2012) ; antioxidant, antiproliferative, anti-inflammatory, cardioprotective ; neuroprotective (Ghosh et al. 2013 ); anti-diabetic [dose-dependent inhibition of both Na ?

ATPase and sodium hydrogen exchanger in type 2 diabetic erythrocytes (Mishra and Rizvi 2012) ; inhibition of PI3K (Koch et al. 2013) ]; antiviral [anti HCV (Khachatoorian et al. 2012) ; HCMV (Cotin et al. 2012) ];

no anti-HIV activity in vitro tested on H9 cells in the absence of toxicity (Tang et al. 1994 ); review of bioactivities by Russo et al. (2012) OH H OH OH OH 7,3 0 -Dimethylquercetin (syn. rhamnazin)

Leaves, green immature fruit (Wollenweber et al. 2008 ) Antimicrobial activity, poor antifungal effect (Omosa et al. 2014 ); low antimicrobial activity, low toxicity against human lymphocytes and monocytes, antioxidant/antiinflammatory activity (Martini et al. 2004; Pelzer et al. 1998 ); low affinity to acetylcholinesterase (Remya et al. 2012) ; low inhibitory effect on NO production in RAW264.7 cells (Sudsai et al. 2013) ; no activity against HSV-1, low toxicity against Vero cells (Tian et al. 2009 ); no antioxidant activity (Takamatsu et al. 2003) ; no trypanocidal activity (Grael et al. 2000) ; activity against lipid peroxidation in rat liver microsomes (Yun et al. 2000) ; cytotoxicity against TK-10, MCF-7 and UACC-62 cells (Lopez-Lazaro et al. 2000) ; no inhibition of glycolysis in various tumor cells (Suolinna et al. 1975 ,4 0 -Trimethylquercetin (7) Thrombin inhibition (Shi et al. 2012 ); inhibition of IL-4 synthesis in basophils (Hirano et al. 2006) ; weak trypanocidal activity (Jordao et al. 2004 ); weak inhibition of NO production in LPS-activated mouse peritoneal macrophages (Matsuda et al. 2003) ; weak inhibition of degranulation of RBL-2H3 cells (Mastuda et al. 2002) ;

inhibition of Pgp activity (Scambia et al. 1994) ; no inhibition of glycolysis in a variety of tumor cells (Suolinna et al. 1975 Flowers Jiang et al. 2004; Kim et al. 2010a , b) Inactive against glutamate-induced neurotoxicity studied in primary-cultured rat cortical cells (Kim et al. 2010a, b) ; no trypanocidal activity (Grael et al. 2000) H H OH OMe OMe 5-Hydroxy-7,3 0

Flowers (Kim et al. 2010a , b) Inactive against glutamate-induced neurotoxicity studied in primary-cultured rat cortical cells (Kim et al. 2010a, b) ; inhibition of inflammation by induction of synovial apoptosis of fibroblast-like synoviocytes through caspase 3 activation in rats with adjuvant arthritis (Li et al. 2010 ; inhibition of JAK2-STAT3 signal pathway in rats ); inhibition of phosphodiesterase 4 (Yang et al. 2011) ; low toxicity on B16F10 and SK-MEL-1 melanoma cells (Rodriguez et al. 2002) ; antimutagenic activity (Miyazawa et al. 2000) H family includes only one genus and between six and ten species. It was originally introduced in 1949 by the research of Nakai (Erbar and G} ulden 2011) .

Biological activity and traditional uses of P. tomentosa extracts According to both legends and records, people were already using Paulownia for various purposes about 2,600 years ago. Chinese herbal medicine has used P. tomentosa traditionally to relieve bronchitis, especially by reducing coughing, asthma, and phlegm (Zhu et al. 1986 ). It has also been used to treat conjunctivitis, dysentery, enteritis, erysipelas, gonorrhea, hemorrhoids, parotitis, traumatic bleeding, and tonsillitis (Jiang et al. 2004; Si et al. 2009 ). Solutions prepared from the leaves and fruit extracted in water have been used in daily applications to promote the healthy growth of hair and turn grey hair dark. An extract prepared from the wood and leaves may relieve swollen feet. Pharmacological experiments have shown that extracts from the fruit can reduce blood pressure. Nowadays, injections and tablets prepared from Paulownia flowers and fruit are used for the herbal treatment of chronic bronchitis and other kinds of inflammation (Zhu et al. 1986 ). More than 130 physiologically active constituents have been isolated from different parts of the Paulownia plant. Their biological activity has been tested using both the isolated compounds and different types of extracts. For example, n-butanol, EtOAc, and MeOH extracts obtained from the fruit have displayed antiradical activity in anti-DPPH and peroxynitrite assays, due to mainly the presence of flavonoids and phenolic glycosides, but not of all compounds present in these extracts have been identified) (Š mejkal et al. 2007b ). An MeOH extract obtained from the fruit inhibited hAChE (IC 50 = 1.44 mg/ml) and BChE (IC 50 = 0.97 mg/ml) significantly more strongly than CHCl 3 and water extracts (possibly due to the content of phenolic glycosides and C-prenylated dihydroflavonols and flavanones) (Cho et al. 2012 ). Significant concentration-dependent anti-inflammatory properties of EtOH extracts of the bark of the tree have also been observed recently using a lipopolysaccharide (LPS)induced nitric oxide production inhibition model in the murine macrophages cell line RAW264.7 (Si et al. 2011a ). Kim et al. (2010a, b) showed potential of aqueous extract of P. tomentosa to suppress glutamate induced toxicity in primary cultured rat cortical cells (with possible sesquiterpene lactone as active substance). The bio-activities of individual compounds and, where possible, the structure-activity relationships are in Tables 1, 2, 3 and 4 and discussed in separate chapters.

Flavonoids represent the most numerous group of secondary metabolites isolated from P. tomentosa. They can be divided into simple non-prenylated flavonoids 1-18 (Table 1) , C-prenylated and C-geranylated flavonoids 19-59 (Tables 2, 3 , respectively), and flavonoid glycosides 60-65. Compounds 16, 17, 19, 20, [25] [26] [27] [28] [29] [30] [31] [33] [34] [35] [36] have never been isolated from any other species. Most of the isolated flavanones are characterized by a 2S configuration in contrast to the dihydroflavonols, for which 2R, 3R isomer is often observed. Some of the flavonoid compounds found in P. tomentosa have been categorized as dietary flavonoids. Consuming these compounds is believed to deliver health benefits. The activities of these flavonoids are frequently been reviewed, for example in the papers of Romano et al. (2013) , Marzocchella et al. (2011) , Ross and Kasum (2002) , and Havsteen (2002) . Some simple flavonoid substances isolated from fruit of P. tomentosa are commonly observed as the lipophilic components of different plant exudates. Flavonoids 1-18 show broad-spectrum pharmacological activities (Table 1) . Many papers report their potential role as anticancer compounds for use against human cervical and breast (Bulzomi et al. 2010 (Bulzomi et al. , 2012 , hepatoma, leukemic , osteosarcoma , gastric carcinoma , colon adenocarcinoma (Sánchez-Tena et al. 2013) , or prostatic (Zhang and Coultas 2013) cancer cell lines. Their antioxidant properties could explain their promising cardioprotective (Paneerselvam et al. 2010; Psotová et al. 2004 ) and neuroprotective effects (Losi et al. 2004 ). Antimicrobial (Betts et al. 2013; Jiang et al. 2004; Mankovskaia et al. 2013 ) and antiviral (Khachatoorian et al. 2012) bio-activities against different pathogens have also been discovered. In some cases, no specific biological activity has been observed (Kim et al. 2010a (Kim et al. , 2010b Tang et al. 1994) .

Paulownia tomentosa is also a rich source of prenylated and geranylated flavonoids (19-59), whose occurrence is limited to relatively a few plant families (Yazaki et al. 2009 ). There are sometimes misunderstandings in the naming of these compounds. A compound containing both a phenolic skeleton and a terpenoid side chain is often designated as a ''prenylated'' phenolic substance, even though it contains not a prenyl, but rather a geranyl or other type of terpenoid side-chain. Prenylated flavonoids are biosynthesized by a combination of several pathways: the acetate, shikimate, and mevalonate ( Fig. 1) . It is now known that the prenyl and geranyl moieties are biosynthesized via mevalonate or deoxyxylulose pathway. The connection of terpenoid and flavonoid biosynthetic Antioxidant ; cytotoxic (A2780 human ovarian cancer cell line) (Murphy et al. 2005 (Murphy et al. , 2006 OH Bark (Sticher and Lahloub 1982; Zhu et al. 1986 ) Antiphlogistic (Choi et al. 2004 ), low COX-2/1 and 5-LOX inhibition (Wang et al. 2013; Diaz Lanza et al. 2001 Kuzuyama et al. 2005) . The side chain can later be converted into different moieties by several reactions. It is unclear, whether the described modifications of the prenyl side-chain are natural-sunlight, the presence of oxygen and an elevated temperature can all affect the terpenoid metabolism-or are artefacts of isolation. Some of the changes in the prenyl moiety have been observed after treatment of an extract, or during the separation of a mixture in the acidic environment of silica gel (Navrátilová et al. 2013 ; Š mejkal 2014) (Fig. 2) . Most of the prenylated flavonoids isolated from P. tomentosa belong to C-geranylated group of flavonoids (21-52). Some of them have their sidechain further modified by hydroxylation (35-44, 50, 51, 53-59), methoxylation (45-47, 49, 50), oxidation (47, 48, 52), cyclization (51, 53-59), or reduction (19, 20, 47-52) . Interestingly, these compounds have been isolated from the leaves, flowers and fruit, but they are most commonly isolated from the roots, root bark, or bark of different plants (Botta et al. 2005) . Compounds 23, 24, and 28 have been found in the yellow dendritic trichomes on the adaxial side of the P. tomentosa leaves. On the other hand, no significant detected concentration of secondary metabolites has been detected in the white dendritic trichomes on the adaxial side of the leaves or the brown dendritic trichomes on the flower buds ). Glandular hairs found on the young reproductive organs of P. tomentosa are rich in flavonoids, with concentrations over 1,000 times greater than those on the surfaces of the young leaves . Some seasonal variations in the appropriate time for harvesting the fruit have been discovered. Autumn is the best time to obtain high concentrations of flavonoids whereas early summer is better for phenylpropanoid glycosides (Holubová and Š mejkal 2011) .

The antioxidant Š mejkal et al. 2007a, b; Zima et al. 2010) , antibacterial (Navrátilová et al. 2013; Š mejkal et al. 2008b) , antiphlogistic , cytotoxic (Kollár et al. 2011; Š mejkal et al. 2007a , and severe acute respiratory syndrome coronavirus papain-like protease (SARS-CoV PLpro) activities (Cho et al. 2013 ) of isolated geranylated flavonoids have been described recently, together with their inhibitory effect on both human acetylcholinesterase and butyrylcholinesterase (Cho et al. 2012) . The great ability of several geranylated flavanones to interact with bacterial sialidase isolated from Clostridum perfringens (Cp-NanI), a bacterium causing various gastrointestinal diseases, has recently been reported (Lee et al. 2014) .

Possible relationships between structure and activity have been proposed for each of these biological activities. Nevertheless, it is difficult to evaluate real structure-activity relationships only by comparing the published studies, because the study conditions and the assays employed are often different. Generally, the addition of an isoprenoid chain renders the derivate molecule more pharmacologically effective than the parent compound, probably because the prenyl group increases the lipophilicity and confers a strong affinity for biological membranes (Botta et al. 2005; Epifano et al. 2007; Chen et al. 2014) . Interestingly, neither the geranyl side-chain nor its substitution affects the antioxidant activity of flavonoids. The spatial arrangement of the substitution of the flavanone skeleton is more important. For example, the antiradical activity is increased by 2 0 -hydroxyl substitution of the ring B, whereas 4 0 -methoxyl substitution diminishes it. The general rules postulated for the antioxidant activity of flavonoids in vitro are applicable (Havsteen 2002; Chen et al. 2002) , there are many review publications that touch on this topic, and it is not aim of this paper to delve deeply into this (Plaza et al. 2014) . The type of antioxidant assays used for the experiment could also be a factor that significantly affects this activity (Zima et al. 2010) .

Numerous reports about structure related antimicrobial activity have been published, but comparison shows the results to be widely conflicting (Cushnie and Lamb 2005) . Based on several studies, it has been postulated that hydroxylation at position C-5 or C-7 of ring A and positions C-2 0 or C-4 0 of ring B increases the antibacterial activity (Š mejkal et al. 2008b; Navrátilová et al. 2013) . However, contrary to this assumption, 45 and 50 had no significant antibacterial activity (Navrátilová et al. 2013) . Interestingly, some C-geranylated flavonoids do not able inhibit the growth of Gram-negative bacteria (21, 22, 25-27, 35, 38, 45, 47-48, 50, 53, and 54) . Resistance to these compounds is probably due to the more complex structure and hydrophilic nature of G-cell walls (Navrátilová et al. 2013; Š mejkal et al. 2008b) . Furthermore, substitution of the geranyl side-chain with carbonyl, hydroxyl or methoxyl groups diminishes the antibacterial activity in a manner similar to what is seen when the geranyl substituent at C-6 forms a ring by reacting with the hydroxyl group at C-7. Compounds 45, 47, 48, 50, 53 , and 54 exhibit some degree of activity in the range of the concentrations tested on the Gram-positive bacteria Staphyloccocus aureus and various methicillin resistant strains of S. aureus. The level of activity varied in depending on both the structure and the bacterial strain used in the assay. Flavonoid structures like 24 are more effective in protecting plants from water loss because of their reduced polarity Navrátilová et al. 2013). Compounds 45, 47, 48, 50 , and 53 were also tested for their ability to affect the initiation of the eukaryotic translation via dual-luciferase reported assay (firefly and renilla), but only 45 showed a modest activity in comparison with anisomycin (Navrátilová et al. 2013) .

The cytotoxicity of the prenylated flavonoids obtained from P. tomentosa has been tested in more than 20 different cell lines. The type of prenylation strongly affects the cytotoxicity of a flavonoid in the traditional P-388 murine leukemia model. The unmodified 3-prenyl group and the presence of corresponding ortho-dihydroxy or trihydroxy substitution of the flavonoid ring B are crucial to its activity against P-388 as compared with other prenyl substituents (Hakim et al. 1999 (Hakim et al. , 2002 (Hakim et al. , 2006 . Similar findings have been observed for modified C-6 geranyl groups and the substitution of the ring B for other cell lines tested (Š mejkal et al. 2010) . However, replacing the parahydroxy group of the ring B of a C-8 prenylated flavanone with several different acyl substituents resulted in greater cytotoxicity (Aniol et al. 2012; Š mejkal 2014) . It has also been found that cytotoxic activity is diminished by the presence of a C-3 hydroxyl substituent on the ring C, 4 0 -methoxy substitution of the ring B or a para-hydroxy substituted ring B (Š mejkal et al. 2008a) . For this reason, it is important to emphasize that the relative importance of the substitution of ring B can differ according to the cell line used. Modification of a prenyl or geranyl sidechain can not only change the direct cytotoxicity, but it may also affect the proliferation cells or trigger apoptosis (Kollár et al. 2011; Šmejkal et al. 2007a Š mejkal 2014) .

Prenylated flavonoids 55-59, modified with an unusual 3,4-dihydro-2H-pyran moiety, have been found to inhibit the severe acute respiratory syndrome corona virus PLpro enzyme more effectively than their parent compounds, the precursors from which were they derived (Cho et al. 2013) .

The presence of a geranyl group at the C-6 position (21, 22, 24-26, 30, 31, 33 , and 34) seems to be crucial for the hAChE and BChE inhibitory effects. The most effective inhibitor was 22. All of the geranylated flavonoids, apart from 26, inhibited hAChE dosedependently. It appears that greater inhibition is observed when ring B of the flavanone bears free hydroxyl groups (Cho et al. 2012 ). Phytochem Rev (2015 The crystal structure of the bacterial sialidase Cp-NanI catalytic domain in a complex with the geranylated flavonoid diplacone (22) provides structural insights into the binding mode of natural flavonoidbased inhibitors at atomic resolution. It shows how the geranyl and C-3 0 hydroxyl groups of 22 contribute to the stability of the enzyme-inhibitor complex. Time-dependent competitive inhibition patterns have been observed. Structural comparison of the human sialidases Neu1-Neu4 with the Cp-NanI-diplacone (22) complex suggests that the interaction between human sialidases and 22 is likely to be unfavourable because of polar or ionic repulsion (Lee et al. 2014) .

Six flavonoid glycosides have been extracted from the stem bark 60-62 (Si et al. 2009 ) and flowers 63-66 (Scogin 1980) of P. tomentosa. Apigenin-7-O-b-D-glucopyranoside (synonym: cosmosiin) (Kurkina et al. 2011) (60) shows anti-HIV activity in vitro on H9 cells (Tang et al. 1994 ) and enhances the secretion of adiponectin, the phosphorylation of the tyrosine residue of insulin receptor-b, and the translocation of GLUT5 (Rao et al. 2011) . Compound 60 shows no significant hepatic Glc-6-phosphatase inhibitory activity in vitro (Kumar et al. 2010 ). Apigenin-7-O-b-D-glucuronopyranoside (61) was more potent than apigenin (2) and omeprazole in an assay analysing the inhibition of reflux esophagitis and gastritis promoted surgically and by application of indomethacine in rats (Min et al. 2005) . No information about the biological activity of apigenin-7-O-[b-D-glucuronopyranosyl (1 ? 2)-O-b-D-glucuronopyranoside] (62) has been found in the literature. Delphinidin-3-O-glucoside (synonym: myrtillin) (63) protects microglia from inflammationinduced stress signaling (Carey et al. 2013) , is cytotoxic against the MCF-7 (breast) cancer cell line (Vareed et al. 2006) , and has an the affinity for the estrogenic ERb receptor (Hidalgo et al. 2012 ). Delphinidin-3,5-di-O-glucoside (64) and cyanidin-3,5-di-O-glucoside (65) are potent antioxidants Tanaka et al. 2013) . Compounds 63 and 65 are potent ACE inhibitors in vitro (Hidalgo et al. 2012; Persson et al. 2009 ).

Only three lignans: (?)-paulownin (66), (?)-sesamin (67), (?)-piperitol (68) have been isolated from the wood of P. tomentosa (Ina et al. 1987; Takahashi and Nakagawa 1966; Zhu et al. 1986) (Fig. 3 ). Several reports have described their pharmacological effects Pan et al. 2009 ). Compound 66 is a promising antifungal agent that acts against the basidiomycetes Fomitopsis palustris and Trametes versicolor (Kawamura et al. 2004) . Sesamin (67) has been previously isolated from the wood of P. tomentosa, and P. kawakamii and the hybrid of P. elongata 9 P. fortunei (Takahashi and Nakagawa 1966; Zhu et al. 1986 ). Compound 67 is the major lignan in sesame, and has various biological activities, such as antioxidant, angiogenic (Chung et al. 2010) , antiphlogistic (Chatrattanakunchai et al. 2000) , antihypertensive (Nakano et al. 2006) , insecticidal (Nascimento et al. 2004) , neuroprotective , and anticarcinogenic ( . However, this compound showed no significant ability to reduce the formation of atherosclerotic lesions in the ApoE (-/-) gene-knockout mouse, whereas specific dietary polyphenols, especially quercetin and theaflavin were more active (Loke et al. 2010) . It has been suggested that some of the biological effects attributed to sezamine (67) may, in fact, be caused by its metabolites and that 67 may be acting as a proactive substance in the body (Yasuda and Sakaki 2012) . The metabolism of sesamim (67) by cytochrome P450 and UDP-glucuronosyltransferase has been found remarkably different in humans as compared to other animals. Further investigation into the safety of taking sesamin (67) with therapeutic drugs that are metabolised by CYP2C9 is also needed (Yasuda and Sakaki 2012) .

A total of thirteen phenylpropanoid glycosides (69-81) with multifarious bioactivities, natural compounds derived biosynthetically from the amino acid phenylalanine, have been isolated from different parts of the P. tomentosa plant (Table 4 ) (Damtoft and Jensen 1993; Kang et al. 1994; Ota et al. 1993; Schilling et al. 1982; Si et al. 2008b , d, Si et al. 2011b Sticher and Lahloub 1982; Šmejkal et al. 2007b; Zhu et al. 1986 ). Phenylpropanoids are of great interest for fabricating effective tonic, anticancer, hepatoprotective, immunostimulating, antimicrobial, and anti-inflammatory phytopreparations (Kurkin 2003; Galvez et al. 2006; Panossian and Wagner 2005; Fu et al. 2008; Pan et al. 2003) .

A new furanoquinone, methyl-5-hydroxy-dinaphthol [1,2-2 0 ,3 0 ]furan-7,12-dione-6-carboxylate (MHDDC) (82) (Fig. 4) identified in P. tomentosa stem bark (MeOH extract) has been shown to possess antiviral activity against poliovirus types 1 and 3, using HeLa cells in vitro (Kang et al. 1999 ). Its cathepsin K and L inhibitory activities in vitro have recently been discovered. The 5-OH functional group may have a favourable effect on this reduction potential which prevents the degradation of bone the matrix carried out by osteoclasts (Park et al. 2009 ).

The naphtoquinone plumbagin (83) has been detected in the leaves and fruit of P. tomentosa (Babula et al. 2006) . It has been used in traditional systems of medicine since ancient times (Pile et al. 2013) . It has exhibited promising antimalarial activity in vitro with IC 50 of 580 (270-640) nM and 370 (270-490) nM, respectively, against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquineresistant P. falciparum clones, using an assay based on SYBR Green I. Toxicity testing indicated relatively low toxicity at dose levels up to 100 mg/kg body weight (for a single oral dose) and 25 mg/kg (for daily dose given for consecutive 14 days) for acute and subacute toxicity, respectively. Based on the results of in vivo antimalarial testing, plumbagin administered at a the dose of 25 mg/kg of body weight for 4 consecutive days exhibited moderate to weak antimalarial activity with regard to its ability to reduce parasitaemia and prolong survival time (Sumsakul et al. 2014) . Other published studies of plumbagin (83) described effects such as antifungal, antibacterial, cytotoxic (Krishnaswamy and Purushothaman 1980) , anticoagulant (Santhakumari et al. 1978) , anthelmintic (antischistosomal) (Zhang and Coultas 2013) and an anti-inflammatory effect on the amelioration of experimental ulcerative colitis in mice at a dose of 8-10 mg/ kg (Pile et al. 2013) .

Six iridoids: 7-b-hydroxyharpagide (84), paulownioside (85), catalpol (86), aucubin (87), tomentoside (88) and 7-hydroxytomentoside (89) have been isolated from the leaves of P. tomentosa (84-87) (Adriani et al. 1981; Franzyk et al. 1999) , the bark of the trunk and roots (86) (Plouvier 1971 ) and parts of the young plant (85, 86, 88, and 89) (Damtoft and Jensen 1993) (Fig.  5) . Compound 86 shows neuroprotective activity (Li et al. 2004 ), a cardioprotective effect against myocardial infarction-specifically reperfusion damage (Huang et al. 2013a, b) , and radioprotective effects . It also increases glucose utilization by increasing the secretion of b-endorphin from the adrenal gland (Shieh et al. 2011) . Compounds 86 and 87 possess antispasmodic activity (Deurbina et al. 1994) . Aucubin (87) had antioxidant and pancreasprotective effects on streptozotocin-induced diabetes in rats (Jin et al. 2008) and it may improve obesityinduced atherosclerosis by attenuating the TNF-ainduced inflammatory response (Park 2013) . A weak antibacterial effect (against Streptococcus pneumoniae and MG-hemolytic streptococcus, MIC 28.946 mg/ml) (Zheng et al. 2012 ) and neuroprotective effects of 87 on diabetes and diabetic encephalopathy (Xue et al. 2012) have also been observed. The sesquiterpenic lacton isoatriplicolide tiglate (90) has been isolated from P. tomentosa flowers. It has neuroprotective effects against glutamate-induced neurotoxicity (Kim et al. 2010a (Kim et al. , 2010b and cytotoxic activity against several cancer cell lines: A549 lung carcinoma; SK-OV-3 adenocarcinoma; SK-Mel-2 malignant melanoma; XF498 central nervous system tumors; HCT15 colon adenocarcinoma, against which its effect is comparable to that of reference substance adriamycin (Moon and Zee 2001) ; human breast cancers MDA-MB-231, MCF7, HS578T, and T47D; and the HeLa, SiHa and C33A cervical cancer cell lines (Jung et al. 2012) .

Seven phytosterols have been isolated from P. tomentosa leaves: ursolic acid (91) (Zhu et al. 1986; Zhang and Li 2011) , 3-epiursolic acid (92), pomolic acid (93), corosolic acid (94), maslinic acid (95), b-sitosterol (96), and daucosterol (97) (Zhang and Li 2011) . Most of these show various biological activities, e.g., 91 is a potentially useful for treating Alzheimer's disease (because of its ability to block the interactions of the amyloid b-CD36) (Wilkinson et al. 2011) . It can prevent the recruitment of the monocytes that accelerate atherosclerosis, a major complication of diabetes, in mice (Ullevig et al. 2011) , and it also possesses antibacterial (Wong et al. 2012) , anti-trypanosomal, and anti-leishmanial properties (Bero et al. 2011) . Compound 91 has also shown cytotoxic effects against K562 and K562/ADR human chronic myelogenous leukaemia, HL60 and HL60/ADR human acute myelocytic leukemia cancer cells, and the human colon cancer cell lines SW480 and SW620 (Shan et al. 2011) . Compounds 93-96 also show promising cytotoxic potential, e.g., 93 is effective against the human chronic myelogenous leukaemia cell line 562 and also against cells derived from chronic myeloid leukaemia patients (Vasconcelos et al. 2007 ). Compound 94 shows cytotoxic effects against osteosarcoma MG-63 cells (Cai et al. 2011) and immunosuppressive activity on myeloid-derived suppressor cells in the murine sarcoma model (Horland et al. 2013 (Deepak and Handa 2000) , and 93 (Schinella et al. 2008 ). An immunomodulatory effect of 97 in protecting mice against candidiasis disseminated by the CD4? Th1 immune response has been seen (Lee et al. 2007 ). Other recently discovered pharmacological effects include antimalarial (95) (Moneriz et al. 2011) , hypotensive and endothelium-dependent vasorelaxant effects (93) (Estrada et al. 2011 ). Compound 95 is potentially useful for treating cerebral ischemic injuries (Guan et al. 2011) , and 94 has promising antidiabetic effects (Sivakumar et al. 2009 ). (127). The relatively most abundant constituents were 111 (20 % of the total glycerides), 126 (14 %), and 120 and 127 (12 %) (Asai et al. 2009 ). Another analysis of the secretions of the glandular hairs on the leaves of both bud flushes and adult trees as well as the flowers of adult trees showed that these secretions contain ten glycerides (106, 108-110, 118, 122, 124-127) . These compounds showed sticky character, but they were not toxic to several insects. Therefore, the glandular hairs on the leaves and flowers may serve only to physically deter herbivores (Fig. 6) .

Six known phenolic acids, namely p-hydroxybenzoic acid (128), vanillic acid (129), gallic acid (130), cinnamic acid (131), p-coumaric acid (132), and caffeic acid (133) have been identified in the leaves of P. tomentosa (128-133), bark (130 and 131) and wood (133) (Ota et al. 1993; Si et al. 2008c Si et al. , 2011b , and p-ethoxybenzaldehyde (134) is present in flowers (Yuan et al. 2009 ). The 5,7-dihydroxy-6-geranylchromone (135) isolated from fruits shows only moderate cytotoxic activity against a suspension culture of Nicotiana tabacum cv. Bright Yellow (BY-2), which confirms that ring B of the flavonoid skeleton is important for this activity (Š mejkal et al. 2008a) . A large group of essential oil substances found in the flowers of P. tomentosa have also been identified (Oprea et al. 2004; Ibrahim et al. 2013) (Fig. 7) .

Plants are still highly esteemed all over the world as rich sources of therapeutic agents. In this context, traditional Chinese herbal medicines, such as Paulownia continue to influence a modern healthcare. It has been estimated that approximately 420,000 plant species exist on Earth, but little is known about the phytochemical or therapeutic qualities of most of them. Thanks to the development of the spectral and other analytical methods used in modern phytochemistry, many of the principal physiologically active secondary metabolites have been identified and researched in detail. The accumulated knowledge of traditional medicine is therefore, playing an important role in enhancing the success of drug discovery in herbal medicine. Approximately 80 % of the currently known antimicrobial, cardiovascular, immunosuppressive, and anticancer drugs are of plant origin (Pan et al. 2013) .

As mentioned in this review, P. tomentosa is a rich source of multifarious secondary metabolites, mainly prenylated flavonoids. As of today 135 compounds, including flavonoids, lignans, phenolic glycosides, quinones, terpenoids, glycerides, phenolic acids, and other miscellaneous compounds have been isolated from various extracts of this plant.

Of increasing interest are the isolation and identification of P. tomentosa prenylated flavonoids, as they have shown promising pharmacological effects. In the first experiments, their antioxidant, antibacterial, antiphlogistic, cytotoxic, and SARS-CoV PL activities have been discovered along with inhibitory effects on human acetylcholinesterase, butyrylcholinesterase, and bacterial neuraminidases. More than 40 compounds with modified prenyl or geranyl side-chains attached at C-6 of the flavonoid skeleton have been isolated from the flowers, fruit, and leaves of P. tomentosa. Only two of these compounds have shown the presence of a five-carbon side-chain; for the others a ten-carbon side-chain is typical. Further, only a few compounds have shown a geranyl moiety modified by hydroxylation at C-6 00 or C-7 00 . Some compounds have a geranyl group modified by formating a heterocyclic moiety, which is also unusual. Most of them have never been isolated from any other plant species. However, further in vivo pharmacology studies are needed to precisely elucidate biological mechanism of action, efficacy, and toxicity of these promising therapeutic agents. Elucidation of the structure-activity relationships is also crucial for their further total syntheses and introduction into medical practice. For these reasons, the study of P. tomentosa as a source of biologically active metabolites is significant and future interest in this plant is ensured.

Isolation and characterization of paulownioside, a new highly oxygenated iridoid glucoside from Paulownia tomentosa

Acteoside: a new antihypertensive drug

In vitro immunomodulatory activity of verbascoside from Nepeta ucrainica L

Antiproliferative activity and synthesis of 8-prenylnaringenin derivatives by demethylation of 7-O-and 4 0 -O-substituted isoxanthohumols

Effects of taxifolin on the activity of angiotensin-converting enzyme and reactive oxygen and nitrogen species in the aorta of aging rats and rats treated with nitric oxide synthase inhibitor and dexamethasone

Geranylated flavanones from the secretion on the surface of the immature fruits of Paulownia tomentosa

Acylglycerols (=gly-cerides) from the glandular trichome exudate on the leaves of Paulownia tomentosa

Chromatografické stanovení naftochinonů v rostlinách (Chromatographic evaluation of naphtochinones in plants)

Active components from Siberian ginseng (Eleutherococcus senticosus) for protection of amyloid b(25-35)-induced neuritic atrophy in cultured rat cortical neurons

Catechin prodrugs and analogs: a new array of chemical entities with improved pharmacological and pharmacokinetic properties

In vitro antitrypanosomal and antileishmanial activity of plants used in Benin in traditional medicine and bio-guided fractionation of the most active extract

Antifungal synergy of theaflavin and epicatechin combinations against Candida albicans

Prenylated flavonoids: pharmacology and biotechnology

Antiproliferative effect of catechin in GRX cells

Naringenin and 17b-estradiol coadministration prevents hormone-induced human cancer cell growth

The naringenininduced proapoptotic effect in breast cancer cell lines holds out against a high bisphenol a background

Corosolic acid triggers mitochondria and caspase-dependent apoptotic cell death in osteosarcoma MG-63 cells

Stilbenes and anthocyanins reduce stress signaling in BV-2 mouse microglia

Investigation of two Flacourtiaceae plants: Bennettiodendron leprosipes and Flacourtia ramontchi

Cardiovascular protective flavonolignans and flavonoids from Calamus quiquesetinervius

Sesamin inhibits lysophosphatidylcholine acyltransferase in Mortierella alpine

A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention

Structure-activity relationship of natural flavonoids in hydroxyl radicalscavenging effects

Propolin C from propolis induces apoptosis through activating caspases, Bid and cytochrome c release in human melanoma cells

Determination of flavonoids in the flowers of Paulownia tomentosa by high-performance liquid chromatography

Chemical modification and anticancer effect of prenylated flavanones from Taiwanese propolis

Radio-protective effect of catalpol in cultured cells and mice

A systematic review on biological activities of prenylated flavonoids

Cholinesterase inhibitory effects of geranylated flavonoids from Paulownia tomentosa fruits

Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa

Anti-inflammatory and antinociceptive effects of sinapyl alcohol and its glucoside syringin

Angiogenic activity of sesamin through the activation of multiple signal pathways

Eight flavonoids and their potential as inhibitors of human cytomegalovirus replication

Antimicrobial activity of flavonoids

Tomentoside and 7-hydroxytomentoside, two new iridoid glucosides from Paulownia tomentosa

Antimicrobial activity of Brazilian propolis extracts against rumen bacteria in vitro

Antiinflammatory activity and chemical composition of extracts of Verbena officinalis

Studies on the vascular effects of the fractions and phenolic compounds isolated from Viscum album ssp. album

In vitro antispasmodic activity of peracetylated penstemoniside, aucubin and catalpol

Lignan and phenylpropanoid glycosides from Phillyrea latifolia and their in vitro anti-inflammatory activity

Phenolic compounds from Artemisia iwayomogi and their effects on osteoblastic MC3T3-E1 cells

Chemistry and pharmacology of oxyprenylated secondary plant metabolites

Ontogeny of the flowers in Paulownia tomentosa-a contribution to the recognition of the resurrected monogeneric family Paulowniaceae

Pomolic acid of Licania pittieri elicits endotheliumdependent relaxation in rat aortic rings

Dietary flavonoids: role of (-)-epicatechin and related procyanidins in cell signaling

Halohydrins of antirrhinoside-the correct structures of muralioside and epimuralioside

Naturally occurring phenylethanoid glycosides: potential leads for new therapeutics

Dietary flavonol epicatechin prevents the onset of type 1 diabetes in nonobese diabetic mice

Effect of different phenolic compounds on a-amylase activity: Screening by microplatereader based kinetic assay

Pharmacological activities of phenylpropanoids glycosides

Neuroprotective role of nanoencapsulated quercetin in combating ischemiareperfusion induced neuronal damage in young and aged rats

Hepatoprotective effects of syringin on fulminant hepatic failure induced by D-galactosamine and lipopolysaccharide in mice

A study of the trypanocidal and analgesic properties [of substances] from Lychnophora granmongolense (Duarte) Semir & Leitao Filho

Maslinic acid, a natural inhibitor of glycogen phosphorylase, reduces cerebral ischemic injury in hyperglycaemic rats by GLT-1 up-regulation

Studies on b-sitosterol and ceramideinduced alterations in the properties of cholesterol/sphingomyelin/ganglioside monolayers

Artoindonesianins A and B, two new prenylated flavones from the root of Artocarpus champeden

Artoindonesianin P, a new prenylated flavone with cytotoxic activity from Artocarpus lanceifolius

Prenylated flavonoids and related compounds of the Indonesian Artocarpus (Moraceae)

The biochemistry and medical significance of the flavonoids

Advanced research on acteoside for chemistry and bioactivities

Potential anti-inflammatory, anti-adhesive, anti/estrogenic, and angiotensin-converting enzyme inhibitory activities of anthocyanins and their gut metabolites

Luteolin, a flavonoid, inhibits AP-1 activation by basophils

Changes in the level of bioactive compounds in Paulownia tomentosa fruits

Corosolic acid impairs tumor development and lung metastasis by inhibiting the immunosuppressive activity of myeloid-derived suppressor cells

Effect of diplacone on LPS-induced inflammatory gene expression in macrophages

Prenylated and geranylated flavonoids increase production of reactive oxygen species in mouse macrophages but inhibit the inflammatory response

Catalpol decreases peroxynitrite formation and consequently exerts cardioprotective effects against ischemia/reperfusion insult

Eleutheroside B or E enhances learning and memory in experimentally aged rats

Anti-oxidant activity and attenuation of bladder hyperactivity by the flavonoid compound kaempferol

Chemical composition, antimicrobial activity of the essential oil of the flowers of Paulownia tomentosa (Thunb.) Steud. growing in Egypt

Antiplatelet aggregatory effects of the constituents isolated from the flower of Carthamus tinctorius

Piperitol from Paulownia tomentosa

Antiinflammatory role of naringenin in rats with ethanol induced liver injury

Determination of flavonoids from Paulownia tomentosa (Thunb) Steud. by micellar electrokinetic capillary electrophoresis

Phenylethanoid glycosides in plants: structure and biological activity

Antioxidant and pancreasprotective effect of aucubin on rats with streptozotocininduced diabetes

Trypanocidal activity of chemical constituents from Lychnophora salicifolia Mart

Inhibitory effect and mechanism on antiproliferation of isoatriplicolide tiglate (PCAC) from Paulownia coreana

Matteuorienate A and B, two new and potent aldose reductase inhibitors from Matteuccia orientalis (Hook.) Trev

Antibacterial phenylpropanoid glycosides from Paulownia tomentosa Steud

An antiviral furanoquinone from Paulownia tomentosa Steud

Angiotensin converting enzyme inhibitory phenylpropanoid glycosides from Clerodendron trichotomum

Antifungal activity of constituents from the heartwood of Gmelina arborea: part 1. Sensitive antifungal assay against Basidiomycetes

Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle

A comprehensive review on flavanones, the major citrus polyphenols

Sesamin, attenuates behavioural, biochemical and histological alterations induced by reversible middle cerebral artery occlusion in the rats

HIV-1 integrase inhibitory phenylpropanoid glycosides from Clerodendron trichotomum

Peroxyl radical scavenging capacity of extracts and isolated components from selected medicinal plants

Neuroprotective effects of a sesquiterpene lactone and flavanones from Paulownia tomentosa Steud against glutamate-induced neurotoxicity in primary cultured rat cortical cells

Inhibition of aldose reductase by phenylethanoid glycoside isolated from the seeds of Paulownia coreana

Anti-herbivore structures of Paulownia tomentosa: morphology, distribution, chemical constituents and changes during shoot and leaf development

The dietary flavonoids naringenin and quercetin acutely impair glucose metabolism in rodents possibly via inhibition of hypothalamic insulin signalling

Geranylated flavanone tomentodiplacone B inhibits proliferation of human monocytic leukaemia (THP-1) cells

Xanthine oxidase inhibitors from Brandisia hancei

In vitro neuroprotective activities of phenylethanoid glycosides from Callicarpa dichotoma

Plumbagin: a study of its anticancer, antibacterial and antifungal properties

Phenolic glycosides from Dodecadenia grandiflora and their glucose-6-phosphatase inhibitory activity

Antioxidant prenylated flavonoids from propolis collected in Okinawa

Phenylpropanoids from medicinal plants: distribution, classification, structural analysis, and biological activity

Antidepressant activity of some phytopharmaceuticals and phenylpropanoids

Flavonoids from Tanacetum vulgare flowers

Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products

Immunoregulatory activity of daucosterol, a beta-sitosterol glycoside, induces protective Th1 immune response against disseminated Candidiasis in mice

Two new triterpenes from the rhizome of Dryopteris crassirhizoma, and inhibitory activities of its constituents on human immunodeficiency virus-1 protease

Anti-inflammatory effect and HPLC analysis of extract from edible Cirsium setidens

Anthocyanin compositions and biological activities from the red petals of Korean edible rose (Rosa hybrid cv. Noblered)

Structural basis of sialidase in complex with geranylated flavonoids as potent natural inhibitors

Neuroprotection of catalpol in transient global ischemia in gerbils

0 -Dimethoxy hesperetin induces apoptosis of fibroblast-like synoviocytes in rats with adjuvant arthritis through caspase 3 activation

Phenolic Compounds of Abies nephrolepis and their NO production inhibitory activities

Therapeutic effect of 7,3 0 -dimethoxy hesperetin on adjuvant arthritis in rats through inhibiting JAK2-STAT3 signal pathway

0 -dimethoxy hesperetin inhibits inflammation by inducing synovial apoptosis in rats with adjuvant-induced arthritis

The inhibitory effect of phenylpropanoid glycosides and iridoid glucosides on free radical production and b2-integrin expression in human leucocytes

Anti-inflammatory effect of the 5,7,4 0 -Trihydroxy-6-geranylflavanone isolated from the fruit of Artocarpus communis in S100B-induced human monocytes

Release of acetylcholine by syringin, an active principle of Eleutherococcus senticosus, to raise insulin secretion in Wistar rats

Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction

Distribution and biological activities of the flavonoid luteolin

Cytotoxic activity of flavonoids and extracts from Retama sphaerocarpa Boissier

Apigenin modulates GABAergic and glutamatergic transmission in cultured cortical neurons

Inhibitory effects of luteolin on human gastric carcinoma xenografts in nude mice and its mechanism

Catechinincorporated dental copolymers inhibit growth of Streptococcus mutans

Biological activity of five antibacterial flavonoids from

erythrophyllum (Combretaceae)

Dietary flavonoids: molecular mechanisms of action as anti-inflammatory agents

Structural requirements of flavonoids for inhibition of antigeninduced degranulation, TNF-a and IL-4 production from RBL-2H3 cells

Studies on physiologically active substances in citrus fruit peel. Part XX. Structure and physiological activity of phenyl propanoid glycosides in lemon (Citrus limon Burm. f.) peel

Structural requirements of flavonoids for nitric oxide production inhibitory activity and mechanism of action

The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus L.) flavonoids

The effects of apigenin-7-O-b-D-glucuronopyranoside on reflux oesophagitis and gastritis in rats

Quercetin modulates Na ? /K ? ATPase and sodium hydrogen exchanger in type 2 diabetic erythrocytes

Antimutagenic activity of flavonoids from Pogostemon cablin

Multi-targeted activity of maslinic acid as an antimalarial natural compound

Anticancer compound of Paulownia tomentosa

Cytotoxic flavanones of Schizolaena hystrix from the Madagascar rainforest

Cytotoxic compounds of Schizolaena hystrix from the Madagascar rainforest

Sesamin metabolites induce an endothelial nitric oxide-dependent vasorelaxation through their antioxidative property-independent mechanisms: possible involvement of the metabolites in the antihypertensive effect of sesamin

Insecticidal activity of chemical constituents from Aristolochia pubescens against Anticarsia gemmatalis larvae

Minor Cgeranylated flavanones from Paulownia tomentosa fruits with MRSA antibacterial activity

Increase of b-endorphin secretion by syringin, an active principle of Eleutherococcus senticosus, to produce antihyperglycemic action in type 1-like diabetic rats

Role of sympathetic tone in the loss of syringin-induced plasma glucose lowering action in conscious Wistar rats

Hypoglycemic effect of syringin from Eleutherococcus senticosus in streptozotocin-induced diabetic rats

Antileishmanial phytochemical phenolics: molecular docking to potential protein targets

Antimicrobial flavonoids and diterpenoids from Dodonaea angustifolia

The analysis of the volatile and semi-volatile compounds of the Paulownia tomentosa flowers by gas chromatography coupled with mass spectrometry

The chemistry of color changes in kiri wood (Paulownia tomentosa Steud.) III. A new caffeic acid sugar ester from Kiri wood

Pharmacological activities and mechanisms of natural phenylpropanoid glycosides

An update on lignans: natural products and synthesis

Bioactive constituents from Chinese natural medicines. XXXVI. Four new acylated phenylethanoid oligoglycosides, Kankanosides J1, J2, K1, and K2, from stems of Cistanche tubulosa

New perspectives on how to discover drugs from herbal medicines: CAM's outstanding contribution to modern therapeutics

Effect of epicatechin and naloxone on cardioprotective phenotype

Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration

Pharmacological activity of phenylpropanoids of the mistletoe, Viscum album, host. Pyrus caucasica

Acteoside and martynoside exhibit estrogenic/antiestrogenic properties

Aucubin, a naturally occurring iridoid glycoside inhibits TNF-a-induced inflammatory responses through suppression of NF-jB activation in 3T3-L1 adipocytes

A Furanquinone from Paulownia tomentosa stem for a new cathepsin K inhibitor

Apigenin and cancer chemoprevention: progress, potential and promise (review)

Xanthohumol and related prenylated flavonoids inhibit inflammatory cytokine production in LPS-activated THP-1 monocytes: structure-activity relationships and in Silico binding to myeloid differentiation protein-2 (MD-2)

Acute and chronic antiinflammatory effects of plant flavonoids

Effect of Vaccinium myrtillus and its polyphenols on angiotensin-converting enzyme activity in human endothelial cells

Constituents of the leaves of Macaranga tanarius

Interventional effects of plumbagin on experimental ulcerative colitis in mice

Substituent effects on in vitro antioxidizing properties, stability, and solubility in flavonoids

The heterosides of Catalpa bignonioides Walt. (Bignoniaceae)

Protective role of apigenin on the status of lipid peroxidation and antioxidant defense against hepatocarcinogenesis in Wistar albino rats

Chemoprotective effect of plant phenolics against anthracyclineinduced toxicity on rat cardiomyocytes. Part III. Apigenin, baicalelin, kaempferol, luteolin and quercetin

Antimethicillinresistant Staphylococcus aureus (MRSA) activity of ''pacific propolis'' and isolated prenylflavanones

Insulin-mimetic action of rhoifolin and cosmosiin isolated from Citrus grandis (L.) osbeck leaves: enhanced adiponectin secretion and insulin receptor phosphorylation in 3T3-L1 cells

Design of potent inhibitors of acetylcholinesterase using morin as the starting compound

The natural triterpene maslinic acid induces apoptosis in HT29 colon cancer cells by a JNK-p53-dependent mechanism

Effects of several flavonoids on the growth of B16F10 and SK-MEL-1 melanoma cell lines: relationship between structure and activity

Novel insights into the pharmacology of flavonoids

Dietary flavonoids: bioavailability, metabolic effects, and safety

Cytotoxic geranylflavonoids from Bonannia graeca

The flavonoid quercetin in disease prevention and therapy: facts and fancies

Antiparasitic activity of C-geranyl flavonoids from Mimulus bigelovii

Epicatechin gallate impairs colon cancer cell metabolic productivity

Angicoagulant activity of plumbagin

Site-specific inhibitory mechanism for amyloid b42 aggregation by catecholtype flavonoids targeting the Lys residues

Quercetin potentiates the effect of Adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target

Verbascoside and isoverbascoside from Paulownia tomentosa Steud

Anti-inflammatory and apoptotic activities of pomolic acid isolated from Cecropia pachystachya

Tomentomimulol and mimulone B: two new C-geranylated flavonoids from Paulownia tomentosa fruits

Anthocyanins of the Bignoniaceae

Proliferation-inhibiting and apoptosis-inducing effects of ursolic acid and oleanolic acid on multi-drug resistance cancer cells in vitro

Immunomodulatory active compounds from Tinospora cordifolia

A new phenolic constituent and a cyanogenic glycoside from Balanophora involucrata (Balanophoraceae)

Metabolism-based synthesis, biologic evaluation and SARs analysis of O-methylated analogs of quercetin as thrombin inhibitors

Plasma glucose lowering mechanisms of catalpol, an active principle from roots of Rehmannia glutinosa, in streptozotocin-induced diabetic rats

Role of apigenin in human health and disease. In: Preedy VR (ed) Beer in health and disease prevention

Structure and activity relationship of antioxidant flavonoids from leaves of Paulownia tomentosa var. tomentosa. In: 2nd international papermaking and environment conference

Studies on the phenylethanoid glycosides with anti-complement activity from Paulownia tomentosa var. tomentosa wood

Characterization of phenolic acids and antioxidant activities of Paulownia tomentosa var. tomentosa leaves

Structure elucidation of phenylethanoid glycosides from Paulownia tomentosa Steud. var. tomentosa wood

Apigenin derivates from Paulownia tomentosa Steud. var. tomentosa stem barks

Evaluation of total phenolics, flavonoids and anti-inflammatory property of ethanolic extracts of Paulownia tomentosa var. tomentosa bark

Phenolic extractives with chemotaxonomic significance from the bark of Paulownia tomentosa var

Antioxidant properties and neuroprotective effects of isocampneoside II on hydrogen peroxide-induced oxidative injury in PC12 cells

Plant-based corosolic acid: future anti-diabetic drug?

Cytotoxic potential of C-prenylated flavonoids

C-geranyl compounds from Paulownia tomentosa Fruits

Antiradical activity of Paulownia tomentosa (Scrophulariaceae) extracts

Cytotoxic activity of C-geranyl compounds from Paulownia tomentosa fruits

Antibacterial Cgeranylflavonoids from Paulownia tomentosa (Scrophulariaceae) fruits

Cytotoxic activities of several geranyl-substituted flavanones

Phenolic glycosides of Paulownia tomentosa bark

Inhibition of nitric oxide production by compounds from Boesenbergia longiflora using lipopolysaccharide-stimulated RAW264.7 macrophage cells

Antimalarial activity of plumbagin in vitro and in animal models

Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay

Effect of flavonoids on aerobic glycolysis and growth of tumor cells

Studies on constituents of medicinal plants. VII. The stereochemistry of paulownin and isopaulownin

Antioxidant effect of flavonoids on DCF production in HL-60 cells

Maqui berry (Aristotelia chilensis) and the constituent delphinidin glycoside inhibit photoreceptor cell death induced by visible light

Apigenin-7-O-b-Dglucopyranoside, an anti-HIV principle from Kummerowia striata

Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: effects of epicatechin rich cocoa

Catechin attenuates behavioral neurotoxicity induced by 6-OHDA in rats

7-O-methylkaempferol and -quercetin glycosides from the whole plant of Nervilia fordii

Inhibitory effects of Eleutherococcus senticosus extracts on amyloid b(25-35)-induced neuritic atrophy and synaptic loss

Synthesis of dihydroxyphenacyl glycosides for biological and medicinal study: b-oxoacteoside from Paulownia tomentosa

Indonesian propolis: chemical composition, biological activity and botanical origin

Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis

Anthocyanins in Cornus alternifolia, Cornus controversa, Cornus kousa and Cornus florida fruits with healt benefits

Pomolic acid-induced apoptosis in cells from patients with chronic myeloid leukemia exhibiting different drug resistance profile

Protective effect of naringenin against lead-inuced oxidative stress in rats

Anti-inflammatory compounds of ''Qin-Jiao'', the roots of Gentiana dahurica (Gentianaceae)

Catechin stimulates osteogenesis by enhancing PP2A activity in human mesenchymal stem cells

Dihydroquercetin: more than just an impurity?

A high-content drug screen identifies ursolic acid as an inhibitor of amyloid-b interactions with its receptor CD36

Surface flavonoids in Catalpa ovata, Greyia sutherlandii and Paulownia tomentosa

Chemical constituents and antibacterial activity of Melastoma malabathricum L

Spectroscopic study on interaction between cistanoside F and bovine serum albumin

Antioxidative effects of phenylethanoids from Cistanche deserticola

Hepatoprotective activity of phenylethanoids from Cistanche deserticola

Neuroprotective properties of aucubin in diabetic rats and diabetic encephalopathy rats

Hesperetin-7,3 0 -Odimethylether selectively inhibits phosphodiesterase 4 and effectively suppresses ovalbumin-induced airway hyperresponsiveness with a high therapeutic ratio

Cytotoxic phenolic glycosides from Boschniakia himalaica

How is sesamin metabolised in the human liver to show its biological effects?

Prenylation of aromatic compounds, a key diversification of plant secondary metabolites

Antiproliferative prenylated stilbenes and flavonoids from Macaranga alnifolia from the Madagascar rainforest

Effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a scopolamine-induced amnesia model

Antifibrotic effects of quercetin in primary orbital fibroblasts and orbital fat tissue cultures of graves' orbitopathy

Phenylethanoid oligoglycosides and acylated oligosugars with vasorelaxant activity from Cistanche tubulosa

Isolation and bioassay of herbicidal active ingredient from Paulownia tomentosa

Lipid peroxidation inhibitory activity of some constituents isolated from the stem bark of Eucalyptus globulus

Taxifolin glycoside blocks human ether-a-go-go related gene K(?) channels

Identification of plumbagin and sanquinarine as effective chemotherapeutic agents for treatment of schistosomiasis

Studies on the chemical constituents from the leave of Paulownia tomentosa

Antitumor activities of extracts and compounds from the roots of Daphne tangutica Maxim

New lignans and their biological activities

Glucosidase inhibitory constituents from Toona sinensis

Isolation, modification and cytotoxic evaluation of flavonoids from Rhododendron hainanense

Enzymatic extraction and antibacterial activity from Eucommia ulmoides leaves

Paulownia in China: cultivation and utilization. Asian Network for Biological Science and International Development Research Centre, Chinese Academy of Forestry

Antiradical and cytoprotective activities of several C-geranyl-substituted flavanones from Paulownia tomentosa Fruit