key: cord-302190-co4tju7u authors: Yu, Sheng; Yan, Hui; Zhang, Li; Shan, Mingqiu; Chen, Peidong; Ding, Anwei; Li, Sam Fong Yau title: A Review on the Phytochemistry, Pharmacology, and Pharmacokinetics of Amentoflavone, a Naturally-Occurring Biflavonoid date: 2017-02-16 journal: Molecules DOI: 10.3390/molecules22020299 sha: doc_id: 302190 cord_uid: co4tju7u Amentoflavone (C(30)H(18)O(10)) is a well-known biflavonoid occurring in many natural plants. This polyphenolic compound has been discovered to have some important bioactivities, including anti-inflammation, anti-oxidation, anti-diabetes, and anti-senescence effects on many important reactions in the cardiovascular and central nervous system, etc. Over 120 plants have been found to contain this bioactive component, such as Selaginellaceae, Cupressaceae, Euphorbiaceae, Podocarpaceae, and Calophyllaceae plant families. This review paper aims to profile amentoflavone on its plant sources, natural derivatives, pharmacology, and pharmacokinetics, and to highlight some existing issues and perspectives in the future. Amentoflavone (C 30 H 18 O 10 ) is a common biflavonoid chemically named as 8-[5-(5,7-dihydroxy-4-oxo-4H-chromen-2-yl)-2-hydroxyphenyl]-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one, which naturally occurs in many plants. It is also considered as an apigenin dimer linked by a C3 -C8 covalent bond (Figure 1 ). This compound was firstly isolated by Okigawa and his colleagues in 1971 from three plants of the Selaginella species (Selaginella tamariscina (Beauv.) Spring, Selaginella nipponica, and Selaginella pachystachys) [1] . From then on, phytochemical researchers have isolated and identified this biflavonoid from more than 120 plants, some of which have been used as traditional folk medicines in many regions of the world for even thousands of years. With the development of modern pharmacology, more and more evidence has proved many of the bioactivities of amentoflavone, including anti-oxidant [2] , anti-inflammatory [3] , anti-senescence [4] , anti-tumor [5] , anti-virus [6] , and anti-fungal [7] effects, as well as therapeutic effects on the central nervous system [8] and cardiovascular system [9] , etc. With its good pharmacological performance and high content, amentoflavone is even listed as the chemical marker of Selaginellae Herba ("Juanbai" in Chinese, which represents the whole plants of Selagenella tamariscina or Selaginella pulvinata) for quality evaluation in the Chinese Pharmacopoeia [10] . Due to its large range of bioactivities and originating from nature, amentoflavone has attracted increasing focus from a number of research fields. Here, in this paper, we aim to provide a review this naturally-occurring biflavonoid, describing its sources, natural derivatives, pharmacological effects, and pharmacokinetics, and to help researchers understand and utilize it in a better way. As a polyphenolic compound, amentoflavone exists in a large number of plants (Table 1) . To our knowledge, the major sources are the plants of Calophyllaceae, Clusiaceae, Cupressaceae, Euphorbiaceae, and Selaginellaceae families, and Calophyllum, Garcinia, and Selaginella species, etc. Some of these plants have been used as folk phytomedicines for a very long time, such as Gingko biloba, Lobelia chinensis, Polygala sibirica, Ranunculus ternatus, Selaginella pulvinata, Selagenella tamariscina for traditional Chinese medicines (TCMs), Calophyllum inophyllum, Selaginella bryopteris for traditional Indian medicines, Byrsonima intermedia for traditional American medicine, and Cnestis ferruginea and Drypetes gerrardii for traditional African medicines. As a polyphenolic compound, amentoflavone exists in a large number of plants (Table 1) . To our knowledge, the major sources are the plants of Calophyllaceae, Clusiaceae, Cupressaceae, Euphorbiaceae, and Selaginellaceae families, and Calophyllum, Garcinia, and Selaginella species, etc. Some of these plants have been used as folk phytomedicines for a very long time, such as Gingko biloba, Lobelia chinensis, Polygala sibirica, Ranunculus ternatus, Selaginella pulvinata, Selagenella tamariscina for traditional Chinese medicines (TCMs), Calophyllum inophyllum, Selaginella bryopteris for traditional Indian medicines, Byrsonima intermedia for traditional American medicine, and Cnestis ferruginea and Drypetes gerrardii for traditional African medicines. To obtain amentoflavone from plants as much as possible, and to fully utilize these plant sources, some studies have been carried out to optimize the extraction technology. A central composite design (CCD) method was used to optimize the extraction technology of amentoflvone from Taxus chinensis by supercritical-CO 2 fluid extraction (SFE-CO 2 ) with methanol as a co-solvent. The highest yield reached 4.47 mg/g when the plant was extracted with 78.5% ethanol at 48 • C under a pressure of 25 Mpa for 2.02 h [135] . With 35% water in ChCl/1,4-butanediol (1:5) as the extraction solvent, 0.518 mg/g of amentoflavone could be extracted from Chamaecyparis obtusa leaves at 70 • C for 40 min with a solid/liquid ratio of 0.1 g/mL, which was optimized by a response surface methodology [136] . Like other phytochemicals, separation and isolation of amentoflavone were mainly performed with conventional thin layer chromatography [23, 24] and column chromatography, in which silica gel [15, 18, 25] , polyamide [16] , macroporous adsorption resin [85, 86] , octadecyl silane [11, 22] , middle chromatogram isolation (MCI) gel [51] , and gel (Sephadex LH-20) [12, 13, 27] were used as stationery phases. In most cases, some of the above methods were combined for use [51, 63, 82, 88, 115, 137] . Additionally, as a novel isolation method, high-speed counter-current chromatography (HSCCC) has been widely used to isolate this bioflavonoid. A preparative isolation method with HSCCC was adopted to isolate amentoflavone from Selaginella doederleinii. The mixed solvent consisting of n-hexane:ethyl acetate:methanol:water (1:2:1.5:1.5, v/v/v/v) was employed for HSGCC of ethyl acetate extract of this plant. As a result, with an approximate yield of 0.34 mg from 1 g of crude plant, amentoflavone of 91.4% purity was obtained [138] . In another experiment, with HSCCC and n-hexane:ethyl acetate:methanol:water (2.2:2.8:2:3, v/v/v), 65.31 mg amentoflavone (98% purity) was isolated from approximately 2.5 g of Selaginella tamariscina [139] . There are also a large number of derivatives with different substitution positions and types in the natural plants ( Figure 2 ). In most cases, they exist in the same plant with amentoflavone. Amentoflavone is considered as a dimer of two apigenins with six hydroxyl groups on the positions of C5, C7, C4 , C5 , C7 , and C4 in its structure ( Figure 1 ). Among these groups the C7-, C4 -, C7 -, or C4 -hydroxyl group is easily substituted by a methoxyl group Table 2 . In the structure of amentoflavone, carbon-carbon double bonds of C2-C3 and C2 -C3 are easily hydrogenated, too. In a large number of plants, the hydrogenation products present and their glycosides (Table 3) . Table 3 . Hydrogenation derivatives of amentoflavone. As a ubiquitous biflavonoid, amentoflavone has been found with a large number of pharmacological functions, such as anti-inflammation, anti-oxidation, anti-tumor, anti-senescence, anti-virus, anti-diabetes, neuroprotective activities, and effects on cardiovascular system and central nervous system. Oxidative stress response is one part of inflammatory response. Amentoflavone, isolated from Garcinia brasiliensis, exhibited inhibitory effects on the productions of superoxide anion and total reactive oxygen species (ROS) inphorbol 12-myristate 13-acetate-stimulated human neutrophils. In human erythrocytes induced by 2,2 -azobis(2-amidinopropane) hydrochloride, it also inhibited the oxidant hemolysis and lipid peroxidation [2] . In rat astrocytoma cell line, lipopolysaccharide (LPS) could increase NO, ROS, malondialdehyde (MDA), and decrease reduced-glutathione (GSH), while tumor necrosis factor-α (TNF-α) was increased by LPS in a human monocytic leukemia cell line. All of the changes above were attenuated by amentoflavone significantly. However, there were no notable effects on the cells [164] . In RAW 264.7 cells stimulated with LPS, amentoflavone was observed to suppress the production of NO, prostaglandin E-2 (PGE-2), and the nuclear translocation of c-Fos, a subunit of activator protein (AP)-1. Additionally, extracellular signal-regulated kinase (ERK), which mediated c-Fos translocation, was inhibited by the active biflavonoid [165] . In the supernatant media of human peripheral blood mononuclear cells (PBMCs), amentoflavne could inhibit the increases of interleukin-1β (IL-1β), IL-6, TNF-α, and PGE2 induced by phytohaemagglutinin (PHA) [3] . The IC 50 Amentoflavone exerted good cytotoxic effect on cervical adenocarcinoma (HeLa) cells with IC 50 values of 20.7 µM [5] . After breast cancer MCF-7 cells were treated with amentoflavone, there were some cellular changes, including DNA and nuclear fragmentation, and down-regulation of calcium and intracellular reactive oxygen species. Additionally, some marks of mitochondrial-mediated apoptosis were observed, such as the activation of caspase 3, the reduction of mitochondrial inner-membrane potential, and the release of cytochrome c from mitochondria [167] . Amentoflavone also could significantly inhibit solid tumor development that was induced by B16F-10 melanoma in C57BL/6 mice. The mechanism might be related to inhibiting cell progression from G0/G1 to S phase and to regulating genes which were involved in cell cycle and apoptosis, such as P21, P27, Bax, caspase-9, etc. [168] . Recently, fatty acid synthase (FASN) has been considered as a potential target to treat cancer. Some studies indicated that amentoflavone could inhibit FASN expression in human epidermal growth factor receptor 2 (HER2)-positive human breast carcinoma SKBR3 cells. The inhibition decreased the translocation of sterol regulatory element-binding protein 1 (SREBP-1) in SKBR3 cells. The biflavonoid was also found to down-regulate HER2 protein and mRNA, to up-regulate polyoma enhancer activator 3 (PEA3), a transcriptional repressor of HER2 and to inhibit phosphorylation of protein kinase B (PKB), mechanistic target of rapamycin (mTOR) and c-Jun N-terminal kinases (c-JNK) [169] . In another experiment, amentoflavone was observed to increase the cleavage-activity of caspase-3, to suppress SKBR3 cell activity, and to have no effect on FASN-nonexpressed NIH-3T3 normal cell growth [170] . Ultraviolet B (UVB) irradiation was found to increase the levels of Lamin A and phospho-H2AX protein in normal human fibroblasts. These cases were present in premature aging diseases or normally old individuals. An investigation indicated amentoflavone was able to ameliorate these damages and to protect nuclear aberration significantly, which showed the anti-senescence activity for some skin aging processes related with UVB [4] . Another investigation in UVB-induced normal human fibroblasts found that amentoflavone could inhibit the activation of ERK without affecting ERK protein level, p38, and JNK activation. In addition, the biflavonoid could decrease phospho-c-Jun and c-Fos protein expressions, which were AP-1 transcription factor components. The findings suggested the potential of amentoflavone to prevent or treat skin photoaging [171] . Amentoflavone was observed to ameliorate glucose disorder, regulate insulin secretion, and restore the pancreas in streptozotocin-induced diabetic mice and the optimum dose was 60 mg/kg [172] . In another anti-diabetes study, this active biflavonoid showed its activities against α-glucosidase (IC 50 8.09 ± 0.023 µM) and α-amylase (IC 50 73.6 ± 0.48 µM) [58] . Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been considered as a strategy to treat type 2 diabetes. Amentoflavone was screened to inhibit PTP1B with IC 50 value of 7.3 ± 0.5 µM and proved to be a non-competitive inhibitor of PTP1B by kinetic study. There was a dose-dependent increase in tyrosine phosphorylation of insulin receptor (IR) after 32D cells with overexpression of IR were treated with amentoflavone [173] . Amentoflavone exhibited its anti-dengue potential in a screening experiment, which may be mediated by inhibiting Dengue virus NS5 RNA-dependent RNA polymerase [6] . Among the isolated twelve components from Torreya nucifera with a bioactivity guide, amentoflavone was proved as the most active one to inhibit severe acute respiratory syndrome coronavirus (SARS-CoA) with IC 50 value of 8.3 µM. The effect was concluded relative to the inhibition of chymotrypsin-like protease (3CL pro ) [131] . Amentoflavone was also found to decrease Coxsackievirus B3 (CVB3) replication by inhibiting fatty acid synthase (FAS) expression [174] . Moreover, in cases of human immunodeficiency virus (HIV) and respiratory syncytial virus (RSV), amentoflavone showed good performance with IC 50 values of 119 µM [102] and 5.5 µg/mL [120] , respectively. After amentoflavone was isolated from Cnestis ferruginea, Ishola et al. carried out some investigations about its effects on central nervous system. In one pharmacological investigation, oral administration of amentoflavone was proved to attenuate depression induced by metergoline (5-HT2 receptor antagonist), prazosin (α1-adrenoceptor antagonist), or yohimbine (α2-adrenoceptor antagonist), and to ameliorate anxiety stimulated by flumazenil (ionotropic GABA receptor antagonist). These findings suggested that the active biflavonoid showed the antidepressant and anxiolytic effects through interactions with the receptors above [175] . In another study, it was found that the naturally-occurring biflavonoid could prevent scopolamine-induced memory impairment, inhibit AChE and enhance antioxidant enzyme activity in mice, which exhibited its protection against memory deficits [176] . In glutamate injured HT22 hippocampal cells, amentoflavone showed neuroprotective activity. The active compound was able to restore the reduced superoxide dismutase (SOD) activity, glutathione reductase (GR) activity and glutathione content induced by glutamate. Additionally, it was found to prevent the phosphorylation of ERK1/2 [177] . Amentoflavone also exerted neuroprotective activity in pilocarpine-induced epileptic mice. After preventive administration of the biflavonoid for three consecutive days, the model mice showed some signs of improvement, including reduction of epileptic seizures, shortened attack time, reduction in hippocampal neuron loss and apoptosis, and suppressed nuclear factor-kappa B (NF-κB) activation and expression [8] . Amentoflavone was tested to have a vasorelaxant effect on thoracic aortic blood vessels of rats in vitro, which was concluded as being endothelium-dependent and involved with NO [178] . Amentoflavone also had a protective effect on vascular endothelial cells. The viability of human umbilical vein endothelial cells (HUVECs) was promoted and the ratio of cells at S phase was increased by treatment with this biflavonoid [179] . Some results of cell studes indicated that amentoflavone could increase the NO content, decrease the levels of VCAM-1, E-selectin, IL-6, IL-8, and ET-1, enhance SOD activity, reduce MDA content, downregulate the protein expressions of VCAM-1, E-selectin, and NF-κB p65, up-regulate IκBα, and attenuate the NF-κB p65 transfer to the cell nucleus, which proved its protection on vascular endothelial cells [9] . Cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) inhibitor has been found to inhibit the activity of cAMP-PDE-3 in myocardial cells and vascular smooth muscle cells, which could enhance myocardial contraction, expand peripheral vessels, and improve hemodynamics of heart failure patients. Amentoflavone showed a potent inhibitory function on cAMP-PDE [180] . The effect study of amentoflavone on isolated rat heart exhibited that the phytochemical significantly increased the beat rate at dosage of 10-50 µg/mL [181] . Amentoflavone was investigated to have antifungal activity against several pathogenic fungal strains, including Candida albicans, Saccharomyces cerevisiae, and Trichosporon beigelii. In Candida albicans, it could stimulate the intracellular trehalose accumulation and disrupt the dimorphic transition, which meant a stress response to the component [182] . Further research on its antifungal mechanism of Candida albicans suggested that this active phytochemical arrested cell cycles during the S-phase and inhibited cell proliferation and division [183] . The anti-candida activity was proved to be related to apoptotic cell death, which may be associated with the mitochondrial dysfunction. Additionally, hydroxyl radicals induced by amentoflavone may play a significant role in apoptosis [7] . In addition to the pharmacological functions above, significant evidence showed its other bioactivities (Table 4) , such as anti-hyperlipidemia [184] , anti-hypertrophic scar [185] , anti-psoriasis [186] , anti-ulcerative colitis [187] , hepatoprotection [184] , osteogenesis effect [188] and radioprotection [189] . In recent years, pharmacokinetic studies of extracts and bioactive compounds from traditional Chinese medicine and natural medicine have become research highlights. As a representative biflavonoid with several pharmacological functions, amentoflavone was not an exception. In a pharmacokinetic investigation, amentoflavone was administrated to rats with different types including oral gavage (po, 300 mg/kg), intravenous (iv, 10 mg/kg) and intraperitoneal (ip, 10 mg/kg) injection. As a result, 90.7% of the total amentoflavone was discovered to circulate as conjugated metabolites after po administration. In the plasma of rats with iv and ip injection, 73.2% ± 6.29% and 70.2% ± 5.18% of the total amentoflavone was present as conjugated metabolites. In addition, the bioavailability of this compound with po administration was 0.04% ± 0.01%, much lower than that with ip injection (77.4% ± 28.0%) [190] . Pharmacokinetic characteristic of amentoflavone individually or together with other components in normal rats and hyperlipidemic model rats have been studied and compared [191] . In the case of oral administration of only this biflavonoid, T 1/2 and T max of amentoflavone were determined as 2.06 h ± 0.13 h, 1.13 h ± 0.44 h in normal rats and 1.91 h ± 0.32 h, 0.96 h ± 0.10 h in model rats, respectively. Shixiao San is a famous TCM formula containing amentoflavone [192] . After oral administration of a Shixiao San decotion, T 1/2 and T max of amentoflavone were determined as 3.34 h ± 0.37 h, 4.00 h ± 0.00 h in normal rats, and 4.19 h ± 0.64 h, 4.17 h ± 0.40 h in model rats. From the contents above, we could conclude that amentoflavone is a bioactive biflavonoid with a variety of pharmacological effects, which has been derived from many natural plants. Emerging pharmacological evidence has proved the effects of amentoflavone on various aspects, including anti-inflammation, anti-oxidation, anti-diabetes, anti-senescence, anti-virus, anti-tumor activities, and effects on the central nervous system and cardiovascular system. However, the majority of these bioactivity data came from studies involved with cells in vitro, while the number of studies with model animals in vivo was very low. As we know, bioactivity in vitro is unable to represent and explain biological effect in vivo, while pharmacological investigations in model animals are indispensable prior to clinical use. Thus, some bioactivities in vitro should be confirmed and proved by integral animal experiments in the future. In terms of present pharmacokinetic study, the findings have suggested that amentoflavone metabolism procedure was very rapid and there was also a very low bioavailability after oral administration of this biflavonoid in rats. This may be one reason why fewer animal model experiments have been performed. We speculate that improving the bioavailability with introduction of structural modification, precursor synthesis, or particular pharmaceutical necessities may be one focus of amentoflavone studies. Meanwhile, since there are some differences of pharmacokinetics between normal and model animals, concerning the specific pharmacological effects, the pharmacokinetic investigations on corresponding model animals should also be carried out. Amentoflavone has been found, isolated, and identified in over 120 natural plants, which exhibited its rich plant source. The content of any phytochemical varies very much in different species or in different regions. Among 11 plants from Selaginella species, the biflavonoid was found with the high contents between 1.0% and 1.1% in Selaginella sinensis, Selaginella davidii, and Selaginella mollendorfii from some specific production areas, while the contents were no more than 1.0% in the rest, and even below 0.1% in some [193, 194] . It is well-known that extraction yield will be lower than the determined content. In addition, most of the sources are perennial plants and their recovery or reproduction will last not a short time. Thus, at present, plant-derived preparation seems to cost too much. This may be another reason of fewer animal model experiments, which would need much higher amounts of the biflavonoid than cell experiments. We must find some solutions to get the sufficient quantity for studies in the future, such as looking for other plants with much higher contents, biological synthesis, and even chemical synthesis. Taken together, since amentoflavone is a promising and naturally-occurring biflavonoid with so many bioactivities, its systematic druggability research as a candidate drug is obviously necessary, including its preparation study (extraction and isolation from plants, chemical synthesis, or biological synthesis), structural modification study, Absorption-Distribution-Metabolism-Excretion (ADME) study in normal animals and animal models, acute and chronic toxicological studies. Thus, we can make full use of amentoflavone as a drug and employ it in the prevention and treatment of diseases. In summary, this paper has provided a full-scale profile of amentoflavone on its plant sources, natural derivatives, pharmacology, and pharmacokinetics, and also proposed some issues and perspectives which may be of concern in the future. We believe this literature review will help us more comprehensively understand, and take advantage more fully, the naturally-occurring biflavonoid amentoflavone. 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Selaginella bryopteris Cytotoxic biflavonoids from Selaginella delicatula Biflavonoids of Selaginella denticulata growing in Spain Phenolic Constituents of Selaginella doederleinii Study on the chemical constituents of Selaginella involvens Spring and antibacterial activity Bioactive compounds of inhibiting xanthine oxidase from Selaginella labordei Selective cytotoxicity of ginkgetin from Selaginella moellendorffii Evaluation of the diuretic activity in two Mexican medicinal species: Selaginella nothohybrida and Selaginella lepidophylla and its effects with ciclooxigenases inhibitors Study on the chemical constituents of Selaginella pulvinata Maxim Biflavonoid constituents from Selaginella remotifolia Spring New biflavonoid from Selaginella rupestris Isolation of amentoflavone from Selaginella rupestris and its pharmacological activity on central nervous system, smooth muscles and isolated frog heart preparations Amentoflavone from Selaginella sanquinolenta The biflavonoid pattern of Selaginella selaginoides Antiviral amentoflavone from Selaginella sinensis Studies on chemical constituents of Selaginella stauntoniana (I) Vasorelaxation by amentoflavone isolated from Selaginella tamariscina New 3 ,8"-linked biflavonoids from Selaginella uncinata displaying protective effect against Anoxia Cytotoxic biflavonoids from Selaginella willdenowii Flavonoids from Speranskia Tuberculata Flavones from Struthiola argentea with anthelmintic activity in vitro Antifungal activity of biflavones from Taxus baccata and Ginkgo biloba Isoquercitrin is the most effective antioxidant in the plant Thuja orientalis and able to counteract oxidative-induced damage to a transformed cell line Free radical scavenging and antielastase activities of flavonoids from the fruits of Thuja orientalis Presence of amentoflavone in Tmesipteris tannensis Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition Chemical constituents from Amentotaxus yunnanensis and Torreya yunnanensis Iridoid glucosides from Viburnum chinshanense Biflavones and furanone glucosides from Zabelia tyaihyonii Optimization of process parameters of extraction of amentoflavone, quercetin and ginkgetin from Taxus chinensis using supercritical CO 2 plus co-solvent Evaluation of alcohol-based deep eutectic solvent in extraction and determination of flavonoids with response surface methodology optimization Flavonoids from Selaginella uncinata Preparative isolation of six anti-tumour biflavonoids from Selaginella doederleinii Hieron by high-speed counter-current chromatography Rapid screening and detection of XOD inhibitors from S. tamariscina by ultrafiltration LC-PDA-ESI-MS combined with HPCCC In vitro peroxynitrite scavenging activity of 6-hydroxykynurenic acid and other flavonoids from Gingko biloba yellow leaves Antiplasmodial and leishmanicidal activity of biflavonoids from Indian Selaginella bryopteris Chemical Constituents of Selaginella mollendorfii Bioactive compounds from Celaenodendron mexicanum Study on chemical constituents of Podocarpus brevifolius Seco-terpenoids and other constituents from Elateriospermum tapos The chemical constituents in Dacrydium pierrei Selaginellin A and B, two novel natural pigments isolated from Selaginella tamariscina Chemical constituents from Selaginella doederleinii and their bioactivities Structrue identification of biflavones and determination of taxol from Taxus madia Antimicrobial activity, toxicity and selectivity index of two biflavonoids and a flavone isolated from Podocarpus henkelii (Podocarpaceae) leaves The chemical constituents from Podocarpus nagi (II) A rare biflavone from Taxus baccata Biflavonoids from the Wollemi Pine, Wollemia nobilis (Araucariaceae) Biflavonoids isolated from Selaginella tamariscina regulate the expression of matrix metalloproteinase in human skin fibroblasts Inhibition of inducible nitric oxide synthase by sumaflavone isolated from Selaginella tamariscina The structures of amentoflavone glycosides isolated from Psilotum nudum A novel cytotoxic C-methylated biflavone from the stem of Cephalotaxus wilsoniana Two new dihydroamentoflavone glycosides from Cycas revoluta Study on Biflavonoids from Selaginella uncinata (Desv.) Spring. Chin Biflavonoids from Cycas beddomei Chemical constituents from Dysoxylum cauliflorum (Meliaceae) Soluble Epoxide Hydrolase Inhibitory Constituents from Selaginella tamariscina Evaluation of amentoflavone isolated from Cnestis ferruginea Vahl ex DC (Connaraceae) on production of inflammatory mediators in LPS stimulated rat astrocytoma cell line (C6) and THP-1 cells Extracellular signal-regulated kinase is a direct target of the anti-inflammatory compound amentoflavone derived from Torreya nucifera Amentoflavone protects against hydroxyl radical-induced DNA damage via antioxidant mechanism Amentoflavone induces cell-cycle arrest and apoptosis in MCF-7 human breast cancer cells via mitochondria-dependent pathway Effect of Amentoflavone, a phenolic component from Biophytum sensitivum, on cell cycling and apoptosis of B16F-10 melanoma cells Fatty acid synthase inhibition by amentoflavone suppresses HER2/neu (erbB2) oncogene in SKBR3 human breast cancer cells Fatty acid synthase inhibition by amentoflavone induces apoptosis and antiproliferation in human breastcancer cells Amentoflavone inhibits UVB-induced matrix metalloproteinase-1 expression through the modulation of AP-1 components in normal human fibroblasts Anti-diabetic activity of amentoflavone in Selaginella tamariscina in diabetic mice Protein tyrosine phosphatase 1B inhibitory activity of amentoflavone and its cellular effect on tyrosine phosphorylation of insulin receptors Inhibition of fatty acid synthase by amentoflavone reduces coxsackievirus B3 replication Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice Protective effect of Cnestis ferruginea and its active constituent on scopolamine-induced memoryimpairment in mice: A behavioral and biochemical study Neuroprotective biflavonoids of Chamaecyparis obtusa leaves against glutamate-induced oxidative stress in HT22 hippocampal cells Experiment study on vasodilative effects of amentoflavone ethyl acetate extract of Selaginella tamariscina Effects of total flavonoids and amentoflavone isolated from Selaginella tamariscina on human umbilical vein endothelial cells proliferation and VEGF expression Inhibition of cAMP-phosphodiesterase by biflavones of Ginkgo biloba in rat adipose tissue Safety of dietary supplements: Chronotropic and inotropic effects on isolated rat atria Antifungal effect of amentoflavone derived from Selaginella tamariscina S-phase accumulation of Candida albicans by anticandidal effect of amentoflavone isolated from Selaginella tamariscina Lowering blood lipid and hepatoprotective activity of amentoflavone from Selaginella tamariscina in vivo Amentoflavone inhibits angiogenesis of endothelial cells and stimulates apoptosis in hypertrophic scar fibroblasts Amentoflavone protects against psoriasis-like skin lesion through suppression of NF-κB-mediated inflammation and keratinocyte proliferation Amentoflavone inhibits iNOS, COX-2 expression and modulates cytokine profile, NF-κB signal transduction pathways in rats with ulcerative colitis Amentoflavone enhances osteogenesis of human mesenchymal stem cells through JNK and p38 MAPK pathways Amentoflavone acts as a radioprotector for irradiated v79 cells by regulating reactive oxygen species(ROS), cell cycle and mitochondrial mass. Asian Pac Liquid chromatography-tandem mass spectrometry determination and pharmacokinetic analysis of amentoflavone and its conjugated metabolites in rats Simultaneous determination of five free and total flavonoids in rat plasma by ultra HPLC-MS/MS and its application to a comparative pharmacokinetic study in normal and hyperlipidemic rats HPLC fingerprint of Shixiao San Determination f 3 biflavonoids in Selaginellae plants by micellar electrokinetic capillary electrophoresis Determination of biflavones from Selaginella by HPLC. Chin All the authors declare no conflict of interest.