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Natural products have been a valuable source of efficient and low-risk pesticides. In this work, a series of novel sesamolin derivatives A0-A31 and B0-B4 were designed and synthesized via structural simplification of furofuran lignan phrymarolin II, and their antiviral and antibacterial activities were systematically evaluated. The bioassay results showed that compound A24 displayed remarkable inactivation activity against tobacco mosaic virus (TMV) with an EC 50 value of 130.4 μg/mL, which was superior to that of commercial ningnanmycin (EC 50 = 202.0 μg/mL). The antiviral mode of action assays suggested that compound A24 may obstruct self-assembly by binding to TMV coat protein (CP), thus resisting the TMV infection. In addition, compound A25 possessed prominent antibacterial activities, especially against Ralstonia solanacearum with an EC 50 value of 43.8 μg/mL, which is better than those of commercial bismerthiazol and thiodiazole copper . This research lays a solid foundation for the utilization of furofuran lignans in crop protection.

Based on the current results, they showed that Schisandra chinensis lignans (SCL) ameliorated depressive-like behaviors in chronic unpredictable mild stress (CUMS) mice, alleviated neuroinflammation, and improved neuronal injury. This study aimed to explore whether SCL exerted antidepressant effects through inhibiting neuroinflammation, in turn improving neuronal injury. In vitro studies revealed that SCL blocked lipopolysaccharide-increased BV2 microglial M1 but promoted the M2 phenotype. The BV2-N2a interaction model suggested that increasing the M2 phenotype of BV2 played neuroprotective effects. The current studies demonstrated that SCL up-regulated the expression of CUMS- and LPS-decreased cannabinoid receptor type-2 (CB2R) mRNA. In vitro studies showed that the transfection of BV2 with siCrn2 blocked the SCL-increased M2 phenotype via the inactivating signal transducer and activator of transcription 6 (STAT6) pathway, further decreasing the viability of N2a cells. Finally, the possible pharmacodynamic compounds, γ-schisandrin and schisantherin A, were indicated by AutoDuck analysis. Overall, our study showed that SCL promoted microglia polarization toward the M2 phenotype, in turn exerting neuroprotective effects by activating CB2R-STAT6 signaling further to play antidepressant roles.

Bronchial asthma poses a considerable burden on both individual patients and public health. Sesamin is a natural lignan that relieves asthma. However, the potential regulatory mechanism has not been fully validated. In this study, we revealed the mechanism of sesamin in inhibiting airway inflammation of asthma. In cockroach extract (CRE)-induced asthmatic mice, sesamin efficiently inhibited inflammatory cell infiltration, expressions of total and CRE-specific IgE in serum, and inflammatory cytokines (including IL-4, 5, 13) in bronchoalveolar lavage fluid. Further study revealed that sesamin inhibited Th2 cells in the mediastinal lymph nodes and spleen, the expression of PTEN-induced putative kinase 1 (PINK1) and Parkin, and apoptosis of lung airway epithelial cells. In vitro , sesamin had no significant cytotoxicity to BEAS-2B cells. Sesamin significantly increased TNF-α/IL-4-induced superoxide dismutase (SOD), catalase (CAT), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2 related factor 2 (Nrf2), and decreased malondialdehyde. Sesamin also inhibited TNF-α/IL-4-induced mitochondrial reactive oxygen species, increased mitochondrial membrane potential, and reduced cell apoptosis as well as PINK1/Parkin expression and translocation to mitochondria. Conclusively, sesamin may relieve asthma airway inflammation by inhibiting mitophagy and mitochondrial apoptosis. Thus, sesamin may become a potential therapeutic agent for asthma.

While lignans and their biogenetic precursors can have various health benefits, the poor liposolubilities of such phenolic systems have restricted their application as antioxidants in the food industry. The research reported here was aimed at addressing these matters through derivatizing certain forms of such compounds and then assessing their properties as potential nutraceuticals. In particular, crude flaxseed lignan was purified to afford secoisolariciresinol diglucoside (SDG, 1 ) that was then subjected to structural modification. By such means, the SDG long-chain fatty acid esters 4 - 9 and 11 - 13 , the fully acetylated SDG 10 , secoisolariciresinol (SECO, 2 ), and anhydrosecoisolariciresinol (ASECO, 14 ) were obtained. The antioxidant activities of these derivatives were determined while their permeability properties were evaluated. Such studies revealed that certain SDG derivatives possessing useful liposolubilities also retained their antioxidative properties, as well as being capable of permeating Caco-2 cell monolayers while being nontoxic to them. SDG fatty acid esters 4 - 9 and 11 - 13 could be developed into emulsifiers with enhanced health benefits, especially considering their improved antioxidative (ca. <11 000 μmol Trolox/g) and permeability properties. This study thus highlights strategies for the structural modification of SDG so as to generate derivatives with superior properties in terms of their utility in the food and pharmaceutical industries.

Sesamin, a representative sesame lignan, has health-promoting activities. Sesamin is converted into catechol derivatives and further into their glucuronides or sulfates in vivo , whereas the biological activities of sesamin metabolites remain unclear. We examined the inhibitory effects of sesamin metabolites on the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse macrophage-like J774.1 cells and found that a monocatechol derivative SC1, (7α,7'α,8α,8'α)-3,4-dihydroxy-3',4'-methylenedioxy-7,9':7',9-diepoxylignane, has a much higher activity than sesamin and other metabolites. The inhibitory effects of SC1 glucuronides were time-dependently enhanced, associated with the intracellular accumulation of SC1 and the methylated form. SC1 glucuronides and SC1 attenuated the expression of inducible NO synthase (iNOS) and upstream interferon-β (IFN-β) in the LPS-stimulated macrophages. The inhibitory effects of SC1 glucuronides against NO production were canceled by the β-glucuronidase inhibitor and enhanced by the catechol- O -methyltransferase inhibitor. Our results suggest that SC1 glucuronides exert the anti-inflammatory effects by inhibiting the IFN-β/iNOS signaling through macrophage-mediated deconjugation.

Arctiin is the most abundant bioactive compound contained in the Arctium lappa plant. In our previous study, we isolated one single bacterium capable of bioconverting arctigenin, an aglycone of arctiin, to 3'-desmethylarctigenin (3'-DMAG) solely. However, to date, a specific bacterium capable of producing other arctiin metabolites has not been reported. In this study, we isolated one single bacterium, which we named Eggerthella sp. AUH-JLD49s, capable of bioconverting 3'-DMAG under anaerobic conditions. The metabolite of 3'-DMAG by strain AUH-JLD49s was identified as 3'-desmethyl-4'-dehydroxyarctigenin (DMDH-AG) based on electrospray ionization mass spectrometry (ESI-MS) and 1 H and 13 C nuclear magnetic resonance spectroscopy. The bioconversion kinetics and bioconversion capacity of strain AUH-JLD49s were investigated. In addition, the metabolite DMDH-AG showed an inhibitory effect on cell growth of human colon cancer cell line HCT116 and human breast cancer cell line MDA-MB-231.

Lignans are a ubiquitous group of natural products of plant or mammalian origin. In the human diet, especially in fiber-rich foods, there are measurable amounts of lignans. Lignan intake is associated with a reduced risk of a range of chronic Western diseases, and in studying these compounds and their biological activity, authentic stable isotope labeled analogues are needed. This review summarizes the reported labeling methods and discusses the selectivity and reactivity in the electrophilic aromatic deuteration of lignans where recently a number of unexpected selectivities or nonselectivities have been encountered.

Cytotoxic activities of synthesized lignan derivatives were estimated by WST-8 reduction assay against HL-60 and HeLa cells to show the structure-activity relationship. The activities of some effective compounds were examined against Colon 26 and Vero cells. Dietary secoisolariciresinol (SECO, 1) and its metabolite, 9,9'-anhydrosecoisolariciresinol (2), did not show the cytotoxic activity. On the other hand, all stereoisomers of dihydroguaiaretic acid (DGA, 9,9'-dehydroxysecoisolariciresinol, 3-5) exhibited the activity (IC50: around 30 μM). The IC50 value of (8R,8'R)-9-butyl DGA derivative 13 was around 6 μM. This fact means that the hydrophobic group was advantageous for higher activity at 9- and 9'-positions. By the evaluation of the effect of 7and 7'-aryl group on the activity, we discovered the highest activity of (8R,8'R)-7-(3-hydroxy-4-methoxyphenyl)-7'-(2-ethoxyphenyl) DGA derivative 47 showing around 1 μM of IC50 value, which is about 24-fold higher activity than that of natural (8R,8'R)-DGA. The derivative of dietary lignan showed the high cytotoxic activity.

Arctium lappa L. (A. lappa) is a popularly used vegetable as well as herbal medicine. Human intestinal microflora was reported to convert arctiin, the lignan compound with highest content in the dried fruits of Arctium lappa, to a series of metabolites. However, the specific bacterium responsible for the formation of 3'-desmethylarctigenin (3'-DMAG), the most predominant metabolite of arctiin by rat or human intestinal microflora, has not been isolated yet. In the present study, we isolated one single bacterium, which we named Blautia sp. AUH-JLD56, capable of solely biotransforming arctiin or arctigenin to (-)-3'-DMAG. The structure of the metabolite 3'-DMAG was elucidated by electrospray ionization mass spectrometry (ESI-MS) and (1)H and (13)C nuclear magnetic resonance spectroscopy. The biotransforming kinetics and maximum biotransforming capacity of strain AUH-JLD56 was investigated. In addition, the metabolite 3'-DMAG showed significantly higher 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity than that of the substrate arctigenin at the concentrations tested.

A metabolic profiling study was carried out on rapeseed ( Brassica napus L.). Eleven glucosinolates were identified by high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD) and mass spectrometry (MS). Additionally, 18 phenolic compounds were profiled from an ethanol extract of rapeseed. Besides two major phenols, sinapine and methyl sinapate, 16 minor phenolic compounds were isolated and identified. Seven of them are new lignans including three (±)-thomasidioic acid derivatives and four (E,E)-dienolignan derivatives. The structures of novel phenolic compounds were elucidated by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and MS. The analytical data of secondary metabolites in rapeseed winter cultivar "Emerald" and information about purification on a microscale are useful for upcoming studies on tissue-specific localization of these compounds.

Starting from previous structure-activity relationship studies of taste modifiers based on homoeriodictyol, dihydrochalcones, deoxybenzoins, and trans-3-hydroxyflavones as obvious analogues were investigated for their masking effect against caffeine. The most active compounds of the newly investigated taste modifiers were phloretin, the related dihydrochalcones 3-methoxy-2',4,4'-trihydroxydihydrochalcone and 2',4-dihydroxy-3-methoxydihydrochalcone, and the deoxybenzoin 2-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)ethanone. Starting with the whole set of compounds showing activity >22%, a (Q)SAR pharmacophore model for maskers of caffeine bitterness was calculated to explain the structural requirements. After docking of the pharmacophore into a structural model of the broadly tuned bitter receptor hTAS2R10 and docking of enterolactone and enterodiol as only very weakly related structures, it was possible to predict qualitatively their modulating activity. Enterodiol (25 mg L(-1)) reduced the bitterness of the 500 mg L(-1) caffeine solution by about 30%, whereas enterolactone showed no masking but a slight bitter-enhancing effect.

Caffeoylquinic acids and lignans in the crude extracts of both roots and seeds from different burdock ( Arctium lappa L.) genotypes were simultaneously characterized and systematically compared by LC-MS and matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight mass spectrometry (MALDI-QIT-TOF MS), and their antioxidant activities were also investigated. A total of 14 lignans were identified in burdock seeds and 12 caffeoylquinic acids in burdock roots. High levels of caffeoylquinic acids were also detected in burdock seeds, but only trace amounts of lignans were found in burdock roots. Burdock seeds contained higher concentrations of lignans and caffeoylquinic acids than burdock roots. Quantitative analysis of caffeoylquinic acids and lignans in roots and seeds of various burdock genotypes was reported for the first time. Great variations in contents of both individual and total phenolic compounds as well as antioxidant activities were found among different genotypes. Burdock as a root vegetable or medicinal plants possessed considerably stronger antioxidant activity than common vegetables and fruits.

Sesame lignans (sesamin, sesamolin) and their metabolites (enterodiol, ED; enterolactone, EL; and sesamol) have been evaluated for their estrogenic activities. ED and EL have been indicated to have estrogenic/antiestrogenic properties on human breast cancer cells; however the estrogenic activities of sesamin, sesamolin and sesamol have not been reported. In the present study, estrogenic potencies of sesame lignans and their metabolites were determined by estrogen responsive element (ERE) luciferase reporter assay in T47D cells stably transfected with ERE-luc (T47D-KBluc cells) and quantifying pS2 and progesterone receptor gene expression in T47D cells. All tested compounds except ED possessed ability of ERE activation with a very low potency compared to estradiol (E2). These effects were abolished by coincubating tested compounds with 1 μM ICI 182 780, suggesting that estrogen receptors were directly involved in their ERE activations. Among tested compounds, sesamol showed the highest ability in ERE induction. The coincubation of increasing concentration of E2 (10(-12)-10(-6) M) with 10 μM of tested compounds resulted in a downward shift of E2-ERE dose-response curves. In contrast, at the low concentration of E2 (10(-12) M), sesamin and sesamol significantly exhibited additive effects on the E2 responses. The inhibitory effect in a dose-dependent manner was also observed when 1-100 μM sesamol was coincubated with 1 nM E2. Sesamin, sesamol and EL significantly induced pS2 gene expression whereas only sesamol could significantly induce progesterone receptor gene. The data obtained in this study suggested that sesame lignans and their metabolites possess weak estrogenic/antiestrogenic activity.

Lignan glycosides are important functional compounds in sesame meal. In the present study, we investigated whether the tissue distribution of nano/submicrosized lignan glycosides from sesame meal (N-LGSM) differs from lignan glycosides from sesame meal (LGSM). LGSM was nano/submicrosized with 0.3 mm zirconia beads as the milling media. The average particle size of the 4% LGSM aqueous suspension reduced rapidly from approximately 2 microm to 200 nm after media milling at an agitation speed of 3600 rpm for 30 min. We examined the tissue distribution of sesaminol triglucoside (ST), the main component in LGSM, in Sprague-Dawley (SD) rats. The concentrations of ST were determined in various tissues and plasma within a 24 h period after oral administration of N-LGSM and LGSM (800 mg/kg of body weight). The results showed that higher concentrations of ST and its metabolites (sesaminol, sesaminol sulfate, and sesaminol glucuronide) were found in N-LGSM compared to those in LGSM in most tissues, especially liver and small intestine. Sesaminol glucuronide was the main metabolite in rats. After 3 h of oral administration, around 70% higher concentration of sesaminol glucuronide was found in N-LGSM compared to that in LGSM. This study clearly showed that LGSM is more bioavailable after nano/submicrosizing.

A human intestinal bacterium Ruminococcus (R.) sp. END-1 capable of oxidizing (-)-enterodiol to (-)-enterolactone, enantioselectively, was further investigated from the perspective of transformation of plant lignans to mammalian lignans; A cell-free extract of the bacterium transformed (-)-enterodiol to (-)-enterolactone through an intermediate, enterolactol. The bacterium showed not only oxidation but also demethylation and deglucosylation activities for plant lignans. Arctiin and secoisolariciresinol diglucoside were converted to (-)-dihydroxyenterolactone and (+)-dihydroxyenterodiol, respectively. Moreover, by coincubation with Eggerthella sp. SDG-2, the bacterium transformed arctiin and secoisolariciresinol diglucoside to (-)-enterolactone and (+)-enterodiol, respectively.

Plant lignans occur widely in foods, with flaxseed recognized as their richest source. Some plant lignans can be converted by intestinal microbiota to the mammalian lignans, enterodiol and enterolactone, which may have protective effects against hormone-related diseases such as breast cancer. This study determined whether plant lignans in sesame seed, particularly sesaminol triglucoside (STG), could be metabolized to mammalian lignans. STG is a furofuran lignan with methylenedioxyphenyls. The transformation of furofuran lignans to mammalian lignans by intestinal microbiota involves the hydrolysis of glucoside, demethylenation of a methylene group, oxidation of dibenzylbutanediol to dibenzylbutyrolactone, and reductive cleavage of furofuran rings. STG has methylenedioxyphenyl moieties in their structures that may require additional oxidative demethylenation of the methylenedioxyphenyl ring for conversion to mammalian lignans. However, STG is metabolized, via intestinal microbiota, to a catechol moiety. The major STG metabolite was characterized as 4-[((3R,4R)-5-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-4-(hydroxymethyl)tetrahydrofuran-3-yl)methyl]benzene-1,2-diol using NMR and mass spectrometry, and STG could be converted to enterolactone and enterodiol by rat intestinal microflora.

Estrogenic plant compounds from the human diet such as the lignan secoisolariciresinol diglucoside (SDG, 1) can exert biological activity in the human body upon ingestion and bioactivation to enterodiol (END, 5) and enterolactone (ENL, 6). Bioavailability of lignans is influenced by the food matrix and gut microbial action, of which the latter is subject to a large interindividual variation. In this study, the fate of the lignan precursor SDG, present in the lignan macromolecule of flax seed ( Linum usitatissimum), was determined during an artificial stomach and small intestinal digestion and during metabolism by two different enterolignan phenotypes in a TWINSHIME environment (TWIN Simulator of the Human Intestinal Microbial Ecosystem). The lignan macromolecule acted as a delivery system of SDG in the large intestine. SDG was only hydrolyzed into secoisolariciresinol (SECO, 2) through microbial action in the ascending colon, after which it was bioactivated into enterolignans from the transverse colon onward. Single demethylation was a first step in the bioactivation, followed by dehydroxylation. Enterolignan phenotypes remained stable throughout the experimental period. The establishment of END and ENL production equilibria reflected the subdominance of ENL-producing bacteria in the gastrointestinal tract.

Sesamin and sesaminol triglucoside in sesame seeds are major lignans that display an abundance of biological activities. Although their antioxidative activity in vitro is weak, they have been reported to suppress oxidative stress in vivo. We investigated the production of new antioxidative lignans from sesame lignans by culturing with the genus Aspergillus to enhance the function of food materials. Media containing sesamin or sesaminol triglucoside increased antioxidative activity for DPPH radical scavenging by culturing with Aspergillus usamii mut. shirousamii RIB2503. The antioxidative lignans in sesamin medium were identified as sesamin 2,6-dicatechol and episesamin 2,6-dicatechol. Those in sesaminol triglucoside medium were identified as sesaminol 6-catechol and episesaminol 6-catechol, which are novel antioxidative lignans. It is suggested that they may exhibit higher antioxidative activity than sesamin and sesaminol triglucoside because they have the catechol functional moiety.

The plant lignans secoisolariciresinol and matairesinol occur in numerous foods such as oil seeds, whole grains, vegetables, and fruits. We have studied the hitherto unknown oxidative metabolism of secoisolariciresinol and matairesinol in hepatic microsomes from untreated and Aroclor 1254-induced Wistar rats and from humans. Five oxidative metabolites of secoisolariciresinol and 10 oxidative metabolites of matairesinol were detected in rat liver microsomes, and their chemical structures were elucidated. The pathways in the metabolism of both secoisolariciresinol and matairesinol included aliphatic and aromatic hydroxylation, whereas oxidative demethylation was only observed for matairesinol. Human hepatic microsomes were able to metabolize secoisolariciresinol whereas matairesinol was only poorly metabolized. This study clearly shows that secoisolariciresinol and matairesinol are substrates of cytochrome P450-mediated metabolism. However, from preliminary experiments with rats dosed orally with secoisolariciresinol and matairesinol, it appears that the intestinal absorption and subsequent oxidative metabolism of these plant lignans occur only to a very small extent due to the highly efficient conversion of secoisolariciresinol and matairesinol to the mammalian lignans enterodiol and enterolactone by the gut microflora.

Sesamin, a major lignan in sesame oil, is known to have many biological activities, especially protective effects against oxidative damage in the liver. As sesamin itself has no antioxidative properties in vitro, to elucidate the mechanism of its antioxidative effects, the reaction products of sesamin in rat liver homogenate were analyzed. The methylenedioxyphenyl moiety in the structure of sesamin was shown to be changed into a dihydrophenyl (catechol) moiety. The enzymatic reaction products in vitro were identified as (1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo[3,3,0]octane and (1R,2S,5R,6S)-2,6-bis(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane, which showed strong radical scavenging activities; the latter was a novel compound. The same metabolites were found as glucuronic acid and/or sulfic acid conjugates in substantial amounts in rat bile after oral administration of sesamin. It is suggested that sesamin is a prodrug and the metabolites containing the catechol moieties in their structures are responsible for the protective effects of sesamin against oxidative damage in the liver.

The metabolism of the plant lignans matairesinol, secoisolariciresinol, pinoresinol, syringaresinol, arctigenin, 7-hydroxymatairesinol, isolariciresinol, and lariciresinol by human fecal microflora was investigated to study their properties as mammalian lignan precursors. The quantitative analyses of lignan precursors and the mammalian lignans enterolactone and enterodiol were performed by HPLC with coulometric electrode array detector. The metabolic products, including mammalian lignans, were characterized as trimethylsilyl derivatives by gas chromatography-mass spectrometry. Matairesinol, secoisolariciresinol, lariciresinol, and pinoresinol were converted to mammalian lignans only. Several metabolites were isolated and tentatively identified as for syringaresinol and arctigenin in addition to the mammalian lignans. Metabolites of 7-hydroxymatairesinol were characterized as enterolactone and 7-hydroxyenterolactone by comparison with authentic reference compounds. A metabolic scheme describing the conversion of the most abundant new mammalian lignan precursors, pinoresinol and lariciresinol, is presented.

Recent studies have shown that the mammalian lignans enterodiol (END) and enterolactone (ENL) are biotransformed in vitro by hepatic microsomes from rats and humans to various metabolites carrying one additional hydroxy group either at the aromatic or at the aliphatic moiety. To clarify whether these metabolites are also formed in vivo, each lignan was administered intraduodenally at a dose of 10 mg/kg of bw to bile duct-catheterized female Wistar rats and the 6 h bile analyzed by HPLC and GC-MS. With END-dosed rats, three products of aromatic and two of aliphatic monohydroxylation were found, whereas six aromatic and five aliphatic monohydroxylated biliary metabolites were detected after administration of ENL. The metabolites hydroxylated at the aromatic rings were unequivocally identified by comparison with synthetic reference compounds. The structures of the in vivo metabolites arising from aliphatic hydroxylation could not be completely elucidated; they were identical with some of the formerly reported microsomal products according to GC retention times and mass spectra. Significant amounts of most of the metabolites of the mammalian lignans identified in bile were also found in the urine of female rats after oral administration of 10 mg/kg of bw END or ENL and in the urine of female and male Wistar rats after they had been fed a diet containing 5% flaxseed. Thus, the mammalian lignans END and ENL give rise to several hydroxylated metabolites in vivo, which may contribute to the biological effects of these important food constituents.

Experiments were designed to determine the relevance of enzyme partitioning, between the cellulose and non-cellulose components of pretreated biomass, with respect to rates of cellulose saccharification in a typical biomass-to-ethanol process. The experimental system included three cellulose preparations (differing in physicochemical properties): a representative lignin-rich noncellulosic residue (prepared from dilute acid-pretreated switchgrass), an acid-extracted lignin preparation, and a complete Trichoderma reesei cellulase preparation. Enzyme-reactor conditions were typical of those commonly used in biomass-to-ethanol studies. The results were found to be dependent on both the lignin and cellulose preparations used. The noncellulosic lignacious residue, when supplemented at up to 40% (w/w) in cellulose-cellulase reaction mixtures, had little effect on rates and extents of cellulose saccharification. Overall, the results suggest that enzyme partitioning between cellulose and the noncellulosic component of a pretreated feedstock is not likely to have a major impact on cellulose saccharification in typical biomass-to-ethanol processes.