lignans and nortrachelogenin

Triple negative breast cancer (TNBC) is the most severe type of breast cancer due to the lack of specific targets and rapid metastasis, which result in the poor prognosis. Recently, phosphatidylinositol 3-kinase (PI3K)/Akt pathway has emerged as a potential target for the treatment of TNBC. In our research interest to discover phytochemicals targeting TNBC, we have investigated wikstromol from Wikstroemia indica using the human TNBC MDA-MB-231 cells. The results showed wikstromol at 10 μM inhibited cell growth of MDA-MB-231 cells which was confirmed by MTT assay. Further DAPI staining has revealed wikstromol at 10 μM induced apoptosis of cancer cells, which was associated with the activation of caspase-3 following down-regulation of Bcl-2 as well as up-regulation of Bax, cleaved PARP and phosphorylated p53. Meanwhile, it was observed at 0.1 μM wikstromol suppressed the migration of the cancer cells via decreasing transcription of NF-κB and reducing activity and secretion of downstream MMP-9. In addition, p-PI3K and p-Akt were down-regulated in MDA-MB-231 cells in the presence of wikstromol at 0.1 μM, which indicated inactivation of PI3K/Akt pathway was involved in these inhibitory effects.

Topics: Apoptosis; Cell Movement; Cell Proliferation; Female; Furans; Humans; Lignans; Male; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Wikstroemia

Excessive alternative macrophage activation contributes to fibrosis. We studied the effects of nortrachelogenin, the major lignan component of Pinus sylvestris knot extract, on alternative (M2) macrophage activation. J774 murine and THP-1 human macrophages were cultured with IL-4+IL-13 to induce alternative activation, together with the extract and its components. Effects of nortrachelogenin were also studied in bleomycin-induced murine dermal fibrosis model. Knot extract significantly decreased the expression of alternative activation markers-arginase 1 in murine macrophages (97.4 ± 1.3% inhibition at 30 μg/mL) and CCL13 and PDGF in human macrophages-as did nortrachelogenin (94.9 ± 2.4% inhibition of arginase 1 at 10 μM). Nortrachelogenin also decreased PPARγ expression but had no effect on STAT6 phosphorylation. In vivo, nortrachelogenin reduced bleomycin-induced increase in skin thickness as well as the expression of collagens COL1A1, COL1A2, and COL3A1 (all by >50%). In conclusion, nortrachelogenin suppressed IL-4+IL-13-induced alternative macrophage activation and ameliorated bleomycin-induced fibrosis, indicating therapeutic potential in fibrosing conditions.

Topics: Animals; Bleomycin; Collagen; Fibrosis; Furans; Humans; Interleukin-13; Interleukin-4; Lignans; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Pinus sylvestris; Plant Extracts; Skin Diseases

Nortrachelogenin is a pharmacologically active lignan found in knot extracts of

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cells, Cultured; Disease Models, Animal; Edema; Furans; Lignans; Macrophages; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type II; Pinus sylvestris; Proteasome Inhibitors

(-)-Nortrachelogenin is a lignan belonging to group of polyphenolic compounds. Its biological properties in mammalian cells are well-studied; however, its biological effects in microorganisms remain poorly understood. Its efficacy against pathogenic bacteria, including antibiotic-resistant strains, was investigated and it was found that bacteria are highly susceptible to the antibacterial effects of this compound. To investigate the antibacterial mode of action(s) against Escherichia coli O157, its effect on the penetration of SYTOX green into bacterial cells was assayed. The penetration of SYTOX Green into a bacterial cell is a measure of permeability of the plasma membrane. An increase in fluorescence intensity using bis-(1,3-dibutylbarbituric acid) trimethine oxonol [DiBAC4(3)] and 3,3'-dipropylthiacarbocyanine iodide [DiSC3(5)] was also observed, indicating membrane depolarization. Potassium ion efflux from the cytosol into the extracellular matrix showed that cellular damage due to (-)-nortrachelogenin treatment resulted in the loss of intracellular components. While cells were damaged by (-)-nortrachelogenin, large unilamellar vesicles containing fluorescein isothiocyanate-dextran were perturbed to migrate molecules between 3.3 and 4.8 nm. The release of calcein from giant unilamellar vesicles, occurring as a result of disruption in artificial membranes, was visualized. Taken together, our results indicate that (-)-nortrachelogenin exerts its antibacterial effect by disorganizing and perturbing the cytoplasmic membrane, demonstrating the potential of this compound as a candidate for antibiotic drug development.

Topics: Anti-Bacterial Agents; Cell Membrane; Escherichia coli O157; Fluorescent Dyes; Furans; Lignans; Permeability

This study analyzes the antifungal properties of (-)-nortrachelogenin and elucidates its mode of action against pathogenic fungi. We performed susceptibility tests against several pathogenic fungi and verified the absence of hemolysis against human erythrocytes. Its antifungal activity increased reactive oxygen species (ROS) in response to intracellular stress and increased concentrations of both intracellular and extracellular trehalose without causing hemolysis. In addition, a cell wall regeneration study indicated its action on the cytoplasmic membrane. A cell surface study using 3,3(')-dipropylthiacarbocyanine iodide [DiSC3(5)] and 1,6-diphenyl-1,3,5-hexatriene (DPH) demonstrated dissipation of the cytoplasmic membrane at high concentrations. Our study revealed a disturbance in the membrane at higher concentrations and externalization of phosphatidylserine in a dose-dependent manner, affecting other intracellular responses. Furthermore, we investigated the late stage of apoptosis using TUNEL and 4('),6-diamidino-2-phenylindole (DAPI) assays. (-)-Nortrachelogenin-treated cells underwent apoptosis which was triggered by mitochondrial dysfunction via depolarization of the mitochondrial membrane, release of cytochrome c and calcium ion signaling, resulting in the activation of metacaspases. Different concentrations of (-)-nortrachelogenin induced membrane disruption and caspase-dependent apoptosis.

Topics: Antifungal Agents; Apoptosis; Candida albicans; Caprifoliaceae; Cell Membrane; Erythrocytes; Furans; Hemolysis; Humans; Lignans; Microbial Sensitivity Tests; Microbial Viability

Chemical investigation from roots of Enkleia siamensis (Kurz) Nervling resulted in the isolation of 10 compounds. Their structures were established on the basis of 1D and 2D NMR spectroscopic data as linobiflavonoid (1), chamaejasmin (2), 7-O-β-D-glucopyranosylchamaejasmin (3), ormocarpin (4), (-)-wikstromol (5), matairesinol (6), (+)-lariciresinol (7), umbelliferone (8), daphnoretin (9) and carthamidin (10). Compounds 2 and 8 showed cytotoxicity against KB, MCF-7 and NCI-H187 cancer cell lines. Compounds 1, 2 and 5 showed weak minimum inhibitory requirements to acetylcholinesterase with values ranging from 50 to 1000 ng. In addition, compound 2 exhibited antimalarial activity against Plasmodium falciparum with an IC50 value of 2.32 μg/mL.

Topics: Antimalarials; Antineoplastic Agents, Phytogenic; Biflavonoids; Cholinesterase Inhibitors; Coumarins; Drug Screening Assays, Antitumor; Flavonoids; Furans; Humans; KB Cells; Lignans; Nuclear Magnetic Resonance, Biomolecular; Plant Roots; Plasmodium falciparum; Thailand; Thymelaeaceae

Prostate cancer is the most common cancer of men in the Western world, and novel approaches for prostate cancer risk reduction are needed. Plant-derived phenolic compounds attenuate prostate cancer growth in preclinical models by several mechanisms, which is in line with epidemiological findings suggesting that consumption of plant-based diets is associated with low risk of prostate cancer. The objective of this study was to assess the effects of a novel lignan-stilbenoid mixture in PC-3M-luc2 human prostate cancer cells in vitro and in orthotopic xenografts. Lignan and stilbenoid -rich extract was obtained from Scots pine (Pinus sylvestris) knots. Pine knot extract as well as stilbenoids (methyl pinosylvin and pinosylvin), and lignans (matairesinol and nortrachelogenin) present in pine knot extract showed antiproliferative and proapoptotic efficacy at ≥ 40 μM concentration in vitro. Furthermore, pine knot extract derived stilbenoids enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis already at ≥ 10 μM concentrations. In orthotopic PC-3M-luc2 xenograft bearing immunocompromized mice, three-week peroral exposure to pine knot extract (52 mg of lignans and stilbenoids per kg of body weight) was well tolerated and showed anti-tumorigenic efficacy, demonstrated by multivariate analysis combining essential markers of tumor growth (i.e. tumor volume, vascularization, and cell proliferation). Methyl pinosylvin, pinosylvin, matairesinol, nortrachelogenin, as well as resveratrol, a metabolite of pinosylvin, were detected in serum at total concentration of 7-73 μM, confirming the bioavailability of pine knot extract derived lignans and stilbenoids. In summary, our data indicates that pine knot extract is a novel and cost-effective source of resveratrol, methyl pinosylvin and other bioactive lignans and stilbenoids. Pine knot extract shows anticarcinogenic efficacy in preclinical prostate cancer model, and our in vitro data suggests that compounds derived from the extract may have potential as novel chemosensitizers to TRAIL. These findings promote further research on health-related applications of wood biochemicals.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Furans; Heterografts; Humans; Lignans; Male; Mice; Pinus sylvestris; Plant Extracts; Prostatic Neoplasms; Stilbenes; TNF-Related Apoptosis-Inducing Ligand

Prostate cancer cells frequently develop resistance toward androgen-deprivation and chemotherapy. To identify new approaches to treat androgen-dependent prostate cancer, we have performed a structure-activity analysis of lignan polyphenols for cancer cell specific sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand that has ability to induce tumor-specific cell death. In this study, we report that the lignan nortrachelogenin (NTG) is the most efficient of the 27 tested lignan compounds in sensitizing prostate cancer cells to TRAIL-induced apoptosis. Importantly, pretreatment with NTG does not sensitize a non-malignant prostate cell line to TRAIL-induced cell death. The structural comparison of lignans reveals that the dibenzylbutyrolactone skeleton is required for the apoptosis-sensitizing activity, while substitutions at the aromatic rings do not seem to play a critical role in this lignan function. Our study also characterizes the cellular effects and molecular mechanisms involved in NTG anticancer activity. We previously reported that specific lignans inhibit the Akt survival-signaling pathway in concert with TRAIL sensitization. While NTG is also shown to be a effective inhibitor of Akt signaling, in this study we further demonstrate that NTG potently inhibits tyrosine kinase (RTK) activation in response to growth factors, such as insulin and insulin-like growth factor I (IGF-I). Our results identify NTG as a novel agent for prostate cancer therapy with ability to inhibit Akt membrane localization and activity as well as the activation of growth factor receptors (GFRs), thereby efficiently synergizing with TRAIL exposure.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Furans; Humans; Insulin-Like Growth Factor I; Lignans; Male; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand

In this greenhouse experiment, 3-year-old Scots pine (Pinus sylvestris L.) seedlings were wounded by drilling holes through the stem. In the xylem next to the wound, the concentration of resin acids (RAC) increased, and the production of extractives typical for heartwood (stilbenes) and knotwood (stilbenes and lignans) of mature trees was induced. The induced stilbenes were pinosylvin (PS) and pinosylvin monomethyl ether (PSM), and the lignans nortrachelogenin (NTG) and matairesinol (MR). There was positive phenotypic correlation between concentrations of the different extractives. Except for the RAC, the extractive concentrations showed no correlation with the size of the seedlings. The treated seedlings belonged to half-sib families, which enabled the estimation of the genetic parameters for the response variables. The proportion of heritable variation (heritability, h(2)) in the concentration of PS, NTG and MR varied between 0.71 and 1.03, whereas for PSM and RAC the heritability was lower (0.35 and 0.31). Genetic correlation was significant between PS and PSM (r = 0.55, P = 0.018), and between NTG and MR (r = 0.50, P = 0.033). Heritabilities were also estimated on the basis of the regression of the offspring on their mothers h(2)(0P). These estimates were assessed for the concentration of PS, PSM and RAC in the wound response area of the seedlings and correspondingly in the heartwood of their mothers. The heritability was highest for the concentration of PS h(2)(0P). The findings of this study support the suggestion that the wounding of Scots pine seedlings may facilitate the development of an early testing method for breeding heartwood durability.

Topics: Furans; Genetic Variation; Genotype; Lignans; Phenotype; Pinus sylvestris; Plant Diseases; Quantitative Trait, Heritable; Resins, Plant; Seedlings; Stilbenes; Trees; Wood; Xylem

Bioassay-guided fractionation of the EtOH extracts obtained from a plant identified as Didymochlaena truncatula led to the isolation of two cytotoxic alkaloids, camptothecin and 9-methoxycamptothecin. A second plant collection yielded three lignan derivatives, didymochlaenone A (1), didymochlaenone B (2), and (-)-wikstromol, one stilbene, (E)-3-methoxy-5-hydroxystilbene, and two stigmasterol derivatives, stigmast-4-en-3beta-ol and stigmast-4-en-3-one, but no camptothecins, and it is probable that a coding error led to a mistaken identification of the original extract. The structures of the new compounds 1 and 2 were established on the basis of extensive interpretation of one- and two-dimensional NMR spectroscopic data.

Topics: Antineoplastic Agents, Phytogenic; Drug Screening Assays, Antitumor; Dryopteridaceae; Female; Furans; Humans; Lignans; Madagascar; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Roots; Plants, Medicinal; Tumor Cells, Cultured

Low risk of breast cancer (BC) has been proposed to be associated with high intake of lignans. Some plant lignans are converted to mammalian lignans, e.g., enterolactone (ENL), suggested to be the biologically active lignan forms. Until now, little attention has been paid to the possible biological activities of plant lignans, even though some plant lignans are absorbed and present in serum and urine. In this study, we have investigated the antitumorigenic and endocrine-modulatory activities of different plant lignans in order to clarify the structure-activity relationships. 7-Hydroxymatairesinol (HMR) is [corrected] converted to ENL, and both HMR and ENL inhibit the growth of 7,12-dimethylbenz[a]-anthracene (DMBA)-induced mammary cancer. Nortrachelogenin (NTG) resembles HMR, but has a hydroxyl group at C-8 instead of C-7 and is not converted to ENL. In DMBA-model, NTG showed no inhibition of tumor growth, but increased the uterine weight. Furthermore, life-long exposure to NTG increased uterine weight in immature females and ventral prostate weight in adult males. In contrast, life-long exposure to HMR had no effects on uterine or prostate weights at any age. Our results indicate that a difference in the position of one hydroxyl group results in distinct biological responses in vivo, as well as different lignan metabolite profiles.

Topics: 4-Butyrolactone; 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Female; Furans; Lignans; Male; Mammary Neoplasms, Experimental; Molecular Structure; Organ Size; Phytotherapy; Plants; Prostate; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Uterus

To study the chemical constituents from the water-extracts of pine needles of Pinus massoniana Lamb.. Chromatographic techniques were used to separate and purify compounds. Their physico-chemical properties and spectral data (UV, IR, MS, 1H-1H, 13C-1H NMR, DEPT, HMBC etc.) were used to elucidate the structures.. Three lignans were isolated from the n-BuOH fraction of water-extracts. Their structures were identified as (7S,8R)-3',4,9'-tridihydroxy-4-methoxy- 9-O-shikimoyl-7,8-dihydrobenzofuran-1'-propylneolignan (massonianoid A, I), (7S,8R)-4,9-dihydroxy-3,3'-dimethoxy-7,8- dihydrobenzofuran-1'-propylneolignan (II) and 4,4',8-trihydroxy-4,4'-dimethoxy-9-lignanolide (III).. Compound I is a new compound. While II and III were isolated from this plant for the first time.

Topics: Furans; Lignans; Molecular Structure; Pinus; Plant Leaves; Plants, Medicinal

The total synthesis of (-)-wikstromol, a bioactive alpha-hydroxylated lactone lignan, from natural malic acid using a consecutive alkylation strategy is presented. First, alkylation of a malic acid ester provided the monobenzyl derivative, which was then converted to an alpha-substituted dioxolanone. This derivative was reacted in a second alkylation step to a double benzylated dioxolanone, which was transformed to bis-O-benzyl-protected (-)-wikstromol and subsequently to the natural product. Only six steps were required to produce wikstromol in 30% overall yield. A second approach from malic acid, the double alkylation of dienolates from 5-oxo-1,3-dioxolan-4-yl acetic acid derivatives, was not successful. No reaction conditions were found to afford the dienolates. Instead, rapid fragmentation of the dioxolanones to fumaric acid derivatives and pivalaldehyde occurred even at -105 degrees C, and aldol reaction products with good stereoselectivity were formed. The relative configuration of the major isomer was determined by X-ray structure analysis. By comparison of NMR data it is shown that a previous assignment of the configuration of one of the described aldol products was incorrect.

Topics: Alkylation; Antineoplastic Agents, Phytogenic; Crystallography, X-Ray; Furans; Lignans; Magnetic Resonance Spectroscopy; Malates; Molecular Structure; Stereoisomerism

Aerial parts of Daphne oleoides Schreber ssp. oleoides (Thymelaeaceae) are used to treat rheumatoid arthritis and lumbago in Turkish folk medicine. In order to evaluate folkloric utilization, in vitro inhibitory effects of the ethyl acetate extract and fractions obtained from this extract on interleukin 1 (IL-1alpha, IL-1beta) and tumour necrosis factor (TNF-alpha) biosynthesis were studied. Through chemical isolation techniques and activity-guided fractionation process, seventeen compounds were isolated and their structures were elucidated (numbered 1-17). Diterpenoids genkwadaphnin (3) and 1,2-dehydrodaphnetoxin (6) and a coumarin derivative daphnetin (9) showed potent inhibitory activity and were found to be the main active ingredients. Furthermore, gnidilatin (4), gnidilatin-20 palmitate (5), genkwadaphnin-20-palmitate (7) and gnidicin-20-palmitate (8), having diterpenoid structure, and eudesmine (12), wikstromol (13) and matairesinol (14), having lignan structure, were determined to possess moderate inhibitory activity and may have a contributory role in the effect of the remedy.

Topics: Acetates; Antineoplastic Agents, Phytogenic; Cytokines; Diterpenes; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Free Radical Scavengers; Furans; Humans; Interleukin-1; Lignans; Models, Chemical; Plant Extracts; Plants, Medicinal; Tumor Necrosis Factor-alpha; Umbelliferones

An activity-directed fractionation and purification process was used to identify the antioxidant components of Cedrus deodara. Dried heartwood powder of C. deodara was first defatted with petroleum ether and then extracted with chloroform. The chloroform extract showed strong antioxidant activity on 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical. This fraction was then subjected to separation and purification using silica gel column chromatography. Three compounds with potent antioxidant activity were isolated in significant yields and identified by spectroscopic methods ((1)H NMR, (13)C NMR, IR, and MS). They were identified as (-)-matairesinol, (-)-nortrachelogenin, and a dibenzylbutyrolactollignan (4,4',9-trihydroxy-3,3'-dimethoxy-9,9'-epoxylignan). This is the first report of the occurrence of these compounds in C. deodara.

Topics: Antioxidants; Cedrus; Chemical Fractionation; Chloroform; Chromatography, Gel; Free Radical Scavengers; Furans; Lignans; Magnetic Resonance Spectroscopy

Topics: Animals; Antineoplastic Agents, Phytogenic; Furans; Leukemia P388; Lignans; Mice; Plants

The ethanol extracts of Wikstroemia foetida var. oahuensis and Wikstroemia uva-ursi showed antitumor activity against the P-388 lymphocytic leukemia (3PS) test system One PS-active constituent of both plants was the lignan wikstromol. Several inactive compounds were identified as daphnoretin, pinoresinol, and syringaresinol.

Topics: Animals; Antineoplastic Agents, Phytogenic; Chemical Phenomena; Chemistry; Furans; Leukemia, Experimental; Lignans