Lignan Glycosides Research Articles

The untargeted metabolomic analysis of Ammodaucus leucotrichus Coss. & Dur. seeds reveals previously undescribed polar lignans and terpenoids

The polar metabolome of the medicinal plant Ammodaucus leucotrichus Coss. & Dur. has not been comprehensively characterised. In this study, the chemical composition of a water/methanol (4:1) extract of seeds was determined through a combination of UHPLC-MS and NMR techniques. Sixty compounds were identified from the extract with 36 of these confirmed using UHPLC-MS and/or NMR data while the remaining 24 were given putative identifications based on UHPLC-MS data. The compounds included lignans, terpenes, phenolics, flavonoids, and alkaloid derivatives together with some amino- and organic acids. Of these 2 terpenoids and 3 lignans were found to be novel and were isolated and structures determined by comprehensive NMR studies. A further novel lignan glycoside was tentatively identified. Together these data represent the most comprehensive profile of this traditional medicinal plant, providing an annotated profile that can form the basis of future correlative metabolomic investigations to determine active principles behind its reported bioactivities.

Polyphenolic Antioxidants in Bilberry Stems and Leaves: A Non-Targeted Analysis by Two-Dimensional NMR Spectroscopy and Liquid Chromatography-High-Resolution Mass Spectrometry.

Compared with those of berries, the stems and leaves of the genus Vaccinium are important and underestimated sources of polyphenols with high antioxidant activity. In the course of this work, aqueous methanol extracts of the aerial parts of common bilberry (Vaccinium myrtillus L.) and bog bilberry (Vaccinium uliginosum L.) were studied to analyze the component compositions of their biologically active polyphenolic compounds. The aqueous methanol fractions of the stems and leaves of the studied samples contained 8.7 and 4.6% extractives, respectively, and were comparable in total polyphenol content, but presented significant differences in antioxidant activity. The identification of polyphenolic compounds was carried out via the following two-stage analytical procedure: (1) non-targeted screening of dominant structures via the 2D NMR method and (2) analysis of HPLC-HRMS data via the scanning of precursor ions for a specific ion. A total of 56 phenolic compounds were identified, including the glycosides quercetin, proanthocyanidins, and catechins, as well as various conjugates of caffeic and p-coumaric acids, including iridoids. Some of the latter, such as caffeoyl and p-coumaroyl hydroxydihydromonotropein, as well as a number of lignan glycosides, were described for the first time in V. uliginósum and V. myrtillus.

Isoorientin Promotes Early Porcine Embryonic Development by Alleviating Oxidative Stress and Improving Lipid Metabolism

Isoorientin (ISO) is a natural lignan glycoside flavonoid found in various plants, including Charcot and Stonecrop. ISO exhibits diverse physiological and pharmacological effects, such as antioxidative, anti-inflammatory, hepatoprotective, antiviral, antianxiety, and anti-myocardial ischaemic properties, as well as lipid metabolism regulation. This study investigated the impact of ISO supplementation on oxidative stress and lipid accumulation in porcine early embryos, along with its underlying mechanisms. Porcine embryos were cultured in vitro under different concentrations of ISO (0, 1, 10, and 100 nM). The results revealed that 10 nM ISO significantly enhanced the blastocyst rate and total embryonic cell count in vitro. ISO-treated embryos exhibited reduced reactive oxygen species levels and elevated glutathione levels compared to the untreated group. In addition, ISO treatment significantly increased the expression of the key antioxidant regulator Nrf2, improved mitochondrial function, and reduced lipid droplet accumulation. Concurrently, early embryo autophagy and apoptosis levels decreased. Furthermore, ISO treatment upregulated antioxidant-related genes (SOD1, SOD2, and CAT) and mitochondrial biogenesis related genes (NRF1, NRF2, and SIRT1), while downregulating lipid synthesis-related genes (SREBP1 and FASN). Additionally, lipid hydrolysis-related genes (ACADS) were elevated. These findings collectively suggest that ISO may facilitate early embryonic development in pigs by ameliorating oxidative stress and lipid metabolism.

Untargeted metabolomic profiling of Prinsepia utilis Royle leaves by Ultra-Performance Liquid Chromatography-Quadrupole-Time of Flight-Mass Spectrometry.

Prinsepia utilis Royle, native to the Himalayas, is esteemed in Chinese and Indian folk medicine for its diverse medicinal benefits, targeting arthritis, pain relief, bone disorders, and joint discomfort. This study examined the 25% aqueous methanol extract of P.utilis leaves using UPLC-Q-TOF-MS/MS, identifying 78 metabolites, 76 of which were reported for the first time in P.utilis. These included 64 phenolics represented by 56 flavonoids, 5 phenolic acids, 3 phenolic glycosides, 4 terpenoids, 2 lignan glycosides, and 8 other compounds, expanding the knowledge of its chemical composition. These findings lay a foundation for further research, providing insights into potential bioactive compounds and opening avenues for applications in natural product drug discovery, traditional medicine, and nutraceutical development, leveraging the plant's established traditional uses.

Construction of lignan glycosides biosynthetic network in Escherichia coli using mutltienzyme modules

BackgroundDue to the complexity of the metabolic pathway network of active ingredients, precise targeted synthesis of any active ingredient on a synthetic network is a huge challenge. Based on a complete analysis of the active ingredient pathway in a species, this goal can be achieved by elucidating the functional differences of each enzyme in the pathway and achieving this goal through different combinations. Lignans are a class of phytoestrogens that are present abundantly in plants and play a role in various physiological activities of plants due to their structural diversity. In addition, lignans offer various medicinal benefits to humans. Despite their value, the low concentration of lignans in plants limits their extraction and utilization. Recently, synthetic biology approaches have been explored for lignan production, but achieving the synthesis of most lignans, especially the more valuable lignan glycosides, across the entire synthetic network remains incomplete.ResultsBy evaluating various gene construction methods and sequences, we determined that the pCDF-Duet-Prx02-PsVAO gene construction was the most effective for the production of (+)-pinoresinol, yielding up to 698.9 mg/L after shake-flask fermentation. Based on the stable production of (+)-pinoresinol, we synthesized downstream metabolites in vivo. By comparing different fermentation methods, including “one-cell, one-pot” and “multicellular one-pot”, we determined that the “multicellular one-pot” method was more effective for producing (+)-lariciresinol, (-)-secoisolariciresinol, (-)-matairesinol, and their glycoside products. The “multicellular one-pot” fermentation yielded 434.08 mg/L of (+)-lariciresinol, 96.81 mg/L of (-)-secoisolariciresinol, and 45.14 mg/L of (-)-matairesinol. Subsequently, ultilizing the strict substrate recognition pecificities of UDP-glycosyltransferase (UGT) incorporating the native uridine diphosphate glucose (UDPG) Module for in vivo synthesis of glycoside products resulted in the following yields: (+)-pinoresinol glucoside: 1.71 mg/L, (+)-lariciresinol-4-O-d-glucopyranoside: 1.3 mg/L, (+)-lariciresinol-4’-O-d-glucopyranoside: 836 µg/L, (-)-secoisolariciresinol monoglucoside: 103.77 µg/L, (-)-matairesinol-4-O-d-glucopyranoside: 86.79 µg/L, and (-)-matairesinol-4’-O-d-glucopyranoside: 74.5 µg/L.ConclusionsBy using various construction and fermentation methods, we successfully synthesized 10 products of the lignan pathway in Isatis indigotica Fort in Escherichia coli, with eugenol as substrate. Additionally, we obtained a diverse range of lignan products by combining different modules, setting a foundation for future high-yield lignan production.

Investigation of the inhibitory activity of triterpenoids isolated from Actinidia polygama stems against β-glucuronidase via enzyme kinetics, molecular docking, and molecular dynamics analyses

Actinidia polygama, well-known for its traditional medicinal properties, has garnered significant attention due to its distinctive chemical composition. In this study, we isolated and structurally elucidated 11 known compounds, including a monoterpene glycoside (1), eight triterpenoids (2–9), and two lignan glycosides (10 and 11), from A. polygama stems. Notably, the inhibitory activity of these compounds on β-glucuronidase activity was evaluated for the first time. Our results show that 2α,3α,24-trihydroxyurs-12-en-28-oic acid (4), strongly inhibited β-glucuronidase (IC50 = 14.36 ± 0.42 μM) to a degree much higher than that of the positive control (d-saccharic acid 1,4-lactone, DSA; IC50 = 16.30 ± 0.21 μM). Furthermore, the results of an enzyme kinetics analysis indicate that compound 4 acts as a non-competitive inhibitor of β-glucuronidase. Finally, the findings from molecular docking and molecular dynamics simulations confirmed the inhibition mode of compound 4, its interaction with the allosteric site of β-glucuronidase, and the stability of the complex in the bound state.

Chemical profiling and biological activities of the roots of Allochrusa gypsophiloides

Allochrusa gypsophiloides is one of the best-known endemic saponin bearing food plants of Central Asia. However, the plant’s secondary metabolites remain unmapped. The current study aimed to chemical profile of the metabolite in the plant roots by an untargeted UHPLC-ESI-MS, together with the isolation of the major compounds followed by a 2D NMR and HR-MS for identification and evaluation of the antioxidant and enzyme inhibitory activity of the extracts. The results revealed the presence of 48 putatively annotated metabolites comprising triterpene glycosides, phenolic compounds and their derivatives, organic acid glycosides, and lignan glycosides. The chromatographic separation and purification of the extract resulted in the isolation of four compounds where two new compounds and along with two known triterpenes were reported. The ethanol/water extracts showed a maximum effect in antioxidant assays, while the ethyl acetate extract achieved the best effect in the enzyme inhibitory assays.

Phillyrin sensitizes lung cancer cells to ferroptosis through inhibiting FTH1/SLC7A11 axis.

Ferroptosis is a newly found form of non-apoptotic regulated cell death that is essential for cancer progression. Phillyrin (PHN), an effective lignan glycoside of Forsythia suspensa, has been explored as a potential anticancer agent in some cancer types. However, it is unclear whether and how PHN could promote the death of non-small cell lung cancer (NSCLC) cells by inducing ferroptosis. Our study showed for the first time that PHN induced cell death and attenuated cell proliferation in NSCLC cells in vitro and in vivo. Functional assays showed that ferroptosis was the predominant form that contributed to PHN-induced cell death of NSCLC cells. Mechanistically, NSCLC cells exposed to PHN had a decreased ferritin heavy chain 1 (FTH1) and SLC7A11 protein expression. Exogenetic overexpression of FTH1 substantially abrogated the tumor-inhibiting effects of PHN and further upregulated the expression of SLC7A11 in NSCLC cells. In conclusion, our findings suggest that the natural product PHN exerted its antitumor activity in NSCLC by promoting ferroptosis, and the FTH1/SLC7A11 axis plays an indispensable role in PHN-induced ferroptotic cell death.

Chemical constituents from the leaves of Nephrolepis exaltata

Twenty-one compounds were isolated from the ethanol extract of the leaves of Nephrolepis exaltata (Nephrolepidaceae), including one furan derivative (1), five phenol derivatives (2–6), two megastigmens (7, 8), one iridoid glycoside (9), nine flavonoids (10–18), and three lignan glycosides (19–21). The structures of the isolated compounds were elucidated by 1D and 2D NMR spectroscopic methods as well as comparison with previously reported data. Among the isolated compounds, phloretic acid (6) was isolated from the specie N. exalata for the first time. Dehydrovomifoliol (7), dehydrololiolide (8), quercitrin (10), kaempferol (11), afzelin (12), quercetin (13), luteolin (14), 3-O-methylquercetin (15), and demethoxymatteucinol (17) were obtained from the genus for the first time while methoxygaertneroside (9), (2S)-5,7,3′,5′-tetrahydroxyflavanone (16), epigallocatechin (18), lanicepside A (19), pinoresinol 4′-O-β-D-glucopyranoside (20), and glochidiobioside (21) were obtained from the family for the first time.

Lignan and phenolic glycosides from Viburnum betulifolium fruits and their α‑amylase and α-glucosidase inhibitory activities

The phytochemical investigation on the methanol extract of Viburnum betulifolium fruits resulted in the isolation and identification of two new lignan constituents (1 and 2) and seven known phenolic glycosides (3–9). The structures of new isolates, including their absolute configurations were elucidated by extensive spectroscopic analyses (1H and 13C NMR, HSQC, HMBC, HRESIMS, and ECD) and chemical methods. In the in vitro enzyme assays, compounds 1, 2, 6, and 8 showed potential α‑amylase and α-glucosidase inhibitory activities. Among them, compound 1 exhibited stronger inhibitory effects towards α-amylase and α-glucosidase with the IC50 values of 12.68 and 15.17 μM, respectively, than those of the positive control acarbose (IC50, 29.19 and 18.15 μM, respectively). In addition, the molecular docking analyses of compound 1 with strongest inhibition against the target enzymes were also performed.

Iridoid and lignan glycosides from Lancea tibetica

One new iridoid glucoside, 7-O-E-feruloylgardoside (1) and two new lignan glycosides, 8′-hydroxyphillyrin (2) and 6''-(p-hydroxybenzyl) phillyrin (3), together with three known compounds, khainaoside B (4), phillyrin (5), and lantibeside (6), were isolated from the whole plants of Lancea tibetica. Their structures were elucidated on the basis of spectroscopic methods and X-ray crystallographic analysis. A DPPH free radical scavenging assay showed that 1 and 4 exhibited moderate antioxidant activity (IC50 45.05 ± 3.04 and 48.00 ± 3.29 μg/ml) compared with vitamin C (IC50 3.31 ± 0.16 μg/ml).

Cistadesertosides B-E, Four New Diastereomeric Lignan Glycosides from the Stems of Cultural Cistanche deserticola in Tarim Desert.

Four previously undescribed diastereomeric lignan glycosides, namely cistadesertosides B-E (1-4) were isolated from the stems of cultural Cistanche deserticola in Tarim desert. The structures of these compounds were elucidated on the basis of extensive spectroscopic analyses, including IR, HR-ESI-MS, 1D and 2D NMR, circular dichroism (CD) data and chemical degradation. The in vitro anti-inflammatory activity of the isolates was also investigated. It showed that compounds 3 and 4 exhibited potential effects with IC50 values of 21.17 μM and 26.97 μM, respectively (positive control quercetin, IC50 , 10.01 μM).

Three new phenolic glycosides and a new lignan glycoside from Gaultheria leucocarpa var. yunnanensis

Three new phenolic glycosides (1–3) and a new lignan glycoside (4), together with five known compounds (5–9) were isolated from the ethanol extract of the aerial part of Gaultheria leucocarpa var. yunnanensis (Franch.) T.Z.Hsu & R.C.Fang. Their structures were determined on the basis of spectroscopic techniques, experimental and calculated ECD spectra, acid hydrolysis, and enzymatic hydrolysis experiments. All the isolates were evaluated for their anti-inflammatory and antioxidant activities. Compounds 7 and 8 exhibited inhibitory effects against the LPS-induced production of NO with IC50 of 63.71 and 10.66 μM, respectively, compared to L-NMMA having an IC50 of 6.95 μM. Besides, compound 7 also represented significant DPPH radical scavenging activity with EC50 of 18.75 μM, comparable with vitamin C (EC50 = 15.77 μM).

Exploring the Synergistic Mechanism of AP2A2 Transcription Factor Inhibition via Molecular Modeling and Simulations as a Novel Computational Approach for Combating Breast Cancer: In Silico Interpretations.

Studies have shown that transcription factor AP2A2 (activator protein-2 alpha-2) is involved in the expression of DLEC1, a tumor suppressor gene, which, when mutated, will cause breast cancer and is thus an excellent target for breast cancer studies. Therefore, in the present research, a synergistic approach toward combating breast cancer is proposed by blocking AP2A2 factor, and allowing the cancer cells to be sensitive to anti-cancer drugs. The effect of AP2A2 on breast cancer was first understood via gene analysis from cBioPortal. AP2A2 was then modeled using RaptorX and its structure was validated from Ramachandran plots. Using all ligands from MolPort database, molecular docking was performed against AP2A2, from which the top three best docked ligands were studied for toxicity in humans using Protox-II. Once the ligands passed these tests, the best complexes were simulated at 200ns in Desmond Maestro, to comprehend their stabilities, followed by the computations of free energies of binding via Molecular mechanics- Generalized Born Solvent Accessibility method (MM-GBSA). The results showed that molecules MolPort-005-945-556 (sachharolipids), MolPort-001-741-124 (flavonoids), and MolPort-005-944-667 (lignan glycosides) with AP2A2 passed toxicity evaluation and belonged to toxicity classes 6, 5, and 5, respectively, with good docking energies. 200ns simulations revealed stable complexes with slight conformational changes. Stability of ligands was confirmed via snapshots at every 20ns of the trajectory. Radial distribution of these molecules against the protein revealed very slight deviation from binding pocket. Additionally, the free binding energies for these complexes were found to be -54.93 ± 12.982kcal/mol, -44.39 ± 14.393kcal/mol, and -66.51 ± 13.522kcal/mol, respectively. A preliminary computational validation of the inability of AP2A2 to bind to DLEC1 in the presence of ligands offers beneficial insights into the potential of these ligands. Therefore, this study sheds light on the potential natural molecules that could stably block AP2A2 with least deviation and act in synergy to aid anti-cancer drugs work on breast cancer cells.

Isolation of Alkaloids from Sinomenium acutum by Centrifugal Partition Chromatography and Their Ameliorating Effects on Dexamethasone-Induced Atrophy in C2C12 Myotubes

Bioactivity-guided isolation was conducted using centrifugal partition chromatography (CPC) from an extract of Sinomenium acutum rhizome, which has shown promising preventive effects in a dexamethasone-induced C2C12 myotube atrophy model. CPC was operated with a solvent system of n-butanol–acetonitrile–water (10:2:8, v/v/v, containing 0.5% triethylamine) in dual mode (ascending to descending), which provided a high recovery rate (>99%) with a high resolution. Then, the preventive effects of the obtained CPC fractions were examined against dexamethasone-induced atrophy in C2C12 myotubes according to the weight ratios of the obtained fractions. The active fractions were further purified by semi-preparative HPLC that led to obtaining five alkaloids, one lignan glycoside, and one phenylpropanoid glycoside. Among these, at a concentration of 1 nM, sinomenine, magnoflorine, and acutumine could ameliorate dexamethasone-induced myotube atrophy in C2C12 myotubes by 9.3%, 13.8%, and 11.3%, respectively.

Lignan glycosides from Fritillaria verticillata Willd. and their anti-inflammatory activities

Three undescribed lignan glycosides, echiunines E-G (1–3), as well as eight known compounds (4–11) were isolated from Fritillaria verticillata Willd. Among them, compounds 1–3 were a series of lignan glycosides reported for the first time from genus Fritillaria. Their structures were elucidated by analyses of extensive spectroscopic data and comparison of the NMR data with those reported previously, the absolute configuration of compounds were further confirmed by calculated ECD method. The NO release inhibitory effects of compounds were evaluated in LPS-activated RAW264.7 macrophages. Compounds 7–8 showed inhibitory acitivities in a dose-dependent manner.

Two new lignan glycosides from Acanthus ilicifoliusL. with their NO inhibition and cytotoxic activity

A phytochemical investigation of the methanolic extract of aerial parts of the Acanthus ilicifolius led to the isolation of two new lignan glycosides, acaniliciosides A and B (1 and 2), together with ten known compounds (3-12). The structures of isolated compounds were elucidated based on HR-ESI-MS, 1D and 2D NMR spectroscopic data. The absolute configurations of two new compounds were established by CD spectra. With the exception of compound 12, other compounds inhibited NO production in LPS activated RAW264.7 cells with IC50 values of 2.14-28.18 µM, as potent as that of the positive control of N G-monomethyl-L-arginine acetate (L-NMMA, IC50 of 32.50 µM). In addition, compounds 5-8 showed cytotoxic effects against SK-LU-1 and HepG2 cell lines with the IC50 values ranging from 16.48 to 76.40 μM compared to the positive control (ellipticine) with the IC50 values ranging from 1.23 to 1.46 μM.

Four new diastereoisomeric neolignan glycosides from the root bark of Lycium chinense Miller. and their α-glucosidase inhibitory activity

Four new diastereoisomeric neolignan glycosides (1–4) along with nine known lignan glycosides (5–13) were isolated from the root bark of Lycium chinense Mill. Their structures with absolute configurations were elucidated on the basis of NMR spectroscopy, ECD, Mo2(OAc)4-induced ECD spectra, enzymatic hydrolysis and acid hydrolysis. The isolated compounds were evaluated for their α-glucosidase inhibitory activity. Compounds 8 and 13 exhibited moderate inhibitory activities against α-glucosidase with IC50 values of 26.82 ± 2.71 and 43.14 ± 2.81 μg/mL.

Phillyrin ameliorated collagen-induced arthritis through inhibition of NF-κB and MAPKs pathways in fibroblast-like synoviocytes

The discovery of alternative medicines with less adverse effects is extremely urgent for rheumatoid arthritis (RA). Phillyrin (Phil), the predominant lignan glycoside of Forsythia suspensa, has been reported to exert several pharmacological effects, such as antivirus, anti-inflammation, anti-oxidation, anti-obesity, and antipyretic activity. However, the effect of Phil on RA remains unknown. In this study, We utilized both in vivo collagen-induced arthritis (CIA) rat models and in vitro TNFα-induced fibroblast-like synoviocytes (FLSs) to study the inhibitory effects of Phil on RA. The in vivo studies revealed that Phil treatment effectively ameliorated synovial inflammation and bone erosion in CIA rats. The in vitro studies demonstrated that Phil could significantly suppress the proliferation and migration of arthritic FLSs. In addition, treatment with Phil resulted in decreased mRNA expression of proinflammatory cytokines including TNFα, IL-1β, IL-6, IL-8 and MMP9. Molecular mechanistic investigations revealed that the suppressive effects of Phil were mediated by blockade of the MAPK (ERK, p38, and JNK) and NF-κB pathways. Taken together, our findings suggest that Phil has an anti-arthritic effect in CIA rats by inhibiting the pathogenic characteristic of arthritic FLSs throught suppression of NF-κB and MAPKs signaling pathways. These results demonstrate the potential of Phil as a novel therapeutic agent for the treatment of RA.

Arctiin alleviates functional constipation by enhancing intestinal motility in mice.

Functional constipation (FC), a common symptom that is primarily associated with intestinal motility dysfunction, is a common problem worldwide. Arctiin (Arc) is a lignan glycoside isolated from the Chinese herbal medicine Arctium lappa L., which is a health food in China. The present study aimed to evaluate the laxative effects of Arc against FC in mice. A model of FC induced by loperamide (5 mg/kg) was established in male Institute of Cancer Research (ICR) mice. Arc was administered at a dose of 100 mg/kg as a protective agent. The faecal status, intestinal motility and histological analyses were evaluated. Furthermore, the levels of gastrointestinal motility-associated neurotransmitters, such as motilin (MTL), nitric oxide (NO), and brain-derived neurotrophic factor (BDNF) and the protective effect of Arc on interstitial cells of Cajal (ICC) were assessed. Arc treatment reversed the loperamide-induced reduction in faecal number and water content and the intestinal transit ratio in ICR mice. Histological analysis confirmed that Arc administration mitigated colonic injury. Moreover, Arc treatment increased levels of motilin and brain-derived neurotrophic factor while decreasing nitric oxide levels and ICC injury in the colon of FC mice. Arc decreased inflammation induction and aquaporin expression levels. Owing to its pro-intestinal motility property, Arc was shown to have a protective effect against FC and may thus serve as a promising therapeutic strategy for the management of FC.